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Immune-agonist combo has activity against several tumor types
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
AT ASCO 2017
Key clinical point: A combination of a GITR-agonist and anti-PD-1 agent was safe and produced partial responses in patients with heavily pretreated advanced cancers.
Major finding: Two patients with cancers that had progression on a PD-1 inhibitor had durable partial responses.
Data source: A phase I/IIa dose-finding and safety study of BMS986156 alone or in combination with nivolumab (Opdivo).
Disclosures: The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising for several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
Biomarker predicts prolonged depression in breast cancer patients
SAN FRANCISCO – Nearly 40% of breast cancer patients experience prolonged depression lasting for at least 16 months after diagnosis of their malignancy; those at increased risk may be identifiable in a timely way by their exaggerated cortisol awakening response when measured after surgery but before adjuvant therapy, according to Kate R. Kuhlman, PhD.
“There are several psychological interventions that mitigate depressive symptoms and psychologic distress in women with breast cancer. This time period immediately following cancer diagnosis and surgery may be the optimal time to intervene,” said Dr. Kuhlman, a psychologist at the University of California, Los Angeles.
She presented a prospective study of 135 women with breast cancer who collected saliva samples for analysis of hypothalamic-pituitary-adrenal axis functioning on 3 consecutive days after their primary surgery but prior to starting adjuvant therapy. Samples were obtained on each of the 3 days upon awakening, 30 minutes later, 8 hours later, and at bedtime. The women also completed the Center for Epidemiologic Studies Depression Scale (CES-D) then and again 6 months after completing their breast cancer treatment.
At baseline, 45 of the 135 women scored 16 points or higher out of a possible 60 on the 20-question CES-D, indicative of clinically significant depression. Hypothalamic-pituitary-adrenal axis functioning wasn’t associated with depressive symptoms at that time. Importantly, however, one measure of baseline HPA axis functioning – the cortisol awakening response – proved to be associated with an increase in depressive symptoms over time, Dr. Kuhlman reported.
In a multivariate analysis adjusted for age, breast cancer stage, type of surgery, and forms of adjuvant therapy, a 1-standard-deviation increase above the mean in baseline cortisol awakening response was associated with a 6-point increase in CES-D score at follow-up 6 months after completion of breast cancer therapy. This association was seen only in the 90 women without significant depressive symptoms at baseline. And that’s exactly the population where a predictive biologic marker for future depression is most needed, Dr. Kuhlman said at the annual conference of the Anxiety and Depression Association of America.
“The people at highest risk of depressive symptoms in the future are the ones who have the most symptoms now. They’re easy to identify. We have good reliable measures. But then there are also people at risk whom we would miss by using those measures because they don’t have high symptoms right now,” the psychologist explained.
She and her coinvestigators zeroed in on cortisol awakening response as a potential biomarker of increased future risk of depression because it reflects the adrenal gland’s sensitivity to adrenocorticotropic hormone and the gland’s ability to signal the pituitary to produce cortisol. This action is triggered when people go from sleep to awakening.
The next steps in this research are to confirm these novel findings and hunt for an alternative marker of adrenal sensitivity to adrenocorticotropic hormone that’s simpler than sending a waking saliva sample off to a laboratory.
This ongoing longitudinal study is funded by the National Cancer Institute. Dr. Kuhlman reported having no relevant financial conflicts.
SAN FRANCISCO – Nearly 40% of breast cancer patients experience prolonged depression lasting for at least 16 months after diagnosis of their malignancy; those at increased risk may be identifiable in a timely way by their exaggerated cortisol awakening response when measured after surgery but before adjuvant therapy, according to Kate R. Kuhlman, PhD.
“There are several psychological interventions that mitigate depressive symptoms and psychologic distress in women with breast cancer. This time period immediately following cancer diagnosis and surgery may be the optimal time to intervene,” said Dr. Kuhlman, a psychologist at the University of California, Los Angeles.
She presented a prospective study of 135 women with breast cancer who collected saliva samples for analysis of hypothalamic-pituitary-adrenal axis functioning on 3 consecutive days after their primary surgery but prior to starting adjuvant therapy. Samples were obtained on each of the 3 days upon awakening, 30 minutes later, 8 hours later, and at bedtime. The women also completed the Center for Epidemiologic Studies Depression Scale (CES-D) then and again 6 months after completing their breast cancer treatment.
At baseline, 45 of the 135 women scored 16 points or higher out of a possible 60 on the 20-question CES-D, indicative of clinically significant depression. Hypothalamic-pituitary-adrenal axis functioning wasn’t associated with depressive symptoms at that time. Importantly, however, one measure of baseline HPA axis functioning – the cortisol awakening response – proved to be associated with an increase in depressive symptoms over time, Dr. Kuhlman reported.
In a multivariate analysis adjusted for age, breast cancer stage, type of surgery, and forms of adjuvant therapy, a 1-standard-deviation increase above the mean in baseline cortisol awakening response was associated with a 6-point increase in CES-D score at follow-up 6 months after completion of breast cancer therapy. This association was seen only in the 90 women without significant depressive symptoms at baseline. And that’s exactly the population where a predictive biologic marker for future depression is most needed, Dr. Kuhlman said at the annual conference of the Anxiety and Depression Association of America.
“The people at highest risk of depressive symptoms in the future are the ones who have the most symptoms now. They’re easy to identify. We have good reliable measures. But then there are also people at risk whom we would miss by using those measures because they don’t have high symptoms right now,” the psychologist explained.
She and her coinvestigators zeroed in on cortisol awakening response as a potential biomarker of increased future risk of depression because it reflects the adrenal gland’s sensitivity to adrenocorticotropic hormone and the gland’s ability to signal the pituitary to produce cortisol. This action is triggered when people go from sleep to awakening.
The next steps in this research are to confirm these novel findings and hunt for an alternative marker of adrenal sensitivity to adrenocorticotropic hormone that’s simpler than sending a waking saliva sample off to a laboratory.
This ongoing longitudinal study is funded by the National Cancer Institute. Dr. Kuhlman reported having no relevant financial conflicts.
SAN FRANCISCO – Nearly 40% of breast cancer patients experience prolonged depression lasting for at least 16 months after diagnosis of their malignancy; those at increased risk may be identifiable in a timely way by their exaggerated cortisol awakening response when measured after surgery but before adjuvant therapy, according to Kate R. Kuhlman, PhD.
“There are several psychological interventions that mitigate depressive symptoms and psychologic distress in women with breast cancer. This time period immediately following cancer diagnosis and surgery may be the optimal time to intervene,” said Dr. Kuhlman, a psychologist at the University of California, Los Angeles.
She presented a prospective study of 135 women with breast cancer who collected saliva samples for analysis of hypothalamic-pituitary-adrenal axis functioning on 3 consecutive days after their primary surgery but prior to starting adjuvant therapy. Samples were obtained on each of the 3 days upon awakening, 30 minutes later, 8 hours later, and at bedtime. The women also completed the Center for Epidemiologic Studies Depression Scale (CES-D) then and again 6 months after completing their breast cancer treatment.
At baseline, 45 of the 135 women scored 16 points or higher out of a possible 60 on the 20-question CES-D, indicative of clinically significant depression. Hypothalamic-pituitary-adrenal axis functioning wasn’t associated with depressive symptoms at that time. Importantly, however, one measure of baseline HPA axis functioning – the cortisol awakening response – proved to be associated with an increase in depressive symptoms over time, Dr. Kuhlman reported.
In a multivariate analysis adjusted for age, breast cancer stage, type of surgery, and forms of adjuvant therapy, a 1-standard-deviation increase above the mean in baseline cortisol awakening response was associated with a 6-point increase in CES-D score at follow-up 6 months after completion of breast cancer therapy. This association was seen only in the 90 women without significant depressive symptoms at baseline. And that’s exactly the population where a predictive biologic marker for future depression is most needed, Dr. Kuhlman said at the annual conference of the Anxiety and Depression Association of America.
“The people at highest risk of depressive symptoms in the future are the ones who have the most symptoms now. They’re easy to identify. We have good reliable measures. But then there are also people at risk whom we would miss by using those measures because they don’t have high symptoms right now,” the psychologist explained.
She and her coinvestigators zeroed in on cortisol awakening response as a potential biomarker of increased future risk of depression because it reflects the adrenal gland’s sensitivity to adrenocorticotropic hormone and the gland’s ability to signal the pituitary to produce cortisol. This action is triggered when people go from sleep to awakening.
The next steps in this research are to confirm these novel findings and hunt for an alternative marker of adrenal sensitivity to adrenocorticotropic hormone that’s simpler than sending a waking saliva sample off to a laboratory.
This ongoing longitudinal study is funded by the National Cancer Institute. Dr. Kuhlman reported having no relevant financial conflicts.
AT ANXIETY AND DEPRESSION CONFERENCE 2017
Key clinical point:
Major finding: Nondepressed breast cancer patients whose saliva samples show an exaggerated cortisol awakening response when measured after surgery but before adjuvant therapy are at increased risk for developing prolonged depression as treatment progresses.
Data source: A prospective longitudinal study of 135 women with breast cancer.
Disclosures: This ongoing study is funded by the National Cancer Institute. The presenter reported having no relevant financial conflicts.
Test goes wide and deep to detect free tumor DNA in blood
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
AT ASCO 2017
Key clinical point: High-intensity sequencing of plasma samples appears capable of detecting actionable tumor mutations in a large proportion of samples.
Major finding: In 89% of patients with advanced cancers, genetic variants were identified in both tumor samples and circulating free DNA testing.
Data source: Prospective study of tissue and plasma samples from 124 patients with non–small cell lung cancer or metastatic breast and prostate cancers.
Disclosures: The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
VIDEO: Olaparib improves outlook in women with BRCA-related HER2-negative MBC
CHICAGO – Compared with single-agent chemotherapy of the oncologist’s choice, the PARP inhibitor olaparib reduced the risk of progression or death by 42% in women with BRCA-related HER2-negative metastatic breast cancer, the OlympiAD trialists reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
Lead author Mark E. Robson, MD, of Memorial Sloan Kettering Cancer Center, New York, discussed findings of the randomized phase III trial, as well as strategies for building on the trial’s success and what the future holds for this class of agents in breast cancer.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives travel, accommodations, and/or expenses from AstraZeneca; receives honoraria from AstraZeneca; and receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro. The trial was funded by AstraZeneca.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Compared with single-agent chemotherapy of the oncologist’s choice, the PARP inhibitor olaparib reduced the risk of progression or death by 42% in women with BRCA-related HER2-negative metastatic breast cancer, the OlympiAD trialists reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
Lead author Mark E. Robson, MD, of Memorial Sloan Kettering Cancer Center, New York, discussed findings of the randomized phase III trial, as well as strategies for building on the trial’s success and what the future holds for this class of agents in breast cancer.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives travel, accommodations, and/or expenses from AstraZeneca; receives honoraria from AstraZeneca; and receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro. The trial was funded by AstraZeneca.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Compared with single-agent chemotherapy of the oncologist’s choice, the PARP inhibitor olaparib reduced the risk of progression or death by 42% in women with BRCA-related HER2-negative metastatic breast cancer, the OlympiAD trialists reported in a plenary session at the annual meeting of the American Society of Clinical Oncology.
Lead author Mark E. Robson, MD, of Memorial Sloan Kettering Cancer Center, New York, discussed findings of the randomized phase III trial, as well as strategies for building on the trial’s success and what the future holds for this class of agents in breast cancer.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives travel, accommodations, and/or expenses from AstraZeneca; receives honoraria from AstraZeneca; and receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro. The trial was funded by AstraZeneca.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
VIDEO: TRK inhibitor shows 76% ORR across diverse cancers harboring TRK fusions
CHICAGO – An integrated analysis of three trials has shown that larotrectinib, an oral selective inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers harboring TRK fusions, netting an impressive 76% overall response rate.
Lead study author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York, discussed highlights of the analysis, larotrectinib’s regulatory status, and implications for TRK fusion testing in clinical care at the annual meeting of the American Society of Clinical Oncology.
Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology. The study was funded by Loxo Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – An integrated analysis of three trials has shown that larotrectinib, an oral selective inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers harboring TRK fusions, netting an impressive 76% overall response rate.
Lead study author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York, discussed highlights of the analysis, larotrectinib’s regulatory status, and implications for TRK fusion testing in clinical care at the annual meeting of the American Society of Clinical Oncology.
Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology. The study was funded by Loxo Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – An integrated analysis of three trials has shown that larotrectinib, an oral selective inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers harboring TRK fusions, netting an impressive 76% overall response rate.
Lead study author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York, discussed highlights of the analysis, larotrectinib’s regulatory status, and implications for TRK fusion testing in clinical care at the annual meeting of the American Society of Clinical Oncology.
Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology. The study was funded by Loxo Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
VIDEO: Helping cancer patients cope with psychological side effects
CHICAGO – Oncologists are highly skilled at minimizing side effects associated with toxic but curative therapies, but are less adept at helping patients cope with the distress, anxiety, fear, and other emotions associated with cancer.
Three studies presented at the annual meeting of the American Society of Clinical Oncology detail randomized, controlled trials of psychological interventions aimed at helping patients cope with a new cancer diagnosis, reduce fears of a recurrence, and come to grips with the realities of advanced disease, including fears of death or disability.
Don S. Dizon, MD, from the Massachusetts General Hospital Cancer Center, Boston, discusses the social and financial barriers that cancer patients face when they experience distress, and the difficulties that providers face with limited time and financial resources to help patients cope in this video interview.
Dr. Dizon reported having no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Oncologists are highly skilled at minimizing side effects associated with toxic but curative therapies, but are less adept at helping patients cope with the distress, anxiety, fear, and other emotions associated with cancer.
Three studies presented at the annual meeting of the American Society of Clinical Oncology detail randomized, controlled trials of psychological interventions aimed at helping patients cope with a new cancer diagnosis, reduce fears of a recurrence, and come to grips with the realities of advanced disease, including fears of death or disability.
Don S. Dizon, MD, from the Massachusetts General Hospital Cancer Center, Boston, discusses the social and financial barriers that cancer patients face when they experience distress, and the difficulties that providers face with limited time and financial resources to help patients cope in this video interview.
Dr. Dizon reported having no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Oncologists are highly skilled at minimizing side effects associated with toxic but curative therapies, but are less adept at helping patients cope with the distress, anxiety, fear, and other emotions associated with cancer.
Three studies presented at the annual meeting of the American Society of Clinical Oncology detail randomized, controlled trials of psychological interventions aimed at helping patients cope with a new cancer diagnosis, reduce fears of a recurrence, and come to grips with the realities of advanced disease, including fears of death or disability.
Don S. Dizon, MD, from the Massachusetts General Hospital Cancer Center, Boston, discusses the social and financial barriers that cancer patients face when they experience distress, and the difficulties that providers face with limited time and financial resources to help patients cope in this video interview.
Dr. Dizon reported having no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
FDA advisory committee supports neratinib approval
of adults with early-stage HER2-positive breast cancer who received prior adjuvant trastuzumab-based therapy.
Members voting during the May 24 meeting expressed concern about the broadness of the indication proposed by the drug’s maker, Puma Biotechnology, but the majority said the risk-benefit profile of the drug is sufficient to support approval, particularly given the unmet need for such an agent. Those voting against approval argued that more data are needed to identify subpopulations of patients who would be most likely to benefit from treatment in order to narrow the indication.
“There are some unknowns that concern me. ... I don’t think I would treat as broadly as the indication describes,” he said, adding that it would be very difficult to decide which patients to treat, and it would be nice to have more data that provide predictive biomarkers to help determine who should be treated. “But at the end of the day I think it’s useful to have this as an option for treating patients.”
Lori M. Minasian, MD, also a temporary voting member from the National Institutes of Health, agreed.
“I think the option should be available,” she said, adding that the analysis was thorough. However, she, too, questioned the proposed indication.
“I remain concerned that the indication is far too broad, and ... I think we need greater understanding of which subsets of patients would be most responsive to this therapy,” she said.
Heidi D. Klepin, MD, of Wake Forest University in Winston-Salem, N.C. said she voted “yes” for similar reasons, despite concerns about the lack of data to help narrow the indication.
“I particularly felt it was important to support this indication because I think this is an unmet need, and I think the primary outcome is an important and relevant outcome for our patients, even though what we’re seeing effect-wise may be modest,” she said.
Patricia A. Spears, a breast cancer survivor and patient representative from Raleigh, N.C., however, voted against approval.
“I think it is important to get drugs out to patients, and I think this will benefit a certain subset of patients. I’m just not sure we know which ones yet. What we do is tend to put a lot of patients at risk to benefit just a few. We do that a lot,” she said.
She expressed concern that the treatment would be “tacked on to the end of trastuzumab” in too many cases without concern for whether the patient is likely to benefit.
Another member who voted no, Courtney J. Preusse, who was a consumer representative on the committee, said she struggled with the decision but ultimately decided that the benefit this drug adds beyond what already exists is “just not compelling.”
Neratinib is a kinase inhibitor that irreversibly binds to epidermal growth factor receptors, HER2, and HER4, and results of the phase III ExteNET trial presented to the committee by representatives of the applicant showed a statistically significant invasive disease-free survival benefit with treatment.
The invasive disease-free survival at 2 years in 1,420 patients with early stage HER2-positive breast cancer after adjuvant treatment with trastuzumab who were randomized to receive neratinib was 94.2%, compared with 91.9% in 1,420 who received placebo (stratified hazard ratio 0.66). Follow-up data from patients who reconsented to participate showed similar outcomes from 2 to 5 years post-randomization.
An exploratory subgroup analysis suggested a possible difference in the magnitude of benefit based on hormone receptor status, with a 51% reduction in recurrence risk among HR-positive patients, compared with a 7% reduction in HR-negative patients (hazard ratios, 0.49 and 0.93, respectively).
Some concern was raised regarding multiple amendments to the protocol during the study, but committee members who spoke about this expressed satisfaction with the way these issues were handled in terms of sensitivity analysis.
As for safety, diarrhea was the most frequently reported adverse reaction, occurring in 95% of treated patients. Grade 3 diarrhea occurred in 40% of treated patients. Additional data were presented showing that antidiarrheal prophylaxis was effective. Several patients who spoke during the public hearing portion of the meeting–some of whom had travel expenses paid by the applicant, said they either had no problem with diarrhea or that it was manageable. Nearly all of those who spoke during the open public hearing, including patients and family members, shared emotional stories about their personal battles with breast cancer and urged the committee to support approval of neratinib to expand the options available to patients.
The FDA will now consider the new drug application for neratinib, and although it is not bound by the advisory committee’s recommendation, it usually follows such recommendations.
The advisory committee members reported having no relevant conflicts of interest.
of adults with early-stage HER2-positive breast cancer who received prior adjuvant trastuzumab-based therapy.
Members voting during the May 24 meeting expressed concern about the broadness of the indication proposed by the drug’s maker, Puma Biotechnology, but the majority said the risk-benefit profile of the drug is sufficient to support approval, particularly given the unmet need for such an agent. Those voting against approval argued that more data are needed to identify subpopulations of patients who would be most likely to benefit from treatment in order to narrow the indication.
“There are some unknowns that concern me. ... I don’t think I would treat as broadly as the indication describes,” he said, adding that it would be very difficult to decide which patients to treat, and it would be nice to have more data that provide predictive biomarkers to help determine who should be treated. “But at the end of the day I think it’s useful to have this as an option for treating patients.”
Lori M. Minasian, MD, also a temporary voting member from the National Institutes of Health, agreed.
“I think the option should be available,” she said, adding that the analysis was thorough. However, she, too, questioned the proposed indication.
“I remain concerned that the indication is far too broad, and ... I think we need greater understanding of which subsets of patients would be most responsive to this therapy,” she said.
Heidi D. Klepin, MD, of Wake Forest University in Winston-Salem, N.C. said she voted “yes” for similar reasons, despite concerns about the lack of data to help narrow the indication.
“I particularly felt it was important to support this indication because I think this is an unmet need, and I think the primary outcome is an important and relevant outcome for our patients, even though what we’re seeing effect-wise may be modest,” she said.
Patricia A. Spears, a breast cancer survivor and patient representative from Raleigh, N.C., however, voted against approval.
“I think it is important to get drugs out to patients, and I think this will benefit a certain subset of patients. I’m just not sure we know which ones yet. What we do is tend to put a lot of patients at risk to benefit just a few. We do that a lot,” she said.
She expressed concern that the treatment would be “tacked on to the end of trastuzumab” in too many cases without concern for whether the patient is likely to benefit.
Another member who voted no, Courtney J. Preusse, who was a consumer representative on the committee, said she struggled with the decision but ultimately decided that the benefit this drug adds beyond what already exists is “just not compelling.”
Neratinib is a kinase inhibitor that irreversibly binds to epidermal growth factor receptors, HER2, and HER4, and results of the phase III ExteNET trial presented to the committee by representatives of the applicant showed a statistically significant invasive disease-free survival benefit with treatment.
The invasive disease-free survival at 2 years in 1,420 patients with early stage HER2-positive breast cancer after adjuvant treatment with trastuzumab who were randomized to receive neratinib was 94.2%, compared with 91.9% in 1,420 who received placebo (stratified hazard ratio 0.66). Follow-up data from patients who reconsented to participate showed similar outcomes from 2 to 5 years post-randomization.
An exploratory subgroup analysis suggested a possible difference in the magnitude of benefit based on hormone receptor status, with a 51% reduction in recurrence risk among HR-positive patients, compared with a 7% reduction in HR-negative patients (hazard ratios, 0.49 and 0.93, respectively).
Some concern was raised regarding multiple amendments to the protocol during the study, but committee members who spoke about this expressed satisfaction with the way these issues were handled in terms of sensitivity analysis.
As for safety, diarrhea was the most frequently reported adverse reaction, occurring in 95% of treated patients. Grade 3 diarrhea occurred in 40% of treated patients. Additional data were presented showing that antidiarrheal prophylaxis was effective. Several patients who spoke during the public hearing portion of the meeting–some of whom had travel expenses paid by the applicant, said they either had no problem with diarrhea or that it was manageable. Nearly all of those who spoke during the open public hearing, including patients and family members, shared emotional stories about their personal battles with breast cancer and urged the committee to support approval of neratinib to expand the options available to patients.
The FDA will now consider the new drug application for neratinib, and although it is not bound by the advisory committee’s recommendation, it usually follows such recommendations.
The advisory committee members reported having no relevant conflicts of interest.
of adults with early-stage HER2-positive breast cancer who received prior adjuvant trastuzumab-based therapy.
Members voting during the May 24 meeting expressed concern about the broadness of the indication proposed by the drug’s maker, Puma Biotechnology, but the majority said the risk-benefit profile of the drug is sufficient to support approval, particularly given the unmet need for such an agent. Those voting against approval argued that more data are needed to identify subpopulations of patients who would be most likely to benefit from treatment in order to narrow the indication.
“There are some unknowns that concern me. ... I don’t think I would treat as broadly as the indication describes,” he said, adding that it would be very difficult to decide which patients to treat, and it would be nice to have more data that provide predictive biomarkers to help determine who should be treated. “But at the end of the day I think it’s useful to have this as an option for treating patients.”
Lori M. Minasian, MD, also a temporary voting member from the National Institutes of Health, agreed.
“I think the option should be available,” she said, adding that the analysis was thorough. However, she, too, questioned the proposed indication.
“I remain concerned that the indication is far too broad, and ... I think we need greater understanding of which subsets of patients would be most responsive to this therapy,” she said.
Heidi D. Klepin, MD, of Wake Forest University in Winston-Salem, N.C. said she voted “yes” for similar reasons, despite concerns about the lack of data to help narrow the indication.
“I particularly felt it was important to support this indication because I think this is an unmet need, and I think the primary outcome is an important and relevant outcome for our patients, even though what we’re seeing effect-wise may be modest,” she said.
Patricia A. Spears, a breast cancer survivor and patient representative from Raleigh, N.C., however, voted against approval.
“I think it is important to get drugs out to patients, and I think this will benefit a certain subset of patients. I’m just not sure we know which ones yet. What we do is tend to put a lot of patients at risk to benefit just a few. We do that a lot,” she said.
She expressed concern that the treatment would be “tacked on to the end of trastuzumab” in too many cases without concern for whether the patient is likely to benefit.
Another member who voted no, Courtney J. Preusse, who was a consumer representative on the committee, said she struggled with the decision but ultimately decided that the benefit this drug adds beyond what already exists is “just not compelling.”
Neratinib is a kinase inhibitor that irreversibly binds to epidermal growth factor receptors, HER2, and HER4, and results of the phase III ExteNET trial presented to the committee by representatives of the applicant showed a statistically significant invasive disease-free survival benefit with treatment.
The invasive disease-free survival at 2 years in 1,420 patients with early stage HER2-positive breast cancer after adjuvant treatment with trastuzumab who were randomized to receive neratinib was 94.2%, compared with 91.9% in 1,420 who received placebo (stratified hazard ratio 0.66). Follow-up data from patients who reconsented to participate showed similar outcomes from 2 to 5 years post-randomization.
An exploratory subgroup analysis suggested a possible difference in the magnitude of benefit based on hormone receptor status, with a 51% reduction in recurrence risk among HR-positive patients, compared with a 7% reduction in HR-negative patients (hazard ratios, 0.49 and 0.93, respectively).
Some concern was raised regarding multiple amendments to the protocol during the study, but committee members who spoke about this expressed satisfaction with the way these issues were handled in terms of sensitivity analysis.
As for safety, diarrhea was the most frequently reported adverse reaction, occurring in 95% of treated patients. Grade 3 diarrhea occurred in 40% of treated patients. Additional data were presented showing that antidiarrheal prophylaxis was effective. Several patients who spoke during the public hearing portion of the meeting–some of whom had travel expenses paid by the applicant, said they either had no problem with diarrhea or that it was manageable. Nearly all of those who spoke during the open public hearing, including patients and family members, shared emotional stories about their personal battles with breast cancer and urged the committee to support approval of neratinib to expand the options available to patients.
The FDA will now consider the new drug application for neratinib, and although it is not bound by the advisory committee’s recommendation, it usually follows such recommendations.
The advisory committee members reported having no relevant conflicts of interest.
Refutes concept of overdiagnosis of breast cancer
“MORE THAN ONE-THIRD OF TUMORS FOUND ON BREAST CANCER SCREENING REPRESENT OVERDIAGNOSIS”
ANDREW M. KAUNITZ, MD (MARCH 2017)
Refutes concept of overdiagnosis of breast cancer
I read with interest and serious concern the commentary and conclusions of “overdiagnosed” breast cancer. Let us revisit a few time-honored principles. Are we throwing away the valued concept of the early diagnosis of node-negative breast cancer? Is it still true that 5-year and long-term survivals are markedly better for stage I and II disease as opposed to stage III and IV disease? Is it still true that treatments designed for cure are substantially less involved, more successful, and more likely to conserve the breast and require less chemotherapy in early stage disease? Is it still true that the majority of women diagnosed with breast cancer are in the lowest risk category, ie, no family history and negative for the BRCA gene? If so, then who can explain the statement that “an invasive breast cancer detected by any means is overdiagnosis”? Would this imply that screening and the biopsy required to make the diagnosis was time poorly spent, the breast cancer should not be treated, and/or we should simply wait for a lump to be found by the patient deep in a large breast most likely at that point representing advanced disease?
The last paragraph notes the current US Preventive Services Task Force (USPSTF) guidance: wait until 50 years of age to start biennial screening. If so, what do we say to women in their 40s who, through screening with mammography and/or ultrasound, were diagnosed with early node-negative invasive breast cancer? That all of that was unnecessary and would not have led to symptoms? Would extreme morbidity from advanced or recurrent disease and the horrors of treatment just to extend a few months of life qualify as a symptom to these investigators? Lax protocols are not for me, my colleagues, or patients that I know. One of the most common reasons for a lawsuit to be brought against a primary care or ObGyn provider is failure to diagnose breast cancer!
John T. Armstrong, MD
Napa, California
Dr. Kaunitz responds
I thank Dr. Armstrong for his interest in my commentary on screening mammography and overdiagnosis. As I indicated in my commentary, I continue to recommend screening mammography for my patients, encouraging average-risk women to begin biennial screens at age 50 (consistent with USPSTF guidance), when the likelihood that tumors found with mammograms representing overdiagnosis is lower. I also indicated that I recognize that some patients prefer to begin screening at a younger age and to be screened more frequently. Dr. Armstrong’s letter refers to the “horrors of treatment” of breast cancer. From my perspective, the most “horrible” treatment is that which is administered to a woman diagnosed with a tumor destined to not cause clinical problems during her lifetime (overdiagnosis). You also refer to a statement, “an invasive breast cancer detected by any means is overdiagnosis.” That statement does not appear in my commentary.
My commentary’s point is that overdiagnosis is common among tumors diagnosed by screening mammography, and likely explains why, in contrast with cervical cancer screening, screening mammography has failed to reduce the incidence of breast cancers presenting as advanced (metastatic) disease. Although this represents a confusing and disquieting reality for our patients, and for us their clinicians, I agree with Dr. Otis Brawley, Chief Medical and Scientific Officer of the American Cancer Society, that we must acknowledge to our patients that overdiagnosis is common, the benefits of screening have been overstated, and that some patients considered as “cured” from breast cancer have in fact been harmed by unneeded treatment.1
Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.
- Brawley OW. Accepting the existence of breast cancer overdiagnosis [published online ahead of print January 10, 2017]. Ann Intern Med. doi:10.7326/M16-2850.
“MORE THAN ONE-THIRD OF TUMORS FOUND ON BREAST CANCER SCREENING REPRESENT OVERDIAGNOSIS”
ANDREW M. KAUNITZ, MD (MARCH 2017)
Refutes concept of overdiagnosis of breast cancer
I read with interest and serious concern the commentary and conclusions of “overdiagnosed” breast cancer. Let us revisit a few time-honored principles. Are we throwing away the valued concept of the early diagnosis of node-negative breast cancer? Is it still true that 5-year and long-term survivals are markedly better for stage I and II disease as opposed to stage III and IV disease? Is it still true that treatments designed for cure are substantially less involved, more successful, and more likely to conserve the breast and require less chemotherapy in early stage disease? Is it still true that the majority of women diagnosed with breast cancer are in the lowest risk category, ie, no family history and negative for the BRCA gene? If so, then who can explain the statement that “an invasive breast cancer detected by any means is overdiagnosis”? Would this imply that screening and the biopsy required to make the diagnosis was time poorly spent, the breast cancer should not be treated, and/or we should simply wait for a lump to be found by the patient deep in a large breast most likely at that point representing advanced disease?
The last paragraph notes the current US Preventive Services Task Force (USPSTF) guidance: wait until 50 years of age to start biennial screening. If so, what do we say to women in their 40s who, through screening with mammography and/or ultrasound, were diagnosed with early node-negative invasive breast cancer? That all of that was unnecessary and would not have led to symptoms? Would extreme morbidity from advanced or recurrent disease and the horrors of treatment just to extend a few months of life qualify as a symptom to these investigators? Lax protocols are not for me, my colleagues, or patients that I know. One of the most common reasons for a lawsuit to be brought against a primary care or ObGyn provider is failure to diagnose breast cancer!
John T. Armstrong, MD
Napa, California
Dr. Kaunitz responds
I thank Dr. Armstrong for his interest in my commentary on screening mammography and overdiagnosis. As I indicated in my commentary, I continue to recommend screening mammography for my patients, encouraging average-risk women to begin biennial screens at age 50 (consistent with USPSTF guidance), when the likelihood that tumors found with mammograms representing overdiagnosis is lower. I also indicated that I recognize that some patients prefer to begin screening at a younger age and to be screened more frequently. Dr. Armstrong’s letter refers to the “horrors of treatment” of breast cancer. From my perspective, the most “horrible” treatment is that which is administered to a woman diagnosed with a tumor destined to not cause clinical problems during her lifetime (overdiagnosis). You also refer to a statement, “an invasive breast cancer detected by any means is overdiagnosis.” That statement does not appear in my commentary.
My commentary’s point is that overdiagnosis is common among tumors diagnosed by screening mammography, and likely explains why, in contrast with cervical cancer screening, screening mammography has failed to reduce the incidence of breast cancers presenting as advanced (metastatic) disease. Although this represents a confusing and disquieting reality for our patients, and for us their clinicians, I agree with Dr. Otis Brawley, Chief Medical and Scientific Officer of the American Cancer Society, that we must acknowledge to our patients that overdiagnosis is common, the benefits of screening have been overstated, and that some patients considered as “cured” from breast cancer have in fact been harmed by unneeded treatment.1
Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.
“MORE THAN ONE-THIRD OF TUMORS FOUND ON BREAST CANCER SCREENING REPRESENT OVERDIAGNOSIS”
ANDREW M. KAUNITZ, MD (MARCH 2017)
Refutes concept of overdiagnosis of breast cancer
I read with interest and serious concern the commentary and conclusions of “overdiagnosed” breast cancer. Let us revisit a few time-honored principles. Are we throwing away the valued concept of the early diagnosis of node-negative breast cancer? Is it still true that 5-year and long-term survivals are markedly better for stage I and II disease as opposed to stage III and IV disease? Is it still true that treatments designed for cure are substantially less involved, more successful, and more likely to conserve the breast and require less chemotherapy in early stage disease? Is it still true that the majority of women diagnosed with breast cancer are in the lowest risk category, ie, no family history and negative for the BRCA gene? If so, then who can explain the statement that “an invasive breast cancer detected by any means is overdiagnosis”? Would this imply that screening and the biopsy required to make the diagnosis was time poorly spent, the breast cancer should not be treated, and/or we should simply wait for a lump to be found by the patient deep in a large breast most likely at that point representing advanced disease?
The last paragraph notes the current US Preventive Services Task Force (USPSTF) guidance: wait until 50 years of age to start biennial screening. If so, what do we say to women in their 40s who, through screening with mammography and/or ultrasound, were diagnosed with early node-negative invasive breast cancer? That all of that was unnecessary and would not have led to symptoms? Would extreme morbidity from advanced or recurrent disease and the horrors of treatment just to extend a few months of life qualify as a symptom to these investigators? Lax protocols are not for me, my colleagues, or patients that I know. One of the most common reasons for a lawsuit to be brought against a primary care or ObGyn provider is failure to diagnose breast cancer!
John T. Armstrong, MD
Napa, California
Dr. Kaunitz responds
I thank Dr. Armstrong for his interest in my commentary on screening mammography and overdiagnosis. As I indicated in my commentary, I continue to recommend screening mammography for my patients, encouraging average-risk women to begin biennial screens at age 50 (consistent with USPSTF guidance), when the likelihood that tumors found with mammograms representing overdiagnosis is lower. I also indicated that I recognize that some patients prefer to begin screening at a younger age and to be screened more frequently. Dr. Armstrong’s letter refers to the “horrors of treatment” of breast cancer. From my perspective, the most “horrible” treatment is that which is administered to a woman diagnosed with a tumor destined to not cause clinical problems during her lifetime (overdiagnosis). You also refer to a statement, “an invasive breast cancer detected by any means is overdiagnosis.” That statement does not appear in my commentary.
My commentary’s point is that overdiagnosis is common among tumors diagnosed by screening mammography, and likely explains why, in contrast with cervical cancer screening, screening mammography has failed to reduce the incidence of breast cancers presenting as advanced (metastatic) disease. Although this represents a confusing and disquieting reality for our patients, and for us their clinicians, I agree with Dr. Otis Brawley, Chief Medical and Scientific Officer of the American Cancer Society, that we must acknowledge to our patients that overdiagnosis is common, the benefits of screening have been overstated, and that some patients considered as “cured” from breast cancer have in fact been harmed by unneeded treatment.1
Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.
- Brawley OW. Accepting the existence of breast cancer overdiagnosis [published online ahead of print January 10, 2017]. Ann Intern Med. doi:10.7326/M16-2850.
- Brawley OW. Accepting the existence of breast cancer overdiagnosis [published online ahead of print January 10, 2017]. Ann Intern Med. doi:10.7326/M16-2850.
Breast cancer liquid biopsies don’t change outcomes....yet
LAS VEGAS – Although circulating tumor cells are prognostic in breast cancer, they aren’t likely to become a part of routine practice until they’ve been shown to improve outcomes, and that hasn’t happened yet, according to Anthony Lucci, MD, professor of breast surgical oncology at MD Anderson Cancer Center, Houston.
MD Anderson and other institutions have established that in breast cancer, from baseline through treatment follow-up, the presence of circulating tumor cells (CTCs) in the blood predicts worse outcomes in both metastatic and local disease, even among women who have a pathologic complete response to treatment.
That knowledge has not yet translated into better outcomes. In a pivotal trial, survival was no better in metastatic breast cancer when women were switched to an alternative chemotherapy regimen after their CTC levels did not fall in response to first-line treatment, compared with women who remained on their initial agent despite persistently high CTCs (J Clin Oncol. 2014 Nov 1;32[31]:3483-9).
“When we tried to switch chemotherapy” based on CTCs, “it really didn’t make a difference, so no one is really quite sure yet what to do with this information. We can’t tell a patient that they are likely to have a much worse outcome, but there’s nothing we can do about it,” and “I don’t think payers will pay” for CTC testing in breast cancer until “we establish a predictive benefit, and show what agents will reduce CTCs and improve outcomes,” Dr. Lucci said at the American Society of Breast Surgeons annual meeting.
Even so, the promise of CTCs as a clinical tool is too great to abandon research, and work continues at MD Anderson and elsewhere. It’s thought that tumor cells in the blood aren’t simply a marker of disease, but rather microscopic disease in themselves that contributes to recurrence and progression. It’s possible that cells shed by tumors lie dormant in the bone marrow, then reactivate and reseed the original tumor site or give rise to distant metastases.
CTCs are similar to tumor cells that have been found in the bone marrow of women with apparently quiescent breast cancer, but finding them in the blood means “you don’t have to poke a needle in someone’s bone. You can just take a sample of their blood, and it tells you the same information,” Dr. Lucci said.
CTCs have been shown in breast cancer to rise and fall depending on tumor response. “In the future, I do think we will [use them] as a serial monitoring tool and a guide to therapy.” There might even be a role for breast cancer screening, he said.
Analyzing the blood for evidence of solid tumors – popularly called “liquid biopsy” – has shown benefits in a variety of cancers, particularly for identifying disease, and in some cases mutations, sooner than with conventional methods. Science is catching up to the old-school notion that cancer spreads through the blood.
Another approach is to look for circulating tumor DNA, which has been shown to be useful for early detection in gynecologic cancers. The idea is that a few tumor cells shatter and spill their genetic material into the blood early on. “In the majority of breast cancer patients,” however, “you don’t find actionable mutations” with circulating tumor DNA, especially in earlier-stage, nonmetastatic disease. “There’s not enough DNA released into the blood,” Dr. Lucci said.
But “we need to be monitoring the blood on a routine basis” for breast cancer clues. “That, I think, is the wave of the future. Just looking at x-rays and waiting for something to happen is too late,” he said.
Dr. Lucci had no disclosures related to his talk.
LAS VEGAS – Although circulating tumor cells are prognostic in breast cancer, they aren’t likely to become a part of routine practice until they’ve been shown to improve outcomes, and that hasn’t happened yet, according to Anthony Lucci, MD, professor of breast surgical oncology at MD Anderson Cancer Center, Houston.
MD Anderson and other institutions have established that in breast cancer, from baseline through treatment follow-up, the presence of circulating tumor cells (CTCs) in the blood predicts worse outcomes in both metastatic and local disease, even among women who have a pathologic complete response to treatment.
That knowledge has not yet translated into better outcomes. In a pivotal trial, survival was no better in metastatic breast cancer when women were switched to an alternative chemotherapy regimen after their CTC levels did not fall in response to first-line treatment, compared with women who remained on their initial agent despite persistently high CTCs (J Clin Oncol. 2014 Nov 1;32[31]:3483-9).
“When we tried to switch chemotherapy” based on CTCs, “it really didn’t make a difference, so no one is really quite sure yet what to do with this information. We can’t tell a patient that they are likely to have a much worse outcome, but there’s nothing we can do about it,” and “I don’t think payers will pay” for CTC testing in breast cancer until “we establish a predictive benefit, and show what agents will reduce CTCs and improve outcomes,” Dr. Lucci said at the American Society of Breast Surgeons annual meeting.
Even so, the promise of CTCs as a clinical tool is too great to abandon research, and work continues at MD Anderson and elsewhere. It’s thought that tumor cells in the blood aren’t simply a marker of disease, but rather microscopic disease in themselves that contributes to recurrence and progression. It’s possible that cells shed by tumors lie dormant in the bone marrow, then reactivate and reseed the original tumor site or give rise to distant metastases.
CTCs are similar to tumor cells that have been found in the bone marrow of women with apparently quiescent breast cancer, but finding them in the blood means “you don’t have to poke a needle in someone’s bone. You can just take a sample of their blood, and it tells you the same information,” Dr. Lucci said.
CTCs have been shown in breast cancer to rise and fall depending on tumor response. “In the future, I do think we will [use them] as a serial monitoring tool and a guide to therapy.” There might even be a role for breast cancer screening, he said.
Analyzing the blood for evidence of solid tumors – popularly called “liquid biopsy” – has shown benefits in a variety of cancers, particularly for identifying disease, and in some cases mutations, sooner than with conventional methods. Science is catching up to the old-school notion that cancer spreads through the blood.
Another approach is to look for circulating tumor DNA, which has been shown to be useful for early detection in gynecologic cancers. The idea is that a few tumor cells shatter and spill their genetic material into the blood early on. “In the majority of breast cancer patients,” however, “you don’t find actionable mutations” with circulating tumor DNA, especially in earlier-stage, nonmetastatic disease. “There’s not enough DNA released into the blood,” Dr. Lucci said.
But “we need to be monitoring the blood on a routine basis” for breast cancer clues. “That, I think, is the wave of the future. Just looking at x-rays and waiting for something to happen is too late,” he said.
Dr. Lucci had no disclosures related to his talk.
LAS VEGAS – Although circulating tumor cells are prognostic in breast cancer, they aren’t likely to become a part of routine practice until they’ve been shown to improve outcomes, and that hasn’t happened yet, according to Anthony Lucci, MD, professor of breast surgical oncology at MD Anderson Cancer Center, Houston.
MD Anderson and other institutions have established that in breast cancer, from baseline through treatment follow-up, the presence of circulating tumor cells (CTCs) in the blood predicts worse outcomes in both metastatic and local disease, even among women who have a pathologic complete response to treatment.
That knowledge has not yet translated into better outcomes. In a pivotal trial, survival was no better in metastatic breast cancer when women were switched to an alternative chemotherapy regimen after their CTC levels did not fall in response to first-line treatment, compared with women who remained on their initial agent despite persistently high CTCs (J Clin Oncol. 2014 Nov 1;32[31]:3483-9).
“When we tried to switch chemotherapy” based on CTCs, “it really didn’t make a difference, so no one is really quite sure yet what to do with this information. We can’t tell a patient that they are likely to have a much worse outcome, but there’s nothing we can do about it,” and “I don’t think payers will pay” for CTC testing in breast cancer until “we establish a predictive benefit, and show what agents will reduce CTCs and improve outcomes,” Dr. Lucci said at the American Society of Breast Surgeons annual meeting.
Even so, the promise of CTCs as a clinical tool is too great to abandon research, and work continues at MD Anderson and elsewhere. It’s thought that tumor cells in the blood aren’t simply a marker of disease, but rather microscopic disease in themselves that contributes to recurrence and progression. It’s possible that cells shed by tumors lie dormant in the bone marrow, then reactivate and reseed the original tumor site or give rise to distant metastases.
CTCs are similar to tumor cells that have been found in the bone marrow of women with apparently quiescent breast cancer, but finding them in the blood means “you don’t have to poke a needle in someone’s bone. You can just take a sample of their blood, and it tells you the same information,” Dr. Lucci said.
CTCs have been shown in breast cancer to rise and fall depending on tumor response. “In the future, I do think we will [use them] as a serial monitoring tool and a guide to therapy.” There might even be a role for breast cancer screening, he said.
Analyzing the blood for evidence of solid tumors – popularly called “liquid biopsy” – has shown benefits in a variety of cancers, particularly for identifying disease, and in some cases mutations, sooner than with conventional methods. Science is catching up to the old-school notion that cancer spreads through the blood.
Another approach is to look for circulating tumor DNA, which has been shown to be useful for early detection in gynecologic cancers. The idea is that a few tumor cells shatter and spill their genetic material into the blood early on. “In the majority of breast cancer patients,” however, “you don’t find actionable mutations” with circulating tumor DNA, especially in earlier-stage, nonmetastatic disease. “There’s not enough DNA released into the blood,” Dr. Lucci said.
But “we need to be monitoring the blood on a routine basis” for breast cancer clues. “That, I think, is the wave of the future. Just looking at x-rays and waiting for something to happen is too late,” he said.
Dr. Lucci had no disclosures related to his talk.
AT ASBS 2017
Five year survival doubles for younger women with de novo MBC
Nearly 155,000 women in the United States are living with metastatic breast cancer (MBC), three-fourths of whom were initially diagnosed with lower-stage disease that progressed to stage IV, based on estimated prevalence data.
The estimates, derived from national breast cancer mortality and survival data, also show positive trends in breast cancer care, especially a doubling of 5-year survival rates among younger women diagnosed with de novo metastatic disease from the 1990s to the 2000s, reported Angela B. Mariotto, PhD, of the National Cancer Institute and her colleagues.
“Despite the progressive and incurable nature of almost all MBC, median survival after diagnosis with metastatic disease has been increasing, resulting in a growing number of women living with MBC in the United States. The increased survival is especially noted for women diagnosed at younger ages,” they wrote in Cancer Epidemiology, Biomarkers, & Prevention (2017 May 18. doi: 10.1158/1055-9965.epi-16-088).
Patients with advanced breast cancer require extensive care and intensive use of medical and other resources, but, until this study, there were no reliable estimates of the number of women actually living with metastatic disease in the United States, the authors said.
To get a clearer picture of the prevalence of advanced breast cancer in the United States, they worked backward from Surveillance, Epidemiology, and End Results data on breast cancer deaths and survival, working on the assumption that each observed breast cancer death is the result of metastatic disease, either in women whose initial diagnosis was stage IV disease (de novo metastatic disease) or disease recurrence with metastases.
They estimated that, in 2013, the most recent year for which there were observed data, the prevalence of metastatic breast cancer was 138,622, and that 38,897 (28%) of survivors were diagnosed with metastatic disease. The remaining 99,725 survivors (72%) were women who were initially diagnosed with stage I-III disease that either recurred or metastasized.
The authors calculated that 50,344 women were diagnosed with de novo metastatic disease in 2013, 12,966 of whom (26%) had de novo metastatic breast cancer and 37,378 of whom had recurrent disease. They projected that, as of Jan. 1, 2017, there are 154,794 women living with metastatic breast cancer in the United States.
They also estimated changes over time in survival and found that, for women diagnosed from the ages of 15 to 49 during the 1992-1994 surveillance period, median survival time was 22.3 months, which improved to 38.7 months during the 2005-2012 surveillance period. The respective survival times for women 50-64 years were 19.1 months and 29.7 months.
For women 15-49 years who were diagnosed with de novo metastatic breast cancer, the 5-year relative survival rates doubled from 18% during 1992-1994 to 36% during 2005-2012.
“Despite a poor prognosis, there is a small but meaningful percentage of these cases who survive 10 years or more. More than 11% of women diagnosed between 2000-2004 under the age of 64 years survived 10 years or more. Younger women diagnosed with de novo MBC have higher survival than women diagnosed at older ages,” Dr. Mariotto and her colleagues wrote.
The investigators pointed to the population size, population-based data, long follow-up, and use of consistent staging definitions over time as study strengths but acknowledged that the study was limited by the absence of population-based estimates of survival following recurrence of metastatic breast cancer.
“To our knowledge, this is the first time that the number of women living with MBC in the United States has been estimated. These estimates provide a new perspective on the population burden of breast cancer and have great potential significance to the research and advocacy community working on behalf of patients with MBC and their families,” the authors wrote.
The study was supported by the National Cancer Institute. The authors reported no relevant financial disclosures.
This article was updated June 5, 2017.
Nearly 155,000 women in the United States are living with metastatic breast cancer (MBC), three-fourths of whom were initially diagnosed with lower-stage disease that progressed to stage IV, based on estimated prevalence data.
The estimates, derived from national breast cancer mortality and survival data, also show positive trends in breast cancer care, especially a doubling of 5-year survival rates among younger women diagnosed with de novo metastatic disease from the 1990s to the 2000s, reported Angela B. Mariotto, PhD, of the National Cancer Institute and her colleagues.
“Despite the progressive and incurable nature of almost all MBC, median survival after diagnosis with metastatic disease has been increasing, resulting in a growing number of women living with MBC in the United States. The increased survival is especially noted for women diagnosed at younger ages,” they wrote in Cancer Epidemiology, Biomarkers, & Prevention (2017 May 18. doi: 10.1158/1055-9965.epi-16-088).
Patients with advanced breast cancer require extensive care and intensive use of medical and other resources, but, until this study, there were no reliable estimates of the number of women actually living with metastatic disease in the United States, the authors said.
To get a clearer picture of the prevalence of advanced breast cancer in the United States, they worked backward from Surveillance, Epidemiology, and End Results data on breast cancer deaths and survival, working on the assumption that each observed breast cancer death is the result of metastatic disease, either in women whose initial diagnosis was stage IV disease (de novo metastatic disease) or disease recurrence with metastases.
They estimated that, in 2013, the most recent year for which there were observed data, the prevalence of metastatic breast cancer was 138,622, and that 38,897 (28%) of survivors were diagnosed with metastatic disease. The remaining 99,725 survivors (72%) were women who were initially diagnosed with stage I-III disease that either recurred or metastasized.
The authors calculated that 50,344 women were diagnosed with de novo metastatic disease in 2013, 12,966 of whom (26%) had de novo metastatic breast cancer and 37,378 of whom had recurrent disease. They projected that, as of Jan. 1, 2017, there are 154,794 women living with metastatic breast cancer in the United States.
They also estimated changes over time in survival and found that, for women diagnosed from the ages of 15 to 49 during the 1992-1994 surveillance period, median survival time was 22.3 months, which improved to 38.7 months during the 2005-2012 surveillance period. The respective survival times for women 50-64 years were 19.1 months and 29.7 months.
For women 15-49 years who were diagnosed with de novo metastatic breast cancer, the 5-year relative survival rates doubled from 18% during 1992-1994 to 36% during 2005-2012.
“Despite a poor prognosis, there is a small but meaningful percentage of these cases who survive 10 years or more. More than 11% of women diagnosed between 2000-2004 under the age of 64 years survived 10 years or more. Younger women diagnosed with de novo MBC have higher survival than women diagnosed at older ages,” Dr. Mariotto and her colleagues wrote.
The investigators pointed to the population size, population-based data, long follow-up, and use of consistent staging definitions over time as study strengths but acknowledged that the study was limited by the absence of population-based estimates of survival following recurrence of metastatic breast cancer.
“To our knowledge, this is the first time that the number of women living with MBC in the United States has been estimated. These estimates provide a new perspective on the population burden of breast cancer and have great potential significance to the research and advocacy community working on behalf of patients with MBC and their families,” the authors wrote.
The study was supported by the National Cancer Institute. The authors reported no relevant financial disclosures.
This article was updated June 5, 2017.
Nearly 155,000 women in the United States are living with metastatic breast cancer (MBC), three-fourths of whom were initially diagnosed with lower-stage disease that progressed to stage IV, based on estimated prevalence data.
The estimates, derived from national breast cancer mortality and survival data, also show positive trends in breast cancer care, especially a doubling of 5-year survival rates among younger women diagnosed with de novo metastatic disease from the 1990s to the 2000s, reported Angela B. Mariotto, PhD, of the National Cancer Institute and her colleagues.
“Despite the progressive and incurable nature of almost all MBC, median survival after diagnosis with metastatic disease has been increasing, resulting in a growing number of women living with MBC in the United States. The increased survival is especially noted for women diagnosed at younger ages,” they wrote in Cancer Epidemiology, Biomarkers, & Prevention (2017 May 18. doi: 10.1158/1055-9965.epi-16-088).
Patients with advanced breast cancer require extensive care and intensive use of medical and other resources, but, until this study, there were no reliable estimates of the number of women actually living with metastatic disease in the United States, the authors said.
To get a clearer picture of the prevalence of advanced breast cancer in the United States, they worked backward from Surveillance, Epidemiology, and End Results data on breast cancer deaths and survival, working on the assumption that each observed breast cancer death is the result of metastatic disease, either in women whose initial diagnosis was stage IV disease (de novo metastatic disease) or disease recurrence with metastases.
They estimated that, in 2013, the most recent year for which there were observed data, the prevalence of metastatic breast cancer was 138,622, and that 38,897 (28%) of survivors were diagnosed with metastatic disease. The remaining 99,725 survivors (72%) were women who were initially diagnosed with stage I-III disease that either recurred or metastasized.
The authors calculated that 50,344 women were diagnosed with de novo metastatic disease in 2013, 12,966 of whom (26%) had de novo metastatic breast cancer and 37,378 of whom had recurrent disease. They projected that, as of Jan. 1, 2017, there are 154,794 women living with metastatic breast cancer in the United States.
They also estimated changes over time in survival and found that, for women diagnosed from the ages of 15 to 49 during the 1992-1994 surveillance period, median survival time was 22.3 months, which improved to 38.7 months during the 2005-2012 surveillance period. The respective survival times for women 50-64 years were 19.1 months and 29.7 months.
For women 15-49 years who were diagnosed with de novo metastatic breast cancer, the 5-year relative survival rates doubled from 18% during 1992-1994 to 36% during 2005-2012.
“Despite a poor prognosis, there is a small but meaningful percentage of these cases who survive 10 years or more. More than 11% of women diagnosed between 2000-2004 under the age of 64 years survived 10 years or more. Younger women diagnosed with de novo MBC have higher survival than women diagnosed at older ages,” Dr. Mariotto and her colleagues wrote.
The investigators pointed to the population size, population-based data, long follow-up, and use of consistent staging definitions over time as study strengths but acknowledged that the study was limited by the absence of population-based estimates of survival following recurrence of metastatic breast cancer.
“To our knowledge, this is the first time that the number of women living with MBC in the United States has been estimated. These estimates provide a new perspective on the population burden of breast cancer and have great potential significance to the research and advocacy community working on behalf of patients with MBC and their families,” the authors wrote.
The study was supported by the National Cancer Institute. The authors reported no relevant financial disclosures.
This article was updated June 5, 2017.
FROM CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION
Key clinical point: An estimated 155,000 women are living with metastatic breast cancer in the United States.
Major finding: Among women diagnosed from ages 15 to 49 with de novo metastatic breast cancer, the 5-year relative survival doubled from 18% during 1992-1994 to 36% during 2005-2012.
Data source: An epidemiologic estimate of metastatic breast cancer prevalence in the United States using SEER data.
Disclosures: The study was supported by the National Cancer Institute. The authors reported no relevant financial disclosures.