SABCS 2015

SAN ANTONIO – Self-administered acupressure focused on enhancing relaxation significantly reduced persistent fatigue symptoms in breast cancer survivors, according to a randomized clinical trial presented at the San Antonio Breast Cancer Symposium.

“Self-administered relaxation acupressure offers an inexpensive, easy-to-learn method to manage fatigue and co-occurring poor sleep quality and overall quality of life in breast cancer survivors with persistent fatigue,” said Suzanna M. Zick, N.D., MPH, of the department of family medicine, and the complementary and alternative medicine research center at the University of Michigan, Ann Arbor.

She conducted the study because persistent fatigue is arguably the most common and debilitating symptom experienced by breast cancer survivors, affecting 30% of women for up to 10 years after they’ve completed their breast cancer therapy. Yet treatment options remain limited, she said.

Acupressure is a form of traditional Chinese medicine in which pressure is applied to a few specific acupoints on the body using the fingers, thumbs, or a device. Two forms were evaluated in the three-arm, single-blind clinical trial: relaxation acupressure, traditionally used to improve sleep, and stimulation acupressure, which targets pressure points that boost energy.

Dr. Zick presented a 10-week study in which 288 breast cancer survivors who had completed cancer therapy other than hormone treatment at least 12 months before and who still experienced persistent fatigue as defined by a score of 4 or more on the validated Brief Fatigue Inventory. Participants were randomized single-blind to usual care as directed by their physician or to 6 weeks of relaxation or stimulation acupressure, which they administered on their own after receiving instruction. After 6 weeks, women were instructed to stop the acupressure. They were reassessed at week 10 to determine whether acupressure had a sustained carryover effect.

At 6 weeks, 66% of the relaxation acupressure group and 61% of the stimulation acupressure cohort had achieved a normal Brief Fatigue Inventory score of less than 4, as did only 31% of the usual-care controls. Both acupressure groups showed maintenance of benefit at week 10, after 4 weeks of no acupressure, indicating the self-treatment isn’t something patients need to do continuously in order to derive the desired effect.

While both forms of acupressure were similarly effective at reducing complaints of fatigue, there was an important difference between the two. Only relaxation acupressure resulted in significant improvement in sleep quality as measured on the Pittsburgh Sleep Quality Index. Moreover, relaxation acupressure but not stimulation acupressure resulted in quality-of-life improvements on the somatic, fitness, and social support subscales of the Long-Term Quality of Life scale. However, neither form of acupressure had a significant on the spiritual subscale, the quality-of-life instrument’s fourth subscale.

“We really have to conclude that even though both forms of acupressure reduce fatigue to a similar extent, relaxation acupressure is the one we should think about as being more effective,” Dr. Zick said.

One might have predicted, incorrectly as it turns out, that breast cancer survivors complaining of persistent fatigue would find stimulation acupressure to be more beneficial than relaxation acupressure. Dr. Zick suspects the two techniques might reduce chronic fatigue via different mechanisms. She and her coinvestigators have conducted brain imaging studies that show patients with persistent cancer-related fatigue have three neurochemical markers: elevated brain levels of insular glutamate, which causes excitation, as well as high brain levels of creatine phosphokinase and proinflammatory cytokines. In their next round of imaging studies, the investigators plan to see whether the two forms of acupressure have differing effects on this markers.

Session moderator Dr. Norah Lynn Henry liked the concept of self-administered acupressure.

“The great thing about this is you don’t have to make appointments with an acupuncturist. You can do it at home. But is acupressure ready for prime time in clinical practice?” asked Dr. Henry, a medical oncologist at the University of Michigan.

“My answer is yes,” Dr. Zick replied, “because it’s got pretty much zero side effects, it’s inexpensive, and it’s easy to learn. If it doesn’t work for a person then they can just stop, but if it works, great.”

As the next step in this research, Dr. Zick and her coinvestigators hope to develop a smartphone app to deliver instruction in self-administered relaxation acupressure in a readily accessible way.

Her clinical trial was funded by the National Cancer Institute. She reported having no financial conflicts.

[email protected]

SAN ANTONIO – Self-administered acupressure focused on enhancing relaxation significantly reduced persistent fatigue symptoms in breast cancer survivors, according to a randomized clinical trial presented at the San Antonio Breast Cancer Symposium.

“Self-administered relaxation acupressure offers an inexpensive, easy-to-learn method to manage fatigue and co-occurring poor sleep quality and overall quality of life in breast cancer survivors with persistent fatigue,” said Suzanna M. Zick, N.D., MPH, of the department of family medicine, and the complementary and alternative medicine research center at the University of Michigan, Ann Arbor.

She conducted the study because persistent fatigue is arguably the most common and debilitating symptom experienced by breast cancer survivors, affecting 30% of women for up to 10 years after they’ve completed their breast cancer therapy. Yet treatment options remain limited, she said.

Acupressure is a form of traditional Chinese medicine in which pressure is applied to a few specific acupoints on the body using the fingers, thumbs, or a device. Two forms were evaluated in the three-arm, single-blind clinical trial: relaxation acupressure, traditionally used to improve sleep, and stimulation acupressure, which targets pressure points that boost energy.

Dr. Zick presented a 10-week study in which 288 breast cancer survivors who had completed cancer therapy other than hormone treatment at least 12 months before and who still experienced persistent fatigue as defined by a score of 4 or more on the validated Brief Fatigue Inventory. Participants were randomized single-blind to usual care as directed by their physician or to 6 weeks of relaxation or stimulation acupressure, which they administered on their own after receiving instruction. After 6 weeks, women were instructed to stop the acupressure. They were reassessed at week 10 to determine whether acupressure had a sustained carryover effect.

At 6 weeks, 66% of the relaxation acupressure group and 61% of the stimulation acupressure cohort had achieved a normal Brief Fatigue Inventory score of less than 4, as did only 31% of the usual-care controls. Both acupressure groups showed maintenance of benefit at week 10, after 4 weeks of no acupressure, indicating the self-treatment isn’t something patients need to do continuously in order to derive the desired effect.

While both forms of acupressure were similarly effective at reducing complaints of fatigue, there was an important difference between the two. Only relaxation acupressure resulted in significant improvement in sleep quality as measured on the Pittsburgh Sleep Quality Index. Moreover, relaxation acupressure but not stimulation acupressure resulted in quality-of-life improvements on the somatic, fitness, and social support subscales of the Long-Term Quality of Life scale. However, neither form of acupressure had a significant on the spiritual subscale, the quality-of-life instrument’s fourth subscale.

“We really have to conclude that even though both forms of acupressure reduce fatigue to a similar extent, relaxation acupressure is the one we should think about as being more effective,” Dr. Zick said.

One might have predicted, incorrectly as it turns out, that breast cancer survivors complaining of persistent fatigue would find stimulation acupressure to be more beneficial than relaxation acupressure. Dr. Zick suspects the two techniques might reduce chronic fatigue via different mechanisms. She and her coinvestigators have conducted brain imaging studies that show patients with persistent cancer-related fatigue have three neurochemical markers: elevated brain levels of insular glutamate, which causes excitation, as well as high brain levels of creatine phosphokinase and proinflammatory cytokines. In their next round of imaging studies, the investigators plan to see whether the two forms of acupressure have differing effects on this markers.

Session moderator Dr. Norah Lynn Henry liked the concept of self-administered acupressure.

“The great thing about this is you don’t have to make appointments with an acupuncturist. You can do it at home. But is acupressure ready for prime time in clinical practice?” asked Dr. Henry, a medical oncologist at the University of Michigan.

“My answer is yes,” Dr. Zick replied, “because it’s got pretty much zero side effects, it’s inexpensive, and it’s easy to learn. If it doesn’t work for a person then they can just stop, but if it works, great.”

As the next step in this research, Dr. Zick and her coinvestigators hope to develop a smartphone app to deliver instruction in self-administered relaxation acupressure in a readily accessible way.

Her clinical trial was funded by the National Cancer Institute. She reported having no financial conflicts.

[email protected]

SAN ANTONIO – Self-administered acupressure focused on enhancing relaxation significantly reduced persistent fatigue symptoms in breast cancer survivors, according to a randomized clinical trial presented at the San Antonio Breast Cancer Symposium.

“Self-administered relaxation acupressure offers an inexpensive, easy-to-learn method to manage fatigue and co-occurring poor sleep quality and overall quality of life in breast cancer survivors with persistent fatigue,” said Suzanna M. Zick, N.D., MPH, of the department of family medicine, and the complementary and alternative medicine research center at the University of Michigan, Ann Arbor.

She conducted the study because persistent fatigue is arguably the most common and debilitating symptom experienced by breast cancer survivors, affecting 30% of women for up to 10 years after they’ve completed their breast cancer therapy. Yet treatment options remain limited, she said.

Acupressure is a form of traditional Chinese medicine in which pressure is applied to a few specific acupoints on the body using the fingers, thumbs, or a device. Two forms were evaluated in the three-arm, single-blind clinical trial: relaxation acupressure, traditionally used to improve sleep, and stimulation acupressure, which targets pressure points that boost energy.

Dr. Zick presented a 10-week study in which 288 breast cancer survivors who had completed cancer therapy other than hormone treatment at least 12 months before and who still experienced persistent fatigue as defined by a score of 4 or more on the validated Brief Fatigue Inventory. Participants were randomized single-blind to usual care as directed by their physician or to 6 weeks of relaxation or stimulation acupressure, which they administered on their own after receiving instruction. After 6 weeks, women were instructed to stop the acupressure. They were reassessed at week 10 to determine whether acupressure had a sustained carryover effect.

At 6 weeks, 66% of the relaxation acupressure group and 61% of the stimulation acupressure cohort had achieved a normal Brief Fatigue Inventory score of less than 4, as did only 31% of the usual-care controls. Both acupressure groups showed maintenance of benefit at week 10, after 4 weeks of no acupressure, indicating the self-treatment isn’t something patients need to do continuously in order to derive the desired effect.

While both forms of acupressure were similarly effective at reducing complaints of fatigue, there was an important difference between the two. Only relaxation acupressure resulted in significant improvement in sleep quality as measured on the Pittsburgh Sleep Quality Index. Moreover, relaxation acupressure but not stimulation acupressure resulted in quality-of-life improvements on the somatic, fitness, and social support subscales of the Long-Term Quality of Life scale. However, neither form of acupressure had a significant on the spiritual subscale, the quality-of-life instrument’s fourth subscale.

“We really have to conclude that even though both forms of acupressure reduce fatigue to a similar extent, relaxation acupressure is the one we should think about as being more effective,” Dr. Zick said.

One might have predicted, incorrectly as it turns out, that breast cancer survivors complaining of persistent fatigue would find stimulation acupressure to be more beneficial than relaxation acupressure. Dr. Zick suspects the two techniques might reduce chronic fatigue via different mechanisms. She and her coinvestigators have conducted brain imaging studies that show patients with persistent cancer-related fatigue have three neurochemical markers: elevated brain levels of insular glutamate, which causes excitation, as well as high brain levels of creatine phosphokinase and proinflammatory cytokines. In their next round of imaging studies, the investigators plan to see whether the two forms of acupressure have differing effects on this markers.

Session moderator Dr. Norah Lynn Henry liked the concept of self-administered acupressure.

“The great thing about this is you don’t have to make appointments with an acupuncturist. You can do it at home. But is acupressure ready for prime time in clinical practice?” asked Dr. Henry, a medical oncologist at the University of Michigan.

“My answer is yes,” Dr. Zick replied, “because it’s got pretty much zero side effects, it’s inexpensive, and it’s easy to learn. If it doesn’t work for a person then they can just stop, but if it works, great.”

As the next step in this research, Dr. Zick and her coinvestigators hope to develop a smartphone app to deliver instruction in self-administered relaxation acupressure in a readily accessible way.

Her clinical trial was funded by the National Cancer Institute. She reported having no financial conflicts.

[email protected]

SAN ANTONIO – Breast cancer survivors who typically didn’t eat for at least 13 hours overnight had a 36% reduction in the risk of breast cancer recurrence compared to those with a shorter duration of overnight fasting in a secondary analysis of the Women’s Healthy Eating and Living Study presented at the San Antonio Breast Cancer Symposium.

“Prolonging the length of the nighttime fasting interval may be a simple nonpharmacologic strategy for reducing the risk of breast cancer recurrence as well as other chronic conditions with etiologic ties to breast cancer, like type 2 diabetes,” concluded to Catherine R. Marinac, a doctoral candidate in public health at the University of California, San Diego.

“A lot of dietary recommendations for cancer prevention really focus on what to eat in order to prevent or recover from breast cancer. For a lot of people that can be a really complicated recommendation, like ‘count your carbs, count your fat, don’t eat this/don’t eat that.’ We think timing of food intake in order to prolong the length of the nightly fasting interval can be a simple strategy most women can understand and adopt and that may reduce their risk of breast cancer,” she added.

The new results from the Women’s Healthy Eating and Living (WHEL) study are encouragingly consistent with the findings of earlier rodent studies demonstrating that intermittent fasting regimens aligned with the sleep cycle bring better glycemic control and protection against carcinogenesis, Ms. Marinac noted.

She presented an analysis of 2,413 nondiabetic breast cancer survivors who participated in the multicenter WHEL study and for whom multiple detailed 24-hour dietary recall records were obtained at baseline and 4 years of followup.

“The diets were very well characterized. We analyzed roughly 30,000 time-stamped dietary recalls,” she said in an interview.

During 7.3 years of follow-up, 390 women experienced recurrent breast cancer. Those in the top tertile for duration of overnight fasting, at 13 hours or longer, were 36% less likely to have a recurrence, according to a Cox proportionate hazard analysis and a multivariate linear regression analysis controlling for patient demographics; calorie consumption and other dietary variables; breast cancer stage, grade, and treatment; body mass index; comorbid conditions; and sleep duration.

During 11.4 years of follow-up, 329 subjects died of their breast cancer. All-cause mortality occurred in 420. Women with an overnight fasting duration of 13 hours or greater were 21% less likely to experience breast cancer mortality and 22% less likely to die of any cause. Neither trend achieved statistical significance.

Looking for potential mechanisms to explain the observed relationship between overnight fasting duration and breast cancer recurrence, Ms. Marinac and coinvestigators considered as evaluable possibilities systemic inflammation, glucoregulation, adiposity, and sleep duration.

C-reactive protein levels and body mass index proved to be unrelated to recurrence risk. However, glucoregulation and sleep duration were. Women with an overnight fasting length of at least 13 hours had a significantly lower glycated hemoglobin level and slept longer than those with a shorter overnight fast. The lower HbA_1c seen in women who fasted for longer at night mimics an intriguing finding from the classic mouse studies that showed fasting is related to better glycemic control, she observed.

The WHEL study is sponsored by the National Cancer Institute, the University of California at San Diego, and a Ruth L. Kirschstein National Research Service Award. Ms. Marinac reported having no financial conflicts of interest.

[email protected]

SAN ANTONIO – Breast cancer survivors who typically didn’t eat for at least 13 hours overnight had a 36% reduction in the risk of breast cancer recurrence compared to those with a shorter duration of overnight fasting in a secondary analysis of the Women’s Healthy Eating and Living Study presented at the San Antonio Breast Cancer Symposium.

“Prolonging the length of the nighttime fasting interval may be a simple nonpharmacologic strategy for reducing the risk of breast cancer recurrence as well as other chronic conditions with etiologic ties to breast cancer, like type 2 diabetes,” concluded to Catherine R. Marinac, a doctoral candidate in public health at the University of California, San Diego.

“A lot of dietary recommendations for cancer prevention really focus on what to eat in order to prevent or recover from breast cancer. For a lot of people that can be a really complicated recommendation, like ‘count your carbs, count your fat, don’t eat this/don’t eat that.’ We think timing of food intake in order to prolong the length of the nightly fasting interval can be a simple strategy most women can understand and adopt and that may reduce their risk of breast cancer,” she added.

The new results from the Women’s Healthy Eating and Living (WHEL) study are encouragingly consistent with the findings of earlier rodent studies demonstrating that intermittent fasting regimens aligned with the sleep cycle bring better glycemic control and protection against carcinogenesis, Ms. Marinac noted.

She presented an analysis of 2,413 nondiabetic breast cancer survivors who participated in the multicenter WHEL study and for whom multiple detailed 24-hour dietary recall records were obtained at baseline and 4 years of followup.

“The diets were very well characterized. We analyzed roughly 30,000 time-stamped dietary recalls,” she said in an interview.

During 7.3 years of follow-up, 390 women experienced recurrent breast cancer. Those in the top tertile for duration of overnight fasting, at 13 hours or longer, were 36% less likely to have a recurrence, according to a Cox proportionate hazard analysis and a multivariate linear regression analysis controlling for patient demographics; calorie consumption and other dietary variables; breast cancer stage, grade, and treatment; body mass index; comorbid conditions; and sleep duration.

During 11.4 years of follow-up, 329 subjects died of their breast cancer. All-cause mortality occurred in 420. Women with an overnight fasting duration of 13 hours or greater were 21% less likely to experience breast cancer mortality and 22% less likely to die of any cause. Neither trend achieved statistical significance.

Looking for potential mechanisms to explain the observed relationship between overnight fasting duration and breast cancer recurrence, Ms. Marinac and coinvestigators considered as evaluable possibilities systemic inflammation, glucoregulation, adiposity, and sleep duration.

C-reactive protein levels and body mass index proved to be unrelated to recurrence risk. However, glucoregulation and sleep duration were. Women with an overnight fasting length of at least 13 hours had a significantly lower glycated hemoglobin level and slept longer than those with a shorter overnight fast. The lower HbA_1c seen in women who fasted for longer at night mimics an intriguing finding from the classic mouse studies that showed fasting is related to better glycemic control, she observed.

The WHEL study is sponsored by the National Cancer Institute, the University of California at San Diego, and a Ruth L. Kirschstein National Research Service Award. Ms. Marinac reported having no financial conflicts of interest.

[email protected]

SAN ANTONIO – Breast cancer survivors who typically didn’t eat for at least 13 hours overnight had a 36% reduction in the risk of breast cancer recurrence compared to those with a shorter duration of overnight fasting in a secondary analysis of the Women’s Healthy Eating and Living Study presented at the San Antonio Breast Cancer Symposium.

“Prolonging the length of the nighttime fasting interval may be a simple nonpharmacologic strategy for reducing the risk of breast cancer recurrence as well as other chronic conditions with etiologic ties to breast cancer, like type 2 diabetes,” concluded to Catherine R. Marinac, a doctoral candidate in public health at the University of California, San Diego.

“A lot of dietary recommendations for cancer prevention really focus on what to eat in order to prevent or recover from breast cancer. For a lot of people that can be a really complicated recommendation, like ‘count your carbs, count your fat, don’t eat this/don’t eat that.’ We think timing of food intake in order to prolong the length of the nightly fasting interval can be a simple strategy most women can understand and adopt and that may reduce their risk of breast cancer,” she added.

The new results from the Women’s Healthy Eating and Living (WHEL) study are encouragingly consistent with the findings of earlier rodent studies demonstrating that intermittent fasting regimens aligned with the sleep cycle bring better glycemic control and protection against carcinogenesis, Ms. Marinac noted.

She presented an analysis of 2,413 nondiabetic breast cancer survivors who participated in the multicenter WHEL study and for whom multiple detailed 24-hour dietary recall records were obtained at baseline and 4 years of followup.

“The diets were very well characterized. We analyzed roughly 30,000 time-stamped dietary recalls,” she said in an interview.

During 7.3 years of follow-up, 390 women experienced recurrent breast cancer. Those in the top tertile for duration of overnight fasting, at 13 hours or longer, were 36% less likely to have a recurrence, according to a Cox proportionate hazard analysis and a multivariate linear regression analysis controlling for patient demographics; calorie consumption and other dietary variables; breast cancer stage, grade, and treatment; body mass index; comorbid conditions; and sleep duration.

During 11.4 years of follow-up, 329 subjects died of their breast cancer. All-cause mortality occurred in 420. Women with an overnight fasting duration of 13 hours or greater were 21% less likely to experience breast cancer mortality and 22% less likely to die of any cause. Neither trend achieved statistical significance.

Looking for potential mechanisms to explain the observed relationship between overnight fasting duration and breast cancer recurrence, Ms. Marinac and coinvestigators considered as evaluable possibilities systemic inflammation, glucoregulation, adiposity, and sleep duration.

C-reactive protein levels and body mass index proved to be unrelated to recurrence risk. However, glucoregulation and sleep duration were. Women with an overnight fasting length of at least 13 hours had a significantly lower glycated hemoglobin level and slept longer than those with a shorter overnight fast. The lower HbA_1c seen in women who fasted for longer at night mimics an intriguing finding from the classic mouse studies that showed fasting is related to better glycemic control, she observed.

The WHEL study is sponsored by the National Cancer Institute, the University of California at San Diego, and a Ruth L. Kirschstein National Research Service Award. Ms. Marinac reported having no financial conflicts of interest.

[email protected]

SAN ANTONIO – The late side effects of modern radiation therapy for breast cancer depend in part on a woman’s smoking status, suggests a meta-analysis of data from more than 40,000 women presented at the San Antonio Breast Cancer Symposium.

For nonsmokers, radiation therapy had little impact on the absolute risks of lung cancer or cardiac death, the main risks identified, which combined totaled less than 1%, Dr. Carolyn Taylor reported on behalf of the Early Breast Cancer Trialists’ Collaborative Group. But for women who had smoked throughout their adult life and continued to do so during and after treatment, it increased that absolute risk to roughly 2%.

“Smoking status can determine the net long-term effects of breast cancer radiotherapy on mortality. Stopping smoking at the time of radiotherapy may avoid much of the risk, and that’s because most of the risk of lung cancer starts more than 10 years after radiotherapy,” said Dr. Taylor, a radiation oncologist at the University of Oxford (England).

Radiation therapy remains an important tool in treating breast cancer, ultimately reducing the likelihood of death from the disease, she reminded symposium attendees. “The absolute benefit in women treated according to current guidelines is a few percent. Let’s remember the magnitude of that benefit as we think about the risks of radiotherapy.”

Attendee Dr. Steven Vogl of Montefiore Medical Center, New York, asked whether information was available on the location of the lung cancers that occurred in the trials.

“We didn’t have location of lung cancers. We didn’t even know if it was ipsilateral or contralateral to the previous breast cancer in this study,” Dr. Taylor replied. “But we’ve done other studies where we have known the location of the lung cancer, and there were similar findings in those studies.”

“In the last 4 years, we’ve had very good information that annual CT screening substantially and very quickly reduces the mortality from lung cancer,” Dr. Vogl added as a comment. “Any of us who care for patients who have been radiated where, really, any lung has been treated, who continue to smoke, should be screened – and screened and screened and screened again,” he recommended.

The investigators analyzed data from 40,781 women with breast cancer from 75 randomized trials conducted worldwide that compared outcomes with versus without radiation therapy. The median year of trial entry was 1983. On average, women in the trials received 10 Gy to both lungs combined and 6 Gy to the heart.

Comparing women who did and did not receive radiation therapy, the rate ratio for lung cancer was 2.10 at 10 or more years out, and the rate ratio for cardiac mortality was 1.30 overall. Given the mean radiation doses in the trials, the excess risk translated to 12% per Gray for lung cancer and 4% per Gray for cardiac mortality. “These rate ratios are likely to apply today,” Dr. Taylor maintained.

However, she noted, contemporary breast cancer radiation therapy techniques are much better at sparing normal tissues. To derive absolute risk estimates that are relevant today, she and her colleagues reviewed the literature for 2010-2015 and determined that women now receive an average of 5 Gy to both lungs combined and 4 Gy to the heart, with some centers achieving even lower values.

Among nonsmokers, the estimated cumulative 30-year risk of lung cancer was 0.5% for women who did not receive radiation therapy and 0.8% for those who received radiation therapy with a mean dose of 5 Gy to both lungs combined, Dr. Taylor reported. However, among long-term smokers, it was 9.4% without radiation and a substantially higher 13.8% with it.

Similarly, among nonsmokers, the estimated cumulative 30-year risk of ischemic heart disease death was 1.8% for women who did not receive radiation therapy and 2.0% for women who received radiation therapy with a mean dose of 2 Gy to the heart. Among long-term smokers, it was 8.0% without radiation and a slightly higher 8.6% with it.

Additional analyses looking at other late side effects showed no radiation therapy–related excess risk of sarcomas, according to Dr. Taylor. The risk of leukemia was increased with radiation, but actual numbers of cases were very small, she cautioned.

Attendee Dr. Pamela Goodwin, University of Toronto, said, “I’m just wondering whether you considered if it was valid to assume that there was a linear relationship between radiation dose and the risk of lung cancer in the range of radiation doses that you looked at, so, from the higher range in the earlier studies to the much lower dose now.”

Numbers of heart disease events were sufficient to establish a linear relationship, according to Dr. Taylor. Numbers of lung cancers were not, but case-control studies in the literature with adequate numbers have identified a linear relationship there, too. “We use what we can, and we have got now several hundred events, if you combine all of the literature together. And they do suggest the dose-response relationship is linear, but we can’t know that for certain,” she said.

SAN ANTONIO – The late side effects of modern radiation therapy for breast cancer depend in part on a woman’s smoking status, suggests a meta-analysis of data from more than 40,000 women presented at the San Antonio Breast Cancer Symposium.

For nonsmokers, radiation therapy had little impact on the absolute risks of lung cancer or cardiac death, the main risks identified, which combined totaled less than 1%, Dr. Carolyn Taylor reported on behalf of the Early Breast Cancer Trialists’ Collaborative Group. But for women who had smoked throughout their adult life and continued to do so during and after treatment, it increased that absolute risk to roughly 2%.

“Smoking status can determine the net long-term effects of breast cancer radiotherapy on mortality. Stopping smoking at the time of radiotherapy may avoid much of the risk, and that’s because most of the risk of lung cancer starts more than 10 years after radiotherapy,” said Dr. Taylor, a radiation oncologist at the University of Oxford (England).

Radiation therapy remains an important tool in treating breast cancer, ultimately reducing the likelihood of death from the disease, she reminded symposium attendees. “The absolute benefit in women treated according to current guidelines is a few percent. Let’s remember the magnitude of that benefit as we think about the risks of radiotherapy.”

Attendee Dr. Steven Vogl of Montefiore Medical Center, New York, asked whether information was available on the location of the lung cancers that occurred in the trials.

“We didn’t have location of lung cancers. We didn’t even know if it was ipsilateral or contralateral to the previous breast cancer in this study,” Dr. Taylor replied. “But we’ve done other studies where we have known the location of the lung cancer, and there were similar findings in those studies.”

“In the last 4 years, we’ve had very good information that annual CT screening substantially and very quickly reduces the mortality from lung cancer,” Dr. Vogl added as a comment. “Any of us who care for patients who have been radiated where, really, any lung has been treated, who continue to smoke, should be screened – and screened and screened and screened again,” he recommended.

The investigators analyzed data from 40,781 women with breast cancer from 75 randomized trials conducted worldwide that compared outcomes with versus without radiation therapy. The median year of trial entry was 1983. On average, women in the trials received 10 Gy to both lungs combined and 6 Gy to the heart.

Comparing women who did and did not receive radiation therapy, the rate ratio for lung cancer was 2.10 at 10 or more years out, and the rate ratio for cardiac mortality was 1.30 overall. Given the mean radiation doses in the trials, the excess risk translated to 12% per Gray for lung cancer and 4% per Gray for cardiac mortality. “These rate ratios are likely to apply today,” Dr. Taylor maintained.

However, she noted, contemporary breast cancer radiation therapy techniques are much better at sparing normal tissues. To derive absolute risk estimates that are relevant today, she and her colleagues reviewed the literature for 2010-2015 and determined that women now receive an average of 5 Gy to both lungs combined and 4 Gy to the heart, with some centers achieving even lower values.

Among nonsmokers, the estimated cumulative 30-year risk of lung cancer was 0.5% for women who did not receive radiation therapy and 0.8% for those who received radiation therapy with a mean dose of 5 Gy to both lungs combined, Dr. Taylor reported. However, among long-term smokers, it was 9.4% without radiation and a substantially higher 13.8% with it.

Similarly, among nonsmokers, the estimated cumulative 30-year risk of ischemic heart disease death was 1.8% for women who did not receive radiation therapy and 2.0% for women who received radiation therapy with a mean dose of 2 Gy to the heart. Among long-term smokers, it was 8.0% without radiation and a slightly higher 8.6% with it.

Additional analyses looking at other late side effects showed no radiation therapy–related excess risk of sarcomas, according to Dr. Taylor. The risk of leukemia was increased with radiation, but actual numbers of cases were very small, she cautioned.

Attendee Dr. Pamela Goodwin, University of Toronto, said, “I’m just wondering whether you considered if it was valid to assume that there was a linear relationship between radiation dose and the risk of lung cancer in the range of radiation doses that you looked at, so, from the higher range in the earlier studies to the much lower dose now.”

Numbers of heart disease events were sufficient to establish a linear relationship, according to Dr. Taylor. Numbers of lung cancers were not, but case-control studies in the literature with adequate numbers have identified a linear relationship there, too. “We use what we can, and we have got now several hundred events, if you combine all of the literature together. And they do suggest the dose-response relationship is linear, but we can’t know that for certain,” she said.

SAN ANTONIO – The late side effects of modern radiation therapy for breast cancer depend in part on a woman’s smoking status, suggests a meta-analysis of data from more than 40,000 women presented at the San Antonio Breast Cancer Symposium.

For nonsmokers, radiation therapy had little impact on the absolute risks of lung cancer or cardiac death, the main risks identified, which combined totaled less than 1%, Dr. Carolyn Taylor reported on behalf of the Early Breast Cancer Trialists’ Collaborative Group. But for women who had smoked throughout their adult life and continued to do so during and after treatment, it increased that absolute risk to roughly 2%.

“Smoking status can determine the net long-term effects of breast cancer radiotherapy on mortality. Stopping smoking at the time of radiotherapy may avoid much of the risk, and that’s because most of the risk of lung cancer starts more than 10 years after radiotherapy,” said Dr. Taylor, a radiation oncologist at the University of Oxford (England).

Radiation therapy remains an important tool in treating breast cancer, ultimately reducing the likelihood of death from the disease, she reminded symposium attendees. “The absolute benefit in women treated according to current guidelines is a few percent. Let’s remember the magnitude of that benefit as we think about the risks of radiotherapy.”

Attendee Dr. Steven Vogl of Montefiore Medical Center, New York, asked whether information was available on the location of the lung cancers that occurred in the trials.

“We didn’t have location of lung cancers. We didn’t even know if it was ipsilateral or contralateral to the previous breast cancer in this study,” Dr. Taylor replied. “But we’ve done other studies where we have known the location of the lung cancer, and there were similar findings in those studies.”

“In the last 4 years, we’ve had very good information that annual CT screening substantially and very quickly reduces the mortality from lung cancer,” Dr. Vogl added as a comment. “Any of us who care for patients who have been radiated where, really, any lung has been treated, who continue to smoke, should be screened – and screened and screened and screened again,” he recommended.

The investigators analyzed data from 40,781 women with breast cancer from 75 randomized trials conducted worldwide that compared outcomes with versus without radiation therapy. The median year of trial entry was 1983. On average, women in the trials received 10 Gy to both lungs combined and 6 Gy to the heart.

Comparing women who did and did not receive radiation therapy, the rate ratio for lung cancer was 2.10 at 10 or more years out, and the rate ratio for cardiac mortality was 1.30 overall. Given the mean radiation doses in the trials, the excess risk translated to 12% per Gray for lung cancer and 4% per Gray for cardiac mortality. “These rate ratios are likely to apply today,” Dr. Taylor maintained.

However, she noted, contemporary breast cancer radiation therapy techniques are much better at sparing normal tissues. To derive absolute risk estimates that are relevant today, she and her colleagues reviewed the literature for 2010-2015 and determined that women now receive an average of 5 Gy to both lungs combined and 4 Gy to the heart, with some centers achieving even lower values.

Among nonsmokers, the estimated cumulative 30-year risk of lung cancer was 0.5% for women who did not receive radiation therapy and 0.8% for those who received radiation therapy with a mean dose of 5 Gy to both lungs combined, Dr. Taylor reported. However, among long-term smokers, it was 9.4% without radiation and a substantially higher 13.8% with it.

Similarly, among nonsmokers, the estimated cumulative 30-year risk of ischemic heart disease death was 1.8% for women who did not receive radiation therapy and 2.0% for women who received radiation therapy with a mean dose of 2 Gy to the heart. Among long-term smokers, it was 8.0% without radiation and a slightly higher 8.6% with it.

Additional analyses looking at other late side effects showed no radiation therapy–related excess risk of sarcomas, according to Dr. Taylor. The risk of leukemia was increased with radiation, but actual numbers of cases were very small, she cautioned.

Attendee Dr. Pamela Goodwin, University of Toronto, said, “I’m just wondering whether you considered if it was valid to assume that there was a linear relationship between radiation dose and the risk of lung cancer in the range of radiation doses that you looked at, so, from the higher range in the earlier studies to the much lower dose now.”

Numbers of heart disease events were sufficient to establish a linear relationship, according to Dr. Taylor. Numbers of lung cancers were not, but case-control studies in the literature with adequate numbers have identified a linear relationship there, too. “We use what we can, and we have got now several hundred events, if you combine all of the literature together. And they do suggest the dose-response relationship is linear, but we can’t know that for certain,” she said.

SAN ANTONIO – In patients with triple-negative breast cancer, the presence of a mutation in the breast cancer susceptibility genes BRCA1 and BRCA2 appears helpful for identifying those who will benefit from neoadjuvant chemotherapy but not very helpful for estimating prognosis, finds a subgroup analysis from the GeparQuinto trial.

Dr. Peter A. Fasching and colleagues studied 471 patients with triple-negative disease who were treated with neoadjuvant therapy in the trial, underwent surgery, and did not receive any postoperative therapy.

©SilverV/Thinkstock.com

Prospectively specified genome-wide association studies showed that 17.4% of the patients had a BRCA1/2 mutation, he reported at the San Antonio Breast Cancer Symposium.

The rate of pathologic complete response (pCR), defined as ypT0/ypN0 stage, was 50% in the patients with a mutation, compared with 30.8% in those with wild-type genes (P = .001).

The patients with a mutation also had better disease-free survival than their wild-type peers (hazard ratio, 0.64), but this difference missed statistical significance (P = .06).

“BRCA mutation carriers had a significantly higher pathologic complete response rate after neoadjuvant chemotherapy,” commented Dr. Fasching, an oncologist the University Hospital Erlangen (Germany), Comprehensive Cancer Center Erlangen-EMN. “And BRCA mutation carriers had a better prognosis.”

Attendee Dr. George Somlo of City of Hope, Duarte, California, wondered if surgical management played a role in the findings. “Can you clarify…whether mastectomies on the ipsilateral side or contralateral side had any effect on the disease-free survival, since I assume once the mutations were known, other interventions might have taken place?”

“Unfortunately, I cannot,” Dr. Fasching replied. “We did not extend the exploratory analysis to that subpoint.”

Giving some background to the analysis, he commented, “Neoadjuvant studies may serve as a very good research ground to look for answers to both questions: whether BRCA mutation status predicts response to a chemotherapy and, furthermore, whether this translates into a prognostic effect.”

All patients with triple-negative disease in the GeparQuinto randomized phase III trial received neoadjuvant chemotherapy (epirubicin, cyclophosphamide, and docetaxel), with or without the antiangiogenic antibody bevacizumab (Avastin).

Additional findings showed that among BRCA mutation carriers, a pCR was not significantly associated with better disease-free survival. In contrast, among patients with wild-type genes, it was associated with a sharply reduced risk of events (HR, 0.21; P less than .0001). However, the interaction was not statistically significant.

“The prognostic information of pCR with regard to prognosis appeared to be somewhat weaker in patients with a BRCA mutation, compared to wild-type patients, but you have to keep in mind the test for interaction in this exploratory analysis was not significant,” Dr. Fasching commented.

The investigators also performed exploratory analyses looking at the impact of achieving a pCR in each treatment arm.

As far as a rationale, hypoxia is known to cause DNA damage, and synthetic lethality has been described in BRCA mutation carriers, Dr. Fasching explained. “There are some data that show that angiogenic factors are as a matter of fact increased in tumors with a BRCA mutation, compared to wild-type patients,” he added.

Results here showed that addition of bevacizumab improved pCR rate among both BRCA1/2 mutation carriers (65.7% vs. 38.3%, P = .025) and patients with wild-type (35.8% vs. 26.2%, P = .048). But addition of bevacizumab did not significantly improve disease-free survival in either group.

SAN ANTONIO – In patients with triple-negative breast cancer, the presence of a mutation in the breast cancer susceptibility genes BRCA1 and BRCA2 appears helpful for identifying those who will benefit from neoadjuvant chemotherapy but not very helpful for estimating prognosis, finds a subgroup analysis from the GeparQuinto trial.

Dr. Peter A. Fasching and colleagues studied 471 patients with triple-negative disease who were treated with neoadjuvant therapy in the trial, underwent surgery, and did not receive any postoperative therapy.

©SilverV/Thinkstock.com

Prospectively specified genome-wide association studies showed that 17.4% of the patients had a BRCA1/2 mutation, he reported at the San Antonio Breast Cancer Symposium.

The rate of pathologic complete response (pCR), defined as ypT0/ypN0 stage, was 50% in the patients with a mutation, compared with 30.8% in those with wild-type genes (P = .001).

The patients with a mutation also had better disease-free survival than their wild-type peers (hazard ratio, 0.64), but this difference missed statistical significance (P = .06).

“BRCA mutation carriers had a significantly higher pathologic complete response rate after neoadjuvant chemotherapy,” commented Dr. Fasching, an oncologist the University Hospital Erlangen (Germany), Comprehensive Cancer Center Erlangen-EMN. “And BRCA mutation carriers had a better prognosis.”

Attendee Dr. George Somlo of City of Hope, Duarte, California, wondered if surgical management played a role in the findings. “Can you clarify…whether mastectomies on the ipsilateral side or contralateral side had any effect on the disease-free survival, since I assume once the mutations were known, other interventions might have taken place?”

“Unfortunately, I cannot,” Dr. Fasching replied. “We did not extend the exploratory analysis to that subpoint.”

Giving some background to the analysis, he commented, “Neoadjuvant studies may serve as a very good research ground to look for answers to both questions: whether BRCA mutation status predicts response to a chemotherapy and, furthermore, whether this translates into a prognostic effect.”

All patients with triple-negative disease in the GeparQuinto randomized phase III trial received neoadjuvant chemotherapy (epirubicin, cyclophosphamide, and docetaxel), with or without the antiangiogenic antibody bevacizumab (Avastin).

Additional findings showed that among BRCA mutation carriers, a pCR was not significantly associated with better disease-free survival. In contrast, among patients with wild-type genes, it was associated with a sharply reduced risk of events (HR, 0.21; P less than .0001). However, the interaction was not statistically significant.

“The prognostic information of pCR with regard to prognosis appeared to be somewhat weaker in patients with a BRCA mutation, compared to wild-type patients, but you have to keep in mind the test for interaction in this exploratory analysis was not significant,” Dr. Fasching commented.

The investigators also performed exploratory analyses looking at the impact of achieving a pCR in each treatment arm.

As far as a rationale, hypoxia is known to cause DNA damage, and synthetic lethality has been described in BRCA mutation carriers, Dr. Fasching explained. “There are some data that show that angiogenic factors are as a matter of fact increased in tumors with a BRCA mutation, compared to wild-type patients,” he added.

Results here showed that addition of bevacizumab improved pCR rate among both BRCA1/2 mutation carriers (65.7% vs. 38.3%, P = .025) and patients with wild-type (35.8% vs. 26.2%, P = .048). But addition of bevacizumab did not significantly improve disease-free survival in either group.

SAN ANTONIO – In patients with triple-negative breast cancer, the presence of a mutation in the breast cancer susceptibility genes BRCA1 and BRCA2 appears helpful for identifying those who will benefit from neoadjuvant chemotherapy but not very helpful for estimating prognosis, finds a subgroup analysis from the GeparQuinto trial.

Dr. Peter A. Fasching and colleagues studied 471 patients with triple-negative disease who were treated with neoadjuvant therapy in the trial, underwent surgery, and did not receive any postoperative therapy.

©SilverV/Thinkstock.com

Prospectively specified genome-wide association studies showed that 17.4% of the patients had a BRCA1/2 mutation, he reported at the San Antonio Breast Cancer Symposium.

The rate of pathologic complete response (pCR), defined as ypT0/ypN0 stage, was 50% in the patients with a mutation, compared with 30.8% in those with wild-type genes (P = .001).

The patients with a mutation also had better disease-free survival than their wild-type peers (hazard ratio, 0.64), but this difference missed statistical significance (P = .06).

“BRCA mutation carriers had a significantly higher pathologic complete response rate after neoadjuvant chemotherapy,” commented Dr. Fasching, an oncologist the University Hospital Erlangen (Germany), Comprehensive Cancer Center Erlangen-EMN. “And BRCA mutation carriers had a better prognosis.”

Attendee Dr. George Somlo of City of Hope, Duarte, California, wondered if surgical management played a role in the findings. “Can you clarify…whether mastectomies on the ipsilateral side or contralateral side had any effect on the disease-free survival, since I assume once the mutations were known, other interventions might have taken place?”

“Unfortunately, I cannot,” Dr. Fasching replied. “We did not extend the exploratory analysis to that subpoint.”

Giving some background to the analysis, he commented, “Neoadjuvant studies may serve as a very good research ground to look for answers to both questions: whether BRCA mutation status predicts response to a chemotherapy and, furthermore, whether this translates into a prognostic effect.”

All patients with triple-negative disease in the GeparQuinto randomized phase III trial received neoadjuvant chemotherapy (epirubicin, cyclophosphamide, and docetaxel), with or without the antiangiogenic antibody bevacizumab (Avastin).

Additional findings showed that among BRCA mutation carriers, a pCR was not significantly associated with better disease-free survival. In contrast, among patients with wild-type genes, it was associated with a sharply reduced risk of events (HR, 0.21; P less than .0001). However, the interaction was not statistically significant.

“The prognostic information of pCR with regard to prognosis appeared to be somewhat weaker in patients with a BRCA mutation, compared to wild-type patients, but you have to keep in mind the test for interaction in this exploratory analysis was not significant,” Dr. Fasching commented.

The investigators also performed exploratory analyses looking at the impact of achieving a pCR in each treatment arm.

As far as a rationale, hypoxia is known to cause DNA damage, and synthetic lethality has been described in BRCA mutation carriers, Dr. Fasching explained. “There are some data that show that angiogenic factors are as a matter of fact increased in tumors with a BRCA mutation, compared to wild-type patients,” he added.

Results here showed that addition of bevacizumab improved pCR rate among both BRCA1/2 mutation carriers (65.7% vs. 38.3%, P = .025) and patients with wild-type (35.8% vs. 26.2%, P = .048). But addition of bevacizumab did not significantly improve disease-free survival in either group.

SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab appears safe and modestly active in women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer that expresses programmed death–ligand 1 (PD-L1), according to preliminary results of a phase Ib trial presented at the San Antonio Breast Cancer Symposium.

Nineteen percent of women screened for the trial, KEYNOTE-028, had archival or fresh tumors from nonirradiated sites that tested positive for this ligand by immunohistochemistry, reported lead investigator Dr. Hope S. Rugo, clinical professor in the department of medicine (hematology/oncology) and director of the breast oncology clinical trials program at the University of California, San Francisco.

A total of 25 of these women received at least one dose of pembrolizumab (Keytruda), an antibody to the PD-1 (programmed death–1) cell surface receptor that blocks interaction of the receptor with its ligands, thereby preventing the inactivation of T cells. (The antibody is currently approved by the Food and Drug Administration for the treatment of melanoma and non–small cell lung cancer.)

With a median duration of follow-up of 7.3 months, the overall response rate as assessed by investigators using RECIST criteria was 12%, and the clinical benefit rate was 20%, Dr. Rugo reported. Responses were durable, lasting anywhere from about 9 weeks to more than 44 weeks.

The rate of grade 3 or 4 adverse events was 16%. Only a single patient had to have interruption of pembrolizumab because of the development of an immune adverse event.

“Based on these data, we believe that further investigation of immune therapies in ER-positive, HER2-negative breast cancer, particularly using combination therapies that can expand the T-cell compartment, are warranted,” Dr. Rugo maintained.

She noted that the trial’s findings differ somewhat from those of a similar trial testing avelumab, an investigational antibody against the PD-L1 ligand itself, that was presented at the symposium (abstract S1-04). That trial found a much higher PD-L1 positivity rate in screened women, 55%, and a much lower overall response rate, 3%.

These differences may have been due to use of different immunohistochemical assays for PD-L1, lack of data for some patients in the other trial, and/or differences in the target of the agent used (PD-1 vs PD-L1), she speculated. “It’s clear that as we move forward in this field of immunotherapy, which we are all very excited about, that standardization of assays assessing PD-L1 positivity are going to be critical,” she concluded.

“After how many studies will we be convinced [given] the discordance between different antibodies [and] scoring mechanisms, and the very, very weak enrichment in responders, that PD-L1 staining is not an adequate biomarker for these agents?” asked session attendee Justin Balko, Pharm.D., Ph.D., of Vanderbilt University, Nashville, Tenn.

“I think that we are going to need a consortium as well as development of guidelines for the best methods to test PD-L1 expression, whether that’s an immunohistochemical test, looking at mRNA, or looking at pathway activation,” Dr. Rugo replied. “Whether we need to include for example TILs [tumor-infiltrating lymphocytes] in evaluation or quantification of lymphocytes, which may or may not be practical, remains to be seen,” she said, adding that this research will require a collaborative effort.

Another attendee speculated that the disparate findings for the two trials may have been due to reliance on RECIST criteria in the KEYNOTE-028 trial. “I wonder if you had the opportunity to explore any of the immune-related response criteria that have been evaluated in other settings like melanoma,” she said.

“As a breast cancer field in immunotherapy, we are kind of behind everybody else, and we are just now starting to use immune RECIST as part of our assessments for the studies going on now prospectively in breast cancer,” Dr. Rugo replied. “ So no, we didn’t use immune RECIST. But it’s an interesting area to go back and look at, to see whether or not we can reclassify any of the responses.”

Giving some background to the research, she noted that PD-L1 expression has been inversely correlated with ER expression. A previous trial found an overall response rate of about 19% in triple-negative breast cancer (SABCS 2014, abstract S1-09).

For KEYNOTE-028, patients were screened for PD-L1 positivity, even though pembrolizumab targets PD-1, because there is much greater variability in ligand levels than in receptor levels when it comes to determining T cell inactivation, Dr. Rugo explained.

Fully 80% of the 25 women treated had received three or more prior lines of therapy for their advanced disease. They were give pembrolizumab every 2 weeks with assessments every 8 weeks initially.

The grade 3 or 4 adverse events observed were cases of autoimmune hepatitis, increased gamma-glutamyl transferase levels, muscle weakness, nausea, and septic shock. However, there were no treatment-related deaths.

In patients who developed any-grade immune-related adverse events of interest, just one – a patient with autoimmune hepatitis – had to have treatment interruption.

All of the responses observed were partial responses. The median time to response was 8 weeks, and the median duration of response was not reached, with a range from about 9 to 44 weeks. The three patients with a response had been in the study for at least 26 weeks as of the data cutoff for analysis.

“Cost is an issue with these drugs,” said attendee Dr. Mark Graham II, an oncologist with Waverly Hematology Oncology, Cary, N.C. “I’m particularly interested in your nonresponders and the fact that we can see pseudoprogression with these drugs. So for the eventual nonresponders, …what is the likely number of cycles that will be necessary to conclude that a patient is not an initial responder?”

That number is difficult to accurately pin down, as patients in the trial were taken off the agent as early as 8 weeks along if they had any evidence of progression, Dr. Rugo said. “I really don’t think we know the answer yet, but if you went out to 16 weeks, all the patients that we saw who were going to respond had responded by 16 weeks.”

An accurate answer will likely require future studies, she added. “I think it’s most complicated in triple-negative disease, where a small phase Ib trial showed a very long median time to response. So this is a good question and it remains to be answered.”

If sufficient tissue is available, the investigators plan to look for other biomarkers of pembrolizumab benefit, such as proliferation markers and intrinsic subtype, according to Dr. Rugo. “Probably those more in-depth investigations are going to occur with future studies, just because of the need to acquire enough tissue to do them. This trial was exploratory,” she said.

Dr. Rugo disclosed that her institution receives research funding from Merck & Co. – the trial sponsor – and Genentech.

SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab appears safe and modestly active in women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer that expresses programmed death–ligand 1 (PD-L1), according to preliminary results of a phase Ib trial presented at the San Antonio Breast Cancer Symposium.

Nineteen percent of women screened for the trial, KEYNOTE-028, had archival or fresh tumors from nonirradiated sites that tested positive for this ligand by immunohistochemistry, reported lead investigator Dr. Hope S. Rugo, clinical professor in the department of medicine (hematology/oncology) and director of the breast oncology clinical trials program at the University of California, San Francisco.

A total of 25 of these women received at least one dose of pembrolizumab (Keytruda), an antibody to the PD-1 (programmed death–1) cell surface receptor that blocks interaction of the receptor with its ligands, thereby preventing the inactivation of T cells. (The antibody is currently approved by the Food and Drug Administration for the treatment of melanoma and non–small cell lung cancer.)

With a median duration of follow-up of 7.3 months, the overall response rate as assessed by investigators using RECIST criteria was 12%, and the clinical benefit rate was 20%, Dr. Rugo reported. Responses were durable, lasting anywhere from about 9 weeks to more than 44 weeks.

The rate of grade 3 or 4 adverse events was 16%. Only a single patient had to have interruption of pembrolizumab because of the development of an immune adverse event.

“Based on these data, we believe that further investigation of immune therapies in ER-positive, HER2-negative breast cancer, particularly using combination therapies that can expand the T-cell compartment, are warranted,” Dr. Rugo maintained.

She noted that the trial’s findings differ somewhat from those of a similar trial testing avelumab, an investigational antibody against the PD-L1 ligand itself, that was presented at the symposium (abstract S1-04). That trial found a much higher PD-L1 positivity rate in screened women, 55%, and a much lower overall response rate, 3%.

These differences may have been due to use of different immunohistochemical assays for PD-L1, lack of data for some patients in the other trial, and/or differences in the target of the agent used (PD-1 vs PD-L1), she speculated. “It’s clear that as we move forward in this field of immunotherapy, which we are all very excited about, that standardization of assays assessing PD-L1 positivity are going to be critical,” she concluded.

“After how many studies will we be convinced [given] the discordance between different antibodies [and] scoring mechanisms, and the very, very weak enrichment in responders, that PD-L1 staining is not an adequate biomarker for these agents?” asked session attendee Justin Balko, Pharm.D., Ph.D., of Vanderbilt University, Nashville, Tenn.

“I think that we are going to need a consortium as well as development of guidelines for the best methods to test PD-L1 expression, whether that’s an immunohistochemical test, looking at mRNA, or looking at pathway activation,” Dr. Rugo replied. “Whether we need to include for example TILs [tumor-infiltrating lymphocytes] in evaluation or quantification of lymphocytes, which may or may not be practical, remains to be seen,” she said, adding that this research will require a collaborative effort.

Another attendee speculated that the disparate findings for the two trials may have been due to reliance on RECIST criteria in the KEYNOTE-028 trial. “I wonder if you had the opportunity to explore any of the immune-related response criteria that have been evaluated in other settings like melanoma,” she said.

“As a breast cancer field in immunotherapy, we are kind of behind everybody else, and we are just now starting to use immune RECIST as part of our assessments for the studies going on now prospectively in breast cancer,” Dr. Rugo replied. “ So no, we didn’t use immune RECIST. But it’s an interesting area to go back and look at, to see whether or not we can reclassify any of the responses.”

Giving some background to the research, she noted that PD-L1 expression has been inversely correlated with ER expression. A previous trial found an overall response rate of about 19% in triple-negative breast cancer (SABCS 2014, abstract S1-09).

For KEYNOTE-028, patients were screened for PD-L1 positivity, even though pembrolizumab targets PD-1, because there is much greater variability in ligand levels than in receptor levels when it comes to determining T cell inactivation, Dr. Rugo explained.

Fully 80% of the 25 women treated had received three or more prior lines of therapy for their advanced disease. They were give pembrolizumab every 2 weeks with assessments every 8 weeks initially.

The grade 3 or 4 adverse events observed were cases of autoimmune hepatitis, increased gamma-glutamyl transferase levels, muscle weakness, nausea, and septic shock. However, there were no treatment-related deaths.

In patients who developed any-grade immune-related adverse events of interest, just one – a patient with autoimmune hepatitis – had to have treatment interruption.

All of the responses observed were partial responses. The median time to response was 8 weeks, and the median duration of response was not reached, with a range from about 9 to 44 weeks. The three patients with a response had been in the study for at least 26 weeks as of the data cutoff for analysis.

“Cost is an issue with these drugs,” said attendee Dr. Mark Graham II, an oncologist with Waverly Hematology Oncology, Cary, N.C. “I’m particularly interested in your nonresponders and the fact that we can see pseudoprogression with these drugs. So for the eventual nonresponders, …what is the likely number of cycles that will be necessary to conclude that a patient is not an initial responder?”

That number is difficult to accurately pin down, as patients in the trial were taken off the agent as early as 8 weeks along if they had any evidence of progression, Dr. Rugo said. “I really don’t think we know the answer yet, but if you went out to 16 weeks, all the patients that we saw who were going to respond had responded by 16 weeks.”

An accurate answer will likely require future studies, she added. “I think it’s most complicated in triple-negative disease, where a small phase Ib trial showed a very long median time to response. So this is a good question and it remains to be answered.”

If sufficient tissue is available, the investigators plan to look for other biomarkers of pembrolizumab benefit, such as proliferation markers and intrinsic subtype, according to Dr. Rugo. “Probably those more in-depth investigations are going to occur with future studies, just because of the need to acquire enough tissue to do them. This trial was exploratory,” she said.

Dr. Rugo disclosed that her institution receives research funding from Merck & Co. – the trial sponsor – and Genentech.

SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab appears safe and modestly active in women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer that expresses programmed death–ligand 1 (PD-L1), according to preliminary results of a phase Ib trial presented at the San Antonio Breast Cancer Symposium.

Nineteen percent of women screened for the trial, KEYNOTE-028, had archival or fresh tumors from nonirradiated sites that tested positive for this ligand by immunohistochemistry, reported lead investigator Dr. Hope S. Rugo, clinical professor in the department of medicine (hematology/oncology) and director of the breast oncology clinical trials program at the University of California, San Francisco.

A total of 25 of these women received at least one dose of pembrolizumab (Keytruda), an antibody to the PD-1 (programmed death–1) cell surface receptor that blocks interaction of the receptor with its ligands, thereby preventing the inactivation of T cells. (The antibody is currently approved by the Food and Drug Administration for the treatment of melanoma and non–small cell lung cancer.)

With a median duration of follow-up of 7.3 months, the overall response rate as assessed by investigators using RECIST criteria was 12%, and the clinical benefit rate was 20%, Dr. Rugo reported. Responses were durable, lasting anywhere from about 9 weeks to more than 44 weeks.

The rate of grade 3 or 4 adverse events was 16%. Only a single patient had to have interruption of pembrolizumab because of the development of an immune adverse event.

“Based on these data, we believe that further investigation of immune therapies in ER-positive, HER2-negative breast cancer, particularly using combination therapies that can expand the T-cell compartment, are warranted,” Dr. Rugo maintained.

She noted that the trial’s findings differ somewhat from those of a similar trial testing avelumab, an investigational antibody against the PD-L1 ligand itself, that was presented at the symposium (abstract S1-04). That trial found a much higher PD-L1 positivity rate in screened women, 55%, and a much lower overall response rate, 3%.

These differences may have been due to use of different immunohistochemical assays for PD-L1, lack of data for some patients in the other trial, and/or differences in the target of the agent used (PD-1 vs PD-L1), she speculated. “It’s clear that as we move forward in this field of immunotherapy, which we are all very excited about, that standardization of assays assessing PD-L1 positivity are going to be critical,” she concluded.

“After how many studies will we be convinced [given] the discordance between different antibodies [and] scoring mechanisms, and the very, very weak enrichment in responders, that PD-L1 staining is not an adequate biomarker for these agents?” asked session attendee Justin Balko, Pharm.D., Ph.D., of Vanderbilt University, Nashville, Tenn.

“I think that we are going to need a consortium as well as development of guidelines for the best methods to test PD-L1 expression, whether that’s an immunohistochemical test, looking at mRNA, or looking at pathway activation,” Dr. Rugo replied. “Whether we need to include for example TILs [tumor-infiltrating lymphocytes] in evaluation or quantification of lymphocytes, which may or may not be practical, remains to be seen,” she said, adding that this research will require a collaborative effort.

Another attendee speculated that the disparate findings for the two trials may have been due to reliance on RECIST criteria in the KEYNOTE-028 trial. “I wonder if you had the opportunity to explore any of the immune-related response criteria that have been evaluated in other settings like melanoma,” she said.

“As a breast cancer field in immunotherapy, we are kind of behind everybody else, and we are just now starting to use immune RECIST as part of our assessments for the studies going on now prospectively in breast cancer,” Dr. Rugo replied. “ So no, we didn’t use immune RECIST. But it’s an interesting area to go back and look at, to see whether or not we can reclassify any of the responses.”

Giving some background to the research, she noted that PD-L1 expression has been inversely correlated with ER expression. A previous trial found an overall response rate of about 19% in triple-negative breast cancer (SABCS 2014, abstract S1-09).

For KEYNOTE-028, patients were screened for PD-L1 positivity, even though pembrolizumab targets PD-1, because there is much greater variability in ligand levels than in receptor levels when it comes to determining T cell inactivation, Dr. Rugo explained.

Fully 80% of the 25 women treated had received three or more prior lines of therapy for their advanced disease. They were give pembrolizumab every 2 weeks with assessments every 8 weeks initially.

The grade 3 or 4 adverse events observed were cases of autoimmune hepatitis, increased gamma-glutamyl transferase levels, muscle weakness, nausea, and septic shock. However, there were no treatment-related deaths.

In patients who developed any-grade immune-related adverse events of interest, just one – a patient with autoimmune hepatitis – had to have treatment interruption.

All of the responses observed were partial responses. The median time to response was 8 weeks, and the median duration of response was not reached, with a range from about 9 to 44 weeks. The three patients with a response had been in the study for at least 26 weeks as of the data cutoff for analysis.

“Cost is an issue with these drugs,” said attendee Dr. Mark Graham II, an oncologist with Waverly Hematology Oncology, Cary, N.C. “I’m particularly interested in your nonresponders and the fact that we can see pseudoprogression with these drugs. So for the eventual nonresponders, …what is the likely number of cycles that will be necessary to conclude that a patient is not an initial responder?”

That number is difficult to accurately pin down, as patients in the trial were taken off the agent as early as 8 weeks along if they had any evidence of progression, Dr. Rugo said. “I really don’t think we know the answer yet, but if you went out to 16 weeks, all the patients that we saw who were going to respond had responded by 16 weeks.”

An accurate answer will likely require future studies, she added. “I think it’s most complicated in triple-negative disease, where a small phase Ib trial showed a very long median time to response. So this is a good question and it remains to be answered.”

If sufficient tissue is available, the investigators plan to look for other biomarkers of pembrolizumab benefit, such as proliferation markers and intrinsic subtype, according to Dr. Rugo. “Probably those more in-depth investigations are going to occur with future studies, just because of the need to acquire enough tissue to do them. This trial was exploratory,” she said.

Dr. Rugo disclosed that her institution receives research funding from Merck & Co. – the trial sponsor – and Genentech.

SAN ANTONIO – The worldwide upsurge in bilateral mastectomy for unilateral breast cancer in the last decade came under withering fire from prominent breast surgeons at the San Antonio Breast Cancer Symposium.

“It seems crazy, doesn’t it, that we’re spending all this time trying to conserve the breast, yet we’re facing a tsunami of requests for bilateral mastectomy,” observed Dr. Fiona MacNeill, chairman of the education and training committee of the Royal College of Surgeons of England.

“A contralateral risk–reducing prophylactic mastectomy undoubtedly will reduce the risk of contralateral breast cancer, since you’re removing the breast, but this is overtreatment for the vast majority of women who request it. At 20 years we haven’t been able to demonstrate that it offers a significant survival advantage. I think a lot of what’s driving bilateral mastectomy is fear and ignorance, a failure to understand risk by patients and often by health professionals,” said Dr. MacNeill, a breast surgeon at Royal Marsden Hospital in London.

In an invited special lecture titled, “Less is more: minimizing breast cancer surgery,” Dr. MacNeill began by observing, “Only a surgeon could give this talk, because only a surgeon can tell you why we’re doing too much surgery.”

She stressed three main points: surgery is, as she put it, “a medieval treatment in a molecular era.” Overwhelming evidence shows that breast cancer outcomes are determined by disease biology, burden, and response to systemic therapy and not by the extent of surgery. And since there is no survival benefit for more aggressive surgery, the surgeon’s goal must be to optimize breast and axillary conservation.

Bruce Jancin/Frontline Medical News

In a separate presentation, Dr. Ismail Jatoi, professor and chief of surgical oncology at the University of Texas, San Antonio, outlined trends in surgical treatment of early-stage breast cancer as documented in a recent major retrospective study conducted in Tennessee of 1.2 million women treated at accredited U.S. breast cancer centers during 1998-2011.

The Tennessee investigators’ analysis points to a polarization in surgical therapy: The rate of unilateral mastectomy without reconstruction has dropped steadily since the beginning of the study period in 1998 among women eligible for breast-conserving surgery (BCS), while starting around 2006 the rate of bilateral mastectomy with reconstruction has surged. This increase in bilateral mastectomies with reconstruction resulted in an adjusted 34% jump in the overall mastectomy rate during 2004-2011 as compared with 1998-2003. As a result, in 2011 nearly 40% of women with early breast cancer underwent mastectomy. Meanwhile, the rate of BCS has been waning since 2006 (JAMA Surg. 2015 Jan;150[1]:9-16).

These disturbing trends have been fueled in part by at least eight published observational studies reporting improved survival with contralateral prophylactic mastectomy (CPM) as compared with unilateral mastectomy or BCS. But these were all observational studies and hence likely compromised by unmeasured confounders, according to Dr. Jatoi.

He presented highlights of his study of National Cancer Institute Surveillance, Epidemiology, and End Results data to support his recommendation that these observational studies be taken with a grain of salt.

His study included nearly 26,000 women who underwent CPM and more than 400,000 who did not. In a multivariate regression analysis adjusted for age, race, tumor stage, hormone receptor status, and histologic grade, CPM was associated with a statistically significant and impressive-sounding 16% reduction in the 5-year risk of breast cancer–specific mortality, a 17% reduction in overall mortality, and … a highly improbable 29% reduction in noncancer mortality (Breast Cancer Res Treat. 2014 Nov;148[2]:389-96).

“Obviously bilateral mastectomy is not going to reduce your risk of dying of heart attack or stroke or other noncancer causes. So even though we adjusted for everything possible in the SEER database, it suggests there were still unmeasured confounders. What this study shows is that it’s these unmeasured confounders that pose a threat to the validity of observational studies,” the surgeon said.

“Randomized data and observational studies consistently show that breast-conserving surgery is the optimal choice for most patients. It’s the safest choice, it’s cost effective, and it should remain in 2015 the optimal treatment for breast cancer,” he declared.

The cost-effectiveness of BCS was underscored during the symposium by means of a retrospective study presented by Dr. Benjamin D. Smith.

Bruce Jancin/Frontline Medical News

He and his coinvestigators analyzed costs and complication rates in the first 2 years following diagnosis of early-stage breast cancer in 44,344 patients under age 65 in the MarketScan database and almost 61,000 older women in the SEER-Medicare database.

The 2-year complication rate related to local therapy in younger breast cancer patients ranged from 30% for lumpectomy plus whole breast irradiation to 56% for mastectomy plus reconstruction. In older patients, the complication rates were 38% for lumpectomy plus whole breast irradiation and 69% for mastectomy plus reconstruction.

Adding together procedural and complication costs, the most expensive therapy in younger women was mastectomy with reconstruction, at an average of $89,140, which was $23,421 more than for lumpectomy plus whole breast irradiation, according to Dr. Smith, a radiation oncologist at MD Anderson Cancer Center in Houston.

“When oncologists offer all appropriate therapy options to patients, some women may choose to avoid radiation and opt for mastectomy and reconstruction instead. This study is helpful to such patients because it provides them with information regarding the trade-offs involved in this choice,” he explained.

Dr. MacNeill noted that in addition to the increased financial cost and physical complication rate entailed by mastectomy plus reconstruction for early breast cancer, this more aggressive surgery has another important unwelcome consequence: it delays the start of adjuvant therapy, which is the intervention that truly affects outcome.

Many women who opt for CPM do so because they can’t face the prospect of going through chemotherapy again should cancer arise in the contralateral breast. What’s often overlooked, she continued, is that the greatest risks of death or need for further systemic treatment due to relapse arise from the index cancer.

“We overestimate our patients’ contralateral risk, we underestimate the risk of dying from relapse of the index cancer, and we very often fail to consider other competing health risks from smoking, obesity, age, and other factors,” according to Dr. MacNeill.

“It’s not as if additional surgery is risk-free. A bilateral mastectomy carries bilateral complications. Our patients expect a perfect outcome because that’s what they see on television, but the reality is that for some women the results can be absolutely disastrous. Whilst women may not regret their choice for bilateral mastectomy with reconstruction because they think it’s lifesaving, the psychosexual impact is phenomenal,” she said.

That being said, Dr. MacNeill continued, “the elephant in the room” regarding BCS is that re-excision rates of up to 40% are common. This high rate of repeat surgery is a huge issue because of the resultant increased costs, morbidity, poor cosmesis, increased risk of mastectomy, and delay to adjuvant therapy.

High re-excision rates aren’t due to surgical incompetence, Dr. MacNeill stressed, but rather to the difficulty in defining microscopic disease intraoperatively. But help is on the way. Several novel approaches that facilitate lower re-excision rates and more breast conservation show considerable promise.

For example, investigators at Yale University have recently demonstrated in a randomized controlled trial that routine intraoperative cavity shave margins taken circumferentially halved the re-excision rate, from 21% to 10% (N Engl J Med. 2015 Aug 6;373[6]:503-10).

A meta-analysis of studies that included nearly 9,000 breast cancer patients who underwent BCS alone or BCS with oncoplastic breast conservation techniques concluded that the re-excision rate was just 4.3% in women who underwent oncoplastic breast conservation, compared with 14.6% with BCS alone (Ann Plast Surg. 2014 Feb;72[2]:145-9).

“This is going to be a driver for many breast cancer units to look at how they can use oncoplastic breast conservation to bring down their resection rates,” Dr. MacNeill predicted.

Neoadjuvant chemotherapy or endocrine therapy, a strategy in which surgery becomes adjuvant therapy, is likely to play an important role in facilitating breast conservation in the future. In the CALGB 40603 trial, for example, neoadjuvant chemotherapy in women with triple-negative breast cancer resulted in an absolute 14% increase in eligibility for BCS. Moreover, BCS was successful with no re-excision in 93% of treated patients (Ann Surg. 2015 Sep;262[3]:434-9).

The ‘less is more’ movement in breast cancer surgery may in the future mean no surgery at all in certain cases. Now underway in the United Kingdom is LORIS (the Low Risk DCIS Trial), in which women with low-risk DCIS are being randomized to surgery or 10 years of monitoring via annual mammograms.

“I’m suggesting that surgery may not exist in the longer term,” Dr. MacNeill said.

She, Dr. Jatoi, and Dr. Smith reported having no financial conflicts regarding their presentations. Dr. Smith’s study was supported by the Cancer Prevention and Research Institute of Texas, the Conquer Cancer Foundation, and the American Society for Radiation Oncology.

[email protected]

SAN ANTONIO – The worldwide upsurge in bilateral mastectomy for unilateral breast cancer in the last decade came under withering fire from prominent breast surgeons at the San Antonio Breast Cancer Symposium.

“It seems crazy, doesn’t it, that we’re spending all this time trying to conserve the breast, yet we’re facing a tsunami of requests for bilateral mastectomy,” observed Dr. Fiona MacNeill, chairman of the education and training committee of the Royal College of Surgeons of England.

“A contralateral risk–reducing prophylactic mastectomy undoubtedly will reduce the risk of contralateral breast cancer, since you’re removing the breast, but this is overtreatment for the vast majority of women who request it. At 20 years we haven’t been able to demonstrate that it offers a significant survival advantage. I think a lot of what’s driving bilateral mastectomy is fear and ignorance, a failure to understand risk by patients and often by health professionals,” said Dr. MacNeill, a breast surgeon at Royal Marsden Hospital in London.

In an invited special lecture titled, “Less is more: minimizing breast cancer surgery,” Dr. MacNeill began by observing, “Only a surgeon could give this talk, because only a surgeon can tell you why we’re doing too much surgery.”

She stressed three main points: surgery is, as she put it, “a medieval treatment in a molecular era.” Overwhelming evidence shows that breast cancer outcomes are determined by disease biology, burden, and response to systemic therapy and not by the extent of surgery. And since there is no survival benefit for more aggressive surgery, the surgeon’s goal must be to optimize breast and axillary conservation.

Bruce Jancin/Frontline Medical News

In a separate presentation, Dr. Ismail Jatoi, professor and chief of surgical oncology at the University of Texas, San Antonio, outlined trends in surgical treatment of early-stage breast cancer as documented in a recent major retrospective study conducted in Tennessee of 1.2 million women treated at accredited U.S. breast cancer centers during 1998-2011.

The Tennessee investigators’ analysis points to a polarization in surgical therapy: The rate of unilateral mastectomy without reconstruction has dropped steadily since the beginning of the study period in 1998 among women eligible for breast-conserving surgery (BCS), while starting around 2006 the rate of bilateral mastectomy with reconstruction has surged. This increase in bilateral mastectomies with reconstruction resulted in an adjusted 34% jump in the overall mastectomy rate during 2004-2011 as compared with 1998-2003. As a result, in 2011 nearly 40% of women with early breast cancer underwent mastectomy. Meanwhile, the rate of BCS has been waning since 2006 (JAMA Surg. 2015 Jan;150[1]:9-16).

These disturbing trends have been fueled in part by at least eight published observational studies reporting improved survival with contralateral prophylactic mastectomy (CPM) as compared with unilateral mastectomy or BCS. But these were all observational studies and hence likely compromised by unmeasured confounders, according to Dr. Jatoi.

He presented highlights of his study of National Cancer Institute Surveillance, Epidemiology, and End Results data to support his recommendation that these observational studies be taken with a grain of salt.

His study included nearly 26,000 women who underwent CPM and more than 400,000 who did not. In a multivariate regression analysis adjusted for age, race, tumor stage, hormone receptor status, and histologic grade, CPM was associated with a statistically significant and impressive-sounding 16% reduction in the 5-year risk of breast cancer–specific mortality, a 17% reduction in overall mortality, and … a highly improbable 29% reduction in noncancer mortality (Breast Cancer Res Treat. 2014 Nov;148[2]:389-96).

“Obviously bilateral mastectomy is not going to reduce your risk of dying of heart attack or stroke or other noncancer causes. So even though we adjusted for everything possible in the SEER database, it suggests there were still unmeasured confounders. What this study shows is that it’s these unmeasured confounders that pose a threat to the validity of observational studies,” the surgeon said.

“Randomized data and observational studies consistently show that breast-conserving surgery is the optimal choice for most patients. It’s the safest choice, it’s cost effective, and it should remain in 2015 the optimal treatment for breast cancer,” he declared.

The cost-effectiveness of BCS was underscored during the symposium by means of a retrospective study presented by Dr. Benjamin D. Smith.

Bruce Jancin/Frontline Medical News

He and his coinvestigators analyzed costs and complication rates in the first 2 years following diagnosis of early-stage breast cancer in 44,344 patients under age 65 in the MarketScan database and almost 61,000 older women in the SEER-Medicare database.

The 2-year complication rate related to local therapy in younger breast cancer patients ranged from 30% for lumpectomy plus whole breast irradiation to 56% for mastectomy plus reconstruction. In older patients, the complication rates were 38% for lumpectomy plus whole breast irradiation and 69% for mastectomy plus reconstruction.

Adding together procedural and complication costs, the most expensive therapy in younger women was mastectomy with reconstruction, at an average of $89,140, which was $23,421 more than for lumpectomy plus whole breast irradiation, according to Dr. Smith, a radiation oncologist at MD Anderson Cancer Center in Houston.

“When oncologists offer all appropriate therapy options to patients, some women may choose to avoid radiation and opt for mastectomy and reconstruction instead. This study is helpful to such patients because it provides them with information regarding the trade-offs involved in this choice,” he explained.

Dr. MacNeill noted that in addition to the increased financial cost and physical complication rate entailed by mastectomy plus reconstruction for early breast cancer, this more aggressive surgery has another important unwelcome consequence: it delays the start of adjuvant therapy, which is the intervention that truly affects outcome.

Many women who opt for CPM do so because they can’t face the prospect of going through chemotherapy again should cancer arise in the contralateral breast. What’s often overlooked, she continued, is that the greatest risks of death or need for further systemic treatment due to relapse arise from the index cancer.

“We overestimate our patients’ contralateral risk, we underestimate the risk of dying from relapse of the index cancer, and we very often fail to consider other competing health risks from smoking, obesity, age, and other factors,” according to Dr. MacNeill.

“It’s not as if additional surgery is risk-free. A bilateral mastectomy carries bilateral complications. Our patients expect a perfect outcome because that’s what they see on television, but the reality is that for some women the results can be absolutely disastrous. Whilst women may not regret their choice for bilateral mastectomy with reconstruction because they think it’s lifesaving, the psychosexual impact is phenomenal,” she said.

That being said, Dr. MacNeill continued, “the elephant in the room” regarding BCS is that re-excision rates of up to 40% are common. This high rate of repeat surgery is a huge issue because of the resultant increased costs, morbidity, poor cosmesis, increased risk of mastectomy, and delay to adjuvant therapy.

High re-excision rates aren’t due to surgical incompetence, Dr. MacNeill stressed, but rather to the difficulty in defining microscopic disease intraoperatively. But help is on the way. Several novel approaches that facilitate lower re-excision rates and more breast conservation show considerable promise.

For example, investigators at Yale University have recently demonstrated in a randomized controlled trial that routine intraoperative cavity shave margins taken circumferentially halved the re-excision rate, from 21% to 10% (N Engl J Med. 2015 Aug 6;373[6]:503-10).

A meta-analysis of studies that included nearly 9,000 breast cancer patients who underwent BCS alone or BCS with oncoplastic breast conservation techniques concluded that the re-excision rate was just 4.3% in women who underwent oncoplastic breast conservation, compared with 14.6% with BCS alone (Ann Plast Surg. 2014 Feb;72[2]:145-9).

“This is going to be a driver for many breast cancer units to look at how they can use oncoplastic breast conservation to bring down their resection rates,” Dr. MacNeill predicted.

Neoadjuvant chemotherapy or endocrine therapy, a strategy in which surgery becomes adjuvant therapy, is likely to play an important role in facilitating breast conservation in the future. In the CALGB 40603 trial, for example, neoadjuvant chemotherapy in women with triple-negative breast cancer resulted in an absolute 14% increase in eligibility for BCS. Moreover, BCS was successful with no re-excision in 93% of treated patients (Ann Surg. 2015 Sep;262[3]:434-9).

The ‘less is more’ movement in breast cancer surgery may in the future mean no surgery at all in certain cases. Now underway in the United Kingdom is LORIS (the Low Risk DCIS Trial), in which women with low-risk DCIS are being randomized to surgery or 10 years of monitoring via annual mammograms.

“I’m suggesting that surgery may not exist in the longer term,” Dr. MacNeill said.

She, Dr. Jatoi, and Dr. Smith reported having no financial conflicts regarding their presentations. Dr. Smith’s study was supported by the Cancer Prevention and Research Institute of Texas, the Conquer Cancer Foundation, and the American Society for Radiation Oncology.

[email protected]

SAN ANTONIO – The worldwide upsurge in bilateral mastectomy for unilateral breast cancer in the last decade came under withering fire from prominent breast surgeons at the San Antonio Breast Cancer Symposium.

“It seems crazy, doesn’t it, that we’re spending all this time trying to conserve the breast, yet we’re facing a tsunami of requests for bilateral mastectomy,” observed Dr. Fiona MacNeill, chairman of the education and training committee of the Royal College of Surgeons of England.

“A contralateral risk–reducing prophylactic mastectomy undoubtedly will reduce the risk of contralateral breast cancer, since you’re removing the breast, but this is overtreatment for the vast majority of women who request it. At 20 years we haven’t been able to demonstrate that it offers a significant survival advantage. I think a lot of what’s driving bilateral mastectomy is fear and ignorance, a failure to understand risk by patients and often by health professionals,” said Dr. MacNeill, a breast surgeon at Royal Marsden Hospital in London.

In an invited special lecture titled, “Less is more: minimizing breast cancer surgery,” Dr. MacNeill began by observing, “Only a surgeon could give this talk, because only a surgeon can tell you why we’re doing too much surgery.”

She stressed three main points: surgery is, as she put it, “a medieval treatment in a molecular era.” Overwhelming evidence shows that breast cancer outcomes are determined by disease biology, burden, and response to systemic therapy and not by the extent of surgery. And since there is no survival benefit for more aggressive surgery, the surgeon’s goal must be to optimize breast and axillary conservation.

Bruce Jancin/Frontline Medical News

In a separate presentation, Dr. Ismail Jatoi, professor and chief of surgical oncology at the University of Texas, San Antonio, outlined trends in surgical treatment of early-stage breast cancer as documented in a recent major retrospective study conducted in Tennessee of 1.2 million women treated at accredited U.S. breast cancer centers during 1998-2011.

The Tennessee investigators’ analysis points to a polarization in surgical therapy: The rate of unilateral mastectomy without reconstruction has dropped steadily since the beginning of the study period in 1998 among women eligible for breast-conserving surgery (BCS), while starting around 2006 the rate of bilateral mastectomy with reconstruction has surged. This increase in bilateral mastectomies with reconstruction resulted in an adjusted 34% jump in the overall mastectomy rate during 2004-2011 as compared with 1998-2003. As a result, in 2011 nearly 40% of women with early breast cancer underwent mastectomy. Meanwhile, the rate of BCS has been waning since 2006 (JAMA Surg. 2015 Jan;150[1]:9-16).

These disturbing trends have been fueled in part by at least eight published observational studies reporting improved survival with contralateral prophylactic mastectomy (CPM) as compared with unilateral mastectomy or BCS. But these were all observational studies and hence likely compromised by unmeasured confounders, according to Dr. Jatoi.

He presented highlights of his study of National Cancer Institute Surveillance, Epidemiology, and End Results data to support his recommendation that these observational studies be taken with a grain of salt.

His study included nearly 26,000 women who underwent CPM and more than 400,000 who did not. In a multivariate regression analysis adjusted for age, race, tumor stage, hormone receptor status, and histologic grade, CPM was associated with a statistically significant and impressive-sounding 16% reduction in the 5-year risk of breast cancer–specific mortality, a 17% reduction in overall mortality, and … a highly improbable 29% reduction in noncancer mortality (Breast Cancer Res Treat. 2014 Nov;148[2]:389-96).

“Obviously bilateral mastectomy is not going to reduce your risk of dying of heart attack or stroke or other noncancer causes. So even though we adjusted for everything possible in the SEER database, it suggests there were still unmeasured confounders. What this study shows is that it’s these unmeasured confounders that pose a threat to the validity of observational studies,” the surgeon said.

“Randomized data and observational studies consistently show that breast-conserving surgery is the optimal choice for most patients. It’s the safest choice, it’s cost effective, and it should remain in 2015 the optimal treatment for breast cancer,” he declared.

The cost-effectiveness of BCS was underscored during the symposium by means of a retrospective study presented by Dr. Benjamin D. Smith.

Bruce Jancin/Frontline Medical News

He and his coinvestigators analyzed costs and complication rates in the first 2 years following diagnosis of early-stage breast cancer in 44,344 patients under age 65 in the MarketScan database and almost 61,000 older women in the SEER-Medicare database.

The 2-year complication rate related to local therapy in younger breast cancer patients ranged from 30% for lumpectomy plus whole breast irradiation to 56% for mastectomy plus reconstruction. In older patients, the complication rates were 38% for lumpectomy plus whole breast irradiation and 69% for mastectomy plus reconstruction.

Adding together procedural and complication costs, the most expensive therapy in younger women was mastectomy with reconstruction, at an average of $89,140, which was $23,421 more than for lumpectomy plus whole breast irradiation, according to Dr. Smith, a radiation oncologist at MD Anderson Cancer Center in Houston.

“When oncologists offer all appropriate therapy options to patients, some women may choose to avoid radiation and opt for mastectomy and reconstruction instead. This study is helpful to such patients because it provides them with information regarding the trade-offs involved in this choice,” he explained.

Dr. MacNeill noted that in addition to the increased financial cost and physical complication rate entailed by mastectomy plus reconstruction for early breast cancer, this more aggressive surgery has another important unwelcome consequence: it delays the start of adjuvant therapy, which is the intervention that truly affects outcome.

Many women who opt for CPM do so because they can’t face the prospect of going through chemotherapy again should cancer arise in the contralateral breast. What’s often overlooked, she continued, is that the greatest risks of death or need for further systemic treatment due to relapse arise from the index cancer.

“We overestimate our patients’ contralateral risk, we underestimate the risk of dying from relapse of the index cancer, and we very often fail to consider other competing health risks from smoking, obesity, age, and other factors,” according to Dr. MacNeill.

“It’s not as if additional surgery is risk-free. A bilateral mastectomy carries bilateral complications. Our patients expect a perfect outcome because that’s what they see on television, but the reality is that for some women the results can be absolutely disastrous. Whilst women may not regret their choice for bilateral mastectomy with reconstruction because they think it’s lifesaving, the psychosexual impact is phenomenal,” she said.

That being said, Dr. MacNeill continued, “the elephant in the room” regarding BCS is that re-excision rates of up to 40% are common. This high rate of repeat surgery is a huge issue because of the resultant increased costs, morbidity, poor cosmesis, increased risk of mastectomy, and delay to adjuvant therapy.

High re-excision rates aren’t due to surgical incompetence, Dr. MacNeill stressed, but rather to the difficulty in defining microscopic disease intraoperatively. But help is on the way. Several novel approaches that facilitate lower re-excision rates and more breast conservation show considerable promise.

For example, investigators at Yale University have recently demonstrated in a randomized controlled trial that routine intraoperative cavity shave margins taken circumferentially halved the re-excision rate, from 21% to 10% (N Engl J Med. 2015 Aug 6;373[6]:503-10).

A meta-analysis of studies that included nearly 9,000 breast cancer patients who underwent BCS alone or BCS with oncoplastic breast conservation techniques concluded that the re-excision rate was just 4.3% in women who underwent oncoplastic breast conservation, compared with 14.6% with BCS alone (Ann Plast Surg. 2014 Feb;72[2]:145-9).

“This is going to be a driver for many breast cancer units to look at how they can use oncoplastic breast conservation to bring down their resection rates,” Dr. MacNeill predicted.

Neoadjuvant chemotherapy or endocrine therapy, a strategy in which surgery becomes adjuvant therapy, is likely to play an important role in facilitating breast conservation in the future. In the CALGB 40603 trial, for example, neoadjuvant chemotherapy in women with triple-negative breast cancer resulted in an absolute 14% increase in eligibility for BCS. Moreover, BCS was successful with no re-excision in 93% of treated patients (Ann Surg. 2015 Sep;262[3]:434-9).

The ‘less is more’ movement in breast cancer surgery may in the future mean no surgery at all in certain cases. Now underway in the United Kingdom is LORIS (the Low Risk DCIS Trial), in which women with low-risk DCIS are being randomized to surgery or 10 years of monitoring via annual mammograms.

“I’m suggesting that surgery may not exist in the longer term,” Dr. MacNeill said.

She, Dr. Jatoi, and Dr. Smith reported having no financial conflicts regarding their presentations. Dr. Smith’s study was supported by the Cancer Prevention and Research Institute of Texas, the Conquer Cancer Foundation, and the American Society for Radiation Oncology.

[email protected]

SAN ANTONIO – Buparlisib, an oral investigational pan-phosphoinositide 3-kinase (pan-PI3) kinase inhibitor, appears to be efficacious for overcoming endocrine resistance in advanced breast cancer, according to first results of the BELLE-2 trialreported at the San Antonio Breast Cancer Symposium. But benefit is likely restricted to patients whose tumors have a mutation of the PI3 kinase alpha gene (PIK3CA) detectable in circulating tumor DNA.

Trial participants were 1,147 postmenopausal women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer that had progressed on or after prior aromatase inhibitor therapy. They were randomized to treatment with buparlisib (formerly BKM120) or placebo, each added to the estrogen-receptor antagonist fulvestrant (Faslodex).

Results showed that buparlisib prolonged progression-free survival by about 2 months relative to placebo, meeting the trial’s primary endpoint, according to data reported in a session and related press briefing.

The presence of a PIK3CA mutation and/or loss of PTEN in archival tumor tissue was not helpful in identifying women who would benefit. But the presence of a PIK3CA mutation detected in circulating cell-free tumor DNA (a so-called liquid biopsy) was, with a progression-free survival advantage from buparlisib approaching 4 months in this subset.

“This is the first time that we showed that eliminating the PI3 kinase pathway may be a viable option for patients with hormone therapy–resistant breast cancer,” coinvestigator Dr. Mario Campone, Institut de Cancérologie de l’Ouest – René Gauducheau Centre de Recherche en Cancérologie, in Nantes, France, commented in the press briefing. “Frequent discontinuations due to adverse events reduced treatment duration in the buparlisib arm, potentially limiting the efficacy of combination therapy.”

“The BELLE-2 study suggests that assessment of PIK3CA mutations in a liquid biopsy may help select patients who benefit from adding a PI3 kinase inhibitor to endocrine therapy,” he added. “Further studies are warranted to confirm the utility and predictive value of PIK3CA mutations detected by liquid biopsy and tumor tissue, which we see in the SOLAR-1 clinical trial” testing the drug alpelisib (BYL719).

He speculated that the lack of predictive value of mutational status in the tumor vs. mutational status in the circulating tumor DNA was due in part to the timing of collection of these samples. In about 80% of cases, the tumor was the primary tumor, collected before any treatment, whereas the circulating tumor DNA was obtained at trial enrollment, after patients had been exposed to aromatase inhibitors.

Press briefing moderator Dr. C. Kent Osborne, a professor and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, commented that buparlisib “is not a home run, if you will, in terms of patients benefiting, probably because there are many other pathways that can contribute [to resistance] … And we just have to identify those and then determine which treatments we can combine together to have a better, more optimal effect.”

The 2-month benefit from buparlisib seen in the entire trial population was modest but based on median values, he cautioned. Looking at the progression-free survival curves at 2-3 years, the proportion of patients still free of events was about 20% with the drug, compared with 10% with placebo.

“It will take time to know whether we see an overall survival benefit. I wouldn’t be surprised if we didn’t,” given that patients in the control group will be given effective therapies at the time of progression, Dr. Osborne further commented. “A lot of studies in metastatic breast cancer show these sort of modest benefits, but then when you take the treatment earlier in the course of disease, such as in the adjuvant setting, for instance, you see a much more dramatic benefit. So this is the first time that a PI3 kinase inhibitor has shown this, and I would say that this is still an advance and tells us that this gives us more information about the importance of this pathway in endocrine-resistant disease.”

BELLE-2 was designed on the basis of data suggesting that activation of the PI3 kinase/mTOR pathway is a hallmark of hormone receptor–positive breast cancers that have become resistant to endocrine therapy, according to the investigators. Thus, a dual blockade of signaling through both the estrogen receptor pathway and the PI3 kinase pathway may circumvent resistance.

Trial results showed that the median duration of treatment was 4.2 months with buparlisib plus fulvestrant (1.9 months, specifically with buparlisib) and 5.0 months with placebo plus fulvestrant (4.0 months, specifically with placebo), reported Dr. Campone.

The drug was associated with a higher rate of grade 3 or 4 adverse events (77% vs. 32%), mainly driven by more cases of transaminitis, hyperglycemia, rash, and mood disorders.

In the entire trial population, median progression-free survival was 6.9 months with buparlisib and 5.0 months with placebo (hazard ratio, 0.78; P less than .001), meeting the trial’s primary endpoint.

In the subset of 372 patients with PI3K activation that was defined by presence of a PIK3CA mutation of any type (activating or not) and/or PTEN loss in archival tumor tissue, median progression-free survival was 6.8 months with buparlisib and 4.0 months with placebo (HR, 0.76), but the P value missed the threshold for significance in this analysis.

In a preplanned exploratory analysis, the investigators analyzed circulating tumor DNA in 587 patients for two PIK3CA mutations known to be activating mutations. Results here suggested that the progression-free survival benefit was limited to those who had a mutation – 7.0 months with buparlisib vs. 3.2 months with placebo (HR, 0.56; P less than .001) – with no significant benefit in patients having the wild-type (nonmutated) gene.

SAN ANTONIO – Buparlisib, an oral investigational pan-phosphoinositide 3-kinase (pan-PI3) kinase inhibitor, appears to be efficacious for overcoming endocrine resistance in advanced breast cancer, according to first results of the BELLE-2 trialreported at the San Antonio Breast Cancer Symposium. But benefit is likely restricted to patients whose tumors have a mutation of the PI3 kinase alpha gene (PIK3CA) detectable in circulating tumor DNA.

Trial participants were 1,147 postmenopausal women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer that had progressed on or after prior aromatase inhibitor therapy. They were randomized to treatment with buparlisib (formerly BKM120) or placebo, each added to the estrogen-receptor antagonist fulvestrant (Faslodex).

Results showed that buparlisib prolonged progression-free survival by about 2 months relative to placebo, meeting the trial’s primary endpoint, according to data reported in a session and related press briefing.

The presence of a PIK3CA mutation and/or loss of PTEN in archival tumor tissue was not helpful in identifying women who would benefit. But the presence of a PIK3CA mutation detected in circulating cell-free tumor DNA (a so-called liquid biopsy) was, with a progression-free survival advantage from buparlisib approaching 4 months in this subset.

“This is the first time that we showed that eliminating the PI3 kinase pathway may be a viable option for patients with hormone therapy–resistant breast cancer,” coinvestigator Dr. Mario Campone, Institut de Cancérologie de l’Ouest – René Gauducheau Centre de Recherche en Cancérologie, in Nantes, France, commented in the press briefing. “Frequent discontinuations due to adverse events reduced treatment duration in the buparlisib arm, potentially limiting the efficacy of combination therapy.”

“The BELLE-2 study suggests that assessment of PIK3CA mutations in a liquid biopsy may help select patients who benefit from adding a PI3 kinase inhibitor to endocrine therapy,” he added. “Further studies are warranted to confirm the utility and predictive value of PIK3CA mutations detected by liquid biopsy and tumor tissue, which we see in the SOLAR-1 clinical trial” testing the drug alpelisib (BYL719).

He speculated that the lack of predictive value of mutational status in the tumor vs. mutational status in the circulating tumor DNA was due in part to the timing of collection of these samples. In about 80% of cases, the tumor was the primary tumor, collected before any treatment, whereas the circulating tumor DNA was obtained at trial enrollment, after patients had been exposed to aromatase inhibitors.

Press briefing moderator Dr. C. Kent Osborne, a professor and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, commented that buparlisib “is not a home run, if you will, in terms of patients benefiting, probably because there are many other pathways that can contribute [to resistance] … And we just have to identify those and then determine which treatments we can combine together to have a better, more optimal effect.”

The 2-month benefit from buparlisib seen in the entire trial population was modest but based on median values, he cautioned. Looking at the progression-free survival curves at 2-3 years, the proportion of patients still free of events was about 20% with the drug, compared with 10% with placebo.

“It will take time to know whether we see an overall survival benefit. I wouldn’t be surprised if we didn’t,” given that patients in the control group will be given effective therapies at the time of progression, Dr. Osborne further commented. “A lot of studies in metastatic breast cancer show these sort of modest benefits, but then when you take the treatment earlier in the course of disease, such as in the adjuvant setting, for instance, you see a much more dramatic benefit. So this is the first time that a PI3 kinase inhibitor has shown this, and I would say that this is still an advance and tells us that this gives us more information about the importance of this pathway in endocrine-resistant disease.”

BELLE-2 was designed on the basis of data suggesting that activation of the PI3 kinase/mTOR pathway is a hallmark of hormone receptor–positive breast cancers that have become resistant to endocrine therapy, according to the investigators. Thus, a dual blockade of signaling through both the estrogen receptor pathway and the PI3 kinase pathway may circumvent resistance.

Trial results showed that the median duration of treatment was 4.2 months with buparlisib plus fulvestrant (1.9 months, specifically with buparlisib) and 5.0 months with placebo plus fulvestrant (4.0 months, specifically with placebo), reported Dr. Campone.

The drug was associated with a higher rate of grade 3 or 4 adverse events (77% vs. 32%), mainly driven by more cases of transaminitis, hyperglycemia, rash, and mood disorders.

In the entire trial population, median progression-free survival was 6.9 months with buparlisib and 5.0 months with placebo (hazard ratio, 0.78; P less than .001), meeting the trial’s primary endpoint.

In the subset of 372 patients with PI3K activation that was defined by presence of a PIK3CA mutation of any type (activating or not) and/or PTEN loss in archival tumor tissue, median progression-free survival was 6.8 months with buparlisib and 4.0 months with placebo (HR, 0.76), but the P value missed the threshold for significance in this analysis.

In a preplanned exploratory analysis, the investigators analyzed circulating tumor DNA in 587 patients for two PIK3CA mutations known to be activating mutations. Results here suggested that the progression-free survival benefit was limited to those who had a mutation – 7.0 months with buparlisib vs. 3.2 months with placebo (HR, 0.56; P less than .001) – with no significant benefit in patients having the wild-type (nonmutated) gene.

SAN ANTONIO – Buparlisib, an oral investigational pan-phosphoinositide 3-kinase (pan-PI3) kinase inhibitor, appears to be efficacious for overcoming endocrine resistance in advanced breast cancer, according to first results of the BELLE-2 trialreported at the San Antonio Breast Cancer Symposium. But benefit is likely restricted to patients whose tumors have a mutation of the PI3 kinase alpha gene (PIK3CA) detectable in circulating tumor DNA.

Trial participants were 1,147 postmenopausal women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer that had progressed on or after prior aromatase inhibitor therapy. They were randomized to treatment with buparlisib (formerly BKM120) or placebo, each added to the estrogen-receptor antagonist fulvestrant (Faslodex).

Results showed that buparlisib prolonged progression-free survival by about 2 months relative to placebo, meeting the trial’s primary endpoint, according to data reported in a session and related press briefing.

The presence of a PIK3CA mutation and/or loss of PTEN in archival tumor tissue was not helpful in identifying women who would benefit. But the presence of a PIK3CA mutation detected in circulating cell-free tumor DNA (a so-called liquid biopsy) was, with a progression-free survival advantage from buparlisib approaching 4 months in this subset.

“This is the first time that we showed that eliminating the PI3 kinase pathway may be a viable option for patients with hormone therapy–resistant breast cancer,” coinvestigator Dr. Mario Campone, Institut de Cancérologie de l’Ouest – René Gauducheau Centre de Recherche en Cancérologie, in Nantes, France, commented in the press briefing. “Frequent discontinuations due to adverse events reduced treatment duration in the buparlisib arm, potentially limiting the efficacy of combination therapy.”

“The BELLE-2 study suggests that assessment of PIK3CA mutations in a liquid biopsy may help select patients who benefit from adding a PI3 kinase inhibitor to endocrine therapy,” he added. “Further studies are warranted to confirm the utility and predictive value of PIK3CA mutations detected by liquid biopsy and tumor tissue, which we see in the SOLAR-1 clinical trial” testing the drug alpelisib (BYL719).

He speculated that the lack of predictive value of mutational status in the tumor vs. mutational status in the circulating tumor DNA was due in part to the timing of collection of these samples. In about 80% of cases, the tumor was the primary tumor, collected before any treatment, whereas the circulating tumor DNA was obtained at trial enrollment, after patients had been exposed to aromatase inhibitors.

Press briefing moderator Dr. C. Kent Osborne, a professor and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, commented that buparlisib “is not a home run, if you will, in terms of patients benefiting, probably because there are many other pathways that can contribute [to resistance] … And we just have to identify those and then determine which treatments we can combine together to have a better, more optimal effect.”

The 2-month benefit from buparlisib seen in the entire trial population was modest but based on median values, he cautioned. Looking at the progression-free survival curves at 2-3 years, the proportion of patients still free of events was about 20% with the drug, compared with 10% with placebo.

“It will take time to know whether we see an overall survival benefit. I wouldn’t be surprised if we didn’t,” given that patients in the control group will be given effective therapies at the time of progression, Dr. Osborne further commented. “A lot of studies in metastatic breast cancer show these sort of modest benefits, but then when you take the treatment earlier in the course of disease, such as in the adjuvant setting, for instance, you see a much more dramatic benefit. So this is the first time that a PI3 kinase inhibitor has shown this, and I would say that this is still an advance and tells us that this gives us more information about the importance of this pathway in endocrine-resistant disease.”

BELLE-2 was designed on the basis of data suggesting that activation of the PI3 kinase/mTOR pathway is a hallmark of hormone receptor–positive breast cancers that have become resistant to endocrine therapy, according to the investigators. Thus, a dual blockade of signaling through both the estrogen receptor pathway and the PI3 kinase pathway may circumvent resistance.

Trial results showed that the median duration of treatment was 4.2 months with buparlisib plus fulvestrant (1.9 months, specifically with buparlisib) and 5.0 months with placebo plus fulvestrant (4.0 months, specifically with placebo), reported Dr. Campone.

The drug was associated with a higher rate of grade 3 or 4 adverse events (77% vs. 32%), mainly driven by more cases of transaminitis, hyperglycemia, rash, and mood disorders.

In the entire trial population, median progression-free survival was 6.9 months with buparlisib and 5.0 months with placebo (hazard ratio, 0.78; P less than .001), meeting the trial’s primary endpoint.

In the subset of 372 patients with PI3K activation that was defined by presence of a PIK3CA mutation of any type (activating or not) and/or PTEN loss in archival tumor tissue, median progression-free survival was 6.8 months with buparlisib and 4.0 months with placebo (HR, 0.76), but the P value missed the threshold for significance in this analysis.

In a preplanned exploratory analysis, the investigators analyzed circulating tumor DNA in 587 patients for two PIK3CA mutations known to be activating mutations. Results here suggested that the progression-free survival benefit was limited to those who had a mutation – 7.0 months with buparlisib vs. 3.2 months with placebo (HR, 0.56; P less than .001) – with no significant benefit in patients having the wild-type (nonmutated) gene.

SAN ANTONIO – Final 10-year analysis of the landmark BCIRG-006 trial underscores the safety advantages of a nonanthracycline, trastuzumab-based adjunctive treatment regimen in early-stage HER2-positive breast cancer.

At a median 10.3 years of follow-up in the phase III randomized trial of 3,222 patients, a substantial reduction in the risk of cardiac toxicity was evident in the women assigned to six cycles of docetaxel (Taxotere) and carboplatin plus 1 year of trastuzumab (the TCH arm), compared with the two anthracycline-containing study arms, Dr. Dennis J. Slamon reported at the San Antonio Breast Cancer Symposium.

Bruce Jancin/Frontline Medical News

At baseline the three treatment groups were well balanced in terms of cardiovascular risk factors. Yet over the course of the study only 4 women in the TCH arm developed clinical heart failure, compared with 21 patients who received four cycles of doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) followed by four cycles of docetaxel and 1 year of trastuzumab (AC-TH), and 8 patients in the control arm who got four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC-T).

Thus, adding docetaxel to 1 year of trastuzumab (Herceptin) conferred a fivefold increase in this major cardiac complication, compared with trastuzumab alone, noted Dr. Slamon, professor of medicine and chief of the division of hematology-oncology at the University of California, Los Angeles.

His presentation of the final analysis also provided important new information on the issue of treatment-related subclinical reductions in cardiac reserve as manifest by decreased left ventricular ejection fraction (LVEF).

A greater than 10% reduction in LVEF occurred in 9.4% of the TCH group, 19.2% of the AC-TH group, and 11.8% of the AC-T control group. In 2009 when Dr. Slamon presented the 5-year follow-up of BCIRG-006 at the San Antonio Breast Cancer Symposium, he was able to report that during the first year post treatment the no-anthracycline TCH group showed a recovery of LVEF to near baseline while in the AC-TH and AC-T groups the LVEF did not bounce back through the 5-year mark. The question raised at that point was how long would their LVEF remain diminished.

“With the 10-year data, with LVEFs measured annually after the end of treatment, this loss is real and is maintained. The question now is, what will become of these patients when they acquire their long-term age-related cardiac risk factors after we’ve already compromised their LVEF to some degree?” he said.

The primary endpoint in BCIRG-006 was disease-free survival (DFS). At final follow-up, with a total of 876 such events, the DFS rate was 74.6% in the AC-TH group and statistically similar at 73% in the TCH group, both of which were superior to the 67.9% figure in the AC-T control arm. Only 10 DFS events separated the TCH and AC-TH groups at 10 years. Overall survival rates in the two trastuzumab arms weren’t significantly different either.

To answer the question of whether patients with higher-risk HER2-positive early breast cancer require anthracycline-based adjunctive therapy in order to maximize benefit, the investigators did a subanalysis restricted to the roughly 400 women with four or more positive lymph nodes. The DFS rate was 62.9% with TCH and a near-identical 62.8% with AC-TH, both superior to the 53.6% DFS rate in the AC-T group.

All eight cases of acute leukemia occurred in the AC-TH and AC-T study arms.

The study was sponsored by Sanofi with additional support from Genentech. The presenter reported serving on advisory boards for BioMarin, Genentech/Roche, Pfizer, and Novartis.

[email protected]

SAN ANTONIO – Final 10-year analysis of the landmark BCIRG-006 trial underscores the safety advantages of a nonanthracycline, trastuzumab-based adjunctive treatment regimen in early-stage HER2-positive breast cancer.

At a median 10.3 years of follow-up in the phase III randomized trial of 3,222 patients, a substantial reduction in the risk of cardiac toxicity was evident in the women assigned to six cycles of docetaxel (Taxotere) and carboplatin plus 1 year of trastuzumab (the TCH arm), compared with the two anthracycline-containing study arms, Dr. Dennis J. Slamon reported at the San Antonio Breast Cancer Symposium.

Bruce Jancin/Frontline Medical News

At baseline the three treatment groups were well balanced in terms of cardiovascular risk factors. Yet over the course of the study only 4 women in the TCH arm developed clinical heart failure, compared with 21 patients who received four cycles of doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) followed by four cycles of docetaxel and 1 year of trastuzumab (AC-TH), and 8 patients in the control arm who got four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC-T).

Thus, adding docetaxel to 1 year of trastuzumab (Herceptin) conferred a fivefold increase in this major cardiac complication, compared with trastuzumab alone, noted Dr. Slamon, professor of medicine and chief of the division of hematology-oncology at the University of California, Los Angeles.

His presentation of the final analysis also provided important new information on the issue of treatment-related subclinical reductions in cardiac reserve as manifest by decreased left ventricular ejection fraction (LVEF).

A greater than 10% reduction in LVEF occurred in 9.4% of the TCH group, 19.2% of the AC-TH group, and 11.8% of the AC-T control group. In 2009 when Dr. Slamon presented the 5-year follow-up of BCIRG-006 at the San Antonio Breast Cancer Symposium, he was able to report that during the first year post treatment the no-anthracycline TCH group showed a recovery of LVEF to near baseline while in the AC-TH and AC-T groups the LVEF did not bounce back through the 5-year mark. The question raised at that point was how long would their LVEF remain diminished.

“With the 10-year data, with LVEFs measured annually after the end of treatment, this loss is real and is maintained. The question now is, what will become of these patients when they acquire their long-term age-related cardiac risk factors after we’ve already compromised their LVEF to some degree?” he said.

The primary endpoint in BCIRG-006 was disease-free survival (DFS). At final follow-up, with a total of 876 such events, the DFS rate was 74.6% in the AC-TH group and statistically similar at 73% in the TCH group, both of which were superior to the 67.9% figure in the AC-T control arm. Only 10 DFS events separated the TCH and AC-TH groups at 10 years. Overall survival rates in the two trastuzumab arms weren’t significantly different either.

To answer the question of whether patients with higher-risk HER2-positive early breast cancer require anthracycline-based adjunctive therapy in order to maximize benefit, the investigators did a subanalysis restricted to the roughly 400 women with four or more positive lymph nodes. The DFS rate was 62.9% with TCH and a near-identical 62.8% with AC-TH, both superior to the 53.6% DFS rate in the AC-T group.

All eight cases of acute leukemia occurred in the AC-TH and AC-T study arms.

The study was sponsored by Sanofi with additional support from Genentech. The presenter reported serving on advisory boards for BioMarin, Genentech/Roche, Pfizer, and Novartis.

[email protected]

SAN ANTONIO – Final 10-year analysis of the landmark BCIRG-006 trial underscores the safety advantages of a nonanthracycline, trastuzumab-based adjunctive treatment regimen in early-stage HER2-positive breast cancer.

At a median 10.3 years of follow-up in the phase III randomized trial of 3,222 patients, a substantial reduction in the risk of cardiac toxicity was evident in the women assigned to six cycles of docetaxel (Taxotere) and carboplatin plus 1 year of trastuzumab (the TCH arm), compared with the two anthracycline-containing study arms, Dr. Dennis J. Slamon reported at the San Antonio Breast Cancer Symposium.

Bruce Jancin/Frontline Medical News

At baseline the three treatment groups were well balanced in terms of cardiovascular risk factors. Yet over the course of the study only 4 women in the TCH arm developed clinical heart failure, compared with 21 patients who received four cycles of doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) followed by four cycles of docetaxel and 1 year of trastuzumab (AC-TH), and 8 patients in the control arm who got four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC-T).

Thus, adding docetaxel to 1 year of trastuzumab (Herceptin) conferred a fivefold increase in this major cardiac complication, compared with trastuzumab alone, noted Dr. Slamon, professor of medicine and chief of the division of hematology-oncology at the University of California, Los Angeles.

His presentation of the final analysis also provided important new information on the issue of treatment-related subclinical reductions in cardiac reserve as manifest by decreased left ventricular ejection fraction (LVEF).

A greater than 10% reduction in LVEF occurred in 9.4% of the TCH group, 19.2% of the AC-TH group, and 11.8% of the AC-T control group. In 2009 when Dr. Slamon presented the 5-year follow-up of BCIRG-006 at the San Antonio Breast Cancer Symposium, he was able to report that during the first year post treatment the no-anthracycline TCH group showed a recovery of LVEF to near baseline while in the AC-TH and AC-T groups the LVEF did not bounce back through the 5-year mark. The question raised at that point was how long would their LVEF remain diminished.

“With the 10-year data, with LVEFs measured annually after the end of treatment, this loss is real and is maintained. The question now is, what will become of these patients when they acquire their long-term age-related cardiac risk factors after we’ve already compromised their LVEF to some degree?” he said.

The primary endpoint in BCIRG-006 was disease-free survival (DFS). At final follow-up, with a total of 876 such events, the DFS rate was 74.6% in the AC-TH group and statistically similar at 73% in the TCH group, both of which were superior to the 67.9% figure in the AC-T control arm. Only 10 DFS events separated the TCH and AC-TH groups at 10 years. Overall survival rates in the two trastuzumab arms weren’t significantly different either.

To answer the question of whether patients with higher-risk HER2-positive early breast cancer require anthracycline-based adjunctive therapy in order to maximize benefit, the investigators did a subanalysis restricted to the roughly 400 women with four or more positive lymph nodes. The DFS rate was 62.9% with TCH and a near-identical 62.8% with AC-TH, both superior to the 53.6% DFS rate in the AC-T group.

All eight cases of acute leukemia occurred in the AC-TH and AC-T study arms.

The study was sponsored by Sanofi with additional support from Genentech. The presenter reported serving on advisory boards for BioMarin, Genentech/Roche, Pfizer, and Novartis.

[email protected]

SAN ANTONIO – Women whose estrogen receptor–positive breast cancers have high expression of a DNA-mutating enzyme called APOBEC3B (A3B for short) are more likely to experience tamoxifen resistance, suggest data reported in a session and press briefing at the San Antonio Breast Cancer Symposium.

In a study of 285 women, the risk of progression or death on first-line tamoxifen was 67% higher for those whose primaries had high versus low expression of the enzyme, a DNA cytosine deaminase that is overexpressed in about half of all breast cancers.

Additionally, companion experiments in a xenograft breast cancer model showed that suppressing the enzyme delayed the development of tamoxifen resistance in tumors, whereas overexpressing it accelerated the development of resistance.

“High APOBECB3 expression levels correlate with poor outcomes for estrogen receptor–positive breast cancer, including recurrence during tamoxifen treatment,” said lead author Reuben Harris, Ph.D., an investigator at the Howard Hughes Medical Institute, professor at the University of Minnesota, Minneapolis, and member of the Masonic Cancer Center.

“One point to emphasize is that this is a gain-of-function mutating enzyme. A lot of things we hear about are loss of functions that are happening in cancer,” and at present, not much can be done about those, he said. But “because [APOBECB3] is an enzyme with an active site, I think that’s targetable.”

Dr. Harris drew an analogy between APOBEC mutagenesis and UV mutagenesis, noting that once the molecular mechanism was defined for the latter, interventions such as UV-blocking sunscreens and protective clothing were harnessed for prevention. “Now we have identified a significant source of mutation in breast cancer (as well as other cancers) and we can begin to think about innovations to control the mutating activity of this enzyme,” he elaborated.

Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos Arteaga, professor of medicine at Vanderbilt University, Nashville, Tenn,, and director of the Breast Cancer Program, asked, “Do you think this is ready to be addressed in the clinic? If you think so, can you speculate how we can do that?”

“I think it’s nearing readiness,” Dr. Harris replied. “We need more clinical studies. So far we’ve been focused on retrospective studies. … Some prospective studies need to be done. Obviously this needs to expand to include other treatments, and we also have to get a better handle on which subtypes are most affected by this mutagenic process.”

Previous research his team did in collaboration with their coinvestigators in the Netherlands showed that women with estrogen receptor–positive primary tumors treated only with resection had poorer progression-free and overall survival if their primaries had up-regulation of the A3B enzyme (Horm Cancer. 2014;5:405-13).

“This suggests that this is a prognostic marker for outcome, but we wanted to go further and ask if this process is contributing to or correlating with poor outcomes such as recurrence and resistance to tamoxifen therapy,” Dr. Harris commented.

In the new retrospective study, this time among women who experienced a recurrence of estrogen receptor–positive breast cancer and were then given first-line tamoxifen, the median progression-free survival was just 7.5 months for those with high A3B expression in the primary tumor, compared with 13.3 months for those with low expression (hazard ratio, 1.67; P = .0001).

“These are correlative studies that really suggest what many of the cellular experiments and genetic experiments in my lab and others have indicated, that this would be an adverse effector in estrogen receptor–positive breast cancer, but we wanted to test this hypothesis with a cause-and-effect experiment,” he said.

In xenograft experiments, they engineered estrogen receptor–positive MCF7L breast cancer cells to have either high or low expression of A3B and grew the cells into small tumors. They then grafted the tumors into female nude mice.

In a first set of experiments, knocking down expression of A3B slowed the development of tamoxifen resistance, and in fact, few tumors had become resistant to the drug even after a year, Dr. Harris reported. In a second set, overexpressing the enzyme in tumor cells by about 100-fold led to almost immediate tamoxifen resistance.

“So we can slow it down, and we can speed it up, and all of this is consistent with the clinical data indicating that those primary breast tumors that have high levels of this enzyme result in poorer outcomes than those tumors that have low levels,” he concluded.

As mutations induced by A3B might also affect the response to other treatments, ongoing research is now looking at its impact on the development of chemotherapy resistance, noted Dr. Harris.

SAN ANTONIO – Women whose estrogen receptor–positive breast cancers have high expression of a DNA-mutating enzyme called APOBEC3B (A3B for short) are more likely to experience tamoxifen resistance, suggest data reported in a session and press briefing at the San Antonio Breast Cancer Symposium.

In a study of 285 women, the risk of progression or death on first-line tamoxifen was 67% higher for those whose primaries had high versus low expression of the enzyme, a DNA cytosine deaminase that is overexpressed in about half of all breast cancers.

Additionally, companion experiments in a xenograft breast cancer model showed that suppressing the enzyme delayed the development of tamoxifen resistance in tumors, whereas overexpressing it accelerated the development of resistance.

“High APOBECB3 expression levels correlate with poor outcomes for estrogen receptor–positive breast cancer, including recurrence during tamoxifen treatment,” said lead author Reuben Harris, Ph.D., an investigator at the Howard Hughes Medical Institute, professor at the University of Minnesota, Minneapolis, and member of the Masonic Cancer Center.

“One point to emphasize is that this is a gain-of-function mutating enzyme. A lot of things we hear about are loss of functions that are happening in cancer,” and at present, not much can be done about those, he said. But “because [APOBECB3] is an enzyme with an active site, I think that’s targetable.”

Dr. Harris drew an analogy between APOBEC mutagenesis and UV mutagenesis, noting that once the molecular mechanism was defined for the latter, interventions such as UV-blocking sunscreens and protective clothing were harnessed for prevention. “Now we have identified a significant source of mutation in breast cancer (as well as other cancers) and we can begin to think about innovations to control the mutating activity of this enzyme,” he elaborated.

Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos Arteaga, professor of medicine at Vanderbilt University, Nashville, Tenn,, and director of the Breast Cancer Program, asked, “Do you think this is ready to be addressed in the clinic? If you think so, can you speculate how we can do that?”

“I think it’s nearing readiness,” Dr. Harris replied. “We need more clinical studies. So far we’ve been focused on retrospective studies. … Some prospective studies need to be done. Obviously this needs to expand to include other treatments, and we also have to get a better handle on which subtypes are most affected by this mutagenic process.”

Previous research his team did in collaboration with their coinvestigators in the Netherlands showed that women with estrogen receptor–positive primary tumors treated only with resection had poorer progression-free and overall survival if their primaries had up-regulation of the A3B enzyme (Horm Cancer. 2014;5:405-13).

“This suggests that this is a prognostic marker for outcome, but we wanted to go further and ask if this process is contributing to or correlating with poor outcomes such as recurrence and resistance to tamoxifen therapy,” Dr. Harris commented.

In the new retrospective study, this time among women who experienced a recurrence of estrogen receptor–positive breast cancer and were then given first-line tamoxifen, the median progression-free survival was just 7.5 months for those with high A3B expression in the primary tumor, compared with 13.3 months for those with low expression (hazard ratio, 1.67; P = .0001).

“These are correlative studies that really suggest what many of the cellular experiments and genetic experiments in my lab and others have indicated, that this would be an adverse effector in estrogen receptor–positive breast cancer, but we wanted to test this hypothesis with a cause-and-effect experiment,” he said.

In xenograft experiments, they engineered estrogen receptor–positive MCF7L breast cancer cells to have either high or low expression of A3B and grew the cells into small tumors. They then grafted the tumors into female nude mice.

In a first set of experiments, knocking down expression of A3B slowed the development of tamoxifen resistance, and in fact, few tumors had become resistant to the drug even after a year, Dr. Harris reported. In a second set, overexpressing the enzyme in tumor cells by about 100-fold led to almost immediate tamoxifen resistance.

“So we can slow it down, and we can speed it up, and all of this is consistent with the clinical data indicating that those primary breast tumors that have high levels of this enzyme result in poorer outcomes than those tumors that have low levels,” he concluded.

As mutations induced by A3B might also affect the response to other treatments, ongoing research is now looking at its impact on the development of chemotherapy resistance, noted Dr. Harris.

SAN ANTONIO – Women whose estrogen receptor–positive breast cancers have high expression of a DNA-mutating enzyme called APOBEC3B (A3B for short) are more likely to experience tamoxifen resistance, suggest data reported in a session and press briefing at the San Antonio Breast Cancer Symposium.

In a study of 285 women, the risk of progression or death on first-line tamoxifen was 67% higher for those whose primaries had high versus low expression of the enzyme, a DNA cytosine deaminase that is overexpressed in about half of all breast cancers.

Additionally, companion experiments in a xenograft breast cancer model showed that suppressing the enzyme delayed the development of tamoxifen resistance in tumors, whereas overexpressing it accelerated the development of resistance.

“High APOBECB3 expression levels correlate with poor outcomes for estrogen receptor–positive breast cancer, including recurrence during tamoxifen treatment,” said lead author Reuben Harris, Ph.D., an investigator at the Howard Hughes Medical Institute, professor at the University of Minnesota, Minneapolis, and member of the Masonic Cancer Center.

“One point to emphasize is that this is a gain-of-function mutating enzyme. A lot of things we hear about are loss of functions that are happening in cancer,” and at present, not much can be done about those, he said. But “because [APOBECB3] is an enzyme with an active site, I think that’s targetable.”

Dr. Harris drew an analogy between APOBEC mutagenesis and UV mutagenesis, noting that once the molecular mechanism was defined for the latter, interventions such as UV-blocking sunscreens and protective clothing were harnessed for prevention. “Now we have identified a significant source of mutation in breast cancer (as well as other cancers) and we can begin to think about innovations to control the mutating activity of this enzyme,” he elaborated.

Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos Arteaga, professor of medicine at Vanderbilt University, Nashville, Tenn,, and director of the Breast Cancer Program, asked, “Do you think this is ready to be addressed in the clinic? If you think so, can you speculate how we can do that?”

“I think it’s nearing readiness,” Dr. Harris replied. “We need more clinical studies. So far we’ve been focused on retrospective studies. … Some prospective studies need to be done. Obviously this needs to expand to include other treatments, and we also have to get a better handle on which subtypes are most affected by this mutagenic process.”

Previous research his team did in collaboration with their coinvestigators in the Netherlands showed that women with estrogen receptor–positive primary tumors treated only with resection had poorer progression-free and overall survival if their primaries had up-regulation of the A3B enzyme (Horm Cancer. 2014;5:405-13).

“This suggests that this is a prognostic marker for outcome, but we wanted to go further and ask if this process is contributing to or correlating with poor outcomes such as recurrence and resistance to tamoxifen therapy,” Dr. Harris commented.

In the new retrospective study, this time among women who experienced a recurrence of estrogen receptor–positive breast cancer and were then given first-line tamoxifen, the median progression-free survival was just 7.5 months for those with high A3B expression in the primary tumor, compared with 13.3 months for those with low expression (hazard ratio, 1.67; P = .0001).

“These are correlative studies that really suggest what many of the cellular experiments and genetic experiments in my lab and others have indicated, that this would be an adverse effector in estrogen receptor–positive breast cancer, but we wanted to test this hypothesis with a cause-and-effect experiment,” he said.

In xenograft experiments, they engineered estrogen receptor–positive MCF7L breast cancer cells to have either high or low expression of A3B and grew the cells into small tumors. They then grafted the tumors into female nude mice.

In a first set of experiments, knocking down expression of A3B slowed the development of tamoxifen resistance, and in fact, few tumors had become resistant to the drug even after a year, Dr. Harris reported. In a second set, overexpressing the enzyme in tumor cells by about 100-fold led to almost immediate tamoxifen resistance.

“So we can slow it down, and we can speed it up, and all of this is consistent with the clinical data indicating that those primary breast tumors that have high levels of this enzyme result in poorer outcomes than those tumors that have low levels,” he concluded.

As mutations induced by A3B might also affect the response to other treatments, ongoing research is now looking at its impact on the development of chemotherapy resistance, noted Dr. Harris.