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Breast conservation safe option in multisite breast cancer
SAN ANTONIO – Women with breast cancer at more than one site can undergo breast-conserving therapy and still have local recurrence rates well under the acceptable threshold of risk, suggest the results of first prospective study of this issue.
The ACOSOG-Z11102 trial involved more than 200 women with primarily endocrine receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer and up to three disease foci, all of whom underwent lumpectomy with nodal staging followed by whole-breast irradiation, then systemic therapy at the oncologist’s discretion.
After 5 years of follow-up, just 3% of women experienced a local recurrence, with none having a local or distant recurrence and one dying of the disease.
The new findings were presented at the San Antonio Breast Cancer Symposium on Dec. 9.
“This study provides important information for clinicians to discuss with patients who have two or three foci of breast cancer in one breast, as it may allow more patients to consider breast-conserving therapy as an option,” said study presenter Judy C. Boughey, MD, chair of the division of breast and melanoma surgical oncology at the Mayo Clinic, Rochester, Minn.
“Lumpectomy with radiation therapy is often preferred to mastectomy, as it is a smaller operation with quicker recovery, resulting in better patient satisfaction and cosmetic outcomes,” Dr. Boughey said in a statement.
“We’ve all been anxiously awaiting the results of this trial,” Andrea V. Barrio, MD, associate attending surgeon, Memorial Sloan Kettering Cancer Center, New York, told this news organization. “We knew that in patients who have a single site tumor in the breast, that outcomes between lumpectomy and mastectomy are the same ... But none of those trials have enrolled women with multiple sites.”
“There were no prospective data out there telling us that doing two lumpectomies in the breast was safe, so a lot of times, women were getting mastectomy for these multiple tumors, even if women had two small tumors in the breast and could easily undergo a lumpectomy with a good cosmetic result,” she said.
“So this data provides very strong evidence that we can begin treating women with small tumors in the breast who can undergo lumpectomy with a good cosmetic results without needing a mastectomy,” Dr. Barrio continued. “From a long-term quality of life standpoint, this is a big deal for women moving forward who really want to keep their breasts.”
Dr. Barrio did highlight, however, that “not everybody routinely does MRI” in women with breast cancer, including her institution, although generally she feels that “our standard imaging has gotten better,” with screening ultrasound identifying more lesions than previously.
She also believes that the numbers of women in the study who did not receive MRI are too small to “draw any definitive conclusions.
“Personally, when I have a patient with multisite disease and I’m going to keep their breasts, that to me is one indication that I would consider an MRI, to make sure that I wasn’t missing intervening disease between the two sites – that there wasn’t something else that would change my mind about doing a two-site lumpectomy,” Dr. Barrio said.
Linda M. Pak, MD, a breast cancer surgeon and surgical oncologist at NYU Langone’s Breast Cancer Center, New York, who was not involved in the study, said that the new study provides “importation information regarding the oncologic safety” of lumpectomy.
These results are “exciting to see, as they provide important information that breast-conserving surgery is safe in these patients, and that we can now share the results of this study with patients when we discuss with them their surgical options.
“I hope this will make more breast surgeons and patients comfortable with this approach and that it will increase the use of breast conservation among these patients,” Dr. Pak said.
Study details
In recent years, there has been increased diagnosis of multiple foci of ipsilateral breast cancer, Dr. Boughey said in her presentation. “This is both as a result of improvements in screening imaging, as well as diagnostic imaging and an increased use of preoperative breast MRI.”
Although historical, retrospective studies have shown high rates of local regional recurrences with breast-conserving therapy in women with more than one foci of breast cancer, more recent analyses have indicated that the approach is associated with “acceptable” recurrence rates.
This, Dr. Boughey explained, is due not only to improvements in breast imaging but also to better pathologic margin assessment, and improved systematic and radiation therapy.
Nevertheless, “most patients who present with two or three sites of cancer in one breast are recommended to undergo a mastectomy,” she noted.
To examine the safety of breast-conserving therapy in such patients, the team conducted a single-arm, phase 2 trial in women at least 40 years of age who had two or three foci of breast cancer, of which at least one site was invasive disease.
“While a randomized trial design would have provided stronger data, we felt that accrual to such a design would be problematic, as many patients and surgeons would not be willing to randomize,” Dr. Boughey explained.
Participants were required to have at least 2 cm of normal tissue between the lesions and disease in no more than two quadrants of the breast. They could have node-negative or N1 disease.
Women were excluded if they had foci > 5 cm on imaging; had bilateral breast cancer; had known BRCA1/2 mutations; had had prior ipsilateral breast cancer; or had received neoadjuvant therapy.
All women in the trial underwent lumpectomy with nodal staging, with adjuvant chemotherapy at the physician’s discretion, followed by whole-breast irradiation, with regional nodal irradiation again at the physician’s discretion. This was followed by systemic therapy, at the discretion of the medical oncologist.
The women were then followed up every 6 months until 5 years after the completion of whole-breast irradiation.
Details of the results
Dr. Boughey said that previously presented data from this study revealed that 67.6% of women achieved a margin-negative excision in a single operation, whereas 7.1% converted to mastectomy. The cosmetic outcome was rated as good or excellent at 2 years by 70.6% of women.
For the current analysis, a total of 204 women were evaluable, who had a median age of 61.1 years. Just over half (59.3%) had T1 stage disease, and 95.6% were node-negative. The majority (83.5%) had ER+/HER2- breast cancer, whereas 5.0% had ER-/HER2- disease and 11.5% had HER2+ positive tumors.
Adjuvant chemotherapy was given to 28.9% of women, whereas 89.7% of those with ER+ disease received adjuvant endocrine therapy.
The primary outcome was local recurrence rate at 5 years, which had a prespecified acceptable rate of less than 8%.
Dr. Boughey showed that, in their series, the 5-year recurrence rate was just 3.1% (95% confidence interval [CI], 1.3%-6.4%), which was “well below” the predefined “clinically significantly threshold.” This involved four cases in the ipsilateral breast, one in the skin, and one in the chest wall.
In addition to the six women with local regional recurrence, six developed contralateral breast cancer and four patients developed distant disease. There were no cases of local and distant recurrence. There were three non–breast cancer primary cancers: one gastric, one lung, and one ovarian.
Eight women died during follow-up; only one of the deaths was related to breast cancer.
Dr. Boughey explained that the small number of local recurrences was too small to identify predictive factors via multivariate analysis.
However, univariate analysis indicated that there were numerical but nonsignificant associations between local recurrence and pathologic stage T2-3 disease, pathologic nodal involvement, and surgical margins just under the negative threshold.
Among the 10 cases of ER–/HER2– breast cancer, there was one local recurrence, giving a 5-year rate of 10.0% vs. 2.6% for women with ER+/HER2– disease.
To examine the role of MRI, Dr. Boughey highlighted that although the imaging modality was initially a requirement for study entry, an amendment to the protocol in 2015 allowed 15 women who had not had MRI to take part.
The local recurrence rate in women who had undergone MRI was 1.7% vs. 22.6% in those who had not, for a hazard ratio of 13.5 (P = .002).
“While this was statistically significant, we need to bear in mind that this was a secondary unplanned analysis,” Dr. Boughey underlined.
Next, the team analyzed the impact of adjuvant endocrine therapy in the 195 women with at least one ER+ lesion, finding that it was associated with a 5-year recurrence rate of 1.9% vs. 12.5% in those who did not receive endocrine therapy, for a hazard ratio of 7.7 (P = .025).
Dr. Boughey highlighted that the study is limited by being single-arm and having only a small subset of patients without preoperative MRI, with HER2+ or ER–/HER2– disease, and with three foci of disease.
She also emphasized that “there is concern that the 5-year follow up on this protocol may be shorter than needed,” especially in women with ER+ disease.
The study was supported by the National Institutes of Health. Dr. Boughey declared relationships with Eli Lilly and Company, Symbiosis Pharma, CairnSurgical, UpToDate, and PeerView.
A version of this article first appeared on Medscape.com.
SAN ANTONIO – Women with breast cancer at more than one site can undergo breast-conserving therapy and still have local recurrence rates well under the acceptable threshold of risk, suggest the results of first prospective study of this issue.
The ACOSOG-Z11102 trial involved more than 200 women with primarily endocrine receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer and up to three disease foci, all of whom underwent lumpectomy with nodal staging followed by whole-breast irradiation, then systemic therapy at the oncologist’s discretion.
After 5 years of follow-up, just 3% of women experienced a local recurrence, with none having a local or distant recurrence and one dying of the disease.
The new findings were presented at the San Antonio Breast Cancer Symposium on Dec. 9.
“This study provides important information for clinicians to discuss with patients who have two or three foci of breast cancer in one breast, as it may allow more patients to consider breast-conserving therapy as an option,” said study presenter Judy C. Boughey, MD, chair of the division of breast and melanoma surgical oncology at the Mayo Clinic, Rochester, Minn.
“Lumpectomy with radiation therapy is often preferred to mastectomy, as it is a smaller operation with quicker recovery, resulting in better patient satisfaction and cosmetic outcomes,” Dr. Boughey said in a statement.
“We’ve all been anxiously awaiting the results of this trial,” Andrea V. Barrio, MD, associate attending surgeon, Memorial Sloan Kettering Cancer Center, New York, told this news organization. “We knew that in patients who have a single site tumor in the breast, that outcomes between lumpectomy and mastectomy are the same ... But none of those trials have enrolled women with multiple sites.”
“There were no prospective data out there telling us that doing two lumpectomies in the breast was safe, so a lot of times, women were getting mastectomy for these multiple tumors, even if women had two small tumors in the breast and could easily undergo a lumpectomy with a good cosmetic result,” she said.
“So this data provides very strong evidence that we can begin treating women with small tumors in the breast who can undergo lumpectomy with a good cosmetic results without needing a mastectomy,” Dr. Barrio continued. “From a long-term quality of life standpoint, this is a big deal for women moving forward who really want to keep their breasts.”
Dr. Barrio did highlight, however, that “not everybody routinely does MRI” in women with breast cancer, including her institution, although generally she feels that “our standard imaging has gotten better,” with screening ultrasound identifying more lesions than previously.
She also believes that the numbers of women in the study who did not receive MRI are too small to “draw any definitive conclusions.
“Personally, when I have a patient with multisite disease and I’m going to keep their breasts, that to me is one indication that I would consider an MRI, to make sure that I wasn’t missing intervening disease between the two sites – that there wasn’t something else that would change my mind about doing a two-site lumpectomy,” Dr. Barrio said.
Linda M. Pak, MD, a breast cancer surgeon and surgical oncologist at NYU Langone’s Breast Cancer Center, New York, who was not involved in the study, said that the new study provides “importation information regarding the oncologic safety” of lumpectomy.
These results are “exciting to see, as they provide important information that breast-conserving surgery is safe in these patients, and that we can now share the results of this study with patients when we discuss with them their surgical options.
“I hope this will make more breast surgeons and patients comfortable with this approach and that it will increase the use of breast conservation among these patients,” Dr. Pak said.
Study details
In recent years, there has been increased diagnosis of multiple foci of ipsilateral breast cancer, Dr. Boughey said in her presentation. “This is both as a result of improvements in screening imaging, as well as diagnostic imaging and an increased use of preoperative breast MRI.”
Although historical, retrospective studies have shown high rates of local regional recurrences with breast-conserving therapy in women with more than one foci of breast cancer, more recent analyses have indicated that the approach is associated with “acceptable” recurrence rates.
This, Dr. Boughey explained, is due not only to improvements in breast imaging but also to better pathologic margin assessment, and improved systematic and radiation therapy.
Nevertheless, “most patients who present with two or three sites of cancer in one breast are recommended to undergo a mastectomy,” she noted.
To examine the safety of breast-conserving therapy in such patients, the team conducted a single-arm, phase 2 trial in women at least 40 years of age who had two or three foci of breast cancer, of which at least one site was invasive disease.
“While a randomized trial design would have provided stronger data, we felt that accrual to such a design would be problematic, as many patients and surgeons would not be willing to randomize,” Dr. Boughey explained.
Participants were required to have at least 2 cm of normal tissue between the lesions and disease in no more than two quadrants of the breast. They could have node-negative or N1 disease.
Women were excluded if they had foci > 5 cm on imaging; had bilateral breast cancer; had known BRCA1/2 mutations; had had prior ipsilateral breast cancer; or had received neoadjuvant therapy.
All women in the trial underwent lumpectomy with nodal staging, with adjuvant chemotherapy at the physician’s discretion, followed by whole-breast irradiation, with regional nodal irradiation again at the physician’s discretion. This was followed by systemic therapy, at the discretion of the medical oncologist.
The women were then followed up every 6 months until 5 years after the completion of whole-breast irradiation.
Details of the results
Dr. Boughey said that previously presented data from this study revealed that 67.6% of women achieved a margin-negative excision in a single operation, whereas 7.1% converted to mastectomy. The cosmetic outcome was rated as good or excellent at 2 years by 70.6% of women.
For the current analysis, a total of 204 women were evaluable, who had a median age of 61.1 years. Just over half (59.3%) had T1 stage disease, and 95.6% were node-negative. The majority (83.5%) had ER+/HER2- breast cancer, whereas 5.0% had ER-/HER2- disease and 11.5% had HER2+ positive tumors.
Adjuvant chemotherapy was given to 28.9% of women, whereas 89.7% of those with ER+ disease received adjuvant endocrine therapy.
The primary outcome was local recurrence rate at 5 years, which had a prespecified acceptable rate of less than 8%.
Dr. Boughey showed that, in their series, the 5-year recurrence rate was just 3.1% (95% confidence interval [CI], 1.3%-6.4%), which was “well below” the predefined “clinically significantly threshold.” This involved four cases in the ipsilateral breast, one in the skin, and one in the chest wall.
In addition to the six women with local regional recurrence, six developed contralateral breast cancer and four patients developed distant disease. There were no cases of local and distant recurrence. There were three non–breast cancer primary cancers: one gastric, one lung, and one ovarian.
Eight women died during follow-up; only one of the deaths was related to breast cancer.
Dr. Boughey explained that the small number of local recurrences was too small to identify predictive factors via multivariate analysis.
However, univariate analysis indicated that there were numerical but nonsignificant associations between local recurrence and pathologic stage T2-3 disease, pathologic nodal involvement, and surgical margins just under the negative threshold.
Among the 10 cases of ER–/HER2– breast cancer, there was one local recurrence, giving a 5-year rate of 10.0% vs. 2.6% for women with ER+/HER2– disease.
To examine the role of MRI, Dr. Boughey highlighted that although the imaging modality was initially a requirement for study entry, an amendment to the protocol in 2015 allowed 15 women who had not had MRI to take part.
The local recurrence rate in women who had undergone MRI was 1.7% vs. 22.6% in those who had not, for a hazard ratio of 13.5 (P = .002).
“While this was statistically significant, we need to bear in mind that this was a secondary unplanned analysis,” Dr. Boughey underlined.
Next, the team analyzed the impact of adjuvant endocrine therapy in the 195 women with at least one ER+ lesion, finding that it was associated with a 5-year recurrence rate of 1.9% vs. 12.5% in those who did not receive endocrine therapy, for a hazard ratio of 7.7 (P = .025).
Dr. Boughey highlighted that the study is limited by being single-arm and having only a small subset of patients without preoperative MRI, with HER2+ or ER–/HER2– disease, and with three foci of disease.
She also emphasized that “there is concern that the 5-year follow up on this protocol may be shorter than needed,” especially in women with ER+ disease.
The study was supported by the National Institutes of Health. Dr. Boughey declared relationships with Eli Lilly and Company, Symbiosis Pharma, CairnSurgical, UpToDate, and PeerView.
A version of this article first appeared on Medscape.com.
SAN ANTONIO – Women with breast cancer at more than one site can undergo breast-conserving therapy and still have local recurrence rates well under the acceptable threshold of risk, suggest the results of first prospective study of this issue.
The ACOSOG-Z11102 trial involved more than 200 women with primarily endocrine receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer and up to three disease foci, all of whom underwent lumpectomy with nodal staging followed by whole-breast irradiation, then systemic therapy at the oncologist’s discretion.
After 5 years of follow-up, just 3% of women experienced a local recurrence, with none having a local or distant recurrence and one dying of the disease.
The new findings were presented at the San Antonio Breast Cancer Symposium on Dec. 9.
“This study provides important information for clinicians to discuss with patients who have two or three foci of breast cancer in one breast, as it may allow more patients to consider breast-conserving therapy as an option,” said study presenter Judy C. Boughey, MD, chair of the division of breast and melanoma surgical oncology at the Mayo Clinic, Rochester, Minn.
“Lumpectomy with radiation therapy is often preferred to mastectomy, as it is a smaller operation with quicker recovery, resulting in better patient satisfaction and cosmetic outcomes,” Dr. Boughey said in a statement.
“We’ve all been anxiously awaiting the results of this trial,” Andrea V. Barrio, MD, associate attending surgeon, Memorial Sloan Kettering Cancer Center, New York, told this news organization. “We knew that in patients who have a single site tumor in the breast, that outcomes between lumpectomy and mastectomy are the same ... But none of those trials have enrolled women with multiple sites.”
“There were no prospective data out there telling us that doing two lumpectomies in the breast was safe, so a lot of times, women were getting mastectomy for these multiple tumors, even if women had two small tumors in the breast and could easily undergo a lumpectomy with a good cosmetic result,” she said.
“So this data provides very strong evidence that we can begin treating women with small tumors in the breast who can undergo lumpectomy with a good cosmetic results without needing a mastectomy,” Dr. Barrio continued. “From a long-term quality of life standpoint, this is a big deal for women moving forward who really want to keep their breasts.”
Dr. Barrio did highlight, however, that “not everybody routinely does MRI” in women with breast cancer, including her institution, although generally she feels that “our standard imaging has gotten better,” with screening ultrasound identifying more lesions than previously.
She also believes that the numbers of women in the study who did not receive MRI are too small to “draw any definitive conclusions.
“Personally, when I have a patient with multisite disease and I’m going to keep their breasts, that to me is one indication that I would consider an MRI, to make sure that I wasn’t missing intervening disease between the two sites – that there wasn’t something else that would change my mind about doing a two-site lumpectomy,” Dr. Barrio said.
Linda M. Pak, MD, a breast cancer surgeon and surgical oncologist at NYU Langone’s Breast Cancer Center, New York, who was not involved in the study, said that the new study provides “importation information regarding the oncologic safety” of lumpectomy.
These results are “exciting to see, as they provide important information that breast-conserving surgery is safe in these patients, and that we can now share the results of this study with patients when we discuss with them their surgical options.
“I hope this will make more breast surgeons and patients comfortable with this approach and that it will increase the use of breast conservation among these patients,” Dr. Pak said.
Study details
In recent years, there has been increased diagnosis of multiple foci of ipsilateral breast cancer, Dr. Boughey said in her presentation. “This is both as a result of improvements in screening imaging, as well as diagnostic imaging and an increased use of preoperative breast MRI.”
Although historical, retrospective studies have shown high rates of local regional recurrences with breast-conserving therapy in women with more than one foci of breast cancer, more recent analyses have indicated that the approach is associated with “acceptable” recurrence rates.
This, Dr. Boughey explained, is due not only to improvements in breast imaging but also to better pathologic margin assessment, and improved systematic and radiation therapy.
Nevertheless, “most patients who present with two or three sites of cancer in one breast are recommended to undergo a mastectomy,” she noted.
To examine the safety of breast-conserving therapy in such patients, the team conducted a single-arm, phase 2 trial in women at least 40 years of age who had two or three foci of breast cancer, of which at least one site was invasive disease.
“While a randomized trial design would have provided stronger data, we felt that accrual to such a design would be problematic, as many patients and surgeons would not be willing to randomize,” Dr. Boughey explained.
Participants were required to have at least 2 cm of normal tissue between the lesions and disease in no more than two quadrants of the breast. They could have node-negative or N1 disease.
Women were excluded if they had foci > 5 cm on imaging; had bilateral breast cancer; had known BRCA1/2 mutations; had had prior ipsilateral breast cancer; or had received neoadjuvant therapy.
All women in the trial underwent lumpectomy with nodal staging, with adjuvant chemotherapy at the physician’s discretion, followed by whole-breast irradiation, with regional nodal irradiation again at the physician’s discretion. This was followed by systemic therapy, at the discretion of the medical oncologist.
The women were then followed up every 6 months until 5 years after the completion of whole-breast irradiation.
Details of the results
Dr. Boughey said that previously presented data from this study revealed that 67.6% of women achieved a margin-negative excision in a single operation, whereas 7.1% converted to mastectomy. The cosmetic outcome was rated as good or excellent at 2 years by 70.6% of women.
For the current analysis, a total of 204 women were evaluable, who had a median age of 61.1 years. Just over half (59.3%) had T1 stage disease, and 95.6% were node-negative. The majority (83.5%) had ER+/HER2- breast cancer, whereas 5.0% had ER-/HER2- disease and 11.5% had HER2+ positive tumors.
Adjuvant chemotherapy was given to 28.9% of women, whereas 89.7% of those with ER+ disease received adjuvant endocrine therapy.
The primary outcome was local recurrence rate at 5 years, which had a prespecified acceptable rate of less than 8%.
Dr. Boughey showed that, in their series, the 5-year recurrence rate was just 3.1% (95% confidence interval [CI], 1.3%-6.4%), which was “well below” the predefined “clinically significantly threshold.” This involved four cases in the ipsilateral breast, one in the skin, and one in the chest wall.
In addition to the six women with local regional recurrence, six developed contralateral breast cancer and four patients developed distant disease. There were no cases of local and distant recurrence. There were three non–breast cancer primary cancers: one gastric, one lung, and one ovarian.
Eight women died during follow-up; only one of the deaths was related to breast cancer.
Dr. Boughey explained that the small number of local recurrences was too small to identify predictive factors via multivariate analysis.
However, univariate analysis indicated that there were numerical but nonsignificant associations between local recurrence and pathologic stage T2-3 disease, pathologic nodal involvement, and surgical margins just under the negative threshold.
Among the 10 cases of ER–/HER2– breast cancer, there was one local recurrence, giving a 5-year rate of 10.0% vs. 2.6% for women with ER+/HER2– disease.
To examine the role of MRI, Dr. Boughey highlighted that although the imaging modality was initially a requirement for study entry, an amendment to the protocol in 2015 allowed 15 women who had not had MRI to take part.
The local recurrence rate in women who had undergone MRI was 1.7% vs. 22.6% in those who had not, for a hazard ratio of 13.5 (P = .002).
“While this was statistically significant, we need to bear in mind that this was a secondary unplanned analysis,” Dr. Boughey underlined.
Next, the team analyzed the impact of adjuvant endocrine therapy in the 195 women with at least one ER+ lesion, finding that it was associated with a 5-year recurrence rate of 1.9% vs. 12.5% in those who did not receive endocrine therapy, for a hazard ratio of 7.7 (P = .025).
Dr. Boughey highlighted that the study is limited by being single-arm and having only a small subset of patients without preoperative MRI, with HER2+ or ER–/HER2– disease, and with three foci of disease.
She also emphasized that “there is concern that the 5-year follow up on this protocol may be shorter than needed,” especially in women with ER+ disease.
The study was supported by the National Institutes of Health. Dr. Boughey declared relationships with Eli Lilly and Company, Symbiosis Pharma, CairnSurgical, UpToDate, and PeerView.
A version of this article first appeared on Medscape.com.
AT SABCS 2022
CTC-guided therapy beats physician choice in metastatic breast cancer
SAN ANTONIO – When choosing between chemotherapy and endocrine therapy for patients with hormone receptor (HR)+/HER2- metastatic breast cancer, allowing the results from a blood test that measures circulating tumor cell (CTC) count to overrule physician’s choice of therapy can significantly improve overall survival.
But One expert reacting to the findings says probably not, and another pointed out that the CTC count test used in the trial (CellSearch), although approved by the Food and Drug Administration, is not widely used in clinical practice.
The findings comes from updated results from the STIC CTC study.
“When the trial was designed, the question related to the choice between single-agent endocrine therapy and chemotherapy [in] first-line therapy,” explained study presenter François-Clément Bidard, MD, PhD, professor of medical oncology at Institut Curie and Versailles Saint-Quentin University, Paris.
Since then, the first-line treatment has changed and can now can also include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but Dr. Bidard said the results are still clinically relevant.
Nowadays, endocrine therapy plus CDK4/6 inhibitors is the “preferred option for treatment-naive patients, but the dilemma between endocrine therapy and chemotherapy remains after disease progression on adjuvant or first-line therapy with CDK4/6 inhibitors, where current guidelines advocate in favor of endocrine therapy, despite its short-lived efficacy.”
“In that scenario, based on the STIC CTC trial results, the CTC count in combination with predictive biomarkers, whenever available, may help customize the early use of chemotherapy or antibody-drug conjugates, which are becoming more and more attractive,” Dr. Bidard said.
The research was presented here at the San Antonio Breast Cancer Symposium (SABCS).
The study involved more than 750 patients with HR+/HER2- metastatic breast cancer randomly assigned to physician choice or CTC-guided therapy, although the physician decision and the recommendation based on the CTC count was recorded in both groups.
Using the CellSearch (Menarini Silicon Biosystems) to perform the CTC count at baseline only, the team defined patients as low or high risk, with low-risk patients deemed to need only endocrine therapy and high-risk patients recommended chemotherapy.
Physicians based their decisions on current guidelines and their clinical experience.
In the 25% of cases where CTC count would recommend chemotherapy while the physician would recommend endocrine therapy, following the CTC count–based choice resulted in a 35% improvement in progression-free survival (PFS) and a 47% increase in overall survival.
In all other situations, including those when the CTC count recommended endocrine therapy in contrast to the physicians, or the approximately 60% of cases in which the two were in agreement, there was no difference in survival outcomes between the approaches.
Reacting to the findings, Nancy Chan, MD, medical oncologist and the director of breast cancer clinical research at NYU Langone’s Perlmutter Cancer Center, said that the “goal is really to understand how we can personalize treatment options for patients.”
Another aim is to avoid performing a tumor biopsy, if possible, “as that has increased morbidity for patients.”
She noted also that choosing between endocrine therapy and chemotherapy is a “big decision.” These researchers “really wanted to help some patients get less chemotherapy,” as they felt that “some patients are getting too much” as they are not really that high risk and should get endocrine therapy instead.
However, Dr. Chan said that the CTC count is a “complicated concept” and is “not something we’re all using in our clinical practice yet.”
With regard to the approximately 40% discordance between the CTC- and physician-guided choices, Dr. Chan said that clinicians are perhaps not as accurate as they believed in predicting risk when relying on the clinical or pathological features of the tumor.
On Twitter, Guilherme Nader-Marta, MD, Jules Bordet Institute, Université Libre de Bruxelles, Belgium, commented that the question behind the study was whether CTC measurement is a “clinically useful strategy for first-line treatment decision-making.”
“Amazingly,” he continued, the trial went “straight to the point” to answer the question and showed that CTC-based decisions can offer a survival benefit.
Daniel F. Hayes, MD, co-director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center, Ann Arbor, echoed these thoughts, saying that the goals of therapy are to make patients live longer and “better.”
He said that the point of any clinical biomarker is not only to show that testing for it offers “analytical validity” but that it also provides “clinical utility” in that it can guide treatment decisions to improve outcomes.
Dr. Hayes, who was not involved in the study but has worked for many years on the development of CellSearch, said that the results do not make it clear whether measuring CTC counts meets the definition of clinical utility, but it’s “very close.”
On the other hand, the analytical validity of the test is “excellent,” and, in that context, was well-chosen, he said, adding that the endpoint of the trial “is the one most important to us: improvement in overall survival.”
Dr. Hayes noted that the magnitude of benefit from CTC-guided therapy was “moderate,” although that is a “matter of perception,” and the “level of evidence is probably 2 or 3.” Although the trial was prospective, he said, the key results were in a “relatively small” subgroup.
The question is, Dr. Hayes continued: “Is this enough to change practice? My conclusions are: probably not.”
Although patients rated as low risk based on their low CTC count avoided chemotherapy, “it’s not clear to me that this whole thing is sufficient for clinical utility in context of what we know today.” The key issue, however, is who decides whether CTC counts are measured and whether they will be used to guide therapy decisions – will it be the patient, the caregiver, an expert guidelines panel, or third party payers/society?
Study details
In his presentation, Dr. Bidard explained that CTC count is an FDA-approved standardized liquid biopsy biomarker, with a count of greater than or equal to 5 cells per 7.5 mL of blood deemed an adverse prognostic marker, regardless of the line of therapy, with a grade 1 level of evidence.
Previous studies have indicated that a high CTC count is strongly associated with overall survival, at a hazard ratio of 2.78.
Crucially, the CTC count “complements” and does not duplicate standard clinicopathological prognostic factors, Dr. Bidard said.
To determine the potential of the CTC count as an aid to treatment decisions, Dr. Bidard and colleagues conducted a trial in pre- and postmenopausal women with untreated HR+/HER2- metastatic breast cancer who were able to receive either endocrine therapy or chemotherapy.
They were randomly assigned to either a standard group, in which the treatment decision followed the physician’s choice, regardless of their CTC count, or to a CTC group, in which the physicians made a treatment recommendation but the choice was driven by the CTC count.
Dr. Bidard reminded the audience that the primary endpoint of PFS to demonstrate the non-inferiority of CTC versus physician treatment decisions has already been met, with the results published in 2020. Those results came from an analysis of 788 patients enrolled between February 2012 and July 2016 at 17 sites in France and showed after 42 months of follow-up that the median PFS in the CTC arm was 15.6 months versus 14 months in the physician choice arm, at a hazard ratio of 0.92.
The current pre-planned analysis involved 755 patients who were followed up for a median of 57 months by the time the trial was stopped in 2021.
In the standard treatment arm, endocrine therapy was favored by physicians in 72.7% of cases (Clin-low), while 27.3% were given chemotherapy (Clin-high).
In the CTC group, 73.5% of patients were recommended to have endocrine therapy by their physician based on their clinical characteristics (Clin-low), whereas 26.5% were suggested to have chemotherapy (Clin-high).
In contrast, 60.1% of patients in the standard arm would have received endocrine therapy based on their CTC count (CTC-low), and 39.9% chemotherapy (CTC-high), while 63.4% of those in the CTC arm were given endocrine therapy based on their CTC count (CTC-low), and 36.6% were assigned to chemotherapy (CTC-high).
Once the allocated treatment was known in both treatment groups, the physicians were free to choose between endocrine therapy (mostly a single-agent aromatase inhibitor or fulvestrant) and chemotherapy (mostly paclitaxel or capecitabine).
Although CDK4/6 inhibitors were not approved at the time of enrollment, 42.2% of patients across both treatment groups received one of these drugs as a second-line or later therapy.
Guiding treatment decisions
Dr. Bidard said that, overall, more patients in the CTC arm were assigned to chemotherapy, at a difference of 9.7%. There was approximately 60% concordance between physician- and CTC-guided treatment choices; in other words, patients were recommended the same treatment by the two approaches in both treatment groups.
In these patients, there was no significant difference in overall survival between the physician choice and CTC groups, at a median of 45.5 months versus 51.3 months (hazard ratio, 0.85; P = .11).
The updated PFS data revealed a median PFS of 15.7 months in the CTC group versus 13.8 months, again at a nonsignificant HR of 0.94.
These results, Dr. Bidard said, indicate that CTC-based treatment choices are “safe.”
However, there was discordance between physician and CTC-based treatment choices in around 40% of cases, meaning that the two approaches recommended different therapies.
The physician recommended endocrine therapy, in contrast to the CTC count indicating chemotherapy, in 25% of patients (Clin-low/CTC-high), whereas 13.6% of cases were recommended chemotherapy while their CTC count indicated otherwise (Clin-high/CTC-low).
In Clin-low/CTC-high patients, this resulted in 26.1% of patients in the standard group receiving endocrine therapy when their CTC count indicated chemotherapy, while 23.9% of patients in the CTC group received chemotherapy even though their physician did not recommended it.
Comparing these two groups, the researchers found that patients in the CTC group had a significantly longer PFS, at 15.7 months versus 10 months (HR, 0.65; P = .005). They also had a significantly longer median overall survival, at a median of 51.8 months versus 35.4 months with physician choice (HR, 0.53; P = .001).
Among Clin-high/CTC-low, there was no benefit from physician’s choice of chemotherapy over the CTC-guided recommendation of endocrine therapy, at an HR for PFS of 1.14 for CTC- versus physician-guided therapy (P = .54), and an HR for overall survival of 0.88 (P = .64).
Dr. Bidard highlighted that the treatment effects were seen across prespecified subgroups.
The study was funded by the Institut National du Cancer, the Institut Curie SIRIC2 program, and Menarini Silicon Biosystems. Dr. Chan reports no relevant financial relationships. Dr. Hayes and Dr. Bidard reported relationships with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
SAN ANTONIO – When choosing between chemotherapy and endocrine therapy for patients with hormone receptor (HR)+/HER2- metastatic breast cancer, allowing the results from a blood test that measures circulating tumor cell (CTC) count to overrule physician’s choice of therapy can significantly improve overall survival.
But One expert reacting to the findings says probably not, and another pointed out that the CTC count test used in the trial (CellSearch), although approved by the Food and Drug Administration, is not widely used in clinical practice.
The findings comes from updated results from the STIC CTC study.
“When the trial was designed, the question related to the choice between single-agent endocrine therapy and chemotherapy [in] first-line therapy,” explained study presenter François-Clément Bidard, MD, PhD, professor of medical oncology at Institut Curie and Versailles Saint-Quentin University, Paris.
Since then, the first-line treatment has changed and can now can also include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but Dr. Bidard said the results are still clinically relevant.
Nowadays, endocrine therapy plus CDK4/6 inhibitors is the “preferred option for treatment-naive patients, but the dilemma between endocrine therapy and chemotherapy remains after disease progression on adjuvant or first-line therapy with CDK4/6 inhibitors, where current guidelines advocate in favor of endocrine therapy, despite its short-lived efficacy.”
“In that scenario, based on the STIC CTC trial results, the CTC count in combination with predictive biomarkers, whenever available, may help customize the early use of chemotherapy or antibody-drug conjugates, which are becoming more and more attractive,” Dr. Bidard said.
The research was presented here at the San Antonio Breast Cancer Symposium (SABCS).
The study involved more than 750 patients with HR+/HER2- metastatic breast cancer randomly assigned to physician choice or CTC-guided therapy, although the physician decision and the recommendation based on the CTC count was recorded in both groups.
Using the CellSearch (Menarini Silicon Biosystems) to perform the CTC count at baseline only, the team defined patients as low or high risk, with low-risk patients deemed to need only endocrine therapy and high-risk patients recommended chemotherapy.
Physicians based their decisions on current guidelines and their clinical experience.
In the 25% of cases where CTC count would recommend chemotherapy while the physician would recommend endocrine therapy, following the CTC count–based choice resulted in a 35% improvement in progression-free survival (PFS) and a 47% increase in overall survival.
In all other situations, including those when the CTC count recommended endocrine therapy in contrast to the physicians, or the approximately 60% of cases in which the two were in agreement, there was no difference in survival outcomes between the approaches.
Reacting to the findings, Nancy Chan, MD, medical oncologist and the director of breast cancer clinical research at NYU Langone’s Perlmutter Cancer Center, said that the “goal is really to understand how we can personalize treatment options for patients.”
Another aim is to avoid performing a tumor biopsy, if possible, “as that has increased morbidity for patients.”
She noted also that choosing between endocrine therapy and chemotherapy is a “big decision.” These researchers “really wanted to help some patients get less chemotherapy,” as they felt that “some patients are getting too much” as they are not really that high risk and should get endocrine therapy instead.
However, Dr. Chan said that the CTC count is a “complicated concept” and is “not something we’re all using in our clinical practice yet.”
With regard to the approximately 40% discordance between the CTC- and physician-guided choices, Dr. Chan said that clinicians are perhaps not as accurate as they believed in predicting risk when relying on the clinical or pathological features of the tumor.
On Twitter, Guilherme Nader-Marta, MD, Jules Bordet Institute, Université Libre de Bruxelles, Belgium, commented that the question behind the study was whether CTC measurement is a “clinically useful strategy for first-line treatment decision-making.”
“Amazingly,” he continued, the trial went “straight to the point” to answer the question and showed that CTC-based decisions can offer a survival benefit.
Daniel F. Hayes, MD, co-director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center, Ann Arbor, echoed these thoughts, saying that the goals of therapy are to make patients live longer and “better.”
He said that the point of any clinical biomarker is not only to show that testing for it offers “analytical validity” but that it also provides “clinical utility” in that it can guide treatment decisions to improve outcomes.
Dr. Hayes, who was not involved in the study but has worked for many years on the development of CellSearch, said that the results do not make it clear whether measuring CTC counts meets the definition of clinical utility, but it’s “very close.”
On the other hand, the analytical validity of the test is “excellent,” and, in that context, was well-chosen, he said, adding that the endpoint of the trial “is the one most important to us: improvement in overall survival.”
Dr. Hayes noted that the magnitude of benefit from CTC-guided therapy was “moderate,” although that is a “matter of perception,” and the “level of evidence is probably 2 or 3.” Although the trial was prospective, he said, the key results were in a “relatively small” subgroup.
The question is, Dr. Hayes continued: “Is this enough to change practice? My conclusions are: probably not.”
Although patients rated as low risk based on their low CTC count avoided chemotherapy, “it’s not clear to me that this whole thing is sufficient for clinical utility in context of what we know today.” The key issue, however, is who decides whether CTC counts are measured and whether they will be used to guide therapy decisions – will it be the patient, the caregiver, an expert guidelines panel, or third party payers/society?
Study details
In his presentation, Dr. Bidard explained that CTC count is an FDA-approved standardized liquid biopsy biomarker, with a count of greater than or equal to 5 cells per 7.5 mL of blood deemed an adverse prognostic marker, regardless of the line of therapy, with a grade 1 level of evidence.
Previous studies have indicated that a high CTC count is strongly associated with overall survival, at a hazard ratio of 2.78.
Crucially, the CTC count “complements” and does not duplicate standard clinicopathological prognostic factors, Dr. Bidard said.
To determine the potential of the CTC count as an aid to treatment decisions, Dr. Bidard and colleagues conducted a trial in pre- and postmenopausal women with untreated HR+/HER2- metastatic breast cancer who were able to receive either endocrine therapy or chemotherapy.
They were randomly assigned to either a standard group, in which the treatment decision followed the physician’s choice, regardless of their CTC count, or to a CTC group, in which the physicians made a treatment recommendation but the choice was driven by the CTC count.
Dr. Bidard reminded the audience that the primary endpoint of PFS to demonstrate the non-inferiority of CTC versus physician treatment decisions has already been met, with the results published in 2020. Those results came from an analysis of 788 patients enrolled between February 2012 and July 2016 at 17 sites in France and showed after 42 months of follow-up that the median PFS in the CTC arm was 15.6 months versus 14 months in the physician choice arm, at a hazard ratio of 0.92.
The current pre-planned analysis involved 755 patients who were followed up for a median of 57 months by the time the trial was stopped in 2021.
In the standard treatment arm, endocrine therapy was favored by physicians in 72.7% of cases (Clin-low), while 27.3% were given chemotherapy (Clin-high).
In the CTC group, 73.5% of patients were recommended to have endocrine therapy by their physician based on their clinical characteristics (Clin-low), whereas 26.5% were suggested to have chemotherapy (Clin-high).
In contrast, 60.1% of patients in the standard arm would have received endocrine therapy based on their CTC count (CTC-low), and 39.9% chemotherapy (CTC-high), while 63.4% of those in the CTC arm were given endocrine therapy based on their CTC count (CTC-low), and 36.6% were assigned to chemotherapy (CTC-high).
Once the allocated treatment was known in both treatment groups, the physicians were free to choose between endocrine therapy (mostly a single-agent aromatase inhibitor or fulvestrant) and chemotherapy (mostly paclitaxel or capecitabine).
Although CDK4/6 inhibitors were not approved at the time of enrollment, 42.2% of patients across both treatment groups received one of these drugs as a second-line or later therapy.
Guiding treatment decisions
Dr. Bidard said that, overall, more patients in the CTC arm were assigned to chemotherapy, at a difference of 9.7%. There was approximately 60% concordance between physician- and CTC-guided treatment choices; in other words, patients were recommended the same treatment by the two approaches in both treatment groups.
In these patients, there was no significant difference in overall survival between the physician choice and CTC groups, at a median of 45.5 months versus 51.3 months (hazard ratio, 0.85; P = .11).
The updated PFS data revealed a median PFS of 15.7 months in the CTC group versus 13.8 months, again at a nonsignificant HR of 0.94.
These results, Dr. Bidard said, indicate that CTC-based treatment choices are “safe.”
However, there was discordance between physician and CTC-based treatment choices in around 40% of cases, meaning that the two approaches recommended different therapies.
The physician recommended endocrine therapy, in contrast to the CTC count indicating chemotherapy, in 25% of patients (Clin-low/CTC-high), whereas 13.6% of cases were recommended chemotherapy while their CTC count indicated otherwise (Clin-high/CTC-low).
In Clin-low/CTC-high patients, this resulted in 26.1% of patients in the standard group receiving endocrine therapy when their CTC count indicated chemotherapy, while 23.9% of patients in the CTC group received chemotherapy even though their physician did not recommended it.
Comparing these two groups, the researchers found that patients in the CTC group had a significantly longer PFS, at 15.7 months versus 10 months (HR, 0.65; P = .005). They also had a significantly longer median overall survival, at a median of 51.8 months versus 35.4 months with physician choice (HR, 0.53; P = .001).
Among Clin-high/CTC-low, there was no benefit from physician’s choice of chemotherapy over the CTC-guided recommendation of endocrine therapy, at an HR for PFS of 1.14 for CTC- versus physician-guided therapy (P = .54), and an HR for overall survival of 0.88 (P = .64).
Dr. Bidard highlighted that the treatment effects were seen across prespecified subgroups.
The study was funded by the Institut National du Cancer, the Institut Curie SIRIC2 program, and Menarini Silicon Biosystems. Dr. Chan reports no relevant financial relationships. Dr. Hayes and Dr. Bidard reported relationships with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
SAN ANTONIO – When choosing between chemotherapy and endocrine therapy for patients with hormone receptor (HR)+/HER2- metastatic breast cancer, allowing the results from a blood test that measures circulating tumor cell (CTC) count to overrule physician’s choice of therapy can significantly improve overall survival.
But One expert reacting to the findings says probably not, and another pointed out that the CTC count test used in the trial (CellSearch), although approved by the Food and Drug Administration, is not widely used in clinical practice.
The findings comes from updated results from the STIC CTC study.
“When the trial was designed, the question related to the choice between single-agent endocrine therapy and chemotherapy [in] first-line therapy,” explained study presenter François-Clément Bidard, MD, PhD, professor of medical oncology at Institut Curie and Versailles Saint-Quentin University, Paris.
Since then, the first-line treatment has changed and can now can also include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but Dr. Bidard said the results are still clinically relevant.
Nowadays, endocrine therapy plus CDK4/6 inhibitors is the “preferred option for treatment-naive patients, but the dilemma between endocrine therapy and chemotherapy remains after disease progression on adjuvant or first-line therapy with CDK4/6 inhibitors, where current guidelines advocate in favor of endocrine therapy, despite its short-lived efficacy.”
“In that scenario, based on the STIC CTC trial results, the CTC count in combination with predictive biomarkers, whenever available, may help customize the early use of chemotherapy or antibody-drug conjugates, which are becoming more and more attractive,” Dr. Bidard said.
The research was presented here at the San Antonio Breast Cancer Symposium (SABCS).
The study involved more than 750 patients with HR+/HER2- metastatic breast cancer randomly assigned to physician choice or CTC-guided therapy, although the physician decision and the recommendation based on the CTC count was recorded in both groups.
Using the CellSearch (Menarini Silicon Biosystems) to perform the CTC count at baseline only, the team defined patients as low or high risk, with low-risk patients deemed to need only endocrine therapy and high-risk patients recommended chemotherapy.
Physicians based their decisions on current guidelines and their clinical experience.
In the 25% of cases where CTC count would recommend chemotherapy while the physician would recommend endocrine therapy, following the CTC count–based choice resulted in a 35% improvement in progression-free survival (PFS) and a 47% increase in overall survival.
In all other situations, including those when the CTC count recommended endocrine therapy in contrast to the physicians, or the approximately 60% of cases in which the two were in agreement, there was no difference in survival outcomes between the approaches.
Reacting to the findings, Nancy Chan, MD, medical oncologist and the director of breast cancer clinical research at NYU Langone’s Perlmutter Cancer Center, said that the “goal is really to understand how we can personalize treatment options for patients.”
Another aim is to avoid performing a tumor biopsy, if possible, “as that has increased morbidity for patients.”
She noted also that choosing between endocrine therapy and chemotherapy is a “big decision.” These researchers “really wanted to help some patients get less chemotherapy,” as they felt that “some patients are getting too much” as they are not really that high risk and should get endocrine therapy instead.
However, Dr. Chan said that the CTC count is a “complicated concept” and is “not something we’re all using in our clinical practice yet.”
With regard to the approximately 40% discordance between the CTC- and physician-guided choices, Dr. Chan said that clinicians are perhaps not as accurate as they believed in predicting risk when relying on the clinical or pathological features of the tumor.
On Twitter, Guilherme Nader-Marta, MD, Jules Bordet Institute, Université Libre de Bruxelles, Belgium, commented that the question behind the study was whether CTC measurement is a “clinically useful strategy for first-line treatment decision-making.”
“Amazingly,” he continued, the trial went “straight to the point” to answer the question and showed that CTC-based decisions can offer a survival benefit.
Daniel F. Hayes, MD, co-director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center, Ann Arbor, echoed these thoughts, saying that the goals of therapy are to make patients live longer and “better.”
He said that the point of any clinical biomarker is not only to show that testing for it offers “analytical validity” but that it also provides “clinical utility” in that it can guide treatment decisions to improve outcomes.
Dr. Hayes, who was not involved in the study but has worked for many years on the development of CellSearch, said that the results do not make it clear whether measuring CTC counts meets the definition of clinical utility, but it’s “very close.”
On the other hand, the analytical validity of the test is “excellent,” and, in that context, was well-chosen, he said, adding that the endpoint of the trial “is the one most important to us: improvement in overall survival.”
Dr. Hayes noted that the magnitude of benefit from CTC-guided therapy was “moderate,” although that is a “matter of perception,” and the “level of evidence is probably 2 or 3.” Although the trial was prospective, he said, the key results were in a “relatively small” subgroup.
The question is, Dr. Hayes continued: “Is this enough to change practice? My conclusions are: probably not.”
Although patients rated as low risk based on their low CTC count avoided chemotherapy, “it’s not clear to me that this whole thing is sufficient for clinical utility in context of what we know today.” The key issue, however, is who decides whether CTC counts are measured and whether they will be used to guide therapy decisions – will it be the patient, the caregiver, an expert guidelines panel, or third party payers/society?
Study details
In his presentation, Dr. Bidard explained that CTC count is an FDA-approved standardized liquid biopsy biomarker, with a count of greater than or equal to 5 cells per 7.5 mL of blood deemed an adverse prognostic marker, regardless of the line of therapy, with a grade 1 level of evidence.
Previous studies have indicated that a high CTC count is strongly associated with overall survival, at a hazard ratio of 2.78.
Crucially, the CTC count “complements” and does not duplicate standard clinicopathological prognostic factors, Dr. Bidard said.
To determine the potential of the CTC count as an aid to treatment decisions, Dr. Bidard and colleagues conducted a trial in pre- and postmenopausal women with untreated HR+/HER2- metastatic breast cancer who were able to receive either endocrine therapy or chemotherapy.
They were randomly assigned to either a standard group, in which the treatment decision followed the physician’s choice, regardless of their CTC count, or to a CTC group, in which the physicians made a treatment recommendation but the choice was driven by the CTC count.
Dr. Bidard reminded the audience that the primary endpoint of PFS to demonstrate the non-inferiority of CTC versus physician treatment decisions has already been met, with the results published in 2020. Those results came from an analysis of 788 patients enrolled between February 2012 and July 2016 at 17 sites in France and showed after 42 months of follow-up that the median PFS in the CTC arm was 15.6 months versus 14 months in the physician choice arm, at a hazard ratio of 0.92.
The current pre-planned analysis involved 755 patients who were followed up for a median of 57 months by the time the trial was stopped in 2021.
In the standard treatment arm, endocrine therapy was favored by physicians in 72.7% of cases (Clin-low), while 27.3% were given chemotherapy (Clin-high).
In the CTC group, 73.5% of patients were recommended to have endocrine therapy by their physician based on their clinical characteristics (Clin-low), whereas 26.5% were suggested to have chemotherapy (Clin-high).
In contrast, 60.1% of patients in the standard arm would have received endocrine therapy based on their CTC count (CTC-low), and 39.9% chemotherapy (CTC-high), while 63.4% of those in the CTC arm were given endocrine therapy based on their CTC count (CTC-low), and 36.6% were assigned to chemotherapy (CTC-high).
Once the allocated treatment was known in both treatment groups, the physicians were free to choose between endocrine therapy (mostly a single-agent aromatase inhibitor or fulvestrant) and chemotherapy (mostly paclitaxel or capecitabine).
Although CDK4/6 inhibitors were not approved at the time of enrollment, 42.2% of patients across both treatment groups received one of these drugs as a second-line or later therapy.
Guiding treatment decisions
Dr. Bidard said that, overall, more patients in the CTC arm were assigned to chemotherapy, at a difference of 9.7%. There was approximately 60% concordance between physician- and CTC-guided treatment choices; in other words, patients were recommended the same treatment by the two approaches in both treatment groups.
In these patients, there was no significant difference in overall survival between the physician choice and CTC groups, at a median of 45.5 months versus 51.3 months (hazard ratio, 0.85; P = .11).
The updated PFS data revealed a median PFS of 15.7 months in the CTC group versus 13.8 months, again at a nonsignificant HR of 0.94.
These results, Dr. Bidard said, indicate that CTC-based treatment choices are “safe.”
However, there was discordance between physician and CTC-based treatment choices in around 40% of cases, meaning that the two approaches recommended different therapies.
The physician recommended endocrine therapy, in contrast to the CTC count indicating chemotherapy, in 25% of patients (Clin-low/CTC-high), whereas 13.6% of cases were recommended chemotherapy while their CTC count indicated otherwise (Clin-high/CTC-low).
In Clin-low/CTC-high patients, this resulted in 26.1% of patients in the standard group receiving endocrine therapy when their CTC count indicated chemotherapy, while 23.9% of patients in the CTC group received chemotherapy even though their physician did not recommended it.
Comparing these two groups, the researchers found that patients in the CTC group had a significantly longer PFS, at 15.7 months versus 10 months (HR, 0.65; P = .005). They also had a significantly longer median overall survival, at a median of 51.8 months versus 35.4 months with physician choice (HR, 0.53; P = .001).
Among Clin-high/CTC-low, there was no benefit from physician’s choice of chemotherapy over the CTC-guided recommendation of endocrine therapy, at an HR for PFS of 1.14 for CTC- versus physician-guided therapy (P = .54), and an HR for overall survival of 0.88 (P = .64).
Dr. Bidard highlighted that the treatment effects were seen across prespecified subgroups.
The study was funded by the Institut National du Cancer, the Institut Curie SIRIC2 program, and Menarini Silicon Biosystems. Dr. Chan reports no relevant financial relationships. Dr. Hayes and Dr. Bidard reported relationships with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
AT SABCS 2022
Women can safely interrupt endocrine therapy to pursue pregnancy
without affecting their short-term disease outcomes, suggest results from the prospective POSITIVE trial.
The study involved more than 500 premenopausal women from 20 countries who had received at least 18 months of endocrine therapy for HR+ breast cancer. After a 3-month washout, they were given 2 years to conceive, deliver, and breastfeed a baby before resuming treatment.
Crucially, taking a treatment break had no impact on recurrence rates, with the 3-year breast cancer–free interval (BCFI) failure rate of nearly 9% comparing favorably with historical controls.
Moreover, almost three-quarters of women achieved at least one pregnancy, the majority within 2 years, and the vast majority had resumed endocrine therapy by the end of the study period.
The research was presented at the San Antonio Breast Cancer Symposium.
“These data stress the need to incorporate patient-centered reproductive health care, treatments, and choices in the treatment and follow-up of our young women with breast cancer so that they can not only survive, but thrive in their survivorship,” said study presenter Ann Partridge, MD, MPH, vice chair of medical oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.
She noted, however, that the results so far are from a 3-year follow-up. The team now plans on following the women for “at least a decade ... to monitor for independent therapy resumption, and disease outcomes, because of course there is great concern about the late return” of HR+ breast cancer.
This point was also raised by Marleen I. Meyers, MD, a medical oncologist New York University Langone Perlmutter Cancer Center, who was not involved in the study. While she praised the study as offering the “first real evidence” that treatment can be interrupted safely, she said she would be “cautious, as the follow-up is short and we know that hormone positive breast cancer can recur within 10 years of diagnosis and beyond.”
Meyer also emphasized that “the potential loss of fertility and ability to have biologic children ... [is] one of the most devastating results for young women with breast cancer.”
“We have come a long way with fertility preservation,” Dr. Meyers continued, but waiting to complete the recommended 5-10 years of endocrine therapy “makes the possibility of carrying a child less realistic.”
“This study offers hope for some women with hormone receptor–positive breast cancer to be able to interrupt cancer treatment and still have good outcomes,” she said.
Dr. Partridge said that “women are often discouraged” from becoming pregnant, in addition to which giving adjuvant endocrine therapy for the standard 5-10 years “compromises conception” in women with HR+ disease.
POSITIVE was a single-arm trial involving premenopausal women aged up to 42 years at study entry. They were required to have undergone at least 18 months and no more than 30 months of adjuvant endocrine therapy for stage I-III HR+ breast cancer, with no clinical evidence of recurrence. The women could also have undergone prior neoadjuvant chemotherapy with or without fertility preservation.
Women halted endocrine therapy within 1 month of trial enrollment and then underwent a 3-month washout period before having up to 2 years to attempt pregnancy, and to conceive, give birth to, and breastfeed a baby. They were then “strongly recommended” to resume endocrine therapy to complete the planned 5-10 years of treatment, with follow-up planned for up to 10 years.
In all, 518 women were enrolled at 116 centers in 20 countries on four continents, of whom 516 were available for the primary efficacy analysis. The median time from breast cancer diagnosis to enrollment was 29 months.
The median age of the participants at enrollment was 37 years, and 75% had no prior births. Stage I or II disease was diagnosed in 93%. The median duration of endocrine therapy prior to enrollment was 23.4 months.
Selective estrogen receptor modulators were given alone in 42% of patients, while 36% had a SERM plus ovarian function suppression. A further 16% of women received an aromatase inhibitor alongside ovarian function suppression. The majority (62%) of women had received prior neoadjuvant chemotherapy.
The primary endpoint of 3-year BCFI was measured after a median follow-up of 41 months. There were 44 events, with a 3-year BCFI failure rate of 8.9%. The 3-year distant recurrence–free interval (DRFI) failure rate was calculated at 4.5%, with 22 events.
To provide an external control, the researchers examined data from the SOFT and TEXT trials to assemble a cohort of 1,499 women balanced for patient, disease, and treatment characteristics.
This revealed no significant differences in BCFI between the two groups (hazard ratio, 0.81; 95% confidence interval, 0.57-1.15) and a difference in BCFI rates at 3 years of 0.2% between the SOFT, TEXT, and POSITIVE trials.
There was also no significant difference in DRFI rates (HR, 0.70; 95% CI, 0.44-1.12), with a 3-year rate difference of 1.4%.
For the secondary endpoint analysis, the team included 497 women from the POSITIVE cohort, of whom 368 (74%) had at least one pregnancy, giving a total of 507 pregnancies. At least one live birth was recorded in 64% of the women, or 86% of those who became pregnant.
Dr. Partridge noted that around 43% of women used some form of assisted reproductive technology at some point during the study period.
Pregnancy complications were observed in 11% of pregnancies, the most common of which were hypertension/preeclampsia in 3%, and diabetes in 2%.
There were a total of 350 live births in 317 women, including 335 singleton births and 15 sets of twins. Only 8% of the offspring had a low birth weight, and 2% had a birth defect. Breastfeeding was reported by 62% of women.
Conducting an 18-month landmark analysis, the team found that pregnancy did not increase BCFI rates, at an HR versus nonpregnant women of 0.53 after controlling for age, body mass index, lymph node status, prior chemotherapy, and prior aromatase inhibitor therapy.
At 48 months of follow-up, 76% of women had resumed endocrine therapy. A further 8% of women had cancer recurrence or death before they could restart therapy, while 15% had not yet resumed treatment for other reasons.
Among disease-free women who had not resumed endocrine therapy, 79% reported at their most recent follow-up continuing to pursue pregnancy, having an active or recent pregnancy, or continuing to breastfeed as the reason.
Commenting on the study, Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said that this was a “challenging study to design and execute.”
“It gives us really a first look into the safety of a practice that was already happening,” she commented, and emphasized that the interruption of treatment to pursue pregnancy remains “an exceptionally individual decision.”
Dr. Litton also underlined that these results apply only to endocrine therapy and not to women on other therapies such as abemaciclib, for example, for which the course should be “fully completed” before considering any treatment interruptions.
She added more generally that “we need to continue to improve discussing fertility concerns with our breast cancer patients who want future pregnancies.”
The study was sponsored and conducted by the International Breast Cancer Study Group, a division of ETOP IBCSG Partners Foundation, and by the Alliance for Clinical Trials in Oncology in North America, in collaboration with the Breast International Group. Dr. Partridge and Dr. Litton reported no relevant relationships.
A version of this article first appeared on Medscape.com.
without affecting their short-term disease outcomes, suggest results from the prospective POSITIVE trial.
The study involved more than 500 premenopausal women from 20 countries who had received at least 18 months of endocrine therapy for HR+ breast cancer. After a 3-month washout, they were given 2 years to conceive, deliver, and breastfeed a baby before resuming treatment.
Crucially, taking a treatment break had no impact on recurrence rates, with the 3-year breast cancer–free interval (BCFI) failure rate of nearly 9% comparing favorably with historical controls.
Moreover, almost three-quarters of women achieved at least one pregnancy, the majority within 2 years, and the vast majority had resumed endocrine therapy by the end of the study period.
The research was presented at the San Antonio Breast Cancer Symposium.
“These data stress the need to incorporate patient-centered reproductive health care, treatments, and choices in the treatment and follow-up of our young women with breast cancer so that they can not only survive, but thrive in their survivorship,” said study presenter Ann Partridge, MD, MPH, vice chair of medical oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.
She noted, however, that the results so far are from a 3-year follow-up. The team now plans on following the women for “at least a decade ... to monitor for independent therapy resumption, and disease outcomes, because of course there is great concern about the late return” of HR+ breast cancer.
This point was also raised by Marleen I. Meyers, MD, a medical oncologist New York University Langone Perlmutter Cancer Center, who was not involved in the study. While she praised the study as offering the “first real evidence” that treatment can be interrupted safely, she said she would be “cautious, as the follow-up is short and we know that hormone positive breast cancer can recur within 10 years of diagnosis and beyond.”
Meyer also emphasized that “the potential loss of fertility and ability to have biologic children ... [is] one of the most devastating results for young women with breast cancer.”
“We have come a long way with fertility preservation,” Dr. Meyers continued, but waiting to complete the recommended 5-10 years of endocrine therapy “makes the possibility of carrying a child less realistic.”
“This study offers hope for some women with hormone receptor–positive breast cancer to be able to interrupt cancer treatment and still have good outcomes,” she said.
Dr. Partridge said that “women are often discouraged” from becoming pregnant, in addition to which giving adjuvant endocrine therapy for the standard 5-10 years “compromises conception” in women with HR+ disease.
POSITIVE was a single-arm trial involving premenopausal women aged up to 42 years at study entry. They were required to have undergone at least 18 months and no more than 30 months of adjuvant endocrine therapy for stage I-III HR+ breast cancer, with no clinical evidence of recurrence. The women could also have undergone prior neoadjuvant chemotherapy with or without fertility preservation.
Women halted endocrine therapy within 1 month of trial enrollment and then underwent a 3-month washout period before having up to 2 years to attempt pregnancy, and to conceive, give birth to, and breastfeed a baby. They were then “strongly recommended” to resume endocrine therapy to complete the planned 5-10 years of treatment, with follow-up planned for up to 10 years.
In all, 518 women were enrolled at 116 centers in 20 countries on four continents, of whom 516 were available for the primary efficacy analysis. The median time from breast cancer diagnosis to enrollment was 29 months.
The median age of the participants at enrollment was 37 years, and 75% had no prior births. Stage I or II disease was diagnosed in 93%. The median duration of endocrine therapy prior to enrollment was 23.4 months.
Selective estrogen receptor modulators were given alone in 42% of patients, while 36% had a SERM plus ovarian function suppression. A further 16% of women received an aromatase inhibitor alongside ovarian function suppression. The majority (62%) of women had received prior neoadjuvant chemotherapy.
The primary endpoint of 3-year BCFI was measured after a median follow-up of 41 months. There were 44 events, with a 3-year BCFI failure rate of 8.9%. The 3-year distant recurrence–free interval (DRFI) failure rate was calculated at 4.5%, with 22 events.
To provide an external control, the researchers examined data from the SOFT and TEXT trials to assemble a cohort of 1,499 women balanced for patient, disease, and treatment characteristics.
This revealed no significant differences in BCFI between the two groups (hazard ratio, 0.81; 95% confidence interval, 0.57-1.15) and a difference in BCFI rates at 3 years of 0.2% between the SOFT, TEXT, and POSITIVE trials.
There was also no significant difference in DRFI rates (HR, 0.70; 95% CI, 0.44-1.12), with a 3-year rate difference of 1.4%.
For the secondary endpoint analysis, the team included 497 women from the POSITIVE cohort, of whom 368 (74%) had at least one pregnancy, giving a total of 507 pregnancies. At least one live birth was recorded in 64% of the women, or 86% of those who became pregnant.
Dr. Partridge noted that around 43% of women used some form of assisted reproductive technology at some point during the study period.
Pregnancy complications were observed in 11% of pregnancies, the most common of which were hypertension/preeclampsia in 3%, and diabetes in 2%.
There were a total of 350 live births in 317 women, including 335 singleton births and 15 sets of twins. Only 8% of the offspring had a low birth weight, and 2% had a birth defect. Breastfeeding was reported by 62% of women.
Conducting an 18-month landmark analysis, the team found that pregnancy did not increase BCFI rates, at an HR versus nonpregnant women of 0.53 after controlling for age, body mass index, lymph node status, prior chemotherapy, and prior aromatase inhibitor therapy.
At 48 months of follow-up, 76% of women had resumed endocrine therapy. A further 8% of women had cancer recurrence or death before they could restart therapy, while 15% had not yet resumed treatment for other reasons.
Among disease-free women who had not resumed endocrine therapy, 79% reported at their most recent follow-up continuing to pursue pregnancy, having an active or recent pregnancy, or continuing to breastfeed as the reason.
Commenting on the study, Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said that this was a “challenging study to design and execute.”
“It gives us really a first look into the safety of a practice that was already happening,” she commented, and emphasized that the interruption of treatment to pursue pregnancy remains “an exceptionally individual decision.”
Dr. Litton also underlined that these results apply only to endocrine therapy and not to women on other therapies such as abemaciclib, for example, for which the course should be “fully completed” before considering any treatment interruptions.
She added more generally that “we need to continue to improve discussing fertility concerns with our breast cancer patients who want future pregnancies.”
The study was sponsored and conducted by the International Breast Cancer Study Group, a division of ETOP IBCSG Partners Foundation, and by the Alliance for Clinical Trials in Oncology in North America, in collaboration with the Breast International Group. Dr. Partridge and Dr. Litton reported no relevant relationships.
A version of this article first appeared on Medscape.com.
without affecting their short-term disease outcomes, suggest results from the prospective POSITIVE trial.
The study involved more than 500 premenopausal women from 20 countries who had received at least 18 months of endocrine therapy for HR+ breast cancer. After a 3-month washout, they were given 2 years to conceive, deliver, and breastfeed a baby before resuming treatment.
Crucially, taking a treatment break had no impact on recurrence rates, with the 3-year breast cancer–free interval (BCFI) failure rate of nearly 9% comparing favorably with historical controls.
Moreover, almost three-quarters of women achieved at least one pregnancy, the majority within 2 years, and the vast majority had resumed endocrine therapy by the end of the study period.
The research was presented at the San Antonio Breast Cancer Symposium.
“These data stress the need to incorporate patient-centered reproductive health care, treatments, and choices in the treatment and follow-up of our young women with breast cancer so that they can not only survive, but thrive in their survivorship,” said study presenter Ann Partridge, MD, MPH, vice chair of medical oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.
She noted, however, that the results so far are from a 3-year follow-up. The team now plans on following the women for “at least a decade ... to monitor for independent therapy resumption, and disease outcomes, because of course there is great concern about the late return” of HR+ breast cancer.
This point was also raised by Marleen I. Meyers, MD, a medical oncologist New York University Langone Perlmutter Cancer Center, who was not involved in the study. While she praised the study as offering the “first real evidence” that treatment can be interrupted safely, she said she would be “cautious, as the follow-up is short and we know that hormone positive breast cancer can recur within 10 years of diagnosis and beyond.”
Meyer also emphasized that “the potential loss of fertility and ability to have biologic children ... [is] one of the most devastating results for young women with breast cancer.”
“We have come a long way with fertility preservation,” Dr. Meyers continued, but waiting to complete the recommended 5-10 years of endocrine therapy “makes the possibility of carrying a child less realistic.”
“This study offers hope for some women with hormone receptor–positive breast cancer to be able to interrupt cancer treatment and still have good outcomes,” she said.
Dr. Partridge said that “women are often discouraged” from becoming pregnant, in addition to which giving adjuvant endocrine therapy for the standard 5-10 years “compromises conception” in women with HR+ disease.
POSITIVE was a single-arm trial involving premenopausal women aged up to 42 years at study entry. They were required to have undergone at least 18 months and no more than 30 months of adjuvant endocrine therapy for stage I-III HR+ breast cancer, with no clinical evidence of recurrence. The women could also have undergone prior neoadjuvant chemotherapy with or without fertility preservation.
Women halted endocrine therapy within 1 month of trial enrollment and then underwent a 3-month washout period before having up to 2 years to attempt pregnancy, and to conceive, give birth to, and breastfeed a baby. They were then “strongly recommended” to resume endocrine therapy to complete the planned 5-10 years of treatment, with follow-up planned for up to 10 years.
In all, 518 women were enrolled at 116 centers in 20 countries on four continents, of whom 516 were available for the primary efficacy analysis. The median time from breast cancer diagnosis to enrollment was 29 months.
The median age of the participants at enrollment was 37 years, and 75% had no prior births. Stage I or II disease was diagnosed in 93%. The median duration of endocrine therapy prior to enrollment was 23.4 months.
Selective estrogen receptor modulators were given alone in 42% of patients, while 36% had a SERM plus ovarian function suppression. A further 16% of women received an aromatase inhibitor alongside ovarian function suppression. The majority (62%) of women had received prior neoadjuvant chemotherapy.
The primary endpoint of 3-year BCFI was measured after a median follow-up of 41 months. There were 44 events, with a 3-year BCFI failure rate of 8.9%. The 3-year distant recurrence–free interval (DRFI) failure rate was calculated at 4.5%, with 22 events.
To provide an external control, the researchers examined data from the SOFT and TEXT trials to assemble a cohort of 1,499 women balanced for patient, disease, and treatment characteristics.
This revealed no significant differences in BCFI between the two groups (hazard ratio, 0.81; 95% confidence interval, 0.57-1.15) and a difference in BCFI rates at 3 years of 0.2% between the SOFT, TEXT, and POSITIVE trials.
There was also no significant difference in DRFI rates (HR, 0.70; 95% CI, 0.44-1.12), with a 3-year rate difference of 1.4%.
For the secondary endpoint analysis, the team included 497 women from the POSITIVE cohort, of whom 368 (74%) had at least one pregnancy, giving a total of 507 pregnancies. At least one live birth was recorded in 64% of the women, or 86% of those who became pregnant.
Dr. Partridge noted that around 43% of women used some form of assisted reproductive technology at some point during the study period.
Pregnancy complications were observed in 11% of pregnancies, the most common of which were hypertension/preeclampsia in 3%, and diabetes in 2%.
There were a total of 350 live births in 317 women, including 335 singleton births and 15 sets of twins. Only 8% of the offspring had a low birth weight, and 2% had a birth defect. Breastfeeding was reported by 62% of women.
Conducting an 18-month landmark analysis, the team found that pregnancy did not increase BCFI rates, at an HR versus nonpregnant women of 0.53 after controlling for age, body mass index, lymph node status, prior chemotherapy, and prior aromatase inhibitor therapy.
At 48 months of follow-up, 76% of women had resumed endocrine therapy. A further 8% of women had cancer recurrence or death before they could restart therapy, while 15% had not yet resumed treatment for other reasons.
Among disease-free women who had not resumed endocrine therapy, 79% reported at their most recent follow-up continuing to pursue pregnancy, having an active or recent pregnancy, or continuing to breastfeed as the reason.
Commenting on the study, Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said that this was a “challenging study to design and execute.”
“It gives us really a first look into the safety of a practice that was already happening,” she commented, and emphasized that the interruption of treatment to pursue pregnancy remains “an exceptionally individual decision.”
Dr. Litton also underlined that these results apply only to endocrine therapy and not to women on other therapies such as abemaciclib, for example, for which the course should be “fully completed” before considering any treatment interruptions.
She added more generally that “we need to continue to improve discussing fertility concerns with our breast cancer patients who want future pregnancies.”
The study was sponsored and conducted by the International Breast Cancer Study Group, a division of ETOP IBCSG Partners Foundation, and by the Alliance for Clinical Trials in Oncology in North America, in collaboration with the Breast International Group. Dr. Partridge and Dr. Litton reported no relevant relationships.
A version of this article first appeared on Medscape.com.
FROM SABCS 2022
High rates of inappropriate PPI use in hospitalized patients
The research was published online in the journal Digestive and Liver Disease.
First author Orly Sneh-Arbib, MD, division of gastroenterology and liver disease, Clalit Health Services, Talpiot, Jerusalem, said in an interview that she and her co-authors were “very surprised” that the rates of inappropriate prescribing remained so high, especially as they had discussed the adverse effects of the drugs numerous times during departmental meetings.
She believes that, for many clinicians, handing out a prescription for PPIs has become a habit, with the thought being: “Just take this; it’s like a vitamin.”
In the paper, the researchers write, “Undoubtedly, more action is needed to raise physicians’ knowledge and attention to the subject while providing automated and standardized technology-based tools to reduce inappropriate PPI use using an acceptable algorithm.”
For the study, Dr. Sneh-Arbib and her colleagues developed an algorithm to assess inappropriate PPI prescribing in almost 4,000 internal medicine patients. To try to limit future overprescribing, their algorithm is now included in the clinical records system.
Consequently, every time a clinician tries to prescribe a PPI, they have to confirm that there is a valid indication for doing so, with the aim of adding an “extra step in the process,” Dr. Sneh-Arbib said.
Clear but complex PPI indications
There are a small, well-defined number of indications for long-term PPI use, the authors write. The indications include prior upper gastrointestinal bleeding, maintenance treatment after healing of erosive esophagitis, Barrett’s esophagus, the use of nonsteroidal anti-inflammatory drugs or antiplatelet agents in patients with increased bleeding risk, and maintenance therapy for symptom control in patients with gastroesophageal reflux disease.
The authors also note that the “appropriateness of PPIs is complex,” with multiple factors to consider for long-term PPI use, including complex drug combinations and medical history.
But having seen patients in their 30s prescribed PPIs “just because of taking steroids or aspirin,” Dr. Sneh-Arbib said she wanted to investigate further.
To examine the rate of inappropriate long-term PPI prescription on discharge from internal medicine departments, the team conducted a retrospective analysis of adults admitted to their institution for the first 6 months of 2014 and the first 6 months of 2017.
They included all patients prescribed PPIs on discharge with a recommendation for long-term use and excluded those who were transferred between departments or who had a hospital stay longer than 3 months.
Information on age, gender, ethnicity, socioeconomic status, current and past diagnoses including all relevant gastrointestinal diagnoses, Charlson comorbidity index, and medications on admission and discharge were recorded.
Guidelines for use of PPIs
To assess inappropriate PPI prescribing, the team searched for published recommendations on long-term use, Dr. Sneh-Arbib said. They developed an algorithm based on the U.K. National Institute for Health and Care Excellence (NICE) clinical guideline, “Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management.”
The guideline is “not perfect,” Dr. Sneh-Arbib said, but it was suitable. The team then randomly chose 100 patients from their records to validate the resulting algorithm, finding an accuracy of 96%.
The full analysis included 3,982 patients, of whom 74% were aged 65 years or older, and 50.8% were women. PPIs were first prescribed before hospital admission in 92.4% of cases.
The researchers found that the overall rate of inappropriate PPI prescriptions was 44.3%, a figure that was stable between the two the study periods. In 2014, the rate of inappropriate use was 43.2%, and it was 45.6% in 2017, a nonsignificant difference.
Inappropriate PPIs were higher (68.1%) in patients younger than 65 years, compared with those aged 65 years and older (36%).
The researchers analyzed factors associated with inappropriate PPIs, first excluding 448 patients with clear gastrointestinal indications.
In the majority of cases, the inappropriate PPI prescriptions occurred in patients who were not taking dual antiplatelet treatment (89.4%), in younger patients who were taking aspirin only (8.6%), and in patients receiving a single antiplatelet agent other than aspirin (1.9%), according to multivariate analysis.
Overall, 42.4% of patients classified as inappropriate PPI use were not using aspirin, nonsteroidal anti-inflammatory drugs, antiplatelets, antiaggregants, anticoagulants, or steroids, the researchers found.
They also note that most patients in the study (92.3%) had received PPIs before admission, prescribed by their general practitioner or during a previous hospitalization. This raises concerns about unneeded continuation of the drugs and lack of review by clinicians, they write.
PPI deprescribing
Approached for comment, Adrienna Jirik, MD, a gastroenterologist at the Cleveland Clinic, told this news organization that “PPI overprescription is a common problem worldwide, with the United States being no exception.”
They are “one of the most prescribed medications in the world, with several formulations readily available as an over-the-counter medication,” she added.
Dr. Jirik, who was not involved with the study, said that the algorithm used is “on par with the United States clinical practice guidelines for PPI use” and a “great start to initiate an encounter with a patient on PPIs in the outpatient setting to review the indications and to de-escalate and deprescribe therapy.”
Indeed, the American Gastroenterological Association recently published a clinical practice update on deprescribing PPIs.
“It may be useful to incorporate a version of this algorithm as a ‘hard stop’ on some outpatient EMR [electronic medical record] templates to remind providers to address this issue prior to closing an encounter,” Dr. Jirik added.
She noted, however, that tackling any medication reconciliation is a very important but difficult and time-consuming task.
“Education is definitely key for both primary and subspecialty providers,” Dr. Jirik said. “If patients have been on a long-term PPI, the inpatient provider can suggest a plan for de-escalation based on practice guidelines and arrange proper outpatient follow-up for eventual deprescribing.”
No funding was declared. The authors and Dr. Jirik report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The research was published online in the journal Digestive and Liver Disease.
First author Orly Sneh-Arbib, MD, division of gastroenterology and liver disease, Clalit Health Services, Talpiot, Jerusalem, said in an interview that she and her co-authors were “very surprised” that the rates of inappropriate prescribing remained so high, especially as they had discussed the adverse effects of the drugs numerous times during departmental meetings.
She believes that, for many clinicians, handing out a prescription for PPIs has become a habit, with the thought being: “Just take this; it’s like a vitamin.”
In the paper, the researchers write, “Undoubtedly, more action is needed to raise physicians’ knowledge and attention to the subject while providing automated and standardized technology-based tools to reduce inappropriate PPI use using an acceptable algorithm.”
For the study, Dr. Sneh-Arbib and her colleagues developed an algorithm to assess inappropriate PPI prescribing in almost 4,000 internal medicine patients. To try to limit future overprescribing, their algorithm is now included in the clinical records system.
Consequently, every time a clinician tries to prescribe a PPI, they have to confirm that there is a valid indication for doing so, with the aim of adding an “extra step in the process,” Dr. Sneh-Arbib said.
Clear but complex PPI indications
There are a small, well-defined number of indications for long-term PPI use, the authors write. The indications include prior upper gastrointestinal bleeding, maintenance treatment after healing of erosive esophagitis, Barrett’s esophagus, the use of nonsteroidal anti-inflammatory drugs or antiplatelet agents in patients with increased bleeding risk, and maintenance therapy for symptom control in patients with gastroesophageal reflux disease.
The authors also note that the “appropriateness of PPIs is complex,” with multiple factors to consider for long-term PPI use, including complex drug combinations and medical history.
But having seen patients in their 30s prescribed PPIs “just because of taking steroids or aspirin,” Dr. Sneh-Arbib said she wanted to investigate further.
To examine the rate of inappropriate long-term PPI prescription on discharge from internal medicine departments, the team conducted a retrospective analysis of adults admitted to their institution for the first 6 months of 2014 and the first 6 months of 2017.
They included all patients prescribed PPIs on discharge with a recommendation for long-term use and excluded those who were transferred between departments or who had a hospital stay longer than 3 months.
Information on age, gender, ethnicity, socioeconomic status, current and past diagnoses including all relevant gastrointestinal diagnoses, Charlson comorbidity index, and medications on admission and discharge were recorded.
Guidelines for use of PPIs
To assess inappropriate PPI prescribing, the team searched for published recommendations on long-term use, Dr. Sneh-Arbib said. They developed an algorithm based on the U.K. National Institute for Health and Care Excellence (NICE) clinical guideline, “Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management.”
The guideline is “not perfect,” Dr. Sneh-Arbib said, but it was suitable. The team then randomly chose 100 patients from their records to validate the resulting algorithm, finding an accuracy of 96%.
The full analysis included 3,982 patients, of whom 74% were aged 65 years or older, and 50.8% were women. PPIs were first prescribed before hospital admission in 92.4% of cases.
The researchers found that the overall rate of inappropriate PPI prescriptions was 44.3%, a figure that was stable between the two the study periods. In 2014, the rate of inappropriate use was 43.2%, and it was 45.6% in 2017, a nonsignificant difference.
Inappropriate PPIs were higher (68.1%) in patients younger than 65 years, compared with those aged 65 years and older (36%).
The researchers analyzed factors associated with inappropriate PPIs, first excluding 448 patients with clear gastrointestinal indications.
In the majority of cases, the inappropriate PPI prescriptions occurred in patients who were not taking dual antiplatelet treatment (89.4%), in younger patients who were taking aspirin only (8.6%), and in patients receiving a single antiplatelet agent other than aspirin (1.9%), according to multivariate analysis.
Overall, 42.4% of patients classified as inappropriate PPI use were not using aspirin, nonsteroidal anti-inflammatory drugs, antiplatelets, antiaggregants, anticoagulants, or steroids, the researchers found.
They also note that most patients in the study (92.3%) had received PPIs before admission, prescribed by their general practitioner or during a previous hospitalization. This raises concerns about unneeded continuation of the drugs and lack of review by clinicians, they write.
PPI deprescribing
Approached for comment, Adrienna Jirik, MD, a gastroenterologist at the Cleveland Clinic, told this news organization that “PPI overprescription is a common problem worldwide, with the United States being no exception.”
They are “one of the most prescribed medications in the world, with several formulations readily available as an over-the-counter medication,” she added.
Dr. Jirik, who was not involved with the study, said that the algorithm used is “on par with the United States clinical practice guidelines for PPI use” and a “great start to initiate an encounter with a patient on PPIs in the outpatient setting to review the indications and to de-escalate and deprescribe therapy.”
Indeed, the American Gastroenterological Association recently published a clinical practice update on deprescribing PPIs.
“It may be useful to incorporate a version of this algorithm as a ‘hard stop’ on some outpatient EMR [electronic medical record] templates to remind providers to address this issue prior to closing an encounter,” Dr. Jirik added.
She noted, however, that tackling any medication reconciliation is a very important but difficult and time-consuming task.
“Education is definitely key for both primary and subspecialty providers,” Dr. Jirik said. “If patients have been on a long-term PPI, the inpatient provider can suggest a plan for de-escalation based on practice guidelines and arrange proper outpatient follow-up for eventual deprescribing.”
No funding was declared. The authors and Dr. Jirik report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The research was published online in the journal Digestive and Liver Disease.
First author Orly Sneh-Arbib, MD, division of gastroenterology and liver disease, Clalit Health Services, Talpiot, Jerusalem, said in an interview that she and her co-authors were “very surprised” that the rates of inappropriate prescribing remained so high, especially as they had discussed the adverse effects of the drugs numerous times during departmental meetings.
She believes that, for many clinicians, handing out a prescription for PPIs has become a habit, with the thought being: “Just take this; it’s like a vitamin.”
In the paper, the researchers write, “Undoubtedly, more action is needed to raise physicians’ knowledge and attention to the subject while providing automated and standardized technology-based tools to reduce inappropriate PPI use using an acceptable algorithm.”
For the study, Dr. Sneh-Arbib and her colleagues developed an algorithm to assess inappropriate PPI prescribing in almost 4,000 internal medicine patients. To try to limit future overprescribing, their algorithm is now included in the clinical records system.
Consequently, every time a clinician tries to prescribe a PPI, they have to confirm that there is a valid indication for doing so, with the aim of adding an “extra step in the process,” Dr. Sneh-Arbib said.
Clear but complex PPI indications
There are a small, well-defined number of indications for long-term PPI use, the authors write. The indications include prior upper gastrointestinal bleeding, maintenance treatment after healing of erosive esophagitis, Barrett’s esophagus, the use of nonsteroidal anti-inflammatory drugs or antiplatelet agents in patients with increased bleeding risk, and maintenance therapy for symptom control in patients with gastroesophageal reflux disease.
The authors also note that the “appropriateness of PPIs is complex,” with multiple factors to consider for long-term PPI use, including complex drug combinations and medical history.
But having seen patients in their 30s prescribed PPIs “just because of taking steroids or aspirin,” Dr. Sneh-Arbib said she wanted to investigate further.
To examine the rate of inappropriate long-term PPI prescription on discharge from internal medicine departments, the team conducted a retrospective analysis of adults admitted to their institution for the first 6 months of 2014 and the first 6 months of 2017.
They included all patients prescribed PPIs on discharge with a recommendation for long-term use and excluded those who were transferred between departments or who had a hospital stay longer than 3 months.
Information on age, gender, ethnicity, socioeconomic status, current and past diagnoses including all relevant gastrointestinal diagnoses, Charlson comorbidity index, and medications on admission and discharge were recorded.
Guidelines for use of PPIs
To assess inappropriate PPI prescribing, the team searched for published recommendations on long-term use, Dr. Sneh-Arbib said. They developed an algorithm based on the U.K. National Institute for Health and Care Excellence (NICE) clinical guideline, “Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management.”
The guideline is “not perfect,” Dr. Sneh-Arbib said, but it was suitable. The team then randomly chose 100 patients from their records to validate the resulting algorithm, finding an accuracy of 96%.
The full analysis included 3,982 patients, of whom 74% were aged 65 years or older, and 50.8% were women. PPIs were first prescribed before hospital admission in 92.4% of cases.
The researchers found that the overall rate of inappropriate PPI prescriptions was 44.3%, a figure that was stable between the two the study periods. In 2014, the rate of inappropriate use was 43.2%, and it was 45.6% in 2017, a nonsignificant difference.
Inappropriate PPIs were higher (68.1%) in patients younger than 65 years, compared with those aged 65 years and older (36%).
The researchers analyzed factors associated with inappropriate PPIs, first excluding 448 patients with clear gastrointestinal indications.
In the majority of cases, the inappropriate PPI prescriptions occurred in patients who were not taking dual antiplatelet treatment (89.4%), in younger patients who were taking aspirin only (8.6%), and in patients receiving a single antiplatelet agent other than aspirin (1.9%), according to multivariate analysis.
Overall, 42.4% of patients classified as inappropriate PPI use were not using aspirin, nonsteroidal anti-inflammatory drugs, antiplatelets, antiaggregants, anticoagulants, or steroids, the researchers found.
They also note that most patients in the study (92.3%) had received PPIs before admission, prescribed by their general practitioner or during a previous hospitalization. This raises concerns about unneeded continuation of the drugs and lack of review by clinicians, they write.
PPI deprescribing
Approached for comment, Adrienna Jirik, MD, a gastroenterologist at the Cleveland Clinic, told this news organization that “PPI overprescription is a common problem worldwide, with the United States being no exception.”
They are “one of the most prescribed medications in the world, with several formulations readily available as an over-the-counter medication,” she added.
Dr. Jirik, who was not involved with the study, said that the algorithm used is “on par with the United States clinical practice guidelines for PPI use” and a “great start to initiate an encounter with a patient on PPIs in the outpatient setting to review the indications and to de-escalate and deprescribe therapy.”
Indeed, the American Gastroenterological Association recently published a clinical practice update on deprescribing PPIs.
“It may be useful to incorporate a version of this algorithm as a ‘hard stop’ on some outpatient EMR [electronic medical record] templates to remind providers to address this issue prior to closing an encounter,” Dr. Jirik added.
She noted, however, that tackling any medication reconciliation is a very important but difficult and time-consuming task.
“Education is definitely key for both primary and subspecialty providers,” Dr. Jirik said. “If patients have been on a long-term PPI, the inpatient provider can suggest a plan for de-escalation based on practice guidelines and arrange proper outpatient follow-up for eventual deprescribing.”
No funding was declared. The authors and Dr. Jirik report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Over half of targetable NSCLC patients miss out on correct tx
because of gaps in clinical practice all along the cancer care spectrum, reveals a new analysis of data from U.S. practices.
For some of these patients, it could mean missing the chance for long-term survival or even cure.
One lung cancer patient, Janet Freeman-Daily, recently tweeted that she entered a targeted therapy clinical trial 10 years ago and is still taking the same, now approved, oral drug, with “no evidence of disease.”
Patients who have lung cancer with mutations that can be targeted with drug therapies – but who do not receive them – are missing this opportunity.
The new study suggests that there are many such patients. The researchers analyzed data on more than 38,000 patients with actively managed advanced NSCLC. They found that about half did not receive biomarker test results for a variety of reasons. But even among the half who were successfully tested, 30% of these patients did not receive the appropriate targeted therapies.
Overall, around 64% of eligible patients with advanced NSCLC are not benefiting from the most appropriate therapies, the team concludes.
The research was published online in JCO Precision Oncology.
Gaps in clinical practice
The high rate of failure points to clinical practice gaps in “many areas” across the cancer care spectrum, lead author Daryl Pritchard, PhD, from the Personalized Medicine Coalition, Washington, told this news organization.
“There’s various steps along the way that affect clinicians, laboratories, payers, the health providers [and] even patients,” he said. He added that product manufacturers also “have a role.”
“So it’s not an individual group that’s causing the problem. It’s a systemic awareness and systemic need to improve the delivery process.”
Dr. Pritchard underlined that the “the main goal of this analysis is to put everybody on alert that we need to do something about it.
“We need to – and this is easy to say but hard to do – evolve health care from a traditional one-size-fits-all mentality to a value-based strategy where you’re saying we want the best treatments” for patients, he said.
This means developing optimized and standardized laboratory processes, as well as clinical guidelines that set out the standard of care and optimized and integrated clinical decision support.
“We need to work as a community to demonstrate the value of this care and improve education and awareness to providers and payers,” Dr. Pritchard said. “That will encourage value-based practice coverage and reimbursement policies, and then also incentivize utilization in validated cases.”
Julie R. Brahmer, MD, who directs the thoracic oncology program at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, who was not involved with the study, said she was not sure whether she would say she was “surprised or disheartened” by the findings.
The study was focused on advanced NSCLC patients treated in 2019. Dr. Brahmer wondered whether the COVID-19 pandemic “might actually have made things worse.”
It will be important to “drill down” into some of the reasons why 30% of patients for whom biomarker testing results were available did not receive the appropriate treatment, she said.
Aside from cost-related problems, one factor at play could be whether the patient saw an oncologist, she said, while another could be that they went “straight to hospice” and were “not healthy enough to be able to tolerate” their targeted therapy.
Greater use of liquid biopsies, which identify biomarkers in the blood, are one way to improve access to biomarker testing, she suggested. It would help if these liquid biopsies were “consistently paid for by the payer, particularly for patients with advanced disease,” she added. Currently, payers often want patients to first undergo a tissue biopsy, which involves lung aspiration and may not be possible for some patients.
“If a Medicare patient is in the hospital when they have their biopsy or surgery, and then they have to wait 14 days in order for mutation tests to be ordered, and then if you add another 2 weeks for that test to come back, or even longer … [These delays] are some of the reasons why patients didn’t end up receiving therapy,” she elaborated.
“Some of these patients just can’t last that long before starting treatment,” she said.
Sandip P. Patel, MD, an oncologist at the Precision Immunotherapy Clinic at the University of California, San Diego, in La Jolla, wondered whether the issue is lack of education among physicians or whether there are potential financial problems. “Is there a financial risk to patients, for example, that is not being captured?” he mused.
It could also be a question of urban vs. rural centers, language barriers in communicating to patients, or other social determinants of health, he added.
At his institution (UCSD), there are “multiple choices” of molecular tests, each with “little nuances that differ among the tests that folks sometimes will take a look at in term of picking the best.
“But the best test is the one that gets done, and here we’re seeing no testing at all” for many patients, he said.
“It’s really unfortunate because for a lot of these patients, not only are they not getting the latest therapy, but they’re often getting something else that’s expensive and toxic instead,” Dr. Patel said.
Referring to the relatively high proportion of patients who didn’t receive targeted therapy even after being tested, he said, “For me, this study leaves more questions and answers.
“We’ve seen a lot of work in this space, showing us the problem,” Dr. Patel said. “What I haven’t yet seen is a very discrete analysis of the cause of that problem upstream.”
Cornerstone of personalized medicine
In their article, Dr. Pritchard and colleagues note that more than 90 targeted therapies have been approved by the U.S. Food and Drug Administration for use in eligible cancer patients. An estimated 55% of recent oncology trials involved the use of biomarkers.
Predictive biomarker testing to identify patients who may benefit from targeted therapies “is a cornerstone of personalized medicine in cancer care, allowing for more rapid diagnosis while informing treatment decisions that could lead to better patient outcomes and systemic efficiencies,” they emphasize.
However, providers “face several challenges” when integrating biomarker testing and targeted therapeutics into cancer care, and the use of biomarker testing varies widely across tumor types, biomarkers, and practice settings.
For their study, the team examined the use of targeted therapy in advanced NSCLC using data from the Diaceutics Data Repository, which includes commercial and Medicare claims, as well as laboratory data.
They focused on 38,068 patients with actively managed advanced NSCLC. Of those patients, 50.80% were women, and 64.6% were aged 71 years or older. The vast majority (84.50%) were non-Hispanic White patients.
The team examined the impact of seven clinical practice gaps on the timeline from ordering a biopsy to delivering targeted treatment. They then normalized the results to a standard patient population of 1,000.
In 6.6% of cases, an initial tissue or liquid biopsy was never performed, meaning that 66 of the 1,000 patients could not progress toward targeted therapy.
Among those who underwent a biopsy, for 4.0%, there was insufficient tissue on the initial biopsy, while for a further 0.97%, there was insufficient tissue on re-biopsy. Moreover, 9.6% could not undergo biopsy testing because of a lack of tumor tissue. Consequently, a further 136 of the 944 remaining patients were lost.
For the third clinical practice gap, the tumor cell content was overestimated in 1.7% of patients. As a result, their biopsy specimen could not be tested because it did not meet the threshold requirements. This resulted in the loss of a further 14 patients.
Moreover, for a further 17.5% of patients, biomarker testing was not ordered at all, owing to cost concerns, a lack of access to testing, a lack of awareness of testing options, and low confidence in the results, among other reasons. An additional 0.6% began treatment before any testing was ordered; together, that accounted for 142 patients being lost.
Even among patients who underwent biomarker testing, 14.5% had uninformative or inconclusive results, and 3.9% had false-negative results, meaning that a further 118 patients were lost.
In another 4.0% of cases, the results of biomarker testing did not arrive within the treatment decision window, owing to delays in reporting the results, and so for these patients, treatment began without the results being taken into consideration. A further 21 patients were lost.
The final clinical practice gap was not choosing the appropriate targeted treatment on the basis of test results. The researchers found that of 27,186 patients who underwent biomarker testing and received a timely result, 29.2% were not given the corresponding therapy. This resulted in the loss of a further 147 of the original 1,000 patients.
Overall, the team calculated that 64.4% of patients newly diagnosed with advanced NSCLC “are not benefiting from precision oncology care options appropriate for their diseases and will likely have suboptimal outcomes.”
The research was supported in part by the Personalized Medicine Coalition, a nonprofit 501c3 organization dedicated to the advancement of personalized medicine. Dr. Pritchard is an employee of the Personalized Medicine Coalition. A coauthor has relationships with Thermo Fisher Scientific, AstraZeneca, Eli Lilly, Blueprint Medicines, and Oncocyte.
A version of this article first appeared on Medscape.com.
because of gaps in clinical practice all along the cancer care spectrum, reveals a new analysis of data from U.S. practices.
For some of these patients, it could mean missing the chance for long-term survival or even cure.
One lung cancer patient, Janet Freeman-Daily, recently tweeted that she entered a targeted therapy clinical trial 10 years ago and is still taking the same, now approved, oral drug, with “no evidence of disease.”
Patients who have lung cancer with mutations that can be targeted with drug therapies – but who do not receive them – are missing this opportunity.
The new study suggests that there are many such patients. The researchers analyzed data on more than 38,000 patients with actively managed advanced NSCLC. They found that about half did not receive biomarker test results for a variety of reasons. But even among the half who were successfully tested, 30% of these patients did not receive the appropriate targeted therapies.
Overall, around 64% of eligible patients with advanced NSCLC are not benefiting from the most appropriate therapies, the team concludes.
The research was published online in JCO Precision Oncology.
Gaps in clinical practice
The high rate of failure points to clinical practice gaps in “many areas” across the cancer care spectrum, lead author Daryl Pritchard, PhD, from the Personalized Medicine Coalition, Washington, told this news organization.
“There’s various steps along the way that affect clinicians, laboratories, payers, the health providers [and] even patients,” he said. He added that product manufacturers also “have a role.”
“So it’s not an individual group that’s causing the problem. It’s a systemic awareness and systemic need to improve the delivery process.”
Dr. Pritchard underlined that the “the main goal of this analysis is to put everybody on alert that we need to do something about it.
“We need to – and this is easy to say but hard to do – evolve health care from a traditional one-size-fits-all mentality to a value-based strategy where you’re saying we want the best treatments” for patients, he said.
This means developing optimized and standardized laboratory processes, as well as clinical guidelines that set out the standard of care and optimized and integrated clinical decision support.
“We need to work as a community to demonstrate the value of this care and improve education and awareness to providers and payers,” Dr. Pritchard said. “That will encourage value-based practice coverage and reimbursement policies, and then also incentivize utilization in validated cases.”
Julie R. Brahmer, MD, who directs the thoracic oncology program at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, who was not involved with the study, said she was not sure whether she would say she was “surprised or disheartened” by the findings.
The study was focused on advanced NSCLC patients treated in 2019. Dr. Brahmer wondered whether the COVID-19 pandemic “might actually have made things worse.”
It will be important to “drill down” into some of the reasons why 30% of patients for whom biomarker testing results were available did not receive the appropriate treatment, she said.
Aside from cost-related problems, one factor at play could be whether the patient saw an oncologist, she said, while another could be that they went “straight to hospice” and were “not healthy enough to be able to tolerate” their targeted therapy.
Greater use of liquid biopsies, which identify biomarkers in the blood, are one way to improve access to biomarker testing, she suggested. It would help if these liquid biopsies were “consistently paid for by the payer, particularly for patients with advanced disease,” she added. Currently, payers often want patients to first undergo a tissue biopsy, which involves lung aspiration and may not be possible for some patients.
“If a Medicare patient is in the hospital when they have their biopsy or surgery, and then they have to wait 14 days in order for mutation tests to be ordered, and then if you add another 2 weeks for that test to come back, or even longer … [These delays] are some of the reasons why patients didn’t end up receiving therapy,” she elaborated.
“Some of these patients just can’t last that long before starting treatment,” she said.
Sandip P. Patel, MD, an oncologist at the Precision Immunotherapy Clinic at the University of California, San Diego, in La Jolla, wondered whether the issue is lack of education among physicians or whether there are potential financial problems. “Is there a financial risk to patients, for example, that is not being captured?” he mused.
It could also be a question of urban vs. rural centers, language barriers in communicating to patients, or other social determinants of health, he added.
At his institution (UCSD), there are “multiple choices” of molecular tests, each with “little nuances that differ among the tests that folks sometimes will take a look at in term of picking the best.
“But the best test is the one that gets done, and here we’re seeing no testing at all” for many patients, he said.
“It’s really unfortunate because for a lot of these patients, not only are they not getting the latest therapy, but they’re often getting something else that’s expensive and toxic instead,” Dr. Patel said.
Referring to the relatively high proportion of patients who didn’t receive targeted therapy even after being tested, he said, “For me, this study leaves more questions and answers.
“We’ve seen a lot of work in this space, showing us the problem,” Dr. Patel said. “What I haven’t yet seen is a very discrete analysis of the cause of that problem upstream.”
Cornerstone of personalized medicine
In their article, Dr. Pritchard and colleagues note that more than 90 targeted therapies have been approved by the U.S. Food and Drug Administration for use in eligible cancer patients. An estimated 55% of recent oncology trials involved the use of biomarkers.
Predictive biomarker testing to identify patients who may benefit from targeted therapies “is a cornerstone of personalized medicine in cancer care, allowing for more rapid diagnosis while informing treatment decisions that could lead to better patient outcomes and systemic efficiencies,” they emphasize.
However, providers “face several challenges” when integrating biomarker testing and targeted therapeutics into cancer care, and the use of biomarker testing varies widely across tumor types, biomarkers, and practice settings.
For their study, the team examined the use of targeted therapy in advanced NSCLC using data from the Diaceutics Data Repository, which includes commercial and Medicare claims, as well as laboratory data.
They focused on 38,068 patients with actively managed advanced NSCLC. Of those patients, 50.80% were women, and 64.6% were aged 71 years or older. The vast majority (84.50%) were non-Hispanic White patients.
The team examined the impact of seven clinical practice gaps on the timeline from ordering a biopsy to delivering targeted treatment. They then normalized the results to a standard patient population of 1,000.
In 6.6% of cases, an initial tissue or liquid biopsy was never performed, meaning that 66 of the 1,000 patients could not progress toward targeted therapy.
Among those who underwent a biopsy, for 4.0%, there was insufficient tissue on the initial biopsy, while for a further 0.97%, there was insufficient tissue on re-biopsy. Moreover, 9.6% could not undergo biopsy testing because of a lack of tumor tissue. Consequently, a further 136 of the 944 remaining patients were lost.
For the third clinical practice gap, the tumor cell content was overestimated in 1.7% of patients. As a result, their biopsy specimen could not be tested because it did not meet the threshold requirements. This resulted in the loss of a further 14 patients.
Moreover, for a further 17.5% of patients, biomarker testing was not ordered at all, owing to cost concerns, a lack of access to testing, a lack of awareness of testing options, and low confidence in the results, among other reasons. An additional 0.6% began treatment before any testing was ordered; together, that accounted for 142 patients being lost.
Even among patients who underwent biomarker testing, 14.5% had uninformative or inconclusive results, and 3.9% had false-negative results, meaning that a further 118 patients were lost.
In another 4.0% of cases, the results of biomarker testing did not arrive within the treatment decision window, owing to delays in reporting the results, and so for these patients, treatment began without the results being taken into consideration. A further 21 patients were lost.
The final clinical practice gap was not choosing the appropriate targeted treatment on the basis of test results. The researchers found that of 27,186 patients who underwent biomarker testing and received a timely result, 29.2% were not given the corresponding therapy. This resulted in the loss of a further 147 of the original 1,000 patients.
Overall, the team calculated that 64.4% of patients newly diagnosed with advanced NSCLC “are not benefiting from precision oncology care options appropriate for their diseases and will likely have suboptimal outcomes.”
The research was supported in part by the Personalized Medicine Coalition, a nonprofit 501c3 organization dedicated to the advancement of personalized medicine. Dr. Pritchard is an employee of the Personalized Medicine Coalition. A coauthor has relationships with Thermo Fisher Scientific, AstraZeneca, Eli Lilly, Blueprint Medicines, and Oncocyte.
A version of this article first appeared on Medscape.com.
because of gaps in clinical practice all along the cancer care spectrum, reveals a new analysis of data from U.S. practices.
For some of these patients, it could mean missing the chance for long-term survival or even cure.
One lung cancer patient, Janet Freeman-Daily, recently tweeted that she entered a targeted therapy clinical trial 10 years ago and is still taking the same, now approved, oral drug, with “no evidence of disease.”
Patients who have lung cancer with mutations that can be targeted with drug therapies – but who do not receive them – are missing this opportunity.
The new study suggests that there are many such patients. The researchers analyzed data on more than 38,000 patients with actively managed advanced NSCLC. They found that about half did not receive biomarker test results for a variety of reasons. But even among the half who were successfully tested, 30% of these patients did not receive the appropriate targeted therapies.
Overall, around 64% of eligible patients with advanced NSCLC are not benefiting from the most appropriate therapies, the team concludes.
The research was published online in JCO Precision Oncology.
Gaps in clinical practice
The high rate of failure points to clinical practice gaps in “many areas” across the cancer care spectrum, lead author Daryl Pritchard, PhD, from the Personalized Medicine Coalition, Washington, told this news organization.
“There’s various steps along the way that affect clinicians, laboratories, payers, the health providers [and] even patients,” he said. He added that product manufacturers also “have a role.”
“So it’s not an individual group that’s causing the problem. It’s a systemic awareness and systemic need to improve the delivery process.”
Dr. Pritchard underlined that the “the main goal of this analysis is to put everybody on alert that we need to do something about it.
“We need to – and this is easy to say but hard to do – evolve health care from a traditional one-size-fits-all mentality to a value-based strategy where you’re saying we want the best treatments” for patients, he said.
This means developing optimized and standardized laboratory processes, as well as clinical guidelines that set out the standard of care and optimized and integrated clinical decision support.
“We need to work as a community to demonstrate the value of this care and improve education and awareness to providers and payers,” Dr. Pritchard said. “That will encourage value-based practice coverage and reimbursement policies, and then also incentivize utilization in validated cases.”
Julie R. Brahmer, MD, who directs the thoracic oncology program at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, who was not involved with the study, said she was not sure whether she would say she was “surprised or disheartened” by the findings.
The study was focused on advanced NSCLC patients treated in 2019. Dr. Brahmer wondered whether the COVID-19 pandemic “might actually have made things worse.”
It will be important to “drill down” into some of the reasons why 30% of patients for whom biomarker testing results were available did not receive the appropriate treatment, she said.
Aside from cost-related problems, one factor at play could be whether the patient saw an oncologist, she said, while another could be that they went “straight to hospice” and were “not healthy enough to be able to tolerate” their targeted therapy.
Greater use of liquid biopsies, which identify biomarkers in the blood, are one way to improve access to biomarker testing, she suggested. It would help if these liquid biopsies were “consistently paid for by the payer, particularly for patients with advanced disease,” she added. Currently, payers often want patients to first undergo a tissue biopsy, which involves lung aspiration and may not be possible for some patients.
“If a Medicare patient is in the hospital when they have their biopsy or surgery, and then they have to wait 14 days in order for mutation tests to be ordered, and then if you add another 2 weeks for that test to come back, or even longer … [These delays] are some of the reasons why patients didn’t end up receiving therapy,” she elaborated.
“Some of these patients just can’t last that long before starting treatment,” she said.
Sandip P. Patel, MD, an oncologist at the Precision Immunotherapy Clinic at the University of California, San Diego, in La Jolla, wondered whether the issue is lack of education among physicians or whether there are potential financial problems. “Is there a financial risk to patients, for example, that is not being captured?” he mused.
It could also be a question of urban vs. rural centers, language barriers in communicating to patients, or other social determinants of health, he added.
At his institution (UCSD), there are “multiple choices” of molecular tests, each with “little nuances that differ among the tests that folks sometimes will take a look at in term of picking the best.
“But the best test is the one that gets done, and here we’re seeing no testing at all” for many patients, he said.
“It’s really unfortunate because for a lot of these patients, not only are they not getting the latest therapy, but they’re often getting something else that’s expensive and toxic instead,” Dr. Patel said.
Referring to the relatively high proportion of patients who didn’t receive targeted therapy even after being tested, he said, “For me, this study leaves more questions and answers.
“We’ve seen a lot of work in this space, showing us the problem,” Dr. Patel said. “What I haven’t yet seen is a very discrete analysis of the cause of that problem upstream.”
Cornerstone of personalized medicine
In their article, Dr. Pritchard and colleagues note that more than 90 targeted therapies have been approved by the U.S. Food and Drug Administration for use in eligible cancer patients. An estimated 55% of recent oncology trials involved the use of biomarkers.
Predictive biomarker testing to identify patients who may benefit from targeted therapies “is a cornerstone of personalized medicine in cancer care, allowing for more rapid diagnosis while informing treatment decisions that could lead to better patient outcomes and systemic efficiencies,” they emphasize.
However, providers “face several challenges” when integrating biomarker testing and targeted therapeutics into cancer care, and the use of biomarker testing varies widely across tumor types, biomarkers, and practice settings.
For their study, the team examined the use of targeted therapy in advanced NSCLC using data from the Diaceutics Data Repository, which includes commercial and Medicare claims, as well as laboratory data.
They focused on 38,068 patients with actively managed advanced NSCLC. Of those patients, 50.80% were women, and 64.6% were aged 71 years or older. The vast majority (84.50%) were non-Hispanic White patients.
The team examined the impact of seven clinical practice gaps on the timeline from ordering a biopsy to delivering targeted treatment. They then normalized the results to a standard patient population of 1,000.
In 6.6% of cases, an initial tissue or liquid biopsy was never performed, meaning that 66 of the 1,000 patients could not progress toward targeted therapy.
Among those who underwent a biopsy, for 4.0%, there was insufficient tissue on the initial biopsy, while for a further 0.97%, there was insufficient tissue on re-biopsy. Moreover, 9.6% could not undergo biopsy testing because of a lack of tumor tissue. Consequently, a further 136 of the 944 remaining patients were lost.
For the third clinical practice gap, the tumor cell content was overestimated in 1.7% of patients. As a result, their biopsy specimen could not be tested because it did not meet the threshold requirements. This resulted in the loss of a further 14 patients.
Moreover, for a further 17.5% of patients, biomarker testing was not ordered at all, owing to cost concerns, a lack of access to testing, a lack of awareness of testing options, and low confidence in the results, among other reasons. An additional 0.6% began treatment before any testing was ordered; together, that accounted for 142 patients being lost.
Even among patients who underwent biomarker testing, 14.5% had uninformative or inconclusive results, and 3.9% had false-negative results, meaning that a further 118 patients were lost.
In another 4.0% of cases, the results of biomarker testing did not arrive within the treatment decision window, owing to delays in reporting the results, and so for these patients, treatment began without the results being taken into consideration. A further 21 patients were lost.
The final clinical practice gap was not choosing the appropriate targeted treatment on the basis of test results. The researchers found that of 27,186 patients who underwent biomarker testing and received a timely result, 29.2% were not given the corresponding therapy. This resulted in the loss of a further 147 of the original 1,000 patients.
Overall, the team calculated that 64.4% of patients newly diagnosed with advanced NSCLC “are not benefiting from precision oncology care options appropriate for their diseases and will likely have suboptimal outcomes.”
The research was supported in part by the Personalized Medicine Coalition, a nonprofit 501c3 organization dedicated to the advancement of personalized medicine. Dr. Pritchard is an employee of the Personalized Medicine Coalition. A coauthor has relationships with Thermo Fisher Scientific, AstraZeneca, Eli Lilly, Blueprint Medicines, and Oncocyte.
A version of this article first appeared on Medscape.com.
Could intermittent fasting improve GERD symptoms?
, suggests a small U.S. study.
Twenty-five individuals with suspected GERD symptoms underwent 96-hour pH monitoring. They were asked to follow their normal diet for the first 48 hours; for the second 48 hours, they were asked to switch to a 16-hour fast, which was followed by an 8-hour eating window.
Just over a third of participants were fully compliant with the 16:8 intermittent fasting. But those who followed the regimen experienced a mild reduction in mean acid exposure time and self-reported GERD symptoms scores.
The research was published online by the Journal of Clinical Gastroenterology.
Costly condition
The prevalence of GERD in the United States is estimated at 18%-28%. Annual costs of the condition are more than $18 billion per year, largely through pharmacologic therapies and diagnostic testing, write lead author Yan Jiang, MD, division of gastrointestinal and liver D-diseases, Keck Medicine of University of Southern California, Los Angeles, and colleagues.
Proton pump inhibitor (PPI) therapy is one of the most prescribed classes of medications in the United States, the authors write. But concerns over the long-term safety of the drugs, as well as the fact that half of patients report breakthrough GERD symptoms, have generated interest in non-PPI treatments among patients and providers.
The role of diet in the management of GERD, however, remains poorly understood, despite the fact that obesity and weight gain have been linked to reflux.
The authors note that intermittent fasting has shown benefits in coronary artery disease, inflammatory disorders, obesity, and diabetes. Proposed mechanisms include anti-inflammatory effects, weight loss, and alterations in hormone secretion.
Intervention test in a 96-hour clinical evaluation for GERD
To investigate the effects of intermittent fasting in GERD, the researchers screened patients referred to the Stanford University gastrointestinal clinic for diagnostic 96-hour ambulatory wireless pH monitoring of suspected acid reflux symptoms.
They excluded patients younger than 18 years, pregnant women, those with insulin-dependent diabetes, and those who had used PPIs within the previous 7 days. There were other exclusion criteria as well.
The study was completed by 25 participants. The mean age of the patients was 43.5 years; 52% were women. Just under half (44%) were White, and the mean body mass index was 25.8 kg/m2.
For the first 48 hours of the pH monitoring, the patients followed their baseline diet. For the second 48 hours, they were asked to follow an intermittent fasting regimen.
In that regimen, during a 24-hour period, there was an 8-hour caloric intake window and no caloric intake during the other 16 consecutive hours. Participants who fasted for at least 15 hours, as indicated on a self-report food log, were considered successful.
Only 36% of participants were fully adherent to the fasting regimen; 84% were partially compliant, defined as following the regimen for at least 1 of the 2 days of intermittent fasting.
On intermittent fasting days, the mean acid exposure time was 3.5%, compared with 4.3% on the baseline diet. The team calculated that adhering to the 16:8 intermittent fasting regimen reduced the mean acid exposure time by 0.64%.
Intermittent fasting was also associated with a reduction in total GERD symptom scores, at 9.9 following day 4 versus 14.3 following day 2. There were reductions in heartburn symptoms scores of 2.6 and in regurgitation scores of 1.8.
When the researchers compared individuals who were compliant with intermittent fasting with those who were only partially compliant, they found that there was still an improvement in GERD symptoms, with a reduction in scores of 3.2.
More acid, bigger benefits
There could be several explanations for the findings, Dr. Jiang said in an interview.
In the short-term study, fewer meals during intermittent fasting and more hours between the last meal and bedtime can help with the supine symptoms of GERD, Dr. Jiang said.
Over the longer term, he added, previous studies have suggested that fasting-induced alterations in inflammatory cytokines or cells could be a contributory mechanism, “but it’s not something that we can glean from our study.”
Participants with elevated acid exposure at baseline and who were more likely to have GERD diagnosed by the pH monitoring seemed to experience the greatest benefit from intermittent fasting, Dr. Jiang pointed out.
“This study looked at all comers with GERD symptoms,” he said. “But if you were to do another study with people with proven GERD, they might experience a bigger impact with intermittent fasting.”
Dr. Jiang added, “If a patient is willing to do intermittent fasting, and certainly if they have other reasons [for doing so], I think it doesn’t hurt, and it might actually help them a little bit in their current symptoms.”
Larger scale, longer follow-up studies needed
Luigi Bonavina, MD, department of biomedical sciences for health, University of Milan, IRCCS Policlinico San Donato, Italy, said in an interview that it was a “nice, original study.”
It is “noteworthy that only one previous study explored the effect of Ramadan on GERD symptoms and found a small improvement of GERD symptoms,” Dr. Bonavina said. “Unfortunately, the magnitude of effect [in the current study] was not as one may have expected, due to small sample size and low compliance with intermittent fasting.”
Although the effect was “mild compared to that seen with PPIs,” it would “be interesting to see whether the results of this pilot, proof-of-concept study can be confirmed on a larger scale with longer follow-up to prove that reflux symptoms will not worsen over time,” he said.
“Intermittent fasting may be recommended, especially in overweight-obese patients with GERD symptoms who are poor responders to gastric acid inhibitors,” Dr. Bonavina added. “Reduction of inflammation, reduction of meal intake, and going to bed with an empty stomach may also work in patients with GERD.”
No funding for the study has been declared. The authors and Dr. Bonavina report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggests a small U.S. study.
Twenty-five individuals with suspected GERD symptoms underwent 96-hour pH monitoring. They were asked to follow their normal diet for the first 48 hours; for the second 48 hours, they were asked to switch to a 16-hour fast, which was followed by an 8-hour eating window.
Just over a third of participants were fully compliant with the 16:8 intermittent fasting. But those who followed the regimen experienced a mild reduction in mean acid exposure time and self-reported GERD symptoms scores.
The research was published online by the Journal of Clinical Gastroenterology.
Costly condition
The prevalence of GERD in the United States is estimated at 18%-28%. Annual costs of the condition are more than $18 billion per year, largely through pharmacologic therapies and diagnostic testing, write lead author Yan Jiang, MD, division of gastrointestinal and liver D-diseases, Keck Medicine of University of Southern California, Los Angeles, and colleagues.
Proton pump inhibitor (PPI) therapy is one of the most prescribed classes of medications in the United States, the authors write. But concerns over the long-term safety of the drugs, as well as the fact that half of patients report breakthrough GERD symptoms, have generated interest in non-PPI treatments among patients and providers.
The role of diet in the management of GERD, however, remains poorly understood, despite the fact that obesity and weight gain have been linked to reflux.
The authors note that intermittent fasting has shown benefits in coronary artery disease, inflammatory disorders, obesity, and diabetes. Proposed mechanisms include anti-inflammatory effects, weight loss, and alterations in hormone secretion.
Intervention test in a 96-hour clinical evaluation for GERD
To investigate the effects of intermittent fasting in GERD, the researchers screened patients referred to the Stanford University gastrointestinal clinic for diagnostic 96-hour ambulatory wireless pH monitoring of suspected acid reflux symptoms.
They excluded patients younger than 18 years, pregnant women, those with insulin-dependent diabetes, and those who had used PPIs within the previous 7 days. There were other exclusion criteria as well.
The study was completed by 25 participants. The mean age of the patients was 43.5 years; 52% were women. Just under half (44%) were White, and the mean body mass index was 25.8 kg/m2.
For the first 48 hours of the pH monitoring, the patients followed their baseline diet. For the second 48 hours, they were asked to follow an intermittent fasting regimen.
In that regimen, during a 24-hour period, there was an 8-hour caloric intake window and no caloric intake during the other 16 consecutive hours. Participants who fasted for at least 15 hours, as indicated on a self-report food log, were considered successful.
Only 36% of participants were fully adherent to the fasting regimen; 84% were partially compliant, defined as following the regimen for at least 1 of the 2 days of intermittent fasting.
On intermittent fasting days, the mean acid exposure time was 3.5%, compared with 4.3% on the baseline diet. The team calculated that adhering to the 16:8 intermittent fasting regimen reduced the mean acid exposure time by 0.64%.
Intermittent fasting was also associated with a reduction in total GERD symptom scores, at 9.9 following day 4 versus 14.3 following day 2. There were reductions in heartburn symptoms scores of 2.6 and in regurgitation scores of 1.8.
When the researchers compared individuals who were compliant with intermittent fasting with those who were only partially compliant, they found that there was still an improvement in GERD symptoms, with a reduction in scores of 3.2.
More acid, bigger benefits
There could be several explanations for the findings, Dr. Jiang said in an interview.
In the short-term study, fewer meals during intermittent fasting and more hours between the last meal and bedtime can help with the supine symptoms of GERD, Dr. Jiang said.
Over the longer term, he added, previous studies have suggested that fasting-induced alterations in inflammatory cytokines or cells could be a contributory mechanism, “but it’s not something that we can glean from our study.”
Participants with elevated acid exposure at baseline and who were more likely to have GERD diagnosed by the pH monitoring seemed to experience the greatest benefit from intermittent fasting, Dr. Jiang pointed out.
“This study looked at all comers with GERD symptoms,” he said. “But if you were to do another study with people with proven GERD, they might experience a bigger impact with intermittent fasting.”
Dr. Jiang added, “If a patient is willing to do intermittent fasting, and certainly if they have other reasons [for doing so], I think it doesn’t hurt, and it might actually help them a little bit in their current symptoms.”
Larger scale, longer follow-up studies needed
Luigi Bonavina, MD, department of biomedical sciences for health, University of Milan, IRCCS Policlinico San Donato, Italy, said in an interview that it was a “nice, original study.”
It is “noteworthy that only one previous study explored the effect of Ramadan on GERD symptoms and found a small improvement of GERD symptoms,” Dr. Bonavina said. “Unfortunately, the magnitude of effect [in the current study] was not as one may have expected, due to small sample size and low compliance with intermittent fasting.”
Although the effect was “mild compared to that seen with PPIs,” it would “be interesting to see whether the results of this pilot, proof-of-concept study can be confirmed on a larger scale with longer follow-up to prove that reflux symptoms will not worsen over time,” he said.
“Intermittent fasting may be recommended, especially in overweight-obese patients with GERD symptoms who are poor responders to gastric acid inhibitors,” Dr. Bonavina added. “Reduction of inflammation, reduction of meal intake, and going to bed with an empty stomach may also work in patients with GERD.”
No funding for the study has been declared. The authors and Dr. Bonavina report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggests a small U.S. study.
Twenty-five individuals with suspected GERD symptoms underwent 96-hour pH monitoring. They were asked to follow their normal diet for the first 48 hours; for the second 48 hours, they were asked to switch to a 16-hour fast, which was followed by an 8-hour eating window.
Just over a third of participants were fully compliant with the 16:8 intermittent fasting. But those who followed the regimen experienced a mild reduction in mean acid exposure time and self-reported GERD symptoms scores.
The research was published online by the Journal of Clinical Gastroenterology.
Costly condition
The prevalence of GERD in the United States is estimated at 18%-28%. Annual costs of the condition are more than $18 billion per year, largely through pharmacologic therapies and diagnostic testing, write lead author Yan Jiang, MD, division of gastrointestinal and liver D-diseases, Keck Medicine of University of Southern California, Los Angeles, and colleagues.
Proton pump inhibitor (PPI) therapy is one of the most prescribed classes of medications in the United States, the authors write. But concerns over the long-term safety of the drugs, as well as the fact that half of patients report breakthrough GERD symptoms, have generated interest in non-PPI treatments among patients and providers.
The role of diet in the management of GERD, however, remains poorly understood, despite the fact that obesity and weight gain have been linked to reflux.
The authors note that intermittent fasting has shown benefits in coronary artery disease, inflammatory disorders, obesity, and diabetes. Proposed mechanisms include anti-inflammatory effects, weight loss, and alterations in hormone secretion.
Intervention test in a 96-hour clinical evaluation for GERD
To investigate the effects of intermittent fasting in GERD, the researchers screened patients referred to the Stanford University gastrointestinal clinic for diagnostic 96-hour ambulatory wireless pH monitoring of suspected acid reflux symptoms.
They excluded patients younger than 18 years, pregnant women, those with insulin-dependent diabetes, and those who had used PPIs within the previous 7 days. There were other exclusion criteria as well.
The study was completed by 25 participants. The mean age of the patients was 43.5 years; 52% were women. Just under half (44%) were White, and the mean body mass index was 25.8 kg/m2.
For the first 48 hours of the pH monitoring, the patients followed their baseline diet. For the second 48 hours, they were asked to follow an intermittent fasting regimen.
In that regimen, during a 24-hour period, there was an 8-hour caloric intake window and no caloric intake during the other 16 consecutive hours. Participants who fasted for at least 15 hours, as indicated on a self-report food log, were considered successful.
Only 36% of participants were fully adherent to the fasting regimen; 84% were partially compliant, defined as following the regimen for at least 1 of the 2 days of intermittent fasting.
On intermittent fasting days, the mean acid exposure time was 3.5%, compared with 4.3% on the baseline diet. The team calculated that adhering to the 16:8 intermittent fasting regimen reduced the mean acid exposure time by 0.64%.
Intermittent fasting was also associated with a reduction in total GERD symptom scores, at 9.9 following day 4 versus 14.3 following day 2. There were reductions in heartburn symptoms scores of 2.6 and in regurgitation scores of 1.8.
When the researchers compared individuals who were compliant with intermittent fasting with those who were only partially compliant, they found that there was still an improvement in GERD symptoms, with a reduction in scores of 3.2.
More acid, bigger benefits
There could be several explanations for the findings, Dr. Jiang said in an interview.
In the short-term study, fewer meals during intermittent fasting and more hours between the last meal and bedtime can help with the supine symptoms of GERD, Dr. Jiang said.
Over the longer term, he added, previous studies have suggested that fasting-induced alterations in inflammatory cytokines or cells could be a contributory mechanism, “but it’s not something that we can glean from our study.”
Participants with elevated acid exposure at baseline and who were more likely to have GERD diagnosed by the pH monitoring seemed to experience the greatest benefit from intermittent fasting, Dr. Jiang pointed out.
“This study looked at all comers with GERD symptoms,” he said. “But if you were to do another study with people with proven GERD, they might experience a bigger impact with intermittent fasting.”
Dr. Jiang added, “If a patient is willing to do intermittent fasting, and certainly if they have other reasons [for doing so], I think it doesn’t hurt, and it might actually help them a little bit in their current symptoms.”
Larger scale, longer follow-up studies needed
Luigi Bonavina, MD, department of biomedical sciences for health, University of Milan, IRCCS Policlinico San Donato, Italy, said in an interview that it was a “nice, original study.”
It is “noteworthy that only one previous study explored the effect of Ramadan on GERD symptoms and found a small improvement of GERD symptoms,” Dr. Bonavina said. “Unfortunately, the magnitude of effect [in the current study] was not as one may have expected, due to small sample size and low compliance with intermittent fasting.”
Although the effect was “mild compared to that seen with PPIs,” it would “be interesting to see whether the results of this pilot, proof-of-concept study can be confirmed on a larger scale with longer follow-up to prove that reflux symptoms will not worsen over time,” he said.
“Intermittent fasting may be recommended, especially in overweight-obese patients with GERD symptoms who are poor responders to gastric acid inhibitors,” Dr. Bonavina added. “Reduction of inflammation, reduction of meal intake, and going to bed with an empty stomach may also work in patients with GERD.”
No funding for the study has been declared. The authors and Dr. Bonavina report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JOURNAL OF CLINICAL GASTROENTEROLOGY
Personalized breast screening a step closer to reality
say researchers.
“Several breast cancer risk prediction models have been created, but we believe this is one of the first models designed to guide breast screening strategies over a person’s lifetime using real data from a screening program,” said study author Javier Louro, PhD, Hospital del Mar Medical Research Institute, Barcelona, Spain.
“Our model might be considered a key for designing personalized screening aimed at reducing the harms and increasing the benefits of mammographic screening,” he said in a statement.
Someone with a low risk “might be offered screening with standard mammography every 3 or 4 years instead of 2 years,” Dr. Louro explained.
“Someone with medium risk might be offered screening with advanced 3D mammography every 3 years, while those at a high risk might be offered a new screening test with mammography or MRI every year.”
However, he cautioned that “all of these strategies are still theoretical and should be studied with regard to their effectiveness.”
Dr. Louro was talking about the new model at the 13th European Breast Cancer Conference.
Details of the new prediction model
To develop the new model, Louro and colleagues conducted a retrospective study of 57,411 women who underwent mammography in four counties in Norway between 2007 and 2019 as part of the BreastScreen Norway program, and followed them up to 2022.
The team gathered data on age, breast density, family history of breast cancer, body mass index, age at menarche, alcohol habit, exercise, pregnancy, hormone replacement therapy, and benign breast disease, and compared women with and those without a breast cancer diagnosis.
All of these 10 variables used were found to significantly explain part of the variability in the breast cancer risk.
Overall, the 4-year breast cancer risk predicted by the resulting model varied across the participants, from 0.22% to 7.43%, at a median of 1.10%.
Bootstrap resampling analysis revealed that the model overestimated the risk for breast cancer, at an expected-to-observed ratio of 1.10.
The largest effect on risk was from breast density on mammography. Women with dense breasts were at much higher risk: the adjusted hazard ratio was 1.71 for women with Volpara Density Grade 4 vs Grade 2 and was 1.37 when compared with Grade 3.
Exercise had a large impact on breast cancer risk, the researchers found. Women who exercised for 4 or more hours per week had an adjusted hazard ratio of 0.65 for breast cancer risk compared with women who never exercised. Although this effect of exercise reducing the risk for breast cancer is now widely known, it is not usually included in models that predict breast cancer risk, the team pointed out.
The team concluded that their prediction model could be used to personalize breast screening for women according to their risk assessment, although they acknowledge that more work is needed. This work is based on one screening program in one country, and similar studies in different settings are needed.
Reacting to the findings, Laura Biganzoli, MD, co-chair of the European Breast Cancer Conference and director of the Breast Centre at Santo Stefano Hospital, Prato, Italy, commented, “We know that breast screening programs are beneficial, but we also know that some people will experience potential harms caused by false-positives or overdiagnosis.”
“This research shows how we might be able to identify people with a high risk of breast cancer, but equally how we could identify those with a low risk. So it’s an important step toward personalized screening,” Dr. Biganzoli said.
This study was supported by a grant from Instituto de Salud Carlos III FEDER (grant PI/00047). No relevant financial relationships declared.
A version of this article first appeared on Medscape.com.
say researchers.
“Several breast cancer risk prediction models have been created, but we believe this is one of the first models designed to guide breast screening strategies over a person’s lifetime using real data from a screening program,” said study author Javier Louro, PhD, Hospital del Mar Medical Research Institute, Barcelona, Spain.
“Our model might be considered a key for designing personalized screening aimed at reducing the harms and increasing the benefits of mammographic screening,” he said in a statement.
Someone with a low risk “might be offered screening with standard mammography every 3 or 4 years instead of 2 years,” Dr. Louro explained.
“Someone with medium risk might be offered screening with advanced 3D mammography every 3 years, while those at a high risk might be offered a new screening test with mammography or MRI every year.”
However, he cautioned that “all of these strategies are still theoretical and should be studied with regard to their effectiveness.”
Dr. Louro was talking about the new model at the 13th European Breast Cancer Conference.
Details of the new prediction model
To develop the new model, Louro and colleagues conducted a retrospective study of 57,411 women who underwent mammography in four counties in Norway between 2007 and 2019 as part of the BreastScreen Norway program, and followed them up to 2022.
The team gathered data on age, breast density, family history of breast cancer, body mass index, age at menarche, alcohol habit, exercise, pregnancy, hormone replacement therapy, and benign breast disease, and compared women with and those without a breast cancer diagnosis.
All of these 10 variables used were found to significantly explain part of the variability in the breast cancer risk.
Overall, the 4-year breast cancer risk predicted by the resulting model varied across the participants, from 0.22% to 7.43%, at a median of 1.10%.
Bootstrap resampling analysis revealed that the model overestimated the risk for breast cancer, at an expected-to-observed ratio of 1.10.
The largest effect on risk was from breast density on mammography. Women with dense breasts were at much higher risk: the adjusted hazard ratio was 1.71 for women with Volpara Density Grade 4 vs Grade 2 and was 1.37 when compared with Grade 3.
Exercise had a large impact on breast cancer risk, the researchers found. Women who exercised for 4 or more hours per week had an adjusted hazard ratio of 0.65 for breast cancer risk compared with women who never exercised. Although this effect of exercise reducing the risk for breast cancer is now widely known, it is not usually included in models that predict breast cancer risk, the team pointed out.
The team concluded that their prediction model could be used to personalize breast screening for women according to their risk assessment, although they acknowledge that more work is needed. This work is based on one screening program in one country, and similar studies in different settings are needed.
Reacting to the findings, Laura Biganzoli, MD, co-chair of the European Breast Cancer Conference and director of the Breast Centre at Santo Stefano Hospital, Prato, Italy, commented, “We know that breast screening programs are beneficial, but we also know that some people will experience potential harms caused by false-positives or overdiagnosis.”
“This research shows how we might be able to identify people with a high risk of breast cancer, but equally how we could identify those with a low risk. So it’s an important step toward personalized screening,” Dr. Biganzoli said.
This study was supported by a grant from Instituto de Salud Carlos III FEDER (grant PI/00047). No relevant financial relationships declared.
A version of this article first appeared on Medscape.com.
say researchers.
“Several breast cancer risk prediction models have been created, but we believe this is one of the first models designed to guide breast screening strategies over a person’s lifetime using real data from a screening program,” said study author Javier Louro, PhD, Hospital del Mar Medical Research Institute, Barcelona, Spain.
“Our model might be considered a key for designing personalized screening aimed at reducing the harms and increasing the benefits of mammographic screening,” he said in a statement.
Someone with a low risk “might be offered screening with standard mammography every 3 or 4 years instead of 2 years,” Dr. Louro explained.
“Someone with medium risk might be offered screening with advanced 3D mammography every 3 years, while those at a high risk might be offered a new screening test with mammography or MRI every year.”
However, he cautioned that “all of these strategies are still theoretical and should be studied with regard to their effectiveness.”
Dr. Louro was talking about the new model at the 13th European Breast Cancer Conference.
Details of the new prediction model
To develop the new model, Louro and colleagues conducted a retrospective study of 57,411 women who underwent mammography in four counties in Norway between 2007 and 2019 as part of the BreastScreen Norway program, and followed them up to 2022.
The team gathered data on age, breast density, family history of breast cancer, body mass index, age at menarche, alcohol habit, exercise, pregnancy, hormone replacement therapy, and benign breast disease, and compared women with and those without a breast cancer diagnosis.
All of these 10 variables used were found to significantly explain part of the variability in the breast cancer risk.
Overall, the 4-year breast cancer risk predicted by the resulting model varied across the participants, from 0.22% to 7.43%, at a median of 1.10%.
Bootstrap resampling analysis revealed that the model overestimated the risk for breast cancer, at an expected-to-observed ratio of 1.10.
The largest effect on risk was from breast density on mammography. Women with dense breasts were at much higher risk: the adjusted hazard ratio was 1.71 for women with Volpara Density Grade 4 vs Grade 2 and was 1.37 when compared with Grade 3.
Exercise had a large impact on breast cancer risk, the researchers found. Women who exercised for 4 or more hours per week had an adjusted hazard ratio of 0.65 for breast cancer risk compared with women who never exercised. Although this effect of exercise reducing the risk for breast cancer is now widely known, it is not usually included in models that predict breast cancer risk, the team pointed out.
The team concluded that their prediction model could be used to personalize breast screening for women according to their risk assessment, although they acknowledge that more work is needed. This work is based on one screening program in one country, and similar studies in different settings are needed.
Reacting to the findings, Laura Biganzoli, MD, co-chair of the European Breast Cancer Conference and director of the Breast Centre at Santo Stefano Hospital, Prato, Italy, commented, “We know that breast screening programs are beneficial, but we also know that some people will experience potential harms caused by false-positives or overdiagnosis.”
“This research shows how we might be able to identify people with a high risk of breast cancer, but equally how we could identify those with a low risk. So it’s an important step toward personalized screening,” Dr. Biganzoli said.
This study was supported by a grant from Instituto de Salud Carlos III FEDER (grant PI/00047). No relevant financial relationships declared.
A version of this article first appeared on Medscape.com.
FROM EBCC-13
Novel vaccine approach halts disease after 23 years of breast cancer
A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.
A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.
The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”
“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”
Ms. Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”
“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.
Ms. Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”
Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”
“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”
Ms. Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York. One other patient also had a partial response, and one patient had a complete response.
However, six patients have progressive disease, and one has stable disease.
These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the recent annual meeting of the Society for Immunotherapy of Cancer.
The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).
The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, said in an interview.
“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.
The hope is that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Dr. Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”
Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).
Mr. Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Mr. Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.
“But the remission lasted for maybe a little over a year,” he said.
The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”
“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”
“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”
Mr. Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.
In contrast, Ms. Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
Need to improve response rate
The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Dr. Marron.
“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.
“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.
“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Dr. Marron commented. For example, Ms. Gangi had already been through 12 different chemotherapy regimens.
Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Dr. Marron explained.
“By the time that I see a patient,” Dr. Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”
Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.
He said in an interview that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”
“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.
“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Dr. Brody said.
Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma.”
Dr. Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, said in an interview that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”
“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”
Dr. Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
Details of the trial and results
The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.
Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.
The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).
Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.
Dr. Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”
He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”
The poly-ICLC is “basically like a fake virus,” Dr. Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.
Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more,” he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.
The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.
The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.
All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.
One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.
The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.
A version of this article first appeared on Medscape.com.
A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.
A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.
The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”
“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”
Ms. Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”
“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.
Ms. Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”
Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”
“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”
Ms. Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York. One other patient also had a partial response, and one patient had a complete response.
However, six patients have progressive disease, and one has stable disease.
These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the recent annual meeting of the Society for Immunotherapy of Cancer.
The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).
The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, said in an interview.
“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.
The hope is that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Dr. Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”
Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).
Mr. Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Mr. Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.
“But the remission lasted for maybe a little over a year,” he said.
The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”
“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”
“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”
Mr. Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.
In contrast, Ms. Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
Need to improve response rate
The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Dr. Marron.
“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.
“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.
“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Dr. Marron commented. For example, Ms. Gangi had already been through 12 different chemotherapy regimens.
Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Dr. Marron explained.
“By the time that I see a patient,” Dr. Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”
Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.
He said in an interview that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”
“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.
“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Dr. Brody said.
Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma.”
Dr. Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, said in an interview that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”
“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”
Dr. Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
Details of the trial and results
The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.
Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.
The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).
Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.
Dr. Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”
He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”
The poly-ICLC is “basically like a fake virus,” Dr. Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.
Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more,” he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.
The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.
The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.
All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.
One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.
The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.
A version of this article first appeared on Medscape.com.
A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.
A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.
The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”
“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”
Ms. Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”
“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.
Ms. Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”
Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”
“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”
Ms. Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York. One other patient also had a partial response, and one patient had a complete response.
However, six patients have progressive disease, and one has stable disease.
These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the recent annual meeting of the Society for Immunotherapy of Cancer.
The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).
The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, said in an interview.
“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.
The hope is that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Dr. Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”
Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).
Mr. Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Mr. Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.
“But the remission lasted for maybe a little over a year,” he said.
The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”
“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”
“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”
Mr. Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.
In contrast, Ms. Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
Need to improve response rate
The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Dr. Marron.
“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.
“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.
“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Dr. Marron commented. For example, Ms. Gangi had already been through 12 different chemotherapy regimens.
Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Dr. Marron explained.
“By the time that I see a patient,” Dr. Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”
Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.
He said in an interview that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”
“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.
“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Dr. Brody said.
Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma.”
Dr. Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, said in an interview that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”
“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”
Dr. Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
Details of the trial and results
The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.
Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.
The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).
Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.
Dr. Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”
He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”
The poly-ICLC is “basically like a fake virus,” Dr. Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.
Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more,” he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.
The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.
The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.
All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.
One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.
The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.
A version of this article first appeared on Medscape.com.
FROM SITC 2022
Major depression treatments boost brain connectivity
VIENNA – , new research suggests.
In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.
“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.
“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.
The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
‘Easily understandable picture’
Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.
“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.
Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.
However, he cautioned that the study included a “small sample” and the results need to be independently replicated.
“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.
The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.
However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.
To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.
They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.
Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
Significant interactions
Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).
This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).
It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.
This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.
Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.
He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”
Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.
“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
Several unanswered questions
Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”
However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”
The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.
“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.
He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”
Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.
Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.
“Again, this is something that needs to be followed up,” said Dr. Ruhe.
No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VIENNA – , new research suggests.
In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.
“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.
“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.
The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
‘Easily understandable picture’
Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.
“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.
Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.
However, he cautioned that the study included a “small sample” and the results need to be independently replicated.
“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.
The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.
However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.
To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.
They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.
Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
Significant interactions
Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).
This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).
It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.
This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.
Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.
He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”
Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.
“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
Several unanswered questions
Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”
However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”
The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.
“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.
He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”
Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.
Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.
“Again, this is something that needs to be followed up,” said Dr. Ruhe.
No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VIENNA – , new research suggests.
In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.
“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.
“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.
The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
‘Easily understandable picture’
Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.
“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.
Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.
However, he cautioned that the study included a “small sample” and the results need to be independently replicated.
“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.
The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.
However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.
To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.
They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.
Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
Significant interactions
Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).
This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).
It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.
This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.
Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.
He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”
Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.
“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
Several unanswered questions
Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”
However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”
The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.
“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.
He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”
Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.
Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.
“Again, this is something that needs to be followed up,” said Dr. Ruhe.
No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ECNP 2022
Nicotine blocks estrogen production in women’s brains
VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.
The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.
They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.
“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.
“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”
Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.
“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”
Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.
There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.
Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.
Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”
Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.
The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.
Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.
To investigate its impact in humans, the researchers performed structural MRI and two 11C-cetrozole PET scans in 10 healthy women.
The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.
A whole brain analysis was then used to determine changes in nondisplaceable binding potential of 11C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.
The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.
However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).
Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.
Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.
While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”
She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.
Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”
“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.
However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”
“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.
The study was funded by the Science for Life Laboratory/Uppsala University.
No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.
The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.
They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.
“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.
“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”
Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.
“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”
Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.
There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.
Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.
Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”
Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.
The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.
Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.
To investigate its impact in humans, the researchers performed structural MRI and two 11C-cetrozole PET scans in 10 healthy women.
The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.
A whole brain analysis was then used to determine changes in nondisplaceable binding potential of 11C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.
The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.
However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).
Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.
Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.
While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”
She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.
Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”
“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.
However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”
“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.
The study was funded by the Science for Life Laboratory/Uppsala University.
No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.
The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.
They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.
“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.
“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”
Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.
“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”
Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.
There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.
Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.
Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”
Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.
The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.
Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.
To investigate its impact in humans, the researchers performed structural MRI and two 11C-cetrozole PET scans in 10 healthy women.
The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.
A whole brain analysis was then used to determine changes in nondisplaceable binding potential of 11C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.
The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.
However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).
Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.
Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.
While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”
She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.
Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”
“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.
However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”
“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.
The study was funded by the Science for Life Laboratory/Uppsala University.
No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
AT ECNP 2022