Breast Cancer

SAN ANTONIO – Hypertension, dyslipidemia, and type 2 diabetes are common among breast cancer survivors – and so is nonadherence to medications prescribed for these major comorbid conditions.

That was the central finding from COMBO (Commonly Used Medications and Breast Cancer Outcomes), a retrospective cohort study of 4,216 breast cancer survivors belonging to Group Health Cooperative, Gregory S. Calip, Pharm.D., reported at the San Antonio Breast Cancer Symposium.

“This is the first study to investigate breast cancer characteristics and treatments in relation to nonadherence to chronic medications for hypertension, diabetes, and dyslipidemia,” said Dr. Calip of the University of Illinois, Chicago. “Our results suggest that some breast cancer treatments may be associated with nonadherence to antihypertensive agents and oral diabetes medications, but not statins. These findings highlight possible opportunities to improve comorbid condition care in the growing population of breast cancer survivors.”

The irony is that while experiencing breast cancer understandably renders survivors deeply concerned about the prospect of cancer-related death, by not taking their medications for these common comorbid conditions these women increase their overall mortality risk, and particularly their risk of death due to cardiovascular disease and stroke.

The women in the COMBO study had been diagnosed with stage I or II breast cancer during 1990-2008 and did not experience recurrence or a second primary breast cancer during their second year after breast cancer diagnosis. Their medication adherence during that second year was measured via automated health plan pharmacy dispensing records. Patients were classified as nonadherent if their medication possession ratio, or MPR, was less than 0.8.

Antihypertensive agents were prescribed for 1,929 of the subjects, statins for 1,072, and oral diabetes drugs for 449.

During days 366-730 post breast cancer diagnosis, 37% of the women were nonadherent to antihypertensive medications, 39% to prescribed statins, and 75% to their oral diabetes medications.

Common forms of breast cancer therapy were independently associated with increased likelihood of nonadherence in multivariate logistic regression analysis. For example, chemotherapy was associated with a 67% increased likelihood of nonadherence to diabetes medications during year 2 after breast cancer diagnosis. Patients who received radiation therapy or hormonal therapy were, respectively, 21% and 25% more likely to be nonadherent to antihypertensive therapy.

One factor associated with increased likelihood of adherence to medications for comorbid conditions was greater contact with a primary care physician. Breast cancer survivors who saw their primary care physicians two or more times during year 2 post diagnosis were 70% less likely to be nonadherent to antihypertensive therapy than were those who visited their primary care physicians less frequently.

Greater body mass index was associated with significantly less likelihood of nonadherence to antihypertensive agents but not statins or diabetes medications. When researchers used a BMI below 25 kg/m² for reference, patients with a BMI of 25-29.9 were 39% less likely to be nonadherent to antihypertensive therapy, those with a BMI of 30-34.9 kg/m² were 46% less likely, and women with a BMI of 35 kg/m² or greater were 63% less likely to be nonadherent to their antihypertensive therapy.

A higher Charlson comorbidity score of 2 or more during the first year following breast cancer diagnosis was associated with a 51% reduction in likelihood of nonadherence to diabetes medications during year 2 and a 46% lower nonadherence rate for statins than in patients with a Charlson score below 2.

As reported in previous studies of non-cancer patients, younger age was associated with increased nonadherence. This was true across the board for all three medication classes, although the age effect was most dramatic with respect to nonadherence to statins and oral diabetes medications. Fifty- to 54-year-olds were 3.4- and 1.8-fold more likely than were women age 65 or older to be nonadherent to diabetes drugs and statins, respectively, while breast cancer survivors under age 50 were 7.1- and 2.8-fold more likely to be nonadherent to those types of medications.

Discussant Dawn L. Hershman called the COMBO study medication nonadherence rates “pretty awful.” And if breast cancer survivors aren’t taking their medications for chronic comorbid conditions, it’s not much of a leap to think they may not be adherent to their breast cancer–related medications, she said. She urged her fellow breast cancer specialists to think beyond their specialty focus, consider the patient as a whole, and do what they can to promote adherence to medications targeting these potentially serious comorbidities.

“So, what can we do? We can try to engage technology,” said Dr. Hershman, a medical oncologist at Columbia University, New York.

She cited a randomized, controlled trial by other investigators which showed that automated phone calls reminding patients to take their cardiovascular medications had a salutary effect. In addition, she was an investigator in a large study of text messaging as an effective tool for improving adherence to hormonal therapy.

The COMBO study was supported by the National Cancer Institute and the University of Washington, Seattle. Dr. Calip reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Hypertension, dyslipidemia, and type 2 diabetes are common among breast cancer survivors – and so is nonadherence to medications prescribed for these major comorbid conditions.

That was the central finding from COMBO (Commonly Used Medications and Breast Cancer Outcomes), a retrospective cohort study of 4,216 breast cancer survivors belonging to Group Health Cooperative, Gregory S. Calip, Pharm.D., reported at the San Antonio Breast Cancer Symposium.

“This is the first study to investigate breast cancer characteristics and treatments in relation to nonadherence to chronic medications for hypertension, diabetes, and dyslipidemia,” said Dr. Calip of the University of Illinois, Chicago. “Our results suggest that some breast cancer treatments may be associated with nonadherence to antihypertensive agents and oral diabetes medications, but not statins. These findings highlight possible opportunities to improve comorbid condition care in the growing population of breast cancer survivors.”

The irony is that while experiencing breast cancer understandably renders survivors deeply concerned about the prospect of cancer-related death, by not taking their medications for these common comorbid conditions these women increase their overall mortality risk, and particularly their risk of death due to cardiovascular disease and stroke.

The women in the COMBO study had been diagnosed with stage I or II breast cancer during 1990-2008 and did not experience recurrence or a second primary breast cancer during their second year after breast cancer diagnosis. Their medication adherence during that second year was measured via automated health plan pharmacy dispensing records. Patients were classified as nonadherent if their medication possession ratio, or MPR, was less than 0.8.

Antihypertensive agents were prescribed for 1,929 of the subjects, statins for 1,072, and oral diabetes drugs for 449.

During days 366-730 post breast cancer diagnosis, 37% of the women were nonadherent to antihypertensive medications, 39% to prescribed statins, and 75% to their oral diabetes medications.

Common forms of breast cancer therapy were independently associated with increased likelihood of nonadherence in multivariate logistic regression analysis. For example, chemotherapy was associated with a 67% increased likelihood of nonadherence to diabetes medications during year 2 after breast cancer diagnosis. Patients who received radiation therapy or hormonal therapy were, respectively, 21% and 25% more likely to be nonadherent to antihypertensive therapy.

One factor associated with increased likelihood of adherence to medications for comorbid conditions was greater contact with a primary care physician. Breast cancer survivors who saw their primary care physicians two or more times during year 2 post diagnosis were 70% less likely to be nonadherent to antihypertensive therapy than were those who visited their primary care physicians less frequently.

Greater body mass index was associated with significantly less likelihood of nonadherence to antihypertensive agents but not statins or diabetes medications. When researchers used a BMI below 25 kg/m² for reference, patients with a BMI of 25-29.9 were 39% less likely to be nonadherent to antihypertensive therapy, those with a BMI of 30-34.9 kg/m² were 46% less likely, and women with a BMI of 35 kg/m² or greater were 63% less likely to be nonadherent to their antihypertensive therapy.

A higher Charlson comorbidity score of 2 or more during the first year following breast cancer diagnosis was associated with a 51% reduction in likelihood of nonadherence to diabetes medications during year 2 and a 46% lower nonadherence rate for statins than in patients with a Charlson score below 2.

As reported in previous studies of non-cancer patients, younger age was associated with increased nonadherence. This was true across the board for all three medication classes, although the age effect was most dramatic with respect to nonadherence to statins and oral diabetes medications. Fifty- to 54-year-olds were 3.4- and 1.8-fold more likely than were women age 65 or older to be nonadherent to diabetes drugs and statins, respectively, while breast cancer survivors under age 50 were 7.1- and 2.8-fold more likely to be nonadherent to those types of medications.

Discussant Dawn L. Hershman called the COMBO study medication nonadherence rates “pretty awful.” And if breast cancer survivors aren’t taking their medications for chronic comorbid conditions, it’s not much of a leap to think they may not be adherent to their breast cancer–related medications, she said. She urged her fellow breast cancer specialists to think beyond their specialty focus, consider the patient as a whole, and do what they can to promote adherence to medications targeting these potentially serious comorbidities.

“So, what can we do? We can try to engage technology,” said Dr. Hershman, a medical oncologist at Columbia University, New York.

She cited a randomized, controlled trial by other investigators which showed that automated phone calls reminding patients to take their cardiovascular medications had a salutary effect. In addition, she was an investigator in a large study of text messaging as an effective tool for improving adherence to hormonal therapy.

The COMBO study was supported by the National Cancer Institute and the University of Washington, Seattle. Dr. Calip reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Hypertension, dyslipidemia, and type 2 diabetes are common among breast cancer survivors – and so is nonadherence to medications prescribed for these major comorbid conditions.

That was the central finding from COMBO (Commonly Used Medications and Breast Cancer Outcomes), a retrospective cohort study of 4,216 breast cancer survivors belonging to Group Health Cooperative, Gregory S. Calip, Pharm.D., reported at the San Antonio Breast Cancer Symposium.

“This is the first study to investigate breast cancer characteristics and treatments in relation to nonadherence to chronic medications for hypertension, diabetes, and dyslipidemia,” said Dr. Calip of the University of Illinois, Chicago. “Our results suggest that some breast cancer treatments may be associated with nonadherence to antihypertensive agents and oral diabetes medications, but not statins. These findings highlight possible opportunities to improve comorbid condition care in the growing population of breast cancer survivors.”

The irony is that while experiencing breast cancer understandably renders survivors deeply concerned about the prospect of cancer-related death, by not taking their medications for these common comorbid conditions these women increase their overall mortality risk, and particularly their risk of death due to cardiovascular disease and stroke.

The women in the COMBO study had been diagnosed with stage I or II breast cancer during 1990-2008 and did not experience recurrence or a second primary breast cancer during their second year after breast cancer diagnosis. Their medication adherence during that second year was measured via automated health plan pharmacy dispensing records. Patients were classified as nonadherent if their medication possession ratio, or MPR, was less than 0.8.

Antihypertensive agents were prescribed for 1,929 of the subjects, statins for 1,072, and oral diabetes drugs for 449.

During days 366-730 post breast cancer diagnosis, 37% of the women were nonadherent to antihypertensive medications, 39% to prescribed statins, and 75% to their oral diabetes medications.

Common forms of breast cancer therapy were independently associated with increased likelihood of nonadherence in multivariate logistic regression analysis. For example, chemotherapy was associated with a 67% increased likelihood of nonadherence to diabetes medications during year 2 after breast cancer diagnosis. Patients who received radiation therapy or hormonal therapy were, respectively, 21% and 25% more likely to be nonadherent to antihypertensive therapy.

One factor associated with increased likelihood of adherence to medications for comorbid conditions was greater contact with a primary care physician. Breast cancer survivors who saw their primary care physicians two or more times during year 2 post diagnosis were 70% less likely to be nonadherent to antihypertensive therapy than were those who visited their primary care physicians less frequently.

Greater body mass index was associated with significantly less likelihood of nonadherence to antihypertensive agents but not statins or diabetes medications. When researchers used a BMI below 25 kg/m² for reference, patients with a BMI of 25-29.9 were 39% less likely to be nonadherent to antihypertensive therapy, those with a BMI of 30-34.9 kg/m² were 46% less likely, and women with a BMI of 35 kg/m² or greater were 63% less likely to be nonadherent to their antihypertensive therapy.

A higher Charlson comorbidity score of 2 or more during the first year following breast cancer diagnosis was associated with a 51% reduction in likelihood of nonadherence to diabetes medications during year 2 and a 46% lower nonadherence rate for statins than in patients with a Charlson score below 2.

As reported in previous studies of non-cancer patients, younger age was associated with increased nonadherence. This was true across the board for all three medication classes, although the age effect was most dramatic with respect to nonadherence to statins and oral diabetes medications. Fifty- to 54-year-olds were 3.4- and 1.8-fold more likely than were women age 65 or older to be nonadherent to diabetes drugs and statins, respectively, while breast cancer survivors under age 50 were 7.1- and 2.8-fold more likely to be nonadherent to those types of medications.

Discussant Dawn L. Hershman called the COMBO study medication nonadherence rates “pretty awful.” And if breast cancer survivors aren’t taking their medications for chronic comorbid conditions, it’s not much of a leap to think they may not be adherent to their breast cancer–related medications, she said. She urged her fellow breast cancer specialists to think beyond their specialty focus, consider the patient as a whole, and do what they can to promote adherence to medications targeting these potentially serious comorbidities.

“So, what can we do? We can try to engage technology,” said Dr. Hershman, a medical oncologist at Columbia University, New York.

She cited a randomized, controlled trial by other investigators which showed that automated phone calls reminding patients to take their cardiovascular medications had a salutary effect. In addition, she was an investigator in a large study of text messaging as an effective tool for improving adherence to hormonal therapy.

The COMBO study was supported by the National Cancer Institute and the University of Washington, Seattle. Dr. Calip reported having no financial conflicts.

bjancin@frontlinemedcom.com

Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has been approved by the Food and Drug Administration for treating postmenopausal women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer as initial endocrine-based therapy for metastatic disease, in combination with letrozole.

The accelerated approval was based on a randomized phase II study of 165 postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, who had not been treated for advanced disease, in which investigators found a progression-free survival rate of about 20.2 months among the women treated with the combination, compared with about 10.2 months among those treated with letrozole, an aromatase inhibitor, alone. Overall survival results are not yet available, according to the Feb. 3 Food and Drug Administration statement announcing the approval.

“The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer,” Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. Palbociclib was approved under the FDA Accelerated Approval Program, which “allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients,” and makes the drug available to patients earlier while the manufacturer conducts trials to confirm the benefits, according to the FDA. The indications and usage section of the prescribing information includes the statement that “continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”

© 2014 AACR/Todd Buchanan

Neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, lack of energy and asthenia, peripheral neuropathy, and epistaxis were the most common adverse effects associated with treatment, according to the FDA statement.

“Healthcare professionals are advised to monitor complete blood count prior to start of therapy and at the beginning of each cycle, as well as on day 14 of the first two cycles, and as clinically indicated,” the statement said.

The recommended starting dose for palbociclib is 125 mg once a day (with food) for 21 days followed by 7 days off treatment.

Palbociclib inhibits cyclin-dependent kinase (CDK) 4 and 6, involved in promoting the growth of cancer cells. Letrozole (Femara), also taken orally, is approved for treatment of breast cancer in postmenopausal women, as adjuvant treatment for hormone receptor–positive early breast cancer, extended adjuvant treatment of early breast cancer for patients who have received prior standard adjuvant tamoxifen therapy, and as first- and second-line treatment of hormone receptor–positive or unknown advanced breast cancer.

In a statement released by the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, the principal investigator of the study that led to the approval, Dr. Richard S. Finn, pointed out that palbociclib is the first drug in its class to be approved. In the statement, Dr. Dennis J. Slamon, director of the Revlon/UCLA Women’s Cancer Research Program and Clinical/Translational Research at the Jonsson Cancer Center, said that he believes that palbociclib will become “a standard treatment approach for postmenopausal women with ER+/HER2– metastatic breast cancer.” He added that the magnitude of the benefit seen in the phase II study “was very gratifying and reminiscent of results we saw when we conducted the initial studies on Herceptin in HER2+ breast cancers 2 decades ago.”

Dr. Finn reported the of the phase II study at the annual meeting of the American Association for Cancer Research in April. He and Dr. Slamon are investigators in the phase III confirmatory trial of palbociclib in over 600 women, which has completed enrollment, according to the UCLA release.

Pfizer will market palbociclib as Ibrance.

emechcatie@frontlinemedcom.com

Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has been approved by the Food and Drug Administration for treating postmenopausal women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer as initial endocrine-based therapy for metastatic disease, in combination with letrozole.

The accelerated approval was based on a randomized phase II study of 165 postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, who had not been treated for advanced disease, in which investigators found a progression-free survival rate of about 20.2 months among the women treated with the combination, compared with about 10.2 months among those treated with letrozole, an aromatase inhibitor, alone. Overall survival results are not yet available, according to the Feb. 3 Food and Drug Administration statement announcing the approval.

“The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer,” Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. Palbociclib was approved under the FDA Accelerated Approval Program, which “allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients,” and makes the drug available to patients earlier while the manufacturer conducts trials to confirm the benefits, according to the FDA. The indications and usage section of the prescribing information includes the statement that “continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”

© 2014 AACR/Todd Buchanan

Neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, lack of energy and asthenia, peripheral neuropathy, and epistaxis were the most common adverse effects associated with treatment, according to the FDA statement.

“Healthcare professionals are advised to monitor complete blood count prior to start of therapy and at the beginning of each cycle, as well as on day 14 of the first two cycles, and as clinically indicated,” the statement said.

The recommended starting dose for palbociclib is 125 mg once a day (with food) for 21 days followed by 7 days off treatment.

Palbociclib inhibits cyclin-dependent kinase (CDK) 4 and 6, involved in promoting the growth of cancer cells. Letrozole (Femara), also taken orally, is approved for treatment of breast cancer in postmenopausal women, as adjuvant treatment for hormone receptor–positive early breast cancer, extended adjuvant treatment of early breast cancer for patients who have received prior standard adjuvant tamoxifen therapy, and as first- and second-line treatment of hormone receptor–positive or unknown advanced breast cancer.

In a statement released by the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, the principal investigator of the study that led to the approval, Dr. Richard S. Finn, pointed out that palbociclib is the first drug in its class to be approved. In the statement, Dr. Dennis J. Slamon, director of the Revlon/UCLA Women’s Cancer Research Program and Clinical/Translational Research at the Jonsson Cancer Center, said that he believes that palbociclib will become “a standard treatment approach for postmenopausal women with ER+/HER2– metastatic breast cancer.” He added that the magnitude of the benefit seen in the phase II study “was very gratifying and reminiscent of results we saw when we conducted the initial studies on Herceptin in HER2+ breast cancers 2 decades ago.”

Dr. Finn reported the of the phase II study at the annual meeting of the American Association for Cancer Research in April. He and Dr. Slamon are investigators in the phase III confirmatory trial of palbociclib in over 600 women, which has completed enrollment, according to the UCLA release.

Pfizer will market palbociclib as Ibrance.

emechcatie@frontlinemedcom.com

Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has been approved by the Food and Drug Administration for treating postmenopausal women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer as initial endocrine-based therapy for metastatic disease, in combination with letrozole.

The accelerated approval was based on a randomized phase II study of 165 postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, who had not been treated for advanced disease, in which investigators found a progression-free survival rate of about 20.2 months among the women treated with the combination, compared with about 10.2 months among those treated with letrozole, an aromatase inhibitor, alone. Overall survival results are not yet available, according to the Feb. 3 Food and Drug Administration statement announcing the approval.

“The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer,” Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. Palbociclib was approved under the FDA Accelerated Approval Program, which “allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients,” and makes the drug available to patients earlier while the manufacturer conducts trials to confirm the benefits, according to the FDA. The indications and usage section of the prescribing information includes the statement that “continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”

© 2014 AACR/Todd Buchanan

Neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, lack of energy and asthenia, peripheral neuropathy, and epistaxis were the most common adverse effects associated with treatment, according to the FDA statement.

“Healthcare professionals are advised to monitor complete blood count prior to start of therapy and at the beginning of each cycle, as well as on day 14 of the first two cycles, and as clinically indicated,” the statement said.

The recommended starting dose for palbociclib is 125 mg once a day (with food) for 21 days followed by 7 days off treatment.

Palbociclib inhibits cyclin-dependent kinase (CDK) 4 and 6, involved in promoting the growth of cancer cells. Letrozole (Femara), also taken orally, is approved for treatment of breast cancer in postmenopausal women, as adjuvant treatment for hormone receptor–positive early breast cancer, extended adjuvant treatment of early breast cancer for patients who have received prior standard adjuvant tamoxifen therapy, and as first- and second-line treatment of hormone receptor–positive or unknown advanced breast cancer.

In a statement released by the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, the principal investigator of the study that led to the approval, Dr. Richard S. Finn, pointed out that palbociclib is the first drug in its class to be approved. In the statement, Dr. Dennis J. Slamon, director of the Revlon/UCLA Women’s Cancer Research Program and Clinical/Translational Research at the Jonsson Cancer Center, said that he believes that palbociclib will become “a standard treatment approach for postmenopausal women with ER+/HER2– metastatic breast cancer.” He added that the magnitude of the benefit seen in the phase II study “was very gratifying and reminiscent of results we saw when we conducted the initial studies on Herceptin in HER2+ breast cancers 2 decades ago.”

Dr. Finn reported the of the phase II study at the annual meeting of the American Association for Cancer Research in April. He and Dr. Slamon are investigators in the phase III confirmatory trial of palbociclib in over 600 women, which has completed enrollment, according to the UCLA release.

Pfizer will market palbociclib as Ibrance.

emechcatie@frontlinemedcom.com

SAN ANTONIO – Low-level laser therapy proved highly effective in managing chemotherapy-induced oral mucositis in a retrospective study.

Although this was the first study of low-level laser therapy in breast cancer patients, this form of therapy is already widely used to prevent and treat oral mucositis in hematopoietic stem cell transplant recipients as well as in patients with head and neck cancer. These preliminary findings in a breast cancer population warrant confirmation in a randomized controlled trial, Sandrine Censabella, Ph.D., said at the San Antonio Breast Cancer Symposium.

Roughly 40% of patients develop oral mucositis as a consequence of standard-dose chemotherapy. Oral mucositis is the most debilitating, severe, and costly nonhematologic complication of oncologic therapy. It compromises both quality of life and treatment outcomes, said Dr. Censabella of Jessa Hospital in Hasselt, Belgium.

She reported on 93 patients with stage 0-IV breast cancer and chemotherapy-induced oral mucositis who received low-level laser therapy using a gallium arsenide laser at 665-nm wavelength and 100 mW of output power combined with a continuous-emission infrared laser with an output power of 500 mW. The laser energy, 4 J per application point, was delivered via a 600-mcm optical fiber.

The treatment schedule was two sessions per week until lesion healing occurred. Depending on the extent of the oral mucositis, up to seven oral sites could be treated: lips, tongue, palate, inside of the two cheeks, tonsils, and mouth floor.

Outcomes were assessed in a standardized fashion by trained nurses using the World Health Organization 0-4 grading scale, where 0 means unaffected, 1 represents soreness and erythema, 2 means erythema and ulcers but with an ability to eat solid foods, 3 is for patients with ulcers who require a liquid diet only, and 4 is for patients incapable of oral nutritional intake. In addition, investigators calculated an oral mucositis score for every patient by adding up the WHO grades at all affected sites.

Laser therapy began a mean of 49 days after the start of chemotherapy, which was anthracycline based in two-thirds of cases. The mean age of the women was 54.8 years.

Subjects received a mean of 5.7 laser treatment sessions, during which they showed a significant reduction in oral mucositis severity. At baseline, 60% of patients had WHO grade 2 lesions, a rate that dropped to 30% at the end of treatment several weeks later. While only 12% of patients were WHO grade 1 at baseline, 65% were at the conclusion of the laser treatment program. Twenty-eight percent of women were WHO grade 3 at entry, compared with just 5.4% after laser treatment.

The mean baseline combined oral mucositis score averaged 6.6, improving to 2.78 at treatment’s end.

Self-reported pain scores improved from 5.14 at baseline on a 10-point scale to 1.64 at the conclusion of laser therapy.

At the end of laser therapy, only 2% had a worse WHO grade than at baseline, 8.6% had a worse composite oral mucositis score, and no one reported more pain than at entry.

“These findings are the first to document a beneficial effect of low-level laser therapy in a large group of breast cancer patients and suggest that low-level laser therapy might become a standard management for oral mucositis in all cancer patients,” Dr. Censabella said.

She reported having no financial conflicts regarding this study.

bjancin@frontlinemedcom.com

SAN ANTONIO – Low-level laser therapy proved highly effective in managing chemotherapy-induced oral mucositis in a retrospective study.

Although this was the first study of low-level laser therapy in breast cancer patients, this form of therapy is already widely used to prevent and treat oral mucositis in hematopoietic stem cell transplant recipients as well as in patients with head and neck cancer. These preliminary findings in a breast cancer population warrant confirmation in a randomized controlled trial, Sandrine Censabella, Ph.D., said at the San Antonio Breast Cancer Symposium.

Roughly 40% of patients develop oral mucositis as a consequence of standard-dose chemotherapy. Oral mucositis is the most debilitating, severe, and costly nonhematologic complication of oncologic therapy. It compromises both quality of life and treatment outcomes, said Dr. Censabella of Jessa Hospital in Hasselt, Belgium.

She reported on 93 patients with stage 0-IV breast cancer and chemotherapy-induced oral mucositis who received low-level laser therapy using a gallium arsenide laser at 665-nm wavelength and 100 mW of output power combined with a continuous-emission infrared laser with an output power of 500 mW. The laser energy, 4 J per application point, was delivered via a 600-mcm optical fiber.

The treatment schedule was two sessions per week until lesion healing occurred. Depending on the extent of the oral mucositis, up to seven oral sites could be treated: lips, tongue, palate, inside of the two cheeks, tonsils, and mouth floor.

Outcomes were assessed in a standardized fashion by trained nurses using the World Health Organization 0-4 grading scale, where 0 means unaffected, 1 represents soreness and erythema, 2 means erythema and ulcers but with an ability to eat solid foods, 3 is for patients with ulcers who require a liquid diet only, and 4 is for patients incapable of oral nutritional intake. In addition, investigators calculated an oral mucositis score for every patient by adding up the WHO grades at all affected sites.

Laser therapy began a mean of 49 days after the start of chemotherapy, which was anthracycline based in two-thirds of cases. The mean age of the women was 54.8 years.

Subjects received a mean of 5.7 laser treatment sessions, during which they showed a significant reduction in oral mucositis severity. At baseline, 60% of patients had WHO grade 2 lesions, a rate that dropped to 30% at the end of treatment several weeks later. While only 12% of patients were WHO grade 1 at baseline, 65% were at the conclusion of the laser treatment program. Twenty-eight percent of women were WHO grade 3 at entry, compared with just 5.4% after laser treatment.

The mean baseline combined oral mucositis score averaged 6.6, improving to 2.78 at treatment’s end.

Self-reported pain scores improved from 5.14 at baseline on a 10-point scale to 1.64 at the conclusion of laser therapy.

At the end of laser therapy, only 2% had a worse WHO grade than at baseline, 8.6% had a worse composite oral mucositis score, and no one reported more pain than at entry.

“These findings are the first to document a beneficial effect of low-level laser therapy in a large group of breast cancer patients and suggest that low-level laser therapy might become a standard management for oral mucositis in all cancer patients,” Dr. Censabella said.

She reported having no financial conflicts regarding this study.

bjancin@frontlinemedcom.com

SAN ANTONIO – Low-level laser therapy proved highly effective in managing chemotherapy-induced oral mucositis in a retrospective study.

Although this was the first study of low-level laser therapy in breast cancer patients, this form of therapy is already widely used to prevent and treat oral mucositis in hematopoietic stem cell transplant recipients as well as in patients with head and neck cancer. These preliminary findings in a breast cancer population warrant confirmation in a randomized controlled trial, Sandrine Censabella, Ph.D., said at the San Antonio Breast Cancer Symposium.

Roughly 40% of patients develop oral mucositis as a consequence of standard-dose chemotherapy. Oral mucositis is the most debilitating, severe, and costly nonhematologic complication of oncologic therapy. It compromises both quality of life and treatment outcomes, said Dr. Censabella of Jessa Hospital in Hasselt, Belgium.

She reported on 93 patients with stage 0-IV breast cancer and chemotherapy-induced oral mucositis who received low-level laser therapy using a gallium arsenide laser at 665-nm wavelength and 100 mW of output power combined with a continuous-emission infrared laser with an output power of 500 mW. The laser energy, 4 J per application point, was delivered via a 600-mcm optical fiber.

The treatment schedule was two sessions per week until lesion healing occurred. Depending on the extent of the oral mucositis, up to seven oral sites could be treated: lips, tongue, palate, inside of the two cheeks, tonsils, and mouth floor.

Outcomes were assessed in a standardized fashion by trained nurses using the World Health Organization 0-4 grading scale, where 0 means unaffected, 1 represents soreness and erythema, 2 means erythema and ulcers but with an ability to eat solid foods, 3 is for patients with ulcers who require a liquid diet only, and 4 is for patients incapable of oral nutritional intake. In addition, investigators calculated an oral mucositis score for every patient by adding up the WHO grades at all affected sites.

Laser therapy began a mean of 49 days after the start of chemotherapy, which was anthracycline based in two-thirds of cases. The mean age of the women was 54.8 years.

Subjects received a mean of 5.7 laser treatment sessions, during which they showed a significant reduction in oral mucositis severity. At baseline, 60% of patients had WHO grade 2 lesions, a rate that dropped to 30% at the end of treatment several weeks later. While only 12% of patients were WHO grade 1 at baseline, 65% were at the conclusion of the laser treatment program. Twenty-eight percent of women were WHO grade 3 at entry, compared with just 5.4% after laser treatment.

The mean baseline combined oral mucositis score averaged 6.6, improving to 2.78 at treatment’s end.

Self-reported pain scores improved from 5.14 at baseline on a 10-point scale to 1.64 at the conclusion of laser therapy.

At the end of laser therapy, only 2% had a worse WHO grade than at baseline, 8.6% had a worse composite oral mucositis score, and no one reported more pain than at entry.

“These findings are the first to document a beneficial effect of low-level laser therapy in a large group of breast cancer patients and suggest that low-level laser therapy might become a standard management for oral mucositis in all cancer patients,” Dr. Censabella said.

She reported having no financial conflicts regarding this study.

bjancin@frontlinemedcom.com

After neoadjuvant chemotherapy, axial ultrasound helps identify residual nodal disease – information that can guide the decision to pursue lymph node surgery, according to a report published online Feb. 2 in the Journal of Clinical Oncology.

This strategy of performing axial ultrasound to guide axillary surgery can reduce the number of both false-negative and false-positive results, thus improving both the rate of undertreating residual breast cancer and the rate of overtreating lymph nodes that have been cleared of the disease, said Dr. Judy C. Boughey of the Mayo Clinic, Rochester, Minn., and her associates.

They investigated two secondary end points of the American College of Surgeons Oncology Group Z1071 phase II clinical trial, which addressed sentinel lymph node surgery in women with initially node-positive breast cancer. The two end points were whether a normal appearance on ultrasound of sentinel lymph nodes after neoadjuvant chemotherapy denoted a decreased risk of residual cancer and whether an abnormal appearance of sentinel lymph nodes on ultrasound after neoadjuvant chemotherapy denoted an increased risk of residual cancer.

For this analysis of the ACSOG Z1071 data, Dr. Boughey and her associates assessed 611 study participants who initially had node-positive (stage T0-4, N1-2, M0) breast cancer treated at 136 medical centers, had completed neoadjuvant chemotherapy, had undergone axial ultrasound with archiving of the images, and had undergone sentinel lymph node surgery and axial dissection. A total of 70.4% of these patients had lymph nodes classified as normal on ultrasound and 29.6% had suspicious lymph nodes.

A total of 56.5% of patients with normal-appearing lymph nodes on ultrasound proved to have positive nodes on final pathology. In contrast, 71.8% – significantly more – of patients who had suspicious-looking lymph nodes on ultrasound proved to have positive nodes on final pathology (P less than .001). Women with suspicious nodal status on ultrasound also were more likely to have a higher number of positive nodes (34.5% vs 21.0%) and a larger median size of nodal metastases, representing a greater nodal disease burden, than those with normal appearance on ultrasound.

The investigators recommended a strategy in which patients with normal-appearing lymph nodes following adjuvant chemotherapy could undergo sentinel lymph node surgery. “If any of the sentinel lymph nodes were positive, the patient would undergo an axillary lymph node dissection, and if the sentinel lymph nodes were negative, then no further axillary surgery would be needed,” they wrote.

This approach yielded a false-negative rate of just 9.8% when applied to the Z1071 study population, compared with a 12.6% false-negative rate when axial ultrasound was not used to select patients for surgery. Any false-negative rate under 10% was predetermined to be acceptable when the study was designed, Dr. Boughey and her associates said (J. Clin. Oncol. 2015 [doi:10.1200/JCO.2014.57.8401]).

Among patients who had a normal node appearance on ultrasound but positive findings on sentinel lymph node surgery, 63% proved to have no additional positive nodes in the axillary lymph node dissection. “Therefore, in patients with normal axial ultrasound, sentinel lymph node surgery could be used to identify patients who may be able to avoid axillary lymph node dissection. This is being evaluated in the Alliance A11202 trial, which is currently enrolling patients and comparing axillary radiation to axillary dissection for patients with positive sentinel lymph nodes after neoadjuvant chemotherapy,” they added.

The ACOSOG Z1071 trial was supported by National Cancer Institute grants to the American College of Surgeons Oncology Group, the Alliance for Clinical Trials in Oncology, and the Alliance Statistics and Data Center. Dr. Boughey reported having no financial disclosures; one of her associates reported receiving research funding from Galena Biopharma and Antigen Express.

After neoadjuvant chemotherapy, axial ultrasound helps identify residual nodal disease – information that can guide the decision to pursue lymph node surgery, according to a report published online Feb. 2 in the Journal of Clinical Oncology.

This strategy of performing axial ultrasound to guide axillary surgery can reduce the number of both false-negative and false-positive results, thus improving both the rate of undertreating residual breast cancer and the rate of overtreating lymph nodes that have been cleared of the disease, said Dr. Judy C. Boughey of the Mayo Clinic, Rochester, Minn., and her associates.

They investigated two secondary end points of the American College of Surgeons Oncology Group Z1071 phase II clinical trial, which addressed sentinel lymph node surgery in women with initially node-positive breast cancer. The two end points were whether a normal appearance on ultrasound of sentinel lymph nodes after neoadjuvant chemotherapy denoted a decreased risk of residual cancer and whether an abnormal appearance of sentinel lymph nodes on ultrasound after neoadjuvant chemotherapy denoted an increased risk of residual cancer.

For this analysis of the ACSOG Z1071 data, Dr. Boughey and her associates assessed 611 study participants who initially had node-positive (stage T0-4, N1-2, M0) breast cancer treated at 136 medical centers, had completed neoadjuvant chemotherapy, had undergone axial ultrasound with archiving of the images, and had undergone sentinel lymph node surgery and axial dissection. A total of 70.4% of these patients had lymph nodes classified as normal on ultrasound and 29.6% had suspicious lymph nodes.

A total of 56.5% of patients with normal-appearing lymph nodes on ultrasound proved to have positive nodes on final pathology. In contrast, 71.8% – significantly more – of patients who had suspicious-looking lymph nodes on ultrasound proved to have positive nodes on final pathology (P less than .001). Women with suspicious nodal status on ultrasound also were more likely to have a higher number of positive nodes (34.5% vs 21.0%) and a larger median size of nodal metastases, representing a greater nodal disease burden, than those with normal appearance on ultrasound.

The investigators recommended a strategy in which patients with normal-appearing lymph nodes following adjuvant chemotherapy could undergo sentinel lymph node surgery. “If any of the sentinel lymph nodes were positive, the patient would undergo an axillary lymph node dissection, and if the sentinel lymph nodes were negative, then no further axillary surgery would be needed,” they wrote.

This approach yielded a false-negative rate of just 9.8% when applied to the Z1071 study population, compared with a 12.6% false-negative rate when axial ultrasound was not used to select patients for surgery. Any false-negative rate under 10% was predetermined to be acceptable when the study was designed, Dr. Boughey and her associates said (J. Clin. Oncol. 2015 [doi:10.1200/JCO.2014.57.8401]).

Among patients who had a normal node appearance on ultrasound but positive findings on sentinel lymph node surgery, 63% proved to have no additional positive nodes in the axillary lymph node dissection. “Therefore, in patients with normal axial ultrasound, sentinel lymph node surgery could be used to identify patients who may be able to avoid axillary lymph node dissection. This is being evaluated in the Alliance A11202 trial, which is currently enrolling patients and comparing axillary radiation to axillary dissection for patients with positive sentinel lymph nodes after neoadjuvant chemotherapy,” they added.

The ACOSOG Z1071 trial was supported by National Cancer Institute grants to the American College of Surgeons Oncology Group, the Alliance for Clinical Trials in Oncology, and the Alliance Statistics and Data Center. Dr. Boughey reported having no financial disclosures; one of her associates reported receiving research funding from Galena Biopharma and Antigen Express.

After neoadjuvant chemotherapy, axial ultrasound helps identify residual nodal disease – information that can guide the decision to pursue lymph node surgery, according to a report published online Feb. 2 in the Journal of Clinical Oncology.

This strategy of performing axial ultrasound to guide axillary surgery can reduce the number of both false-negative and false-positive results, thus improving both the rate of undertreating residual breast cancer and the rate of overtreating lymph nodes that have been cleared of the disease, said Dr. Judy C. Boughey of the Mayo Clinic, Rochester, Minn., and her associates.

They investigated two secondary end points of the American College of Surgeons Oncology Group Z1071 phase II clinical trial, which addressed sentinel lymph node surgery in women with initially node-positive breast cancer. The two end points were whether a normal appearance on ultrasound of sentinel lymph nodes after neoadjuvant chemotherapy denoted a decreased risk of residual cancer and whether an abnormal appearance of sentinel lymph nodes on ultrasound after neoadjuvant chemotherapy denoted an increased risk of residual cancer.

For this analysis of the ACSOG Z1071 data, Dr. Boughey and her associates assessed 611 study participants who initially had node-positive (stage T0-4, N1-2, M0) breast cancer treated at 136 medical centers, had completed neoadjuvant chemotherapy, had undergone axial ultrasound with archiving of the images, and had undergone sentinel lymph node surgery and axial dissection. A total of 70.4% of these patients had lymph nodes classified as normal on ultrasound and 29.6% had suspicious lymph nodes.

A total of 56.5% of patients with normal-appearing lymph nodes on ultrasound proved to have positive nodes on final pathology. In contrast, 71.8% – significantly more – of patients who had suspicious-looking lymph nodes on ultrasound proved to have positive nodes on final pathology (P less than .001). Women with suspicious nodal status on ultrasound also were more likely to have a higher number of positive nodes (34.5% vs 21.0%) and a larger median size of nodal metastases, representing a greater nodal disease burden, than those with normal appearance on ultrasound.

The investigators recommended a strategy in which patients with normal-appearing lymph nodes following adjuvant chemotherapy could undergo sentinel lymph node surgery. “If any of the sentinel lymph nodes were positive, the patient would undergo an axillary lymph node dissection, and if the sentinel lymph nodes were negative, then no further axillary surgery would be needed,” they wrote.

This approach yielded a false-negative rate of just 9.8% when applied to the Z1071 study population, compared with a 12.6% false-negative rate when axial ultrasound was not used to select patients for surgery. Any false-negative rate under 10% was predetermined to be acceptable when the study was designed, Dr. Boughey and her associates said (J. Clin. Oncol. 2015 [doi:10.1200/JCO.2014.57.8401]).

Among patients who had a normal node appearance on ultrasound but positive findings on sentinel lymph node surgery, 63% proved to have no additional positive nodes in the axillary lymph node dissection. “Therefore, in patients with normal axial ultrasound, sentinel lymph node surgery could be used to identify patients who may be able to avoid axillary lymph node dissection. This is being evaluated in the Alliance A11202 trial, which is currently enrolling patients and comparing axillary radiation to axillary dissection for patients with positive sentinel lymph nodes after neoadjuvant chemotherapy,” they added.

The ACOSOG Z1071 trial was supported by National Cancer Institute grants to the American College of Surgeons Oncology Group, the Alliance for Clinical Trials in Oncology, and the Alliance Statistics and Data Center. Dr. Boughey reported having no financial disclosures; one of her associates reported receiving research funding from Galena Biopharma and Antigen Express.

“THE FDA’S REVIEW OF THE DATA ON OPEN POWER MORCELLATION WAS INADEQUATE”
WILLIAM H. PARKER, MD (AUDIO; NOVEMBER 2014)

Why is traditional open myomectomy acceptable if power morcellation isn’t?
The actions taken by the US Food and Drug Administration (FDA) and medical device companies to limit use of power morcellation have effectively led to a halt in the use of minimally invasive surgery for removal of large uterine fibroids. This would seem to leave open laparotomy as the only viable choice for the conservative removal of these benign tumors in women who choose to retain their uterus for personal, cultural, or childbearing reasons. Or does it?

Any open myomectomy of an intramural or subserosal myoma involves an incision into the uterine serosa and muscularis, thus exposing the surface of the tumor to the peritoneal environment. The mass is then grasped with penetrating instruments and manipulated free of its myometrial attachments with other instruments such as forceps, scissors, and electrocautery devices. Suction instruments are freely employed over the operative field. The gloved digits of the surgeon are frequently used to bluntly dissect the tumor from the surrounding myometrial bed.

Because of the desire to maximize future fertility potential by minimizing adhesions, frequent irrigation is considered by most reproductive surgeons to be a necessary part of good surgical technique. Irrigation hydrates the tissues and carries away blood, but it can be counted on to disperse countless cells from the exposed surface of the tumor. After resection, the tumor is removed from the operative field and handed off, usually to the gloved hand of an assistant who will be handling all of the tools that are used from that point forward. If an abscess is a “dirty case” from the standpoint of the spread of infection, then any myomectomy is a potentially “dirty case” from the standpoint of the spread of neoplasia. Given the fundamental nature of this procedure, there seems to be no way to do a “clean” myomectomy. 

Since any form of myomectomy involves at least as much manipulation of the tumor mass as morcellation, it should be at least as likely as morcellation to spread aberrant cells. An inadvertent exposure of the unprotected surface of a leiomyosarcoma at the time of a traditional open myomectomy is not different in any essential way from the exposure of the surface of the same tumor at the time of a myomectomy followed by any type of morcellation. 

It is logical then that if morcellation can be proscribed by regulation and litigation, myomectomy itself will be proscribed on the exact same lines of reasoning.

Despite the widespread use of either abdominal or minimally invasive myomectomy over the last 75 years, disseminated uterine leiomyosarcoma is now and always has been a rare disease. This fact has always been accounted for in our risk assessments of leiomyoma surgeries. In addition, there is no scientific evidence that power morcellation, nonpowered morcellation, or abdominal myomectomy without morcellation has ever been causative in the spread of even one patient’s leiomyosarcoma. Leiomyosarcoma is by definition capable of disseminating by itself.

No medical authority would recommend total hysterectomy for every patient with any myoma, based on the possibility that any individual patient might be harboring a uterine cancer that can spread. This is, however, the exact evolutionary endpoint of the reasoning of the FDA and our legal system. The device companies are to be the deep pockets of the morcellation lawsuits and physicians will be the deep pockets of future myomectomy lawsuits. Gynecologists have always considered risk/reward factors in decisions regarding myomectomy and morcellation. We have an obligation to defend the reproductive rights of our patients. Lawyers, regulators, and even the corporations that dominate the medical device market are motivated by other concerns.

The practice of modern medicine aggressively challenges clinical decision-making based solely on anecdotal evidence. It has done so for well over a century now. It is one of the few standards that still unites good doctors under the battered and tattered umbrella of our professionalism. Our challenge as modern physicians is to stand fast against our new regulatory masters (as well as their former and future law partners) with their grave misunderstandings of the very character of gynecologic decision-making.
Michael C. Doody, MD, PhD
Knoxville, Tennessee
 

“THE EXTRACORPOREAL C-INCISION TISSUE EXTRACTION (EXCITE) TECHNIQUE”
MIREILLE D. TRUONG, MD, AND ARNOLD P. ADVINCULA, MD (VIDEO; NOVEMBER 2014)

Awesome video!
I tried this technique as outlined in the video—totally awesome! It worked really well! Thanks to the surgeons who came up with it!
Ravindhra Mamilla, MD
Thief River Falls, Minnesota
 

“HOW USEFUL IS RANDOM BIOPSY WHEN NO COLPOSCOPIC LESIONS ARE SEEN?”
ANDREW M. KAUNITZ, MD (EXAMINING THE EVIDENCE; OCTOBER 2014)

Additional clarification would be appreciated
According to Dr. Kaunitz’s summary of the findings of Huh and colleagues,¹ the population group included women with low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL) (ie, anything above atypical cells of undetermined significance [ASCUS]), along with women who tested positive for human papillomavirus (HPV) 16/18, regardless of cytology.

It would have been useful to have the LSIL and HSIL populations (independent or dependent of HPV status) broken down into subgroups.

The expert commentary does not indicate whether the 2.7% of biopsy-proven cervical ­intraepithelial neoplasia (CIN) 2 and CIN 3 were predominantly confined to women with HSIL or equally prevalent in the LSIL population.

Without this information, I am not convinced that LSIL requires a random biopsy when colposcopy is adequate and normal, regardless of HPV status.
Jonathan Kew
Maitland, New South Wales, Australia

Reference
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

Are we reverting to past practices?
For someone who has done colposcopy for about 35 years, I find the conclusions of Huh and colleagues nonsensical. If the squamocolumnar junction is visible and an endocervical curettage is done, this is adequate. Performing random biopsies takes us back to the days before we had the colposcope. I was there, and I’m not proud of how we handled abnormal Pap results.

Another issue: If you find severe dysplasia on random biopsy in a 40-year-old woman, how and what do you treat? Is this a case of treating the lab and not the patient? Or is this a case of inadequately trained gynecologists and/or pathologists?
Anton Strocel, MD
Grand Blanc, Michigan
 

Dr. Kaunitz responds
I thank Dr. Kew and Dr. Strocel for their interest in this commentary on the value of random biopsies during colposcopy when lesions are not visualized. Dr. Kew is correct that the authors did not separate findings in women with low-grade versus high-grade intraepithelial cytology. Dr. Strocel refers to the value of ­clinical experience when performing colposcopy. Both the current article by Huh and colleagues,¹ as well an earlier high-quality report by Gage and colleagues,² point out that, even in skilled hands, colposcopy is not as sensitive in detecting CIN as we have believed in the past. These reports present convincing evidence that, regardless of clinical experience, when no lesion is seen at the time of colposcopy, performing one or two random biopsies substantially increases diagnostic yield of clinically actionable (CIN 2 or worse) disease. 

References
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

2. Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108(2):264–272.
 

“CONJUGATED ESTROGEN PLUS BAZEDOXIFENE—A NEW APPROACH TO ESTROGEN THERAPY”
ANNE A. MOORE, DNP, APN (CASES IN MENOPAUSE; OCTOBER 2014)

Why not encourage soy intake?
Thanks for an interesting discussion on conjugated estrogen/bazedoxifene (CE/BZA; Duavee). I note that:

• CE/BZA is manufactured by Pfizer
• Dr. JoAnn Pinkerton, who is interviewed by Anne Moore, DNP, APN, is affiliated with Pfizer, and
• CE/BZA costs $120 per month.

Since menopausal symptoms are caused by the decreased production of ovarian estradiol, why not prescribe estradiol 0.5–1 mg, which costs only $4 monthly?

Another point to consider: Over several decades of providing care to ethnically diverse women, my observation is that Japanese/Korean and Latina women report far fewer hot flushes than their white sisters.

I believe that it is because of their soy and yam intake. I personally eat about 0.25 lb of tofu per week. It can be diced for salad or soup or served with soy sauce, ginger, and bonito (fish) flakes. It can also be crushed and mixed with lean ground beef, pork, chicken, or turkey to make lean, healthy meatloaf.

Tofu is rich in phytoestrogens, lowers cholesterol, and promotes local soy farmers—a win-win situation.
Yasuo Ishida, MD
St. Louis, Missouri
 

‡‡Dr. Barbieri responds
Dr. Ishida raises an important issue of managing conflicts of interest in medical publications. Dr. Ishida notes that, in the past, Dr. Pinkerton was supported by Pfizer, the company that manufactures (CE/BZA, Duavee). Dr. Ishida also points out that, in a recent OBG Management article, Dr. Pinkerton provided her clinical perspective on the use of CE/BZA in practice.

Often, with a new medication, the physicians with the most expertise in using it have helped with key clinical trials. The results of these trials provide the basis for FDA approval of the medication. Prior to FDA approval of a drug, only experts involved in the clinical trial have first-hand experience with the new treatment.

Dr. Pinkerton is an internationally respected expert in the field and provided a balanced overview of CE/BZA and how it might be used in practice. Dr. Pinkerton disclosed that she personally receives no current support from Pfizer, but that she was supported by Pfizer years ago.

This potential conflict of interest was reported in the article.

Dr. Pinkerton responds
I am proud to serve as a key researcher, consultant, and writer for publications exploring the newest hormonal option for menopausal women—CE/BZA. All of my contracting and fees for my research and consulting with Pfizer have been paid through the University of Virginia, not to me personally. This allows me to be involved in innovative women’s health research and disseminate results without the same conflicts as those who receive reimbursements directly from Pfizer. My relationship to any pharmaceutical company with which I am involved is always through my university and disclosed on every paper, presentation, and talk that I give.

The best way to learn about the pros and cons of a product is to be involved in the sentinel research, to have access to all data, including adverse effects, and to be able to evaluate who might be the best candidates for a new product in women’s health.

Although oral estradiol is inexpensive, women with a uterus also need a progestogen to protect against uterine cancer. It appears that the combination of estrogen and synthetic progestins carry a greater risk of breast cancer than estrogen alone. Estradiol is also available as a patch, gel, lotion, and ring but, again, needs to be paired with a progestogen if a woman has a uterus.

This new drug is well established in published randomized clinical trial data as an effective alternative to traditional estrogen-progestogen therapy (EPT) in symptomatic postmenopausal women with a uterus. Results from Selective Estrogens, Menopause, and Response to Therapy (SMART)¹ randomized controlled trials (RCTs) have shown improvements in symptoms similar to those seen with EPT. These include a reduction in hot flash frequency and severity; a reduction in night sweats, with fewer sleep disruptions; and bone loss prevention. The effects on total cholesterol (an increase in triglycerides) and the drug’s mild effect on vulvovaginal atrophy (VVA) also are similar to those observed with EPT. The drug has a neutral effect on breast tenderness, breast density, and the risk of breast cancer.^1,2 It also protects against endometrial hyperplasia and cancer and increases amenorrhea rates. VTE and stroke risks are expected to be similar to traditional oral hormone therapy (HT). The major benefit of CE/BZA, compared with traditional EPT, is the lack of significant breast tenderness and changes in breast density or vaginal bleeding often seen with traditional EPT.³ 

As for the benefits of soy for menopausal women, clinical data imply that phytoestrogens and soy foods may be of benefit for postmenopausal women. According to a recent review article by Messina⁴ (an international authority on phytoestrogens), isoflavone supplements relieve menopausal hot flashes if they have enough of the isoflavone genistein. Soy has shown benefits with regard to ischemic heart disease—by lowering low-density lipoprotein (LDL) levels and providing a source of omega fatty acids. However, no clear effect has been seen with soy for the prevention of bone loss. The effect on breast cancer risk is unclear. Soy binds to estrogen receptors, which could be harmful. However, soy may bind preferentially to estrogen-receptor beta, thus acting more SERM-like or protective, particularly if given during childhood or adolescence.

For any woman, the decision about using a food source, such as tofu, or isoflavone-rich supplements, such as one containing equol, should be based on a discussion with her clinician regarding her individual needs and the risks and benefits of all options.

In our Midlife Clinic at University of Virginia, we discuss over-the-counter products, lifestyle and dietary changes, and nonhormonal and hormonal options with our patients to help them identify the best choices.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

“THE FDA’S REVIEW OF THE DATA ON OPEN POWER MORCELLATION WAS INADEQUATE”
WILLIAM H. PARKER, MD (AUDIO; NOVEMBER 2014)

Why is traditional open myomectomy acceptable if power morcellation isn’t?
The actions taken by the US Food and Drug Administration (FDA) and medical device companies to limit use of power morcellation have effectively led to a halt in the use of minimally invasive surgery for removal of large uterine fibroids. This would seem to leave open laparotomy as the only viable choice for the conservative removal of these benign tumors in women who choose to retain their uterus for personal, cultural, or childbearing reasons. Or does it?

Any open myomectomy of an intramural or subserosal myoma involves an incision into the uterine serosa and muscularis, thus exposing the surface of the tumor to the peritoneal environment. The mass is then grasped with penetrating instruments and manipulated free of its myometrial attachments with other instruments such as forceps, scissors, and electrocautery devices. Suction instruments are freely employed over the operative field. The gloved digits of the surgeon are frequently used to bluntly dissect the tumor from the surrounding myometrial bed.

Because of the desire to maximize future fertility potential by minimizing adhesions, frequent irrigation is considered by most reproductive surgeons to be a necessary part of good surgical technique. Irrigation hydrates the tissues and carries away blood, but it can be counted on to disperse countless cells from the exposed surface of the tumor. After resection, the tumor is removed from the operative field and handed off, usually to the gloved hand of an assistant who will be handling all of the tools that are used from that point forward. If an abscess is a “dirty case” from the standpoint of the spread of infection, then any myomectomy is a potentially “dirty case” from the standpoint of the spread of neoplasia. Given the fundamental nature of this procedure, there seems to be no way to do a “clean” myomectomy. 

Since any form of myomectomy involves at least as much manipulation of the tumor mass as morcellation, it should be at least as likely as morcellation to spread aberrant cells. An inadvertent exposure of the unprotected surface of a leiomyosarcoma at the time of a traditional open myomectomy is not different in any essential way from the exposure of the surface of the same tumor at the time of a myomectomy followed by any type of morcellation. 

It is logical then that if morcellation can be proscribed by regulation and litigation, myomectomy itself will be proscribed on the exact same lines of reasoning.

Despite the widespread use of either abdominal or minimally invasive myomectomy over the last 75 years, disseminated uterine leiomyosarcoma is now and always has been a rare disease. This fact has always been accounted for in our risk assessments of leiomyoma surgeries. In addition, there is no scientific evidence that power morcellation, nonpowered morcellation, or abdominal myomectomy without morcellation has ever been causative in the spread of even one patient’s leiomyosarcoma. Leiomyosarcoma is by definition capable of disseminating by itself.

No medical authority would recommend total hysterectomy for every patient with any myoma, based on the possibility that any individual patient might be harboring a uterine cancer that can spread. This is, however, the exact evolutionary endpoint of the reasoning of the FDA and our legal system. The device companies are to be the deep pockets of the morcellation lawsuits and physicians will be the deep pockets of future myomectomy lawsuits. Gynecologists have always considered risk/reward factors in decisions regarding myomectomy and morcellation. We have an obligation to defend the reproductive rights of our patients. Lawyers, regulators, and even the corporations that dominate the medical device market are motivated by other concerns.

The practice of modern medicine aggressively challenges clinical decision-making based solely on anecdotal evidence. It has done so for well over a century now. It is one of the few standards that still unites good doctors under the battered and tattered umbrella of our professionalism. Our challenge as modern physicians is to stand fast against our new regulatory masters (as well as their former and future law partners) with their grave misunderstandings of the very character of gynecologic decision-making.
Michael C. Doody, MD, PhD
Knoxville, Tennessee
 

“THE EXTRACORPOREAL C-INCISION TISSUE EXTRACTION (EXCITE) TECHNIQUE”
MIREILLE D. TRUONG, MD, AND ARNOLD P. ADVINCULA, MD (VIDEO; NOVEMBER 2014)

Awesome video!
I tried this technique as outlined in the video—totally awesome! It worked really well! Thanks to the surgeons who came up with it!
Ravindhra Mamilla, MD
Thief River Falls, Minnesota
 

“HOW USEFUL IS RANDOM BIOPSY WHEN NO COLPOSCOPIC LESIONS ARE SEEN?”
ANDREW M. KAUNITZ, MD (EXAMINING THE EVIDENCE; OCTOBER 2014)

Additional clarification would be appreciated
According to Dr. Kaunitz’s summary of the findings of Huh and colleagues,¹ the population group included women with low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL) (ie, anything above atypical cells of undetermined significance [ASCUS]), along with women who tested positive for human papillomavirus (HPV) 16/18, regardless of cytology.

It would have been useful to have the LSIL and HSIL populations (independent or dependent of HPV status) broken down into subgroups.

The expert commentary does not indicate whether the 2.7% of biopsy-proven cervical ­intraepithelial neoplasia (CIN) 2 and CIN 3 were predominantly confined to women with HSIL or equally prevalent in the LSIL population.

Without this information, I am not convinced that LSIL requires a random biopsy when colposcopy is adequate and normal, regardless of HPV status.
Jonathan Kew
Maitland, New South Wales, Australia

Reference
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

Are we reverting to past practices?
For someone who has done colposcopy for about 35 years, I find the conclusions of Huh and colleagues nonsensical. If the squamocolumnar junction is visible and an endocervical curettage is done, this is adequate. Performing random biopsies takes us back to the days before we had the colposcope. I was there, and I’m not proud of how we handled abnormal Pap results.

Another issue: If you find severe dysplasia on random biopsy in a 40-year-old woman, how and what do you treat? Is this a case of treating the lab and not the patient? Or is this a case of inadequately trained gynecologists and/or pathologists?
Anton Strocel, MD
Grand Blanc, Michigan
 

Dr. Kaunitz responds
I thank Dr. Kew and Dr. Strocel for their interest in this commentary on the value of random biopsies during colposcopy when lesions are not visualized. Dr. Kew is correct that the authors did not separate findings in women with low-grade versus high-grade intraepithelial cytology. Dr. Strocel refers to the value of ­clinical experience when performing colposcopy. Both the current article by Huh and colleagues,¹ as well an earlier high-quality report by Gage and colleagues,² point out that, even in skilled hands, colposcopy is not as sensitive in detecting CIN as we have believed in the past. These reports present convincing evidence that, regardless of clinical experience, when no lesion is seen at the time of colposcopy, performing one or two random biopsies substantially increases diagnostic yield of clinically actionable (CIN 2 or worse) disease. 

References
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

2. Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108(2):264–272.
 

“CONJUGATED ESTROGEN PLUS BAZEDOXIFENE—A NEW APPROACH TO ESTROGEN THERAPY”
ANNE A. MOORE, DNP, APN (CASES IN MENOPAUSE; OCTOBER 2014)

Why not encourage soy intake?
Thanks for an interesting discussion on conjugated estrogen/bazedoxifene (CE/BZA; Duavee). I note that:

• CE/BZA is manufactured by Pfizer
• Dr. JoAnn Pinkerton, who is interviewed by Anne Moore, DNP, APN, is affiliated with Pfizer, and
• CE/BZA costs $120 per month.

Since menopausal symptoms are caused by the decreased production of ovarian estradiol, why not prescribe estradiol 0.5–1 mg, which costs only $4 monthly?

Another point to consider: Over several decades of providing care to ethnically diverse women, my observation is that Japanese/Korean and Latina women report far fewer hot flushes than their white sisters.

I believe that it is because of their soy and yam intake. I personally eat about 0.25 lb of tofu per week. It can be diced for salad or soup or served with soy sauce, ginger, and bonito (fish) flakes. It can also be crushed and mixed with lean ground beef, pork, chicken, or turkey to make lean, healthy meatloaf.

Tofu is rich in phytoestrogens, lowers cholesterol, and promotes local soy farmers—a win-win situation.
Yasuo Ishida, MD
St. Louis, Missouri
 

‡‡Dr. Barbieri responds
Dr. Ishida raises an important issue of managing conflicts of interest in medical publications. Dr. Ishida notes that, in the past, Dr. Pinkerton was supported by Pfizer, the company that manufactures (CE/BZA, Duavee). Dr. Ishida also points out that, in a recent OBG Management article, Dr. Pinkerton provided her clinical perspective on the use of CE/BZA in practice.

Often, with a new medication, the physicians with the most expertise in using it have helped with key clinical trials. The results of these trials provide the basis for FDA approval of the medication. Prior to FDA approval of a drug, only experts involved in the clinical trial have first-hand experience with the new treatment.

Dr. Pinkerton is an internationally respected expert in the field and provided a balanced overview of CE/BZA and how it might be used in practice. Dr. Pinkerton disclosed that she personally receives no current support from Pfizer, but that she was supported by Pfizer years ago.

This potential conflict of interest was reported in the article.

Dr. Pinkerton responds
I am proud to serve as a key researcher, consultant, and writer for publications exploring the newest hormonal option for menopausal women—CE/BZA. All of my contracting and fees for my research and consulting with Pfizer have been paid through the University of Virginia, not to me personally. This allows me to be involved in innovative women’s health research and disseminate results without the same conflicts as those who receive reimbursements directly from Pfizer. My relationship to any pharmaceutical company with which I am involved is always through my university and disclosed on every paper, presentation, and talk that I give.

The best way to learn about the pros and cons of a product is to be involved in the sentinel research, to have access to all data, including adverse effects, and to be able to evaluate who might be the best candidates for a new product in women’s health.

Although oral estradiol is inexpensive, women with a uterus also need a progestogen to protect against uterine cancer. It appears that the combination of estrogen and synthetic progestins carry a greater risk of breast cancer than estrogen alone. Estradiol is also available as a patch, gel, lotion, and ring but, again, needs to be paired with a progestogen if a woman has a uterus.

This new drug is well established in published randomized clinical trial data as an effective alternative to traditional estrogen-progestogen therapy (EPT) in symptomatic postmenopausal women with a uterus. Results from Selective Estrogens, Menopause, and Response to Therapy (SMART)¹ randomized controlled trials (RCTs) have shown improvements in symptoms similar to those seen with EPT. These include a reduction in hot flash frequency and severity; a reduction in night sweats, with fewer sleep disruptions; and bone loss prevention. The effects on total cholesterol (an increase in triglycerides) and the drug’s mild effect on vulvovaginal atrophy (VVA) also are similar to those observed with EPT. The drug has a neutral effect on breast tenderness, breast density, and the risk of breast cancer.^1,2 It also protects against endometrial hyperplasia and cancer and increases amenorrhea rates. VTE and stroke risks are expected to be similar to traditional oral hormone therapy (HT). The major benefit of CE/BZA, compared with traditional EPT, is the lack of significant breast tenderness and changes in breast density or vaginal bleeding often seen with traditional EPT.³ 

As for the benefits of soy for menopausal women, clinical data imply that phytoestrogens and soy foods may be of benefit for postmenopausal women. According to a recent review article by Messina⁴ (an international authority on phytoestrogens), isoflavone supplements relieve menopausal hot flashes if they have enough of the isoflavone genistein. Soy has shown benefits with regard to ischemic heart disease—by lowering low-density lipoprotein (LDL) levels and providing a source of omega fatty acids. However, no clear effect has been seen with soy for the prevention of bone loss. The effect on breast cancer risk is unclear. Soy binds to estrogen receptors, which could be harmful. However, soy may bind preferentially to estrogen-receptor beta, thus acting more SERM-like or protective, particularly if given during childhood or adolescence.

For any woman, the decision about using a food source, such as tofu, or isoflavone-rich supplements, such as one containing equol, should be based on a discussion with her clinician regarding her individual needs and the risks and benefits of all options.

In our Midlife Clinic at University of Virginia, we discuss over-the-counter products, lifestyle and dietary changes, and nonhormonal and hormonal options with our patients to help them identify the best choices.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

“THE FDA’S REVIEW OF THE DATA ON OPEN POWER MORCELLATION WAS INADEQUATE”
WILLIAM H. PARKER, MD (AUDIO; NOVEMBER 2014)

Why is traditional open myomectomy acceptable if power morcellation isn’t?
The actions taken by the US Food and Drug Administration (FDA) and medical device companies to limit use of power morcellation have effectively led to a halt in the use of minimally invasive surgery for removal of large uterine fibroids. This would seem to leave open laparotomy as the only viable choice for the conservative removal of these benign tumors in women who choose to retain their uterus for personal, cultural, or childbearing reasons. Or does it?

Any open myomectomy of an intramural or subserosal myoma involves an incision into the uterine serosa and muscularis, thus exposing the surface of the tumor to the peritoneal environment. The mass is then grasped with penetrating instruments and manipulated free of its myometrial attachments with other instruments such as forceps, scissors, and electrocautery devices. Suction instruments are freely employed over the operative field. The gloved digits of the surgeon are frequently used to bluntly dissect the tumor from the surrounding myometrial bed.

Because of the desire to maximize future fertility potential by minimizing adhesions, frequent irrigation is considered by most reproductive surgeons to be a necessary part of good surgical technique. Irrigation hydrates the tissues and carries away blood, but it can be counted on to disperse countless cells from the exposed surface of the tumor. After resection, the tumor is removed from the operative field and handed off, usually to the gloved hand of an assistant who will be handling all of the tools that are used from that point forward. If an abscess is a “dirty case” from the standpoint of the spread of infection, then any myomectomy is a potentially “dirty case” from the standpoint of the spread of neoplasia. Given the fundamental nature of this procedure, there seems to be no way to do a “clean” myomectomy. 

Since any form of myomectomy involves at least as much manipulation of the tumor mass as morcellation, it should be at least as likely as morcellation to spread aberrant cells. An inadvertent exposure of the unprotected surface of a leiomyosarcoma at the time of a traditional open myomectomy is not different in any essential way from the exposure of the surface of the same tumor at the time of a myomectomy followed by any type of morcellation. 

It is logical then that if morcellation can be proscribed by regulation and litigation, myomectomy itself will be proscribed on the exact same lines of reasoning.

Despite the widespread use of either abdominal or minimally invasive myomectomy over the last 75 years, disseminated uterine leiomyosarcoma is now and always has been a rare disease. This fact has always been accounted for in our risk assessments of leiomyoma surgeries. In addition, there is no scientific evidence that power morcellation, nonpowered morcellation, or abdominal myomectomy without morcellation has ever been causative in the spread of even one patient’s leiomyosarcoma. Leiomyosarcoma is by definition capable of disseminating by itself.

No medical authority would recommend total hysterectomy for every patient with any myoma, based on the possibility that any individual patient might be harboring a uterine cancer that can spread. This is, however, the exact evolutionary endpoint of the reasoning of the FDA and our legal system. The device companies are to be the deep pockets of the morcellation lawsuits and physicians will be the deep pockets of future myomectomy lawsuits. Gynecologists have always considered risk/reward factors in decisions regarding myomectomy and morcellation. We have an obligation to defend the reproductive rights of our patients. Lawyers, regulators, and even the corporations that dominate the medical device market are motivated by other concerns.

The practice of modern medicine aggressively challenges clinical decision-making based solely on anecdotal evidence. It has done so for well over a century now. It is one of the few standards that still unites good doctors under the battered and tattered umbrella of our professionalism. Our challenge as modern physicians is to stand fast against our new regulatory masters (as well as their former and future law partners) with their grave misunderstandings of the very character of gynecologic decision-making.
Michael C. Doody, MD, PhD
Knoxville, Tennessee
 

“THE EXTRACORPOREAL C-INCISION TISSUE EXTRACTION (EXCITE) TECHNIQUE”
MIREILLE D. TRUONG, MD, AND ARNOLD P. ADVINCULA, MD (VIDEO; NOVEMBER 2014)

Awesome video!
I tried this technique as outlined in the video—totally awesome! It worked really well! Thanks to the surgeons who came up with it!
Ravindhra Mamilla, MD
Thief River Falls, Minnesota
 

“HOW USEFUL IS RANDOM BIOPSY WHEN NO COLPOSCOPIC LESIONS ARE SEEN?”
ANDREW M. KAUNITZ, MD (EXAMINING THE EVIDENCE; OCTOBER 2014)

Additional clarification would be appreciated
According to Dr. Kaunitz’s summary of the findings of Huh and colleagues,¹ the population group included women with low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL) (ie, anything above atypical cells of undetermined significance [ASCUS]), along with women who tested positive for human papillomavirus (HPV) 16/18, regardless of cytology.

It would have been useful to have the LSIL and HSIL populations (independent or dependent of HPV status) broken down into subgroups.

The expert commentary does not indicate whether the 2.7% of biopsy-proven cervical ­intraepithelial neoplasia (CIN) 2 and CIN 3 were predominantly confined to women with HSIL or equally prevalent in the LSIL population.

Without this information, I am not convinced that LSIL requires a random biopsy when colposcopy is adequate and normal, regardless of HPV status.
Jonathan Kew
Maitland, New South Wales, Australia

Reference
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

Are we reverting to past practices?
For someone who has done colposcopy for about 35 years, I find the conclusions of Huh and colleagues nonsensical. If the squamocolumnar junction is visible and an endocervical curettage is done, this is adequate. Performing random biopsies takes us back to the days before we had the colposcope. I was there, and I’m not proud of how we handled abnormal Pap results.

Another issue: If you find severe dysplasia on random biopsy in a 40-year-old woman, how and what do you treat? Is this a case of treating the lab and not the patient? Or is this a case of inadequately trained gynecologists and/or pathologists?
Anton Strocel, MD
Grand Blanc, Michigan
 

Dr. Kaunitz responds
I thank Dr. Kew and Dr. Strocel for their interest in this commentary on the value of random biopsies during colposcopy when lesions are not visualized. Dr. Kew is correct that the authors did not separate findings in women with low-grade versus high-grade intraepithelial cytology. Dr. Strocel refers to the value of ­clinical experience when performing colposcopy. Both the current article by Huh and colleagues,¹ as well an earlier high-quality report by Gage and colleagues,² point out that, even in skilled hands, colposcopy is not as sensitive in detecting CIN as we have believed in the past. These reports present convincing evidence that, regardless of clinical experience, when no lesion is seen at the time of colposcopy, performing one or two random biopsies substantially increases diagnostic yield of clinically actionable (CIN 2 or worse) disease. 

References
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

2. Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108(2):264–272.
 

“CONJUGATED ESTROGEN PLUS BAZEDOXIFENE—A NEW APPROACH TO ESTROGEN THERAPY”
ANNE A. MOORE, DNP, APN (CASES IN MENOPAUSE; OCTOBER 2014)

Why not encourage soy intake?
Thanks for an interesting discussion on conjugated estrogen/bazedoxifene (CE/BZA; Duavee). I note that:

• CE/BZA is manufactured by Pfizer
• Dr. JoAnn Pinkerton, who is interviewed by Anne Moore, DNP, APN, is affiliated with Pfizer, and
• CE/BZA costs $120 per month.

Since menopausal symptoms are caused by the decreased production of ovarian estradiol, why not prescribe estradiol 0.5–1 mg, which costs only $4 monthly?

Another point to consider: Over several decades of providing care to ethnically diverse women, my observation is that Japanese/Korean and Latina women report far fewer hot flushes than their white sisters.

I believe that it is because of their soy and yam intake. I personally eat about 0.25 lb of tofu per week. It can be diced for salad or soup or served with soy sauce, ginger, and bonito (fish) flakes. It can also be crushed and mixed with lean ground beef, pork, chicken, or turkey to make lean, healthy meatloaf.

Tofu is rich in phytoestrogens, lowers cholesterol, and promotes local soy farmers—a win-win situation.
Yasuo Ishida, MD
St. Louis, Missouri
 

‡‡Dr. Barbieri responds
Dr. Ishida raises an important issue of managing conflicts of interest in medical publications. Dr. Ishida notes that, in the past, Dr. Pinkerton was supported by Pfizer, the company that manufactures (CE/BZA, Duavee). Dr. Ishida also points out that, in a recent OBG Management article, Dr. Pinkerton provided her clinical perspective on the use of CE/BZA in practice.

Often, with a new medication, the physicians with the most expertise in using it have helped with key clinical trials. The results of these trials provide the basis for FDA approval of the medication. Prior to FDA approval of a drug, only experts involved in the clinical trial have first-hand experience with the new treatment.

Dr. Pinkerton is an internationally respected expert in the field and provided a balanced overview of CE/BZA and how it might be used in practice. Dr. Pinkerton disclosed that she personally receives no current support from Pfizer, but that she was supported by Pfizer years ago.

This potential conflict of interest was reported in the article.

Dr. Pinkerton responds
I am proud to serve as a key researcher, consultant, and writer for publications exploring the newest hormonal option for menopausal women—CE/BZA. All of my contracting and fees for my research and consulting with Pfizer have been paid through the University of Virginia, not to me personally. This allows me to be involved in innovative women’s health research and disseminate results without the same conflicts as those who receive reimbursements directly from Pfizer. My relationship to any pharmaceutical company with which I am involved is always through my university and disclosed on every paper, presentation, and talk that I give.

The best way to learn about the pros and cons of a product is to be involved in the sentinel research, to have access to all data, including adverse effects, and to be able to evaluate who might be the best candidates for a new product in women’s health.

Although oral estradiol is inexpensive, women with a uterus also need a progestogen to protect against uterine cancer. It appears that the combination of estrogen and synthetic progestins carry a greater risk of breast cancer than estrogen alone. Estradiol is also available as a patch, gel, lotion, and ring but, again, needs to be paired with a progestogen if a woman has a uterus.

This new drug is well established in published randomized clinical trial data as an effective alternative to traditional estrogen-progestogen therapy (EPT) in symptomatic postmenopausal women with a uterus. Results from Selective Estrogens, Menopause, and Response to Therapy (SMART)¹ randomized controlled trials (RCTs) have shown improvements in symptoms similar to those seen with EPT. These include a reduction in hot flash frequency and severity; a reduction in night sweats, with fewer sleep disruptions; and bone loss prevention. The effects on total cholesterol (an increase in triglycerides) and the drug’s mild effect on vulvovaginal atrophy (VVA) also are similar to those observed with EPT. The drug has a neutral effect on breast tenderness, breast density, and the risk of breast cancer.^1,2 It also protects against endometrial hyperplasia and cancer and increases amenorrhea rates. VTE and stroke risks are expected to be similar to traditional oral hormone therapy (HT). The major benefit of CE/BZA, compared with traditional EPT, is the lack of significant breast tenderness and changes in breast density or vaginal bleeding often seen with traditional EPT.³ 

As for the benefits of soy for menopausal women, clinical data imply that phytoestrogens and soy foods may be of benefit for postmenopausal women. According to a recent review article by Messina⁴ (an international authority on phytoestrogens), isoflavone supplements relieve menopausal hot flashes if they have enough of the isoflavone genistein. Soy has shown benefits with regard to ischemic heart disease—by lowering low-density lipoprotein (LDL) levels and providing a source of omega fatty acids. However, no clear effect has been seen with soy for the prevention of bone loss. The effect on breast cancer risk is unclear. Soy binds to estrogen receptors, which could be harmful. However, soy may bind preferentially to estrogen-receptor beta, thus acting more SERM-like or protective, particularly if given during childhood or adolescence.

For any woman, the decision about using a food source, such as tofu, or isoflavone-rich supplements, such as one containing equol, should be based on a discussion with her clinician regarding her individual needs and the risks and benefits of all options.

In our Midlife Clinic at University of Virginia, we discuss over-the-counter products, lifestyle and dietary changes, and nonhormonal and hormonal options with our patients to help them identify the best choices.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

SAN ANTONIO – Breast cancer patients are often advised that in order to avoid developing lymphedema they should shun blood pressure cuffs, injections, and blood draws on their at-risk arm as well as airplane travel unless wearing a compression sleeve.

All these recommendations are anecdotally based. None withstood formal evaluation in a prospective study of 710 breast cancer patients with 860 treated and thus potentially at-risk breasts, Chantal M. Ferguson reported at the San Antonio Breast Cancer Symposium.

“Our findings don’t support current guidelines regarding these activities and suggest that further studies are needed to determine if these guidelines are appropriate,” said Ms. Ferguson of Massachusetts General Hospital, Boston.

Standard practice for newly diagnosed breast cancer patients at Mass. General is to enter into a prospective screening program for lymphedema, a chronic, painful swelling caused by damage to the lymphatic system secondary to breast cancer therapy.

Breast cancer patients routinely have bilateral arm volume measurements taken using a perometer preoperatively, postoperatively, after finishing chemotherapy and radiotherapy, and at 3- to 7-month intervals thereafter following completion of treatment. At each measurement, data are collected on exposures to airplane flights, blood pressure readings, and the other often-cited putative risk factors.

The incidence of lymphedema among the 710 patients in the study at 24 months was 7.05%. The diagnosis required at least a 10% increase in arm volume, compared with the untreated side. For women who underwent bilateral breast surgery, a weight-adjusted volume change formula was employed.

Consistent with the medical literature, axial lymph node dissection and a higher preoperative body mass index were significantly associated with the development of lymphedema. So was self-reported trauma to the at-risk arm, although the reported trauma ranged in severity from bruises to fractures in motor vehicle accidents.

Session cochair Dr. Michelle E. Melisko observed that few medical oncologists are well informed about lymphedema or the numerous and highly complex functions of the lymphatic system, so she was favorably impressed that physicians at Mass. General have incorporated structured screening for the disorder as part of the institutional standard of care.

She cautioned, however, that rates of the risk factor events under study were relatively low. For example, only 17% of the breast cancer patients had one or more blood pressure measurements taken on their at-risk arm during 2 years of prospective follow-up, 9% had one or more blood draws, and 15% of patients flew for a total of 12 hours or more.

“I’m not sure that we can take these data to say we can let patients go hog wild and get their blood pressure measured all the time on that arm. This is a large prospective trial featuring a broad range of patient ages and BMIs, and both lumpectomy and mastectomy patients, and the trial adds a lot to the literature, but it does need to be interpreted with caution,” said Dr. Melisko of the University of California, San Francisco.

The study was funded by the National Cancer Institute and the Adele McKinnon Research Fund for Breast Cancer–related Lymphedema. Ms. Ferguson reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Breast cancer patients are often advised that in order to avoid developing lymphedema they should shun blood pressure cuffs, injections, and blood draws on their at-risk arm as well as airplane travel unless wearing a compression sleeve.

All these recommendations are anecdotally based. None withstood formal evaluation in a prospective study of 710 breast cancer patients with 860 treated and thus potentially at-risk breasts, Chantal M. Ferguson reported at the San Antonio Breast Cancer Symposium.

“Our findings don’t support current guidelines regarding these activities and suggest that further studies are needed to determine if these guidelines are appropriate,” said Ms. Ferguson of Massachusetts General Hospital, Boston.

Standard practice for newly diagnosed breast cancer patients at Mass. General is to enter into a prospective screening program for lymphedema, a chronic, painful swelling caused by damage to the lymphatic system secondary to breast cancer therapy.

Breast cancer patients routinely have bilateral arm volume measurements taken using a perometer preoperatively, postoperatively, after finishing chemotherapy and radiotherapy, and at 3- to 7-month intervals thereafter following completion of treatment. At each measurement, data are collected on exposures to airplane flights, blood pressure readings, and the other often-cited putative risk factors.

The incidence of lymphedema among the 710 patients in the study at 24 months was 7.05%. The diagnosis required at least a 10% increase in arm volume, compared with the untreated side. For women who underwent bilateral breast surgery, a weight-adjusted volume change formula was employed.

Consistent with the medical literature, axial lymph node dissection and a higher preoperative body mass index were significantly associated with the development of lymphedema. So was self-reported trauma to the at-risk arm, although the reported trauma ranged in severity from bruises to fractures in motor vehicle accidents.

Session cochair Dr. Michelle E. Melisko observed that few medical oncologists are well informed about lymphedema or the numerous and highly complex functions of the lymphatic system, so she was favorably impressed that physicians at Mass. General have incorporated structured screening for the disorder as part of the institutional standard of care.

She cautioned, however, that rates of the risk factor events under study were relatively low. For example, only 17% of the breast cancer patients had one or more blood pressure measurements taken on their at-risk arm during 2 years of prospective follow-up, 9% had one or more blood draws, and 15% of patients flew for a total of 12 hours or more.

“I’m not sure that we can take these data to say we can let patients go hog wild and get their blood pressure measured all the time on that arm. This is a large prospective trial featuring a broad range of patient ages and BMIs, and both lumpectomy and mastectomy patients, and the trial adds a lot to the literature, but it does need to be interpreted with caution,” said Dr. Melisko of the University of California, San Francisco.

The study was funded by the National Cancer Institute and the Adele McKinnon Research Fund for Breast Cancer–related Lymphedema. Ms. Ferguson reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Breast cancer patients are often advised that in order to avoid developing lymphedema they should shun blood pressure cuffs, injections, and blood draws on their at-risk arm as well as airplane travel unless wearing a compression sleeve.

All these recommendations are anecdotally based. None withstood formal evaluation in a prospective study of 710 breast cancer patients with 860 treated and thus potentially at-risk breasts, Chantal M. Ferguson reported at the San Antonio Breast Cancer Symposium.

“Our findings don’t support current guidelines regarding these activities and suggest that further studies are needed to determine if these guidelines are appropriate,” said Ms. Ferguson of Massachusetts General Hospital, Boston.

Standard practice for newly diagnosed breast cancer patients at Mass. General is to enter into a prospective screening program for lymphedema, a chronic, painful swelling caused by damage to the lymphatic system secondary to breast cancer therapy.

Breast cancer patients routinely have bilateral arm volume measurements taken using a perometer preoperatively, postoperatively, after finishing chemotherapy and radiotherapy, and at 3- to 7-month intervals thereafter following completion of treatment. At each measurement, data are collected on exposures to airplane flights, blood pressure readings, and the other often-cited putative risk factors.

The incidence of lymphedema among the 710 patients in the study at 24 months was 7.05%. The diagnosis required at least a 10% increase in arm volume, compared with the untreated side. For women who underwent bilateral breast surgery, a weight-adjusted volume change formula was employed.

Consistent with the medical literature, axial lymph node dissection and a higher preoperative body mass index were significantly associated with the development of lymphedema. So was self-reported trauma to the at-risk arm, although the reported trauma ranged in severity from bruises to fractures in motor vehicle accidents.

Session cochair Dr. Michelle E. Melisko observed that few medical oncologists are well informed about lymphedema or the numerous and highly complex functions of the lymphatic system, so she was favorably impressed that physicians at Mass. General have incorporated structured screening for the disorder as part of the institutional standard of care.

She cautioned, however, that rates of the risk factor events under study were relatively low. For example, only 17% of the breast cancer patients had one or more blood pressure measurements taken on their at-risk arm during 2 years of prospective follow-up, 9% had one or more blood draws, and 15% of patients flew for a total of 12 hours or more.

“I’m not sure that we can take these data to say we can let patients go hog wild and get their blood pressure measured all the time on that arm. This is a large prospective trial featuring a broad range of patient ages and BMIs, and both lumpectomy and mastectomy patients, and the trial adds a lot to the literature, but it does need to be interpreted with caution,” said Dr. Melisko of the University of California, San Francisco.

The study was funded by the National Cancer Institute and the Adele McKinnon Research Fund for Breast Cancer–related Lymphedema. Ms. Ferguson reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Adjuvant aromatase inhibitor therapy in postmenopausal breast cancer survivors was associated with an increased risk of incident nonischemic cardiovascular disease, compared with tamoxifen users in a large prospective study conducted at Kaiser Permanente.

The elevation in risk was comparable in women on aromatase inhibitors (AIs) only and in those who used sequential tamoxifen followed by an AI, Reina Haque, Ph.D., reported at the San Antonio Breast Cancer Symposium.

She presented a prospective cohort study of 13,273 postmenopausal women free of known cardiovascular disease at the time of their breast cancer diagnosis during 1991-2010. Thirty-two percent of them used adjuvant tamoxifen only, 29% used an aromatase inhibitor (AI) only, 20% switched from adjuvant tamoxifen to an AI, and the rest used neither endocrine therapy.

Bruce Jancin/Frontline Medical News

During a mean of 5.5 and maximum 22 years of prospective follow-up, 3,711 women experienced their first cardiovascular disease event. Neither rates of ischemic heart disease nor stroke differed significantly among the groups on tamoxifen, AIs, both in sequence, or neither. However, those on adjuvant AI therapy had an adjusted 26% greater risk of ‘other’ cardiovascular disease, compared with women on tamoxifen only.

The category of ‘other’ cardiovascular disease was comprised of heart failure, arrhythmia, cardiomyopathy, pericarditis, and valvular dysfunction, explained Dr. Haque, a research scientist at Kaiser Permanente of Southern California, Pasadena.

Similarly, women who switched from tamoxifen to an AI were at 28% greater risk of developing ‘other’ cardiovascular disease, compared with those on tamoxifen alone in a multivariate Cox analysis adjusted for age, demographics, comorbid conditions, cancer treatment, tumor characteristics, and use of antihypertensive agents and other cardiovascular medications.

In the subset of 7,982 patients who underwent breast irradiation, those on an adjuvant AI who received left-sided breast radiation therapy were at an adjusted 21% increased risk of all forms of cardiovascular disease – ischemic as well as other – compared with those who got left-sided breast irradiation and took tamoxifen.

As this was an observational study, the results warrant cautious interpretation, Dr. Haque said. Nevertheless, this is a study based upon 72,886 women-years of prospective follow-up and a large number of cardiovascular events, she noted.

The study was funded by the California Breast Cancer Research Program and the National Cancer Institute. Dr. Haque reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Adjuvant aromatase inhibitor therapy in postmenopausal breast cancer survivors was associated with an increased risk of incident nonischemic cardiovascular disease, compared with tamoxifen users in a large prospective study conducted at Kaiser Permanente.

The elevation in risk was comparable in women on aromatase inhibitors (AIs) only and in those who used sequential tamoxifen followed by an AI, Reina Haque, Ph.D., reported at the San Antonio Breast Cancer Symposium.

She presented a prospective cohort study of 13,273 postmenopausal women free of known cardiovascular disease at the time of their breast cancer diagnosis during 1991-2010. Thirty-two percent of them used adjuvant tamoxifen only, 29% used an aromatase inhibitor (AI) only, 20% switched from adjuvant tamoxifen to an AI, and the rest used neither endocrine therapy.

Bruce Jancin/Frontline Medical News

During a mean of 5.5 and maximum 22 years of prospective follow-up, 3,711 women experienced their first cardiovascular disease event. Neither rates of ischemic heart disease nor stroke differed significantly among the groups on tamoxifen, AIs, both in sequence, or neither. However, those on adjuvant AI therapy had an adjusted 26% greater risk of ‘other’ cardiovascular disease, compared with women on tamoxifen only.

The category of ‘other’ cardiovascular disease was comprised of heart failure, arrhythmia, cardiomyopathy, pericarditis, and valvular dysfunction, explained Dr. Haque, a research scientist at Kaiser Permanente of Southern California, Pasadena.

Similarly, women who switched from tamoxifen to an AI were at 28% greater risk of developing ‘other’ cardiovascular disease, compared with those on tamoxifen alone in a multivariate Cox analysis adjusted for age, demographics, comorbid conditions, cancer treatment, tumor characteristics, and use of antihypertensive agents and other cardiovascular medications.

In the subset of 7,982 patients who underwent breast irradiation, those on an adjuvant AI who received left-sided breast radiation therapy were at an adjusted 21% increased risk of all forms of cardiovascular disease – ischemic as well as other – compared with those who got left-sided breast irradiation and took tamoxifen.

As this was an observational study, the results warrant cautious interpretation, Dr. Haque said. Nevertheless, this is a study based upon 72,886 women-years of prospective follow-up and a large number of cardiovascular events, she noted.

The study was funded by the California Breast Cancer Research Program and the National Cancer Institute. Dr. Haque reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Adjuvant aromatase inhibitor therapy in postmenopausal breast cancer survivors was associated with an increased risk of incident nonischemic cardiovascular disease, compared with tamoxifen users in a large prospective study conducted at Kaiser Permanente.

The elevation in risk was comparable in women on aromatase inhibitors (AIs) only and in those who used sequential tamoxifen followed by an AI, Reina Haque, Ph.D., reported at the San Antonio Breast Cancer Symposium.

She presented a prospective cohort study of 13,273 postmenopausal women free of known cardiovascular disease at the time of their breast cancer diagnosis during 1991-2010. Thirty-two percent of them used adjuvant tamoxifen only, 29% used an aromatase inhibitor (AI) only, 20% switched from adjuvant tamoxifen to an AI, and the rest used neither endocrine therapy.

Bruce Jancin/Frontline Medical News

During a mean of 5.5 and maximum 22 years of prospective follow-up, 3,711 women experienced their first cardiovascular disease event. Neither rates of ischemic heart disease nor stroke differed significantly among the groups on tamoxifen, AIs, both in sequence, or neither. However, those on adjuvant AI therapy had an adjusted 26% greater risk of ‘other’ cardiovascular disease, compared with women on tamoxifen only.

The category of ‘other’ cardiovascular disease was comprised of heart failure, arrhythmia, cardiomyopathy, pericarditis, and valvular dysfunction, explained Dr. Haque, a research scientist at Kaiser Permanente of Southern California, Pasadena.

Similarly, women who switched from tamoxifen to an AI were at 28% greater risk of developing ‘other’ cardiovascular disease, compared with those on tamoxifen alone in a multivariate Cox analysis adjusted for age, demographics, comorbid conditions, cancer treatment, tumor characteristics, and use of antihypertensive agents and other cardiovascular medications.

In the subset of 7,982 patients who underwent breast irradiation, those on an adjuvant AI who received left-sided breast radiation therapy were at an adjusted 21% increased risk of all forms of cardiovascular disease – ischemic as well as other – compared with those who got left-sided breast irradiation and took tamoxifen.

As this was an observational study, the results warrant cautious interpretation, Dr. Haque said. Nevertheless, this is a study based upon 72,886 women-years of prospective follow-up and a large number of cardiovascular events, she noted.

The study was funded by the California Breast Cancer Research Program and the National Cancer Institute. Dr. Haque reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Though breast cancer survivors have a two- to sixfold higher risk of developing a second primary cancer compared with women in the general population, only a handful of studies have investigated potential ways for women to mitigate this risk, Dr. Christopher I. Li said at the San Antonio Breast Cancer Symposium.

The best established modifiable risk factors for a second primary contralateral breast cancer are obesity, smoking, and excessive alcohol consumption, while chemotherapy, adjuvant aromatase inhibitors, and tamoxifen are protective, he said

In addition, one study has found bisphosphonates have a protective effect against contralateral breast cancer (CBC), and another has identified diabetes mellitus as a significant risk factor. However, these two studies – both conducted by Dr. Li and coworkers – are the only ones to date that have looked at these potential risk modifiers. Confirmatory studies are warranted, emphasized Dr. Li, professor of epidemiology at the University of Washington and head of the translational research program at the Fred Hutchinson Cancer Research Center, Seattle.

An estimated 10% of breast cancer survivors will develop a second, distinct primary cancer. The most common site is the contralateral breast. Indeed, 35% of all second primary cancers in breast cancer survivors occur there. Lung cancer is next most common, accounting for 18%, followed by endometrial cancer at 10%, and colorectal cancer, which comprises 8% of all secondary primary cancers in breast cancer survivors.

Despite the high incidence of CBC, only three studies with 200 or more cases have looked at modifiable risk factors.

One was a population-based nested case-control study by Dr. Li and coworkers. It included 367 CBC cases and a control group of 734 matched breast cancer survivors without a second primary cancer. The investigators identified three modifiable risk factors for CBC: a body mass index of 30 kg/m² or greater, associated with an adjusted 1.5-fold increased risk; consumption of at least seven alcoholic drinks per week after the first breast cancer diagnosis, with a 1.9-fold risk; and current smoking, which conferred a 2.2-fold increased risk.

Upon further analysis, however, an important interaction was noted between alcohol consumption and current smoking such that neither behavior alone was associated with significantly increased risk of CBC. But current smokers who also drank at least seven alcoholic beverages per week were at a highly significant 7.2-fold increased risk (J. Clin. Oncol. 2009;27:5312-8).

Today, bisphosphonates are widely prescribed to prevent and treat bone metastases in breast cancer patients. Dr. Li and coinvestigators conducted a nested case-control study looking at the use of bisphosphonates for another indication: the prevention of osteoporosis-related events. The study comparison involved 351 patients with CBC and 662 controls who were breast cancer survivors without CBC. They found that patients who had ever used a bisphosphonate for 6 months or longer were 47% less likely to develop a CBC.

Moreover, the protective effect increased with duration of therapy. Among current bisphosphonate users who had been taking the medication for at least 6 months, there was an adjusted 59% reduction in the risk of CBC. For current users of at least 12 months, there was a 69% reduction in relative risk compared to nonusers. And among current users of a bisphosphonate for 24 months or longer, the relative risk reduction climbed to 79%, (J. Natl. Cancer Inst. 2011;103:1752-60).

The diabetes study included 332 patients who developed a second primary CBC and 616 matched controls with only a first breast cancer. Women diagnosed with diabetes prior to age 54 had a 6.2-fold increased risk of CBC after Dr. Li and coworkers controlled for obesity and other potential confounders in a conditional logistic regression analysis, while those diagnosed with diabetes at age 55 or older had a twofold increased risk (Breast Cancer Res. Treat. 2011;125:545-51). If these findings are confirmed in another study, more frequent surveillance for CBC will be warranted in diabetic breast cancer survivors, Dr. Li said.

One risk factor for CBC that patients can’t modify involves their breast cancer subtype. In another population-based nested case-control study, this one involving 482 women with a first breast cancer followed by a CBC and 1,506 controls with only a first breast cancer, Dr. Li and colleagues showed that women with HER2-overexpressing primary disease – estrogen receptor-negative/HER2-positive tumors – had a twofold greater likelihood of CBC compared with women who were ER-positive/HER2 positive.

Women with triple-negative breast cancer had an increased risk of CBC that did not become significant until at least 4 years had gone by since diagnosis of the first breast cancer. At that point they had a 2.2-fold greater risk of CBC and patients with HER2-overexpressing disease had a 2.7-fold greater risk compared with ER-positive/HER2-positive patients.

Patients with these more aggressive breast cancer subtypes – the HER2-overexpressing and triple-negative forms of the disease – were also at particularly high risk for more advanced stage CBC. Their CBCs were greater than three times more likely to be at a regional or distant stage at diagnosis than those occurring in patients with ER-positive/HER2-positive primary breast cancer (Breast Cancer Res. Treat. 2012;135:849-55).

Dr. Li closed by noting that the growing problem of CBC is finally receiving extra attention from funding agencies. A new Consortium of CBC has been created, enabling investigators from 28 different CBC studies to interact more closely. The consortium is led by physicians at Memorial Sloan Kettering Cancer Center in New York, and at Fred Hutchinson.

The National Cancer Institute recently approved funding for a new population-based case-control study focusing on second primary cancers. It will include 700 controls with only a single breast cancer diagnosis along with 600 women with a second primary cancer of the lung, 600 with CBC, 350 with a second primary colorectal cancer, and another 350 with a second primary in the endometrium. The study will look in-depth at risk factors, treatments, and clinical and molecular characteristics and their impact on second primary cancers in breast cancer patients.

“We really hope through this study to move the field forward,” Dr. Li said.

His studies have been funded by the National Institutes of Health. He reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Though breast cancer survivors have a two- to sixfold higher risk of developing a second primary cancer compared with women in the general population, only a handful of studies have investigated potential ways for women to mitigate this risk, Dr. Christopher I. Li said at the San Antonio Breast Cancer Symposium.

The best established modifiable risk factors for a second primary contralateral breast cancer are obesity, smoking, and excessive alcohol consumption, while chemotherapy, adjuvant aromatase inhibitors, and tamoxifen are protective, he said

In addition, one study has found bisphosphonates have a protective effect against contralateral breast cancer (CBC), and another has identified diabetes mellitus as a significant risk factor. However, these two studies – both conducted by Dr. Li and coworkers – are the only ones to date that have looked at these potential risk modifiers. Confirmatory studies are warranted, emphasized Dr. Li, professor of epidemiology at the University of Washington and head of the translational research program at the Fred Hutchinson Cancer Research Center, Seattle.

An estimated 10% of breast cancer survivors will develop a second, distinct primary cancer. The most common site is the contralateral breast. Indeed, 35% of all second primary cancers in breast cancer survivors occur there. Lung cancer is next most common, accounting for 18%, followed by endometrial cancer at 10%, and colorectal cancer, which comprises 8% of all secondary primary cancers in breast cancer survivors.

Despite the high incidence of CBC, only three studies with 200 or more cases have looked at modifiable risk factors.

One was a population-based nested case-control study by Dr. Li and coworkers. It included 367 CBC cases and a control group of 734 matched breast cancer survivors without a second primary cancer. The investigators identified three modifiable risk factors for CBC: a body mass index of 30 kg/m² or greater, associated with an adjusted 1.5-fold increased risk; consumption of at least seven alcoholic drinks per week after the first breast cancer diagnosis, with a 1.9-fold risk; and current smoking, which conferred a 2.2-fold increased risk.

Upon further analysis, however, an important interaction was noted between alcohol consumption and current smoking such that neither behavior alone was associated with significantly increased risk of CBC. But current smokers who also drank at least seven alcoholic beverages per week were at a highly significant 7.2-fold increased risk (J. Clin. Oncol. 2009;27:5312-8).

Today, bisphosphonates are widely prescribed to prevent and treat bone metastases in breast cancer patients. Dr. Li and coinvestigators conducted a nested case-control study looking at the use of bisphosphonates for another indication: the prevention of osteoporosis-related events. The study comparison involved 351 patients with CBC and 662 controls who were breast cancer survivors without CBC. They found that patients who had ever used a bisphosphonate for 6 months or longer were 47% less likely to develop a CBC.

Moreover, the protective effect increased with duration of therapy. Among current bisphosphonate users who had been taking the medication for at least 6 months, there was an adjusted 59% reduction in the risk of CBC. For current users of at least 12 months, there was a 69% reduction in relative risk compared to nonusers. And among current users of a bisphosphonate for 24 months or longer, the relative risk reduction climbed to 79%, (J. Natl. Cancer Inst. 2011;103:1752-60).

The diabetes study included 332 patients who developed a second primary CBC and 616 matched controls with only a first breast cancer. Women diagnosed with diabetes prior to age 54 had a 6.2-fold increased risk of CBC after Dr. Li and coworkers controlled for obesity and other potential confounders in a conditional logistic regression analysis, while those diagnosed with diabetes at age 55 or older had a twofold increased risk (Breast Cancer Res. Treat. 2011;125:545-51). If these findings are confirmed in another study, more frequent surveillance for CBC will be warranted in diabetic breast cancer survivors, Dr. Li said.

One risk factor for CBC that patients can’t modify involves their breast cancer subtype. In another population-based nested case-control study, this one involving 482 women with a first breast cancer followed by a CBC and 1,506 controls with only a first breast cancer, Dr. Li and colleagues showed that women with HER2-overexpressing primary disease – estrogen receptor-negative/HER2-positive tumors – had a twofold greater likelihood of CBC compared with women who were ER-positive/HER2 positive.

Women with triple-negative breast cancer had an increased risk of CBC that did not become significant until at least 4 years had gone by since diagnosis of the first breast cancer. At that point they had a 2.2-fold greater risk of CBC and patients with HER2-overexpressing disease had a 2.7-fold greater risk compared with ER-positive/HER2-positive patients.

Patients with these more aggressive breast cancer subtypes – the HER2-overexpressing and triple-negative forms of the disease – were also at particularly high risk for more advanced stage CBC. Their CBCs were greater than three times more likely to be at a regional or distant stage at diagnosis than those occurring in patients with ER-positive/HER2-positive primary breast cancer (Breast Cancer Res. Treat. 2012;135:849-55).

Dr. Li closed by noting that the growing problem of CBC is finally receiving extra attention from funding agencies. A new Consortium of CBC has been created, enabling investigators from 28 different CBC studies to interact more closely. The consortium is led by physicians at Memorial Sloan Kettering Cancer Center in New York, and at Fred Hutchinson.

The National Cancer Institute recently approved funding for a new population-based case-control study focusing on second primary cancers. It will include 700 controls with only a single breast cancer diagnosis along with 600 women with a second primary cancer of the lung, 600 with CBC, 350 with a second primary colorectal cancer, and another 350 with a second primary in the endometrium. The study will look in-depth at risk factors, treatments, and clinical and molecular characteristics and their impact on second primary cancers in breast cancer patients.

“We really hope through this study to move the field forward,” Dr. Li said.

His studies have been funded by the National Institutes of Health. He reported having no financial conflicts.

bjancin@frontlinemedcom.com

SAN ANTONIO – Though breast cancer survivors have a two- to sixfold higher risk of developing a second primary cancer compared with women in the general population, only a handful of studies have investigated potential ways for women to mitigate this risk, Dr. Christopher I. Li said at the San Antonio Breast Cancer Symposium.

The best established modifiable risk factors for a second primary contralateral breast cancer are obesity, smoking, and excessive alcohol consumption, while chemotherapy, adjuvant aromatase inhibitors, and tamoxifen are protective, he said

In addition, one study has found bisphosphonates have a protective effect against contralateral breast cancer (CBC), and another has identified diabetes mellitus as a significant risk factor. However, these two studies – both conducted by Dr. Li and coworkers – are the only ones to date that have looked at these potential risk modifiers. Confirmatory studies are warranted, emphasized Dr. Li, professor of epidemiology at the University of Washington and head of the translational research program at the Fred Hutchinson Cancer Research Center, Seattle.

An estimated 10% of breast cancer survivors will develop a second, distinct primary cancer. The most common site is the contralateral breast. Indeed, 35% of all second primary cancers in breast cancer survivors occur there. Lung cancer is next most common, accounting for 18%, followed by endometrial cancer at 10%, and colorectal cancer, which comprises 8% of all secondary primary cancers in breast cancer survivors.

Despite the high incidence of CBC, only three studies with 200 or more cases have looked at modifiable risk factors.

One was a population-based nested case-control study by Dr. Li and coworkers. It included 367 CBC cases and a control group of 734 matched breast cancer survivors without a second primary cancer. The investigators identified three modifiable risk factors for CBC: a body mass index of 30 kg/m² or greater, associated with an adjusted 1.5-fold increased risk; consumption of at least seven alcoholic drinks per week after the first breast cancer diagnosis, with a 1.9-fold risk; and current smoking, which conferred a 2.2-fold increased risk.

Upon further analysis, however, an important interaction was noted between alcohol consumption and current smoking such that neither behavior alone was associated with significantly increased risk of CBC. But current smokers who also drank at least seven alcoholic beverages per week were at a highly significant 7.2-fold increased risk (J. Clin. Oncol. 2009;27:5312-8).

Today, bisphosphonates are widely prescribed to prevent and treat bone metastases in breast cancer patients. Dr. Li and coinvestigators conducted a nested case-control study looking at the use of bisphosphonates for another indication: the prevention of osteoporosis-related events. The study comparison involved 351 patients with CBC and 662 controls who were breast cancer survivors without CBC. They found that patients who had ever used a bisphosphonate for 6 months or longer were 47% less likely to develop a CBC.

Moreover, the protective effect increased with duration of therapy. Among current bisphosphonate users who had been taking the medication for at least 6 months, there was an adjusted 59% reduction in the risk of CBC. For current users of at least 12 months, there was a 69% reduction in relative risk compared to nonusers. And among current users of a bisphosphonate for 24 months or longer, the relative risk reduction climbed to 79%, (J. Natl. Cancer Inst. 2011;103:1752-60).

The diabetes study included 332 patients who developed a second primary CBC and 616 matched controls with only a first breast cancer. Women diagnosed with diabetes prior to age 54 had a 6.2-fold increased risk of CBC after Dr. Li and coworkers controlled for obesity and other potential confounders in a conditional logistic regression analysis, while those diagnosed with diabetes at age 55 or older had a twofold increased risk (Breast Cancer Res. Treat. 2011;125:545-51). If these findings are confirmed in another study, more frequent surveillance for CBC will be warranted in diabetic breast cancer survivors, Dr. Li said.

One risk factor for CBC that patients can’t modify involves their breast cancer subtype. In another population-based nested case-control study, this one involving 482 women with a first breast cancer followed by a CBC and 1,506 controls with only a first breast cancer, Dr. Li and colleagues showed that women with HER2-overexpressing primary disease – estrogen receptor-negative/HER2-positive tumors – had a twofold greater likelihood of CBC compared with women who were ER-positive/HER2 positive.

Women with triple-negative breast cancer had an increased risk of CBC that did not become significant until at least 4 years had gone by since diagnosis of the first breast cancer. At that point they had a 2.2-fold greater risk of CBC and patients with HER2-overexpressing disease had a 2.7-fold greater risk compared with ER-positive/HER2-positive patients.

Patients with these more aggressive breast cancer subtypes – the HER2-overexpressing and triple-negative forms of the disease – were also at particularly high risk for more advanced stage CBC. Their CBCs were greater than three times more likely to be at a regional or distant stage at diagnosis than those occurring in patients with ER-positive/HER2-positive primary breast cancer (Breast Cancer Res. Treat. 2012;135:849-55).

Dr. Li closed by noting that the growing problem of CBC is finally receiving extra attention from funding agencies. A new Consortium of CBC has been created, enabling investigators from 28 different CBC studies to interact more closely. The consortium is led by physicians at Memorial Sloan Kettering Cancer Center in New York, and at Fred Hutchinson.

The National Cancer Institute recently approved funding for a new population-based case-control study focusing on second primary cancers. It will include 700 controls with only a single breast cancer diagnosis along with 600 women with a second primary cancer of the lung, 600 with CBC, 350 with a second primary colorectal cancer, and another 350 with a second primary in the endometrium. The study will look in-depth at risk factors, treatments, and clinical and molecular characteristics and their impact on second primary cancers in breast cancer patients.

“We really hope through this study to move the field forward,” Dr. Li said.

His studies have been funded by the National Institutes of Health. He reported having no financial conflicts.

bjancin@frontlinemedcom.com