Breast Cancer

SAN ANTONIO – Although adding concurrent estrogen deprivation to a standard combination chemotherapy regimen for women with breast cancers positive for the estrogen receptors (ER+) and the human epidermal growth factor receptor–2 (HER2+) did not add to the already considerable toxicity, it also did not seem to add much benefit, according to an investigator in the NSABP B-52 trial.

Among 311 women with ER+/HER2+ tumors randomized to neoadjuvant therapy with docetaxel, carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta) with or without estrogen deprivation therapy, there was no statistically significant difference in the primary endpoint of pathologic complete response (pCR) rates, reported Mothaffar F. Rimawi, MD, of the breast center at Baylor College of Medicine in Houston.

Neil Osterweil/Frontline Medical News

Endocrine/chemo interplay?

The rationale for the trial was based on several previous findings, including the propensity for ER+/HER2+ tumors to be less responsive to dual anti-HER2 therapy with trastuzumab (Herceptin) and pertuzumab (Perjeta).

There is also evidence to suggest that the estrogen receptor may act as a pathway of resistance to anti-HER2 therapy, and evidence from older trials suggested that chemotherapy and endocrine therapy may have antagonistic effects, he said.

The investigators hypothesized that concurrent inhibition of ER and HER2 tumors with neoadjuvant chemotherapy consisting of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) would not be antagonistic, and could overcome resistance to treatment as shown by improvements in pathologic complete response rates.

The investigators enrolled women with HER+ and ER+ and/or progresterone receptor–positive (PR+) invasive breast cancer diagnosed by core needle biopsy, stratified them by premenopausal or postmenopausal status, and then randomized them to receive chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab every 21 days for six cycles, with or without estrogen deprivation therapy. Postmenopausal women received an aromatase inhibitor, and premenopausal women received an aromatase inhibitor plus ovarian suppression with goserelin and a lutenizing hormone–releasing hormone agonist.

For the primary endpoint, overall rates of pCR in the breast and nodes were 41% among 154 patients treated with TCHP chemotherapy alone, vs. 46% for 157 women treated with TCHP and estrogen deprivation, a difference that was not statistically significant. The results were similar in an analysis stratified by menopausal status: 44% vs. 46%, respectively, in premenopausal women, and 38% vs. 45% in postmenopausal women. Neither comparison was statistically significant.

In addition, no overall or stratified differences were seen in terms of pCR in the breast alone, and no differences were seen in clinical complete response rates, at 68.1% vs. 73.9%, respectively.

Nearly 100% of patients in the TCHP chemotherapy alone arm had diarrhea, ranging from 42% with grade 1, to 34% with grade 2, to 23% with grade 3, to less than 1% with grade 4. The distribution of diarrhea severity was virtually identical among patients treated with TCHP plus estrogen deprivation, all of whom experienced some grade. Other common gastrointestinal side effects in each study arm included nausea, vomiting, and dehydration, occurring in nearly all patients with equal distribution of severity between the two arms.

Hematologic toxicities included anemia, hypokalemia, and febrile neutropenia, again distributed evenly in severity between the trial arms.

Alternative endpoint?

Dr. Rimawi said the pCR endpoint commonly used in clinical trials may not be ideal for studying therapy in this population, because it generally correlates with outcomes among women when tumors are ER negative,“but when they are ER positive, the absence of a pathologic complete response is not necessarily a bad thing.”

He said that residual cancer burden, or RCB, appears to be a better marker for prognosis than pCR in patients with ER+/HER2+ tumors.

“In this population we need a different metric, a metric that is not path CR,” agreed Carlos Arteaga, MD, professor of cancer biology and medicine, and coleader of the breast cancer research program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

“We need other metrics that are more objective and more correlated with long-term outcomes. Path CR is not,” said Dr. Arteaga, who moderated a briefing where NSABP B-52 data were discussed prior to their presentation in the general session.

Regarding the lack of statistical significance, Dr. Rimawi said it is possible that the effects of chemotherapy may have blunted the responses that might otherwise have been seen with the addition of estrogen deprivation.

“We believe that if we de-escalate treatment, we could see a higher response to the estrogen receptor inhibitor,” he said.

NSABP B-52 was supported by the National Cancer Institute and Genentech. Dr. Rimawi reported contracted research from Genentech and GlaxoSmithKline. Dr. Arteaga reported no disclosures relevant to the trial.

SAN ANTONIO – Although adding concurrent estrogen deprivation to a standard combination chemotherapy regimen for women with breast cancers positive for the estrogen receptors (ER+) and the human epidermal growth factor receptor–2 (HER2+) did not add to the already considerable toxicity, it also did not seem to add much benefit, according to an investigator in the NSABP B-52 trial.

Among 311 women with ER+/HER2+ tumors randomized to neoadjuvant therapy with docetaxel, carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta) with or without estrogen deprivation therapy, there was no statistically significant difference in the primary endpoint of pathologic complete response (pCR) rates, reported Mothaffar F. Rimawi, MD, of the breast center at Baylor College of Medicine in Houston.

Neil Osterweil/Frontline Medical News

Endocrine/chemo interplay?

The rationale for the trial was based on several previous findings, including the propensity for ER+/HER2+ tumors to be less responsive to dual anti-HER2 therapy with trastuzumab (Herceptin) and pertuzumab (Perjeta).

There is also evidence to suggest that the estrogen receptor may act as a pathway of resistance to anti-HER2 therapy, and evidence from older trials suggested that chemotherapy and endocrine therapy may have antagonistic effects, he said.

The investigators hypothesized that concurrent inhibition of ER and HER2 tumors with neoadjuvant chemotherapy consisting of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) would not be antagonistic, and could overcome resistance to treatment as shown by improvements in pathologic complete response rates.

The investigators enrolled women with HER+ and ER+ and/or progresterone receptor–positive (PR+) invasive breast cancer diagnosed by core needle biopsy, stratified them by premenopausal or postmenopausal status, and then randomized them to receive chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab every 21 days for six cycles, with or without estrogen deprivation therapy. Postmenopausal women received an aromatase inhibitor, and premenopausal women received an aromatase inhibitor plus ovarian suppression with goserelin and a lutenizing hormone–releasing hormone agonist.

For the primary endpoint, overall rates of pCR in the breast and nodes were 41% among 154 patients treated with TCHP chemotherapy alone, vs. 46% for 157 women treated with TCHP and estrogen deprivation, a difference that was not statistically significant. The results were similar in an analysis stratified by menopausal status: 44% vs. 46%, respectively, in premenopausal women, and 38% vs. 45% in postmenopausal women. Neither comparison was statistically significant.

In addition, no overall or stratified differences were seen in terms of pCR in the breast alone, and no differences were seen in clinical complete response rates, at 68.1% vs. 73.9%, respectively.

Nearly 100% of patients in the TCHP chemotherapy alone arm had diarrhea, ranging from 42% with grade 1, to 34% with grade 2, to 23% with grade 3, to less than 1% with grade 4. The distribution of diarrhea severity was virtually identical among patients treated with TCHP plus estrogen deprivation, all of whom experienced some grade. Other common gastrointestinal side effects in each study arm included nausea, vomiting, and dehydration, occurring in nearly all patients with equal distribution of severity between the two arms.

Hematologic toxicities included anemia, hypokalemia, and febrile neutropenia, again distributed evenly in severity between the trial arms.

Alternative endpoint?

Dr. Rimawi said the pCR endpoint commonly used in clinical trials may not be ideal for studying therapy in this population, because it generally correlates with outcomes among women when tumors are ER negative,“but when they are ER positive, the absence of a pathologic complete response is not necessarily a bad thing.”

He said that residual cancer burden, or RCB, appears to be a better marker for prognosis than pCR in patients with ER+/HER2+ tumors.

“In this population we need a different metric, a metric that is not path CR,” agreed Carlos Arteaga, MD, professor of cancer biology and medicine, and coleader of the breast cancer research program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

“We need other metrics that are more objective and more correlated with long-term outcomes. Path CR is not,” said Dr. Arteaga, who moderated a briefing where NSABP B-52 data were discussed prior to their presentation in the general session.

Regarding the lack of statistical significance, Dr. Rimawi said it is possible that the effects of chemotherapy may have blunted the responses that might otherwise have been seen with the addition of estrogen deprivation.

“We believe that if we de-escalate treatment, we could see a higher response to the estrogen receptor inhibitor,” he said.

NSABP B-52 was supported by the National Cancer Institute and Genentech. Dr. Rimawi reported contracted research from Genentech and GlaxoSmithKline. Dr. Arteaga reported no disclosures relevant to the trial.

SAN ANTONIO – Although adding concurrent estrogen deprivation to a standard combination chemotherapy regimen for women with breast cancers positive for the estrogen receptors (ER+) and the human epidermal growth factor receptor–2 (HER2+) did not add to the already considerable toxicity, it also did not seem to add much benefit, according to an investigator in the NSABP B-52 trial.

Among 311 women with ER+/HER2+ tumors randomized to neoadjuvant therapy with docetaxel, carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta) with or without estrogen deprivation therapy, there was no statistically significant difference in the primary endpoint of pathologic complete response (pCR) rates, reported Mothaffar F. Rimawi, MD, of the breast center at Baylor College of Medicine in Houston.

Neil Osterweil/Frontline Medical News

Endocrine/chemo interplay?

The rationale for the trial was based on several previous findings, including the propensity for ER+/HER2+ tumors to be less responsive to dual anti-HER2 therapy with trastuzumab (Herceptin) and pertuzumab (Perjeta).

There is also evidence to suggest that the estrogen receptor may act as a pathway of resistance to anti-HER2 therapy, and evidence from older trials suggested that chemotherapy and endocrine therapy may have antagonistic effects, he said.

The investigators hypothesized that concurrent inhibition of ER and HER2 tumors with neoadjuvant chemotherapy consisting of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) would not be antagonistic, and could overcome resistance to treatment as shown by improvements in pathologic complete response rates.

The investigators enrolled women with HER+ and ER+ and/or progresterone receptor–positive (PR+) invasive breast cancer diagnosed by core needle biopsy, stratified them by premenopausal or postmenopausal status, and then randomized them to receive chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab every 21 days for six cycles, with or without estrogen deprivation therapy. Postmenopausal women received an aromatase inhibitor, and premenopausal women received an aromatase inhibitor plus ovarian suppression with goserelin and a lutenizing hormone–releasing hormone agonist.

For the primary endpoint, overall rates of pCR in the breast and nodes were 41% among 154 patients treated with TCHP chemotherapy alone, vs. 46% for 157 women treated with TCHP and estrogen deprivation, a difference that was not statistically significant. The results were similar in an analysis stratified by menopausal status: 44% vs. 46%, respectively, in premenopausal women, and 38% vs. 45% in postmenopausal women. Neither comparison was statistically significant.

In addition, no overall or stratified differences were seen in terms of pCR in the breast alone, and no differences were seen in clinical complete response rates, at 68.1% vs. 73.9%, respectively.

Nearly 100% of patients in the TCHP chemotherapy alone arm had diarrhea, ranging from 42% with grade 1, to 34% with grade 2, to 23% with grade 3, to less than 1% with grade 4. The distribution of diarrhea severity was virtually identical among patients treated with TCHP plus estrogen deprivation, all of whom experienced some grade. Other common gastrointestinal side effects in each study arm included nausea, vomiting, and dehydration, occurring in nearly all patients with equal distribution of severity between the two arms.

Hematologic toxicities included anemia, hypokalemia, and febrile neutropenia, again distributed evenly in severity between the trial arms.

Alternative endpoint?

Dr. Rimawi said the pCR endpoint commonly used in clinical trials may not be ideal for studying therapy in this population, because it generally correlates with outcomes among women when tumors are ER negative,“but when they are ER positive, the absence of a pathologic complete response is not necessarily a bad thing.”

He said that residual cancer burden, or RCB, appears to be a better marker for prognosis than pCR in patients with ER+/HER2+ tumors.

“In this population we need a different metric, a metric that is not path CR,” agreed Carlos Arteaga, MD, professor of cancer biology and medicine, and coleader of the breast cancer research program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

“We need other metrics that are more objective and more correlated with long-term outcomes. Path CR is not,” said Dr. Arteaga, who moderated a briefing where NSABP B-52 data were discussed prior to their presentation in the general session.

Regarding the lack of statistical significance, Dr. Rimawi said it is possible that the effects of chemotherapy may have blunted the responses that might otherwise have been seen with the addition of estrogen deprivation.

“We believe that if we de-escalate treatment, we could see a higher response to the estrogen receptor inhibitor,” he said.

NSABP B-52 was supported by the National Cancer Institute and Genentech. Dr. Rimawi reported contracted research from Genentech and GlaxoSmithKline. Dr. Arteaga reported no disclosures relevant to the trial.

SAN ANTONIO – Breast cancers that are positive for the estrogen receptor (ER) and human epidermal growth factor receptor–2 (HER2) are less likely than ER-negative/HER2-positive tumors to respond to dual anti-HER2 therapy, suggesting that the estrogen receptor may act as a pathway of resistance to anti-HER2 treatment.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-52 trial was designed to test the hypothesis that concurrent inhibition of both ER and HER2 added to chemotherapy with a platinum compound and a taxane will overcome resistance to treatment and improve pathologic complete response (pCR) rates in patients with ER-positive/HER2-positive breast cancer.

In a video interview at the San Antonio Breast Cancer Symposium, Mothaffar F. Rimawi, MD, discusses the trial results, which failed to show a significant difference in pCR rates between women who received chemotherapy with estrogen deprivation or chemotherapy alone. However, the trial still provided important information about the interplay between hormonal and HER2 receptors, and may inform future clinical trials examining reduction in tumor burden as a prognostic measure, says Dr. Rimawi from the Breast Center at Baylor College of Medicine, Houston.

[email protected]

SAN ANTONIO – Breast cancers that are positive for the estrogen receptor (ER) and human epidermal growth factor receptor–2 (HER2) are less likely than ER-negative/HER2-positive tumors to respond to dual anti-HER2 therapy, suggesting that the estrogen receptor may act as a pathway of resistance to anti-HER2 treatment.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-52 trial was designed to test the hypothesis that concurrent inhibition of both ER and HER2 added to chemotherapy with a platinum compound and a taxane will overcome resistance to treatment and improve pathologic complete response (pCR) rates in patients with ER-positive/HER2-positive breast cancer.

In a video interview at the San Antonio Breast Cancer Symposium, Mothaffar F. Rimawi, MD, discusses the trial results, which failed to show a significant difference in pCR rates between women who received chemotherapy with estrogen deprivation or chemotherapy alone. However, the trial still provided important information about the interplay between hormonal and HER2 receptors, and may inform future clinical trials examining reduction in tumor burden as a prognostic measure, says Dr. Rimawi from the Breast Center at Baylor College of Medicine, Houston.

[email protected]

SAN ANTONIO – Breast cancers that are positive for the estrogen receptor (ER) and human epidermal growth factor receptor–2 (HER2) are less likely than ER-negative/HER2-positive tumors to respond to dual anti-HER2 therapy, suggesting that the estrogen receptor may act as a pathway of resistance to anti-HER2 treatment.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-52 trial was designed to test the hypothesis that concurrent inhibition of both ER and HER2 added to chemotherapy with a platinum compound and a taxane will overcome resistance to treatment and improve pathologic complete response (pCR) rates in patients with ER-positive/HER2-positive breast cancer.

In a video interview at the San Antonio Breast Cancer Symposium, Mothaffar F. Rimawi, MD, discusses the trial results, which failed to show a significant difference in pCR rates between women who received chemotherapy with estrogen deprivation or chemotherapy alone. However, the trial still provided important information about the interplay between hormonal and HER2 receptors, and may inform future clinical trials examining reduction in tumor burden as a prognostic measure, says Dr. Rimawi from the Breast Center at Baylor College of Medicine, Houston.

[email protected]

SAN ANTONIO – When does adjuvant therapy with an aromatase inhibitor become too much of a good thing? Or to put it another way, what’s the optimal duration of extended aromatase inhibitor therapy? That’s the question that three clinical trials have tried – but largely failed – to answer.

For example, the randomized, double-blinded NSABP B-42 trial, comparing extended therapy with letrozole (Femara) in postmenopausal women with hormone receptor–positive (HR+) breast cancer who have completed previous adjuvant therapy with an aromatase inhibitor (AI) showed no difference in disease-free survival (DFS) after 7 years of follow-up between women treated with extended letrozole or placebo.

DATA data

In the DATA study, also presented here, investigators from the Netherlands compared 6 years of anastrozole (Arimidex) to 3 years of anastrozole following 2 or 3 years of adjuvant tamoxifen for postmenopausal women with estrogen receptor–positive (ER+), and/or progesterone receptor–positive (PR+) breast cancer.

They found that “adapted” DFS (DFS starting 3 years after randomization) and adapted overall survival (OS) were similar between the two groups.

“The findings of the DATA study do not support extended adjuvant AI use after 5 years of sequential endocrine therapy for all postmenopausal hormone receptor–positive breast cancer patients,” said Vivianne Tjan-Heijnen, MD, of Maastricht University Medical Center in the Netherlands.

Less than ideal

In the optimistically named IDEAL trial, a separate team of investigators, also from the Netherlands, looked at the relative merits of continuing adjuvant therapy with letrozole for 2.5 or 5 years following 5 years of adjuvant therapy with tamoxifen, an AI, or a combination in postmenopausal women with HR+ breast cancer.

They found no differences in either DFS or OS between patients treated for 5 years or those treated for only half that long.

“We conclude that there is no benefit of extending AI-based therapy longer than two-and-a-half years,” said Erik Blok, MD, of Leiden University Medical Center in the Netherlands.

Give what to whom for how long?

Results of the trials raise more questions than they answer, said Michael Gnant, MD, of the Medical University of Vienna, the invited discussant.

“Essentially, these three trials did not reach the necessary statistical significance levels to demonstrate a clear benefit for the respective AI extension,” he said.

“Can other agents we use in luminal breast cancer help? Frankly, I don’t think so. Based on their tolerability profile, and in part also on financial toxicity, I don’t think that the promising agents we explore in many situations for the treatment of hormone receptor–positive breast cancer will realistically be used in the extended adjuvant setting,” he said.

What’s needed, he said, are new strategies for targeting the chronic part of luminal breast cancer recurrence risk. Using endocrine therapies in this setting will likely be ineffective. Instead, agents that could directly target dormant cancer stem cells would “eliminate the source of late metastases for good.”

The best evidence to date clearly points to individualized treatment plans for patients, Dr. Gnant said.

For example, for a patient who has had 2-5 years of tamoxifen, an AI for 2.5-5 additional years can help to prevent recurrences, provided that the patient has risk factors for recurrence and excellent bone health.

“Based on the trial results, it is more complex for a patient who comes off initial or sequential AI. There are factors favoring the extension of AI treatment, and other factors to speak against such extension. I suggest to start with patient features at this time,” he said.

Currently, the main factor driving the choice of extended AI therapy will be how well the patient has tolerated AIs in the first years of therapy and whether she is at increased risk for fractures, suggesting younger age as a factor favoring extended AI use.

Patients with higher clinicopathologic risk factors such as node positivity or more luminal type tumors, as well as higher risk according to genomic studies, might also benefit from extended AI therapy, he said.

Biomarkers needed

“What the data from these and other trials tell us is that endocrine therapy is not for everyone. We need biomarkers that can tell us who should be getting extended endocrine therapy, be it 10 years or even a longer duration of time, versus a subgroup that might do very well with 5 five years of AI,” Aditya Bardia, MBBS, MPH, of the breast cancer division at Massachusetts General Hospital Cancer Center in Boston, said in an interview.

There are several such biomarkers under investigation, but they need validation and testing in large scale clinical trials before they find their way into day-to-practice, he said.

Dr. Bardia was not involved in the studies.

NSABP B-42 was sponsored by PrECOG with financial support from Novartis. Dr. Mamounas reported having no conflicts of interest. The DATA trial was sponsored by the Dutch Breast Cancer Research Group and Novartis. Dr. Tjan-Heijnen reported nothing to disclose. IDEAL was supported by the Dutch Breast Cancer Research Group and Novartis. Dr. Blok reported nothing to disclose.

SAN ANTONIO – When does adjuvant therapy with an aromatase inhibitor become too much of a good thing? Or to put it another way, what’s the optimal duration of extended aromatase inhibitor therapy? That’s the question that three clinical trials have tried – but largely failed – to answer.

For example, the randomized, double-blinded NSABP B-42 trial, comparing extended therapy with letrozole (Femara) in postmenopausal women with hormone receptor–positive (HR+) breast cancer who have completed previous adjuvant therapy with an aromatase inhibitor (AI) showed no difference in disease-free survival (DFS) after 7 years of follow-up between women treated with extended letrozole or placebo.

DATA data

In the DATA study, also presented here, investigators from the Netherlands compared 6 years of anastrozole (Arimidex) to 3 years of anastrozole following 2 or 3 years of adjuvant tamoxifen for postmenopausal women with estrogen receptor–positive (ER+), and/or progesterone receptor–positive (PR+) breast cancer.

They found that “adapted” DFS (DFS starting 3 years after randomization) and adapted overall survival (OS) were similar between the two groups.

“The findings of the DATA study do not support extended adjuvant AI use after 5 years of sequential endocrine therapy for all postmenopausal hormone receptor–positive breast cancer patients,” said Vivianne Tjan-Heijnen, MD, of Maastricht University Medical Center in the Netherlands.

Less than ideal

In the optimistically named IDEAL trial, a separate team of investigators, also from the Netherlands, looked at the relative merits of continuing adjuvant therapy with letrozole for 2.5 or 5 years following 5 years of adjuvant therapy with tamoxifen, an AI, or a combination in postmenopausal women with HR+ breast cancer.

They found no differences in either DFS or OS between patients treated for 5 years or those treated for only half that long.

“We conclude that there is no benefit of extending AI-based therapy longer than two-and-a-half years,” said Erik Blok, MD, of Leiden University Medical Center in the Netherlands.

Give what to whom for how long?

Results of the trials raise more questions than they answer, said Michael Gnant, MD, of the Medical University of Vienna, the invited discussant.

“Essentially, these three trials did not reach the necessary statistical significance levels to demonstrate a clear benefit for the respective AI extension,” he said.

“Can other agents we use in luminal breast cancer help? Frankly, I don’t think so. Based on their tolerability profile, and in part also on financial toxicity, I don’t think that the promising agents we explore in many situations for the treatment of hormone receptor–positive breast cancer will realistically be used in the extended adjuvant setting,” he said.

What’s needed, he said, are new strategies for targeting the chronic part of luminal breast cancer recurrence risk. Using endocrine therapies in this setting will likely be ineffective. Instead, agents that could directly target dormant cancer stem cells would “eliminate the source of late metastases for good.”

The best evidence to date clearly points to individualized treatment plans for patients, Dr. Gnant said.

For example, for a patient who has had 2-5 years of tamoxifen, an AI for 2.5-5 additional years can help to prevent recurrences, provided that the patient has risk factors for recurrence and excellent bone health.

“Based on the trial results, it is more complex for a patient who comes off initial or sequential AI. There are factors favoring the extension of AI treatment, and other factors to speak against such extension. I suggest to start with patient features at this time,” he said.

Currently, the main factor driving the choice of extended AI therapy will be how well the patient has tolerated AIs in the first years of therapy and whether she is at increased risk for fractures, suggesting younger age as a factor favoring extended AI use.

Patients with higher clinicopathologic risk factors such as node positivity or more luminal type tumors, as well as higher risk according to genomic studies, might also benefit from extended AI therapy, he said.

Biomarkers needed

“What the data from these and other trials tell us is that endocrine therapy is not for everyone. We need biomarkers that can tell us who should be getting extended endocrine therapy, be it 10 years or even a longer duration of time, versus a subgroup that might do very well with 5 five years of AI,” Aditya Bardia, MBBS, MPH, of the breast cancer division at Massachusetts General Hospital Cancer Center in Boston, said in an interview.

There are several such biomarkers under investigation, but they need validation and testing in large scale clinical trials before they find their way into day-to-practice, he said.

Dr. Bardia was not involved in the studies.

NSABP B-42 was sponsored by PrECOG with financial support from Novartis. Dr. Mamounas reported having no conflicts of interest. The DATA trial was sponsored by the Dutch Breast Cancer Research Group and Novartis. Dr. Tjan-Heijnen reported nothing to disclose. IDEAL was supported by the Dutch Breast Cancer Research Group and Novartis. Dr. Blok reported nothing to disclose.

SAN ANTONIO – When does adjuvant therapy with an aromatase inhibitor become too much of a good thing? Or to put it another way, what’s the optimal duration of extended aromatase inhibitor therapy? That’s the question that three clinical trials have tried – but largely failed – to answer.

For example, the randomized, double-blinded NSABP B-42 trial, comparing extended therapy with letrozole (Femara) in postmenopausal women with hormone receptor–positive (HR+) breast cancer who have completed previous adjuvant therapy with an aromatase inhibitor (AI) showed no difference in disease-free survival (DFS) after 7 years of follow-up between women treated with extended letrozole or placebo.

DATA data

In the DATA study, also presented here, investigators from the Netherlands compared 6 years of anastrozole (Arimidex) to 3 years of anastrozole following 2 or 3 years of adjuvant tamoxifen for postmenopausal women with estrogen receptor–positive (ER+), and/or progesterone receptor–positive (PR+) breast cancer.

They found that “adapted” DFS (DFS starting 3 years after randomization) and adapted overall survival (OS) were similar between the two groups.

“The findings of the DATA study do not support extended adjuvant AI use after 5 years of sequential endocrine therapy for all postmenopausal hormone receptor–positive breast cancer patients,” said Vivianne Tjan-Heijnen, MD, of Maastricht University Medical Center in the Netherlands.

Less than ideal

In the optimistically named IDEAL trial, a separate team of investigators, also from the Netherlands, looked at the relative merits of continuing adjuvant therapy with letrozole for 2.5 or 5 years following 5 years of adjuvant therapy with tamoxifen, an AI, or a combination in postmenopausal women with HR+ breast cancer.

They found no differences in either DFS or OS between patients treated for 5 years or those treated for only half that long.

“We conclude that there is no benefit of extending AI-based therapy longer than two-and-a-half years,” said Erik Blok, MD, of Leiden University Medical Center in the Netherlands.

Give what to whom for how long?

Results of the trials raise more questions than they answer, said Michael Gnant, MD, of the Medical University of Vienna, the invited discussant.

“Essentially, these three trials did not reach the necessary statistical significance levels to demonstrate a clear benefit for the respective AI extension,” he said.

“Can other agents we use in luminal breast cancer help? Frankly, I don’t think so. Based on their tolerability profile, and in part also on financial toxicity, I don’t think that the promising agents we explore in many situations for the treatment of hormone receptor–positive breast cancer will realistically be used in the extended adjuvant setting,” he said.

What’s needed, he said, are new strategies for targeting the chronic part of luminal breast cancer recurrence risk. Using endocrine therapies in this setting will likely be ineffective. Instead, agents that could directly target dormant cancer stem cells would “eliminate the source of late metastases for good.”

The best evidence to date clearly points to individualized treatment plans for patients, Dr. Gnant said.

For example, for a patient who has had 2-5 years of tamoxifen, an AI for 2.5-5 additional years can help to prevent recurrences, provided that the patient has risk factors for recurrence and excellent bone health.

“Based on the trial results, it is more complex for a patient who comes off initial or sequential AI. There are factors favoring the extension of AI treatment, and other factors to speak against such extension. I suggest to start with patient features at this time,” he said.

Currently, the main factor driving the choice of extended AI therapy will be how well the patient has tolerated AIs in the first years of therapy and whether she is at increased risk for fractures, suggesting younger age as a factor favoring extended AI use.

Patients with higher clinicopathologic risk factors such as node positivity or more luminal type tumors, as well as higher risk according to genomic studies, might also benefit from extended AI therapy, he said.

Biomarkers needed

“What the data from these and other trials tell us is that endocrine therapy is not for everyone. We need biomarkers that can tell us who should be getting extended endocrine therapy, be it 10 years or even a longer duration of time, versus a subgroup that might do very well with 5 five years of AI,” Aditya Bardia, MBBS, MPH, of the breast cancer division at Massachusetts General Hospital Cancer Center in Boston, said in an interview.

There are several such biomarkers under investigation, but they need validation and testing in large scale clinical trials before they find their way into day-to-practice, he said.

Dr. Bardia was not involved in the studies.

NSABP B-42 was sponsored by PrECOG with financial support from Novartis. Dr. Mamounas reported having no conflicts of interest. The DATA trial was sponsored by the Dutch Breast Cancer Research Group and Novartis. Dr. Tjan-Heijnen reported nothing to disclose. IDEAL was supported by the Dutch Breast Cancer Research Group and Novartis. Dr. Blok reported nothing to disclose.

SAN ANTONIO – The “genomic landscape” of resistant estrogen receptor–positive (ER+) metastatic breast cancer differs significantly from that of ER+ primary breast cancer, according to findings from a study involving whole-exome sequencing and transcriptome sequencing of such cancers.

Multiple genes were recurrently altered in ER+ metastatic breast cancers at a rate significantly higher than in ER+ primary breast cancers (with 3- to 33-fold enrichment in metastatic vs. primary samples), Ofir Cohen, PhD, explained at the San Antonio Breast Cancer Symposium.

This finding, which suggests that recurrent alterations in genes in ER+ metastatic breast cancers are often acquired after treatment and thus may play a role in resistance to ER-directed therapies and/or metastasis, highlights the value of genomic profiling of metastatic biopsies and has implications for drug development, said Dr. Cohen of the Broad Institute of MIT (Massachusetts Institute of Technology) and Harvard in Cambridge.

Although the genomic and molecular landscape of ER+ primary breast cancer is better understood, that of ER+ metastatic breast cancer is underexplored, he noted.

Thus, he and his colleagues performed whole-exome sequencing on 149 metastatic tumor biopsies from patients with ER+ metastatic tumors and resistance to at least one ER-directed therapy and compared the results with those from 44 matched primary samples from the same patient. They also performed transcriptome sequencing (RNA-seq) of 128 metastatic biopsies.

A key observation from the study is that ESR1 genes were mutated in 24% of the cohort, and the mutations were acquired in 14 of the 15 samples with matched primary samples.

“This emphasized the important role that these mutations may play, specifically in the metastatic and drug-resistant settings,” Dr. Cohen said.

Similarly, ERBB2 mutations occurred in 7% of samples, and seemed to be acquired in five of six metastatic samples with matched primary samples, he said.

“For both of these genes, other than being acquired and suggestive of importance, they also have clear clinical implications, as finding those mutations may guide treatment choices for those patients,” he said.

Another example involves RB1 mutations, which were found in 5% of samples, and which appeared to be acquired in three of five of those with matched primaries. More frequent alterations were also found in PIK3CA, PTEN, and AKTI genes, among others, in metastatic vs. primary cancers.

The observation that these tumors evolve and have different mutations in the primary and metastatic settings may be important, because this suggests that knowledge of the alterations and mutations in the primary setting is insufficient to guide treatment in the metastatic setting.

“So the take-home message here is that tumors do evolve, and that the metastatic setting is different than the primary setting,” Dr. Cohen said.

Sequencing both the exome and the transcriptome may “give us a handle to assess that,” he said.

“Our goal is really to understand evolved resistance. That is, to try and understand the mechanisms that drive the evolution of resistance in ER+ metastatic breast cancer, and, once we understand that, [to determine] how we can translate that knowledge in the clinic,” he said, noting that resistance also may develop through other nongenomic mechanisms, such as epigenetic and regulatory mechanisms.

“As long as those mechanisms leave a footprint on the transcriptome … sequencing the transcriptome together with the exome may yield relevant insights into resistance states that do not derive specifically from exome mutations,” he added.

The findings are important because, despite tremendous advances in the treatment of ER+ metastatic breast cancer, therapeutic resistance remains a common problem, and improved understanding of the underlying resistance mechanisms is critical for enabling durable control of this disease, Dr. Cohen said, explaining that resistant tumors remain the most common cause of breast cancer death and that there is an urgent need to develop new therapeutic strategies for patients who no longer respond to existing therapies.

In a written statement, senior investigator Nikhil Wagle, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, said that the ultimate goal of the project is “to integrate the functional and clinical findings into a unified ‘Resistance Atlas’ for ER+ metastatic breast cancer, which should help inform treatment decisions for individual patients as well as propel the development of new combination treatment strategies for ER-positive metastatic breast cancer.”

This study was funded by the National Cancer Institute, the National Human Genome Research Institute, the Department of Defense Breast Cancer Research Program, Susan G. Komen, the V Foundation, the Breast Cancer Alliance, the AACR-Landon Foundation, the Friends of Dana-Farber Cancer Institute, and the Breast Cancer Research Foundation. Dr. Cohen reported having no conflicts of interest. Dr. Wagle is an equity holder in Foundation Medicine, a consultant to Novartis, and a recipient of sponsored research support from Novartis, Genentech, and Merck.

[email protected]

SAN ANTONIO – The “genomic landscape” of resistant estrogen receptor–positive (ER+) metastatic breast cancer differs significantly from that of ER+ primary breast cancer, according to findings from a study involving whole-exome sequencing and transcriptome sequencing of such cancers.

Multiple genes were recurrently altered in ER+ metastatic breast cancers at a rate significantly higher than in ER+ primary breast cancers (with 3- to 33-fold enrichment in metastatic vs. primary samples), Ofir Cohen, PhD, explained at the San Antonio Breast Cancer Symposium.

This finding, which suggests that recurrent alterations in genes in ER+ metastatic breast cancers are often acquired after treatment and thus may play a role in resistance to ER-directed therapies and/or metastasis, highlights the value of genomic profiling of metastatic biopsies and has implications for drug development, said Dr. Cohen of the Broad Institute of MIT (Massachusetts Institute of Technology) and Harvard in Cambridge.

Although the genomic and molecular landscape of ER+ primary breast cancer is better understood, that of ER+ metastatic breast cancer is underexplored, he noted.

Thus, he and his colleagues performed whole-exome sequencing on 149 metastatic tumor biopsies from patients with ER+ metastatic tumors and resistance to at least one ER-directed therapy and compared the results with those from 44 matched primary samples from the same patient. They also performed transcriptome sequencing (RNA-seq) of 128 metastatic biopsies.

A key observation from the study is that ESR1 genes were mutated in 24% of the cohort, and the mutations were acquired in 14 of the 15 samples with matched primary samples.

“This emphasized the important role that these mutations may play, specifically in the metastatic and drug-resistant settings,” Dr. Cohen said.

Similarly, ERBB2 mutations occurred in 7% of samples, and seemed to be acquired in five of six metastatic samples with matched primary samples, he said.

“For both of these genes, other than being acquired and suggestive of importance, they also have clear clinical implications, as finding those mutations may guide treatment choices for those patients,” he said.

Another example involves RB1 mutations, which were found in 5% of samples, and which appeared to be acquired in three of five of those with matched primaries. More frequent alterations were also found in PIK3CA, PTEN, and AKTI genes, among others, in metastatic vs. primary cancers.

The observation that these tumors evolve and have different mutations in the primary and metastatic settings may be important, because this suggests that knowledge of the alterations and mutations in the primary setting is insufficient to guide treatment in the metastatic setting.

“So the take-home message here is that tumors do evolve, and that the metastatic setting is different than the primary setting,” Dr. Cohen said.

Sequencing both the exome and the transcriptome may “give us a handle to assess that,” he said.

“Our goal is really to understand evolved resistance. That is, to try and understand the mechanisms that drive the evolution of resistance in ER+ metastatic breast cancer, and, once we understand that, [to determine] how we can translate that knowledge in the clinic,” he said, noting that resistance also may develop through other nongenomic mechanisms, such as epigenetic and regulatory mechanisms.

“As long as those mechanisms leave a footprint on the transcriptome … sequencing the transcriptome together with the exome may yield relevant insights into resistance states that do not derive specifically from exome mutations,” he added.

The findings are important because, despite tremendous advances in the treatment of ER+ metastatic breast cancer, therapeutic resistance remains a common problem, and improved understanding of the underlying resistance mechanisms is critical for enabling durable control of this disease, Dr. Cohen said, explaining that resistant tumors remain the most common cause of breast cancer death and that there is an urgent need to develop new therapeutic strategies for patients who no longer respond to existing therapies.

In a written statement, senior investigator Nikhil Wagle, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, said that the ultimate goal of the project is “to integrate the functional and clinical findings into a unified ‘Resistance Atlas’ for ER+ metastatic breast cancer, which should help inform treatment decisions for individual patients as well as propel the development of new combination treatment strategies for ER-positive metastatic breast cancer.”

This study was funded by the National Cancer Institute, the National Human Genome Research Institute, the Department of Defense Breast Cancer Research Program, Susan G. Komen, the V Foundation, the Breast Cancer Alliance, the AACR-Landon Foundation, the Friends of Dana-Farber Cancer Institute, and the Breast Cancer Research Foundation. Dr. Cohen reported having no conflicts of interest. Dr. Wagle is an equity holder in Foundation Medicine, a consultant to Novartis, and a recipient of sponsored research support from Novartis, Genentech, and Merck.

[email protected]

SAN ANTONIO – The “genomic landscape” of resistant estrogen receptor–positive (ER+) metastatic breast cancer differs significantly from that of ER+ primary breast cancer, according to findings from a study involving whole-exome sequencing and transcriptome sequencing of such cancers.

Multiple genes were recurrently altered in ER+ metastatic breast cancers at a rate significantly higher than in ER+ primary breast cancers (with 3- to 33-fold enrichment in metastatic vs. primary samples), Ofir Cohen, PhD, explained at the San Antonio Breast Cancer Symposium.

This finding, which suggests that recurrent alterations in genes in ER+ metastatic breast cancers are often acquired after treatment and thus may play a role in resistance to ER-directed therapies and/or metastasis, highlights the value of genomic profiling of metastatic biopsies and has implications for drug development, said Dr. Cohen of the Broad Institute of MIT (Massachusetts Institute of Technology) and Harvard in Cambridge.

Although the genomic and molecular landscape of ER+ primary breast cancer is better understood, that of ER+ metastatic breast cancer is underexplored, he noted.

Thus, he and his colleagues performed whole-exome sequencing on 149 metastatic tumor biopsies from patients with ER+ metastatic tumors and resistance to at least one ER-directed therapy and compared the results with those from 44 matched primary samples from the same patient. They also performed transcriptome sequencing (RNA-seq) of 128 metastatic biopsies.

A key observation from the study is that ESR1 genes were mutated in 24% of the cohort, and the mutations were acquired in 14 of the 15 samples with matched primary samples.

“This emphasized the important role that these mutations may play, specifically in the metastatic and drug-resistant settings,” Dr. Cohen said.

Similarly, ERBB2 mutations occurred in 7% of samples, and seemed to be acquired in five of six metastatic samples with matched primary samples, he said.

“For both of these genes, other than being acquired and suggestive of importance, they also have clear clinical implications, as finding those mutations may guide treatment choices for those patients,” he said.

Another example involves RB1 mutations, which were found in 5% of samples, and which appeared to be acquired in three of five of those with matched primaries. More frequent alterations were also found in PIK3CA, PTEN, and AKTI genes, among others, in metastatic vs. primary cancers.

The observation that these tumors evolve and have different mutations in the primary and metastatic settings may be important, because this suggests that knowledge of the alterations and mutations in the primary setting is insufficient to guide treatment in the metastatic setting.

“So the take-home message here is that tumors do evolve, and that the metastatic setting is different than the primary setting,” Dr. Cohen said.

Sequencing both the exome and the transcriptome may “give us a handle to assess that,” he said.

“Our goal is really to understand evolved resistance. That is, to try and understand the mechanisms that drive the evolution of resistance in ER+ metastatic breast cancer, and, once we understand that, [to determine] how we can translate that knowledge in the clinic,” he said, noting that resistance also may develop through other nongenomic mechanisms, such as epigenetic and regulatory mechanisms.

“As long as those mechanisms leave a footprint on the transcriptome … sequencing the transcriptome together with the exome may yield relevant insights into resistance states that do not derive specifically from exome mutations,” he added.

The findings are important because, despite tremendous advances in the treatment of ER+ metastatic breast cancer, therapeutic resistance remains a common problem, and improved understanding of the underlying resistance mechanisms is critical for enabling durable control of this disease, Dr. Cohen said, explaining that resistant tumors remain the most common cause of breast cancer death and that there is an urgent need to develop new therapeutic strategies for patients who no longer respond to existing therapies.

In a written statement, senior investigator Nikhil Wagle, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, said that the ultimate goal of the project is “to integrate the functional and clinical findings into a unified ‘Resistance Atlas’ for ER+ metastatic breast cancer, which should help inform treatment decisions for individual patients as well as propel the development of new combination treatment strategies for ER-positive metastatic breast cancer.”

This study was funded by the National Cancer Institute, the National Human Genome Research Institute, the Department of Defense Breast Cancer Research Program, Susan G. Komen, the V Foundation, the Breast Cancer Alliance, the AACR-Landon Foundation, the Friends of Dana-Farber Cancer Institute, and the Breast Cancer Research Foundation. Dr. Cohen reported having no conflicts of interest. Dr. Wagle is an equity holder in Foundation Medicine, a consultant to Novartis, and a recipient of sponsored research support from Novartis, Genentech, and Merck.

[email protected]

SAN ANTONIO – The investigational selective PARP-1 and PARP-2 inhibitor veliparib failed to significantly improve progression-free or overall survival, compared with placebo, when added to carboplatin and paclitaxel in patients with BRCA1 or BRCA2 mutations and locally recurrent or metastatic breast cancer in the randomized phase II BROCADE study.

The potent, orally bioavailable drug did, however, show a trend toward improvement on these measures, as well as a significant improvement in overall response-rate findings that warrant further investigation in a phase III trial, Hyo Han, MD, said at the San Antonio Breast Cancer Symposium.

Patients were randomized to receive placebo (98 patients) or 120 mg veliparib twice daily on days 1-7 (95 patients) in addition to carboplatin and 175 mg/m² of paclitaxel every 3 weeks.

Median progression-free survival – the primary endpoint of the study – was 12.3 months in the placebo group and 14.1 months in the veliparib group (hazard ratio, 0.789), and overall survival was 25.9 and 28.3 months, respectively (HR, 0.750), said Dr. Han of Moffitt Cancer Center, Tampa, Fla.

The overall response rate was 61.3% vs. 77.8% in the groups, respectively.

Although the study did not meet its primary endpoint, the findings are encouraging as it was powered to detect only dramatic differences between the groups, Dr. Han said.

In a video interview, she discussed veliparib, its safety, the BROCADE findings – including data from a third study arm looking at veliparib in combination with temozolomide, and plans for evaluating veliparib in the ongoing phase III BROCADE3 trial.

[email protected]

SAN ANTONIO – The investigational selective PARP-1 and PARP-2 inhibitor veliparib failed to significantly improve progression-free or overall survival, compared with placebo, when added to carboplatin and paclitaxel in patients with BRCA1 or BRCA2 mutations and locally recurrent or metastatic breast cancer in the randomized phase II BROCADE study.

The potent, orally bioavailable drug did, however, show a trend toward improvement on these measures, as well as a significant improvement in overall response-rate findings that warrant further investigation in a phase III trial, Hyo Han, MD, said at the San Antonio Breast Cancer Symposium.

Patients were randomized to receive placebo (98 patients) or 120 mg veliparib twice daily on days 1-7 (95 patients) in addition to carboplatin and 175 mg/m² of paclitaxel every 3 weeks.

Median progression-free survival – the primary endpoint of the study – was 12.3 months in the placebo group and 14.1 months in the veliparib group (hazard ratio, 0.789), and overall survival was 25.9 and 28.3 months, respectively (HR, 0.750), said Dr. Han of Moffitt Cancer Center, Tampa, Fla.

The overall response rate was 61.3% vs. 77.8% in the groups, respectively.

Although the study did not meet its primary endpoint, the findings are encouraging as it was powered to detect only dramatic differences between the groups, Dr. Han said.

In a video interview, she discussed veliparib, its safety, the BROCADE findings – including data from a third study arm looking at veliparib in combination with temozolomide, and plans for evaluating veliparib in the ongoing phase III BROCADE3 trial.

[email protected]

SAN ANTONIO – The investigational selective PARP-1 and PARP-2 inhibitor veliparib failed to significantly improve progression-free or overall survival, compared with placebo, when added to carboplatin and paclitaxel in patients with BRCA1 or BRCA2 mutations and locally recurrent or metastatic breast cancer in the randomized phase II BROCADE study.

The potent, orally bioavailable drug did, however, show a trend toward improvement on these measures, as well as a significant improvement in overall response-rate findings that warrant further investigation in a phase III trial, Hyo Han, MD, said at the San Antonio Breast Cancer Symposium.

Patients were randomized to receive placebo (98 patients) or 120 mg veliparib twice daily on days 1-7 (95 patients) in addition to carboplatin and 175 mg/m² of paclitaxel every 3 weeks.

Median progression-free survival – the primary endpoint of the study – was 12.3 months in the placebo group and 14.1 months in the veliparib group (hazard ratio, 0.789), and overall survival was 25.9 and 28.3 months, respectively (HR, 0.750), said Dr. Han of Moffitt Cancer Center, Tampa, Fla.

The overall response rate was 61.3% vs. 77.8% in the groups, respectively.

Although the study did not meet its primary endpoint, the findings are encouraging as it was powered to detect only dramatic differences between the groups, Dr. Han said.

In a video interview, she discussed veliparib, its safety, the BROCADE findings – including data from a third study arm looking at veliparib in combination with temozolomide, and plans for evaluating veliparib in the ongoing phase III BROCADE3 trial.

[email protected]

SAN ANTONIO – Adding everolimus to fulvestrant doubled median progression-free survival among postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor 2–negative (HER2-negative) metastatic breast cancer resistant to therapy with an aromatase inhibitor [AI] in the PrECOG 0102 study.

In the randomized phase II trial, the combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) with the selective estrogen receptor down-regulator [SERD] fulvestrant (Faslodex) was associated with a median progression-free survival of 10.4 months, compared with 5.1 months for fulvestrant plus placebo, reported Noah S. Kornblum, MD, of Montefiore Einstein Center for Cancer Care, New York.

This study provides additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes,” he said at the San Antonio Breast Cancer Symposium.

Potential role for the combination?

Following the presentation, SABCS fixture Steven “Vogl, New York” Vogl, MD, asked what to do when fulvestrant-based therapy fails.*

“I’m interested in what to do after progression. Let’s say the patient gets fulvestrant, gets everolimus, has a nice response – 9 months later, the tumor gets worse. We’re all pretty sure we shouldn’t continue the fulvestrant. I would love PrECOG to do a study in those patients of giving megestrol or megestrol/everolimus, and see if the everolimus extended beyond progression does the patient some good, as does trastuzumab,” he said.

“Sounds like a good idea. I’m game, let’s roll up our sleeves and do it together,” Dr. Kornblum replied.

The study was sponsored by PrECOG with financial support from Novartis. Dr. Kornblum reported having no conflicts of interest.

Correction 12/8/16: An earlier version of this article misstated Dr. Steven Vogl's name.

SAN ANTONIO – Adding everolimus to fulvestrant doubled median progression-free survival among postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor 2–negative (HER2-negative) metastatic breast cancer resistant to therapy with an aromatase inhibitor [AI] in the PrECOG 0102 study.

In the randomized phase II trial, the combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) with the selective estrogen receptor down-regulator [SERD] fulvestrant (Faslodex) was associated with a median progression-free survival of 10.4 months, compared with 5.1 months for fulvestrant plus placebo, reported Noah S. Kornblum, MD, of Montefiore Einstein Center for Cancer Care, New York.

This study provides additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes,” he said at the San Antonio Breast Cancer Symposium.

Potential role for the combination?

Following the presentation, SABCS fixture Steven “Vogl, New York” Vogl, MD, asked what to do when fulvestrant-based therapy fails.*

“I’m interested in what to do after progression. Let’s say the patient gets fulvestrant, gets everolimus, has a nice response – 9 months later, the tumor gets worse. We’re all pretty sure we shouldn’t continue the fulvestrant. I would love PrECOG to do a study in those patients of giving megestrol or megestrol/everolimus, and see if the everolimus extended beyond progression does the patient some good, as does trastuzumab,” he said.

“Sounds like a good idea. I’m game, let’s roll up our sleeves and do it together,” Dr. Kornblum replied.

The study was sponsored by PrECOG with financial support from Novartis. Dr. Kornblum reported having no conflicts of interest.

Correction 12/8/16: An earlier version of this article misstated Dr. Steven Vogl's name.

SAN ANTONIO – Adding everolimus to fulvestrant doubled median progression-free survival among postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor 2–negative (HER2-negative) metastatic breast cancer resistant to therapy with an aromatase inhibitor [AI] in the PrECOG 0102 study.

In the randomized phase II trial, the combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) with the selective estrogen receptor down-regulator [SERD] fulvestrant (Faslodex) was associated with a median progression-free survival of 10.4 months, compared with 5.1 months for fulvestrant plus placebo, reported Noah S. Kornblum, MD, of Montefiore Einstein Center for Cancer Care, New York.

This study provides additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes,” he said at the San Antonio Breast Cancer Symposium.

Potential role for the combination?

Following the presentation, SABCS fixture Steven “Vogl, New York” Vogl, MD, asked what to do when fulvestrant-based therapy fails.*

“I’m interested in what to do after progression. Let’s say the patient gets fulvestrant, gets everolimus, has a nice response – 9 months later, the tumor gets worse. We’re all pretty sure we shouldn’t continue the fulvestrant. I would love PrECOG to do a study in those patients of giving megestrol or megestrol/everolimus, and see if the everolimus extended beyond progression does the patient some good, as does trastuzumab,” he said.

“Sounds like a good idea. I’m game, let’s roll up our sleeves and do it together,” Dr. Kornblum replied.

The study was sponsored by PrECOG with financial support from Novartis. Dr. Kornblum reported having no conflicts of interest.

Correction 12/8/16: An earlier version of this article misstated Dr. Steven Vogl's name.

SAN ANTONIO – Most women with hormone receptor–positive breast cancer treated with an aromatase inhibitor will eventually develop resistance to these agents. Strategies for overcoming resistance include the addition of everolimus (Affinitor) to a steroidal aromatase inhibitor (AI) such as exemestane (Aromasin), as in the BOLERO-2 trial.

Alternatively, blocking estrogen-receptor signaling through the use of a selective estrogen receptor down regulator, such as fulvestrant (Faslodex), may result in more complete blockade of the ER signaling pathway than would a steroidal AI such as exemestane.

In this video interview at the San Antonio Breast Cancer Symposium, Noah S. Kornblum, MD, of the Montefiore-Einstein Center for Cancer Care, New York, discusses findings from the phase II PrECOG 0102 trial comparing a combination of fulvestrant and everolimus to fulvestrant and placebo for the treatment of postmenopausal women with hormone receptor–positive, HER2-negative breast cancer resistant to AI therapy.

The combination was associated with a median progression-free survival of 10.4 months, compared with 5.1 months for fulvestrant plus placebo (hazard ratio, 0.60; P = .02).

Dr. Kornblum says that the study provides additional evidence for adding everolimus to anti-estrogen therapy in AI-resistant disease.

SAN ANTONIO – Most women with hormone receptor–positive breast cancer treated with an aromatase inhibitor will eventually develop resistance to these agents. Strategies for overcoming resistance include the addition of everolimus (Affinitor) to a steroidal aromatase inhibitor (AI) such as exemestane (Aromasin), as in the BOLERO-2 trial.

Alternatively, blocking estrogen-receptor signaling through the use of a selective estrogen receptor down regulator, such as fulvestrant (Faslodex), may result in more complete blockade of the ER signaling pathway than would a steroidal AI such as exemestane.

In this video interview at the San Antonio Breast Cancer Symposium, Noah S. Kornblum, MD, of the Montefiore-Einstein Center for Cancer Care, New York, discusses findings from the phase II PrECOG 0102 trial comparing a combination of fulvestrant and everolimus to fulvestrant and placebo for the treatment of postmenopausal women with hormone receptor–positive, HER2-negative breast cancer resistant to AI therapy.

The combination was associated with a median progression-free survival of 10.4 months, compared with 5.1 months for fulvestrant plus placebo (hazard ratio, 0.60; P = .02).

Dr. Kornblum says that the study provides additional evidence for adding everolimus to anti-estrogen therapy in AI-resistant disease.

SAN ANTONIO – Most women with hormone receptor–positive breast cancer treated with an aromatase inhibitor will eventually develop resistance to these agents. Strategies for overcoming resistance include the addition of everolimus (Affinitor) to a steroidal aromatase inhibitor (AI) such as exemestane (Aromasin), as in the BOLERO-2 trial.

Alternatively, blocking estrogen-receptor signaling through the use of a selective estrogen receptor down regulator, such as fulvestrant (Faslodex), may result in more complete blockade of the ER signaling pathway than would a steroidal AI such as exemestane.

In this video interview at the San Antonio Breast Cancer Symposium, Noah S. Kornblum, MD, of the Montefiore-Einstein Center for Cancer Care, New York, discusses findings from the phase II PrECOG 0102 trial comparing a combination of fulvestrant and everolimus to fulvestrant and placebo for the treatment of postmenopausal women with hormone receptor–positive, HER2-negative breast cancer resistant to AI therapy.

The combination was associated with a median progression-free survival of 10.4 months, compared with 5.1 months for fulvestrant plus placebo (hazard ratio, 0.60; P = .02).

Dr. Kornblum says that the study provides additional evidence for adding everolimus to anti-estrogen therapy in AI-resistant disease.

Younger age, bilateral procedure, and presurgery depression and anxiety are among the significant contributors to pain after breast reconstruction surgery, according to findings from a prospective study of 2,207 women who underwent several types of breast reconstruction procedures.

Although breast reconstruction is an important element of breast cancer treatment, and most acute postoperative pain resolves with time and pain management intervention, some patients suffer from persistent, severe postoperative pain that increases their risk for long-term pain and clinical morbidity, wrote Anita R. Kulkarni, MD, of Memorial Sloan-Kettering Cancer Center, New York, and her colleagues.

Pradit_Ph/Thinkstock

Overall, greater acute postoperative pain was significantly associated with younger age, bilateral procedures, higher levels of preoperative pain, and higher levels of preoperative anxiety and depression, the researchers said.

“Moreover, the degree of patients’ self-reported preoperative anxiety and depressive symptoms both appeared to bear a linear relationship with the magnitude of increased postoperative pain at 1 week” on the MPQ sensory pain rating, they noted.

Similarly, lower scores of physical well-being based on the BREAST-Q physical well-being scale were significantly associated with younger age, bilateral procedures, immediate reconstruction, and higher levels of preoperative pain, anxiety, and depression.

The average age of the women was 50 years, and 87% were white. Most patients (69%) had tissue expander (TE)/implant reconstruction procedures; 93% were immediate reconstruction; and 53% were bilateral reconstruction. The majority (90%) underwent surgery as part of breast cancer treatment.

“The comparative effect of procedure type on postoperative pain showed variable results across our multiple pain scales,” the researchers said.

The patients who underwent autologous flap reconstruction procedures – pedicled transverse rectus abdominis myocutaneous flap (PTRAMS), deep inferior epigastric perforator (DIEP), or superficial inferior epigastric artery (SIEA) – reported less-severe postoperative pain than did those who had TE/Implant procedures. Specifically, patients with SIEA and DIEP procedures reported significantly less pain 1 week after surgery than did those who had TE/Implant procedures, based on the MPQ sensory scale. In addition, patients with PTRAMS reported significantly less postoperative pain 1 week after surgery than did those who had TE/Implant procedures based on the NPRS scale. All three flap procedures were significantly associated with less-severe postoperative pain, compared with TE/Implant procedures.

The findings support data from previous studies that identified preoperative pain, mood disturbance, and age as factors for increased risk of acute postoperative pain, the researchers noted. In addition, “the findings have important implications for the identification of women who might be at risk for significant early postoperative pain following breast reconstruction, as acute postoperative pain is associated with poor functional outcomes, diminished quality of life, and the risk for development of persistent postsurgical pain,” they wrote.

The study results were limited by several factors, including the lack of standardization for postoperative pain treatment regimens, variability in the timing of preoperative assessment, and nonresponder bias, the researchers said.

However, “Once high-risk patients are identified, appropriate referrals can be considered to facilitate careful monitoring of postsurgical pain for selected patients,” they said. “Early intervention can give clinicians the opportunity to reduce postoperative morbidity and improve patients’ surgical experience and satisfaction with breast reconstruction outcome,” they added.

The researchers had no financial conflicts to disclose. The study was supported in part by a grant from the National Institutes of Health/National Cancer Institute.

Younger age, bilateral procedure, and presurgery depression and anxiety are among the significant contributors to pain after breast reconstruction surgery, according to findings from a prospective study of 2,207 women who underwent several types of breast reconstruction procedures.

Although breast reconstruction is an important element of breast cancer treatment, and most acute postoperative pain resolves with time and pain management intervention, some patients suffer from persistent, severe postoperative pain that increases their risk for long-term pain and clinical morbidity, wrote Anita R. Kulkarni, MD, of Memorial Sloan-Kettering Cancer Center, New York, and her colleagues.

Pradit_Ph/Thinkstock

Overall, greater acute postoperative pain was significantly associated with younger age, bilateral procedures, higher levels of preoperative pain, and higher levels of preoperative anxiety and depression, the researchers said.

“Moreover, the degree of patients’ self-reported preoperative anxiety and depressive symptoms both appeared to bear a linear relationship with the magnitude of increased postoperative pain at 1 week” on the MPQ sensory pain rating, they noted.

Similarly, lower scores of physical well-being based on the BREAST-Q physical well-being scale were significantly associated with younger age, bilateral procedures, immediate reconstruction, and higher levels of preoperative pain, anxiety, and depression.

The average age of the women was 50 years, and 87% were white. Most patients (69%) had tissue expander (TE)/implant reconstruction procedures; 93% were immediate reconstruction; and 53% were bilateral reconstruction. The majority (90%) underwent surgery as part of breast cancer treatment.

“The comparative effect of procedure type on postoperative pain showed variable results across our multiple pain scales,” the researchers said.

The patients who underwent autologous flap reconstruction procedures – pedicled transverse rectus abdominis myocutaneous flap (PTRAMS), deep inferior epigastric perforator (DIEP), or superficial inferior epigastric artery (SIEA) – reported less-severe postoperative pain than did those who had TE/Implant procedures. Specifically, patients with SIEA and DIEP procedures reported significantly less pain 1 week after surgery than did those who had TE/Implant procedures, based on the MPQ sensory scale. In addition, patients with PTRAMS reported significantly less postoperative pain 1 week after surgery than did those who had TE/Implant procedures based on the NPRS scale. All three flap procedures were significantly associated with less-severe postoperative pain, compared with TE/Implant procedures.

The findings support data from previous studies that identified preoperative pain, mood disturbance, and age as factors for increased risk of acute postoperative pain, the researchers noted. In addition, “the findings have important implications for the identification of women who might be at risk for significant early postoperative pain following breast reconstruction, as acute postoperative pain is associated with poor functional outcomes, diminished quality of life, and the risk for development of persistent postsurgical pain,” they wrote.

The study results were limited by several factors, including the lack of standardization for postoperative pain treatment regimens, variability in the timing of preoperative assessment, and nonresponder bias, the researchers said.

However, “Once high-risk patients are identified, appropriate referrals can be considered to facilitate careful monitoring of postsurgical pain for selected patients,” they said. “Early intervention can give clinicians the opportunity to reduce postoperative morbidity and improve patients’ surgical experience and satisfaction with breast reconstruction outcome,” they added.

The researchers had no financial conflicts to disclose. The study was supported in part by a grant from the National Institutes of Health/National Cancer Institute.

Younger age, bilateral procedure, and presurgery depression and anxiety are among the significant contributors to pain after breast reconstruction surgery, according to findings from a prospective study of 2,207 women who underwent several types of breast reconstruction procedures.

Although breast reconstruction is an important element of breast cancer treatment, and most acute postoperative pain resolves with time and pain management intervention, some patients suffer from persistent, severe postoperative pain that increases their risk for long-term pain and clinical morbidity, wrote Anita R. Kulkarni, MD, of Memorial Sloan-Kettering Cancer Center, New York, and her colleagues.

Pradit_Ph/Thinkstock

Overall, greater acute postoperative pain was significantly associated with younger age, bilateral procedures, higher levels of preoperative pain, and higher levels of preoperative anxiety and depression, the researchers said.

“Moreover, the degree of patients’ self-reported preoperative anxiety and depressive symptoms both appeared to bear a linear relationship with the magnitude of increased postoperative pain at 1 week” on the MPQ sensory pain rating, they noted.

Similarly, lower scores of physical well-being based on the BREAST-Q physical well-being scale were significantly associated with younger age, bilateral procedures, immediate reconstruction, and higher levels of preoperative pain, anxiety, and depression.

The average age of the women was 50 years, and 87% were white. Most patients (69%) had tissue expander (TE)/implant reconstruction procedures; 93% were immediate reconstruction; and 53% were bilateral reconstruction. The majority (90%) underwent surgery as part of breast cancer treatment.

“The comparative effect of procedure type on postoperative pain showed variable results across our multiple pain scales,” the researchers said.

The patients who underwent autologous flap reconstruction procedures – pedicled transverse rectus abdominis myocutaneous flap (PTRAMS), deep inferior epigastric perforator (DIEP), or superficial inferior epigastric artery (SIEA) – reported less-severe postoperative pain than did those who had TE/Implant procedures. Specifically, patients with SIEA and DIEP procedures reported significantly less pain 1 week after surgery than did those who had TE/Implant procedures, based on the MPQ sensory scale. In addition, patients with PTRAMS reported significantly less postoperative pain 1 week after surgery than did those who had TE/Implant procedures based on the NPRS scale. All three flap procedures were significantly associated with less-severe postoperative pain, compared with TE/Implant procedures.

The findings support data from previous studies that identified preoperative pain, mood disturbance, and age as factors for increased risk of acute postoperative pain, the researchers noted. In addition, “the findings have important implications for the identification of women who might be at risk for significant early postoperative pain following breast reconstruction, as acute postoperative pain is associated with poor functional outcomes, diminished quality of life, and the risk for development of persistent postsurgical pain,” they wrote.

The study results were limited by several factors, including the lack of standardization for postoperative pain treatment regimens, variability in the timing of preoperative assessment, and nonresponder bias, the researchers said.

However, “Once high-risk patients are identified, appropriate referrals can be considered to facilitate careful monitoring of postsurgical pain for selected patients,” they said. “Early intervention can give clinicians the opportunity to reduce postoperative morbidity and improve patients’ surgical experience and satisfaction with breast reconstruction outcome,” they added.

The researchers had no financial conflicts to disclose. The study was supported in part by a grant from the National Institutes of Health/National Cancer Institute.

The use of halogenated agents for anesthetic during a mastectomy operation may be associated with a lower incidence of long-term chronic postmastectomy pain (CPMP), according to a paper published in the the Journal of Clinical Anesthesia.

The retrospective cross-sectional survey of 128 women who underwent mastectomy with axillary lymph node dissection set out to determine whether the anesthetic or analgesic regimen used perioperatively had any impact on the risk of long-term chronic postoperative pain.

Overall, 43.8% of the women reported chronic pain, and nearly half of these showed neuropathic characteristics with an ID Pain score greater than or equal to 2 (J Clin Anesthesia. 2016;33:20-25. doi: 10.1016/j.jclinane.2015.07.010).

Those who were given a halogenated agent for anesthesia during the operation – 64% of patients in the survey - had a significant 19% lower incidence of chronic long-term postoperative mastectomy pain (95% CI, 0.70-0.95; P = .012).

Arnaud Steyaert, MD, and colleagues at the Catholic University of Louvain (Belgium) described this result as surprising, noting that sevoflurane use was recently found to be a risk factor for chronic pain after breast cancer surgery.

“An explanation for this discrepancy could be that the influence of sevoflurane on the development of CPMP depends on the other components of the anesthetic regimen,” the authors wrote, pointing out that the aforementioned study included the use of remifentanil in all patients, which can trigger acute opioid-induced hyperalgesia and chronic pain after surgery.

Apart from this effect, the authors said they did not see any impact from other analgesics – which included sufentanil, ketamine, clonidine, NSAIDs, and/or magnesium sulfate – on the risk of long-term chronic pain. However, patients treated with piritramide in the recovery room did have a significant 30% greater risk of chronic postoperative pain.

The study also found that patients who needed strong opioids in the postanesthesia care unit had a 30% higher risk of chronic long-term pain (95% CI, 1.11-1.53). “This was expected, as more intense acute postoperative pain is a known risk factor for developing chronic postsurgical pain, including CPMP,” the authors wrote.

Patients who had received adjuvant chemotherapy had a 32% higher incidence of chronic long-term pain, but there was no increase in risk associated with adjuvant radiotherapy. Both are known to cause neurotoxicity and therefore neuropathic pain, the authors commented.

No conflicts of interest were declared.

The use of halogenated agents for anesthetic during a mastectomy operation may be associated with a lower incidence of long-term chronic postmastectomy pain (CPMP), according to a paper published in the the Journal of Clinical Anesthesia.

The retrospective cross-sectional survey of 128 women who underwent mastectomy with axillary lymph node dissection set out to determine whether the anesthetic or analgesic regimen used perioperatively had any impact on the risk of long-term chronic postoperative pain.

Overall, 43.8% of the women reported chronic pain, and nearly half of these showed neuropathic characteristics with an ID Pain score greater than or equal to 2 (J Clin Anesthesia. 2016;33:20-25. doi: 10.1016/j.jclinane.2015.07.010).

Those who were given a halogenated agent for anesthesia during the operation – 64% of patients in the survey - had a significant 19% lower incidence of chronic long-term postoperative mastectomy pain (95% CI, 0.70-0.95; P = .012).

Arnaud Steyaert, MD, and colleagues at the Catholic University of Louvain (Belgium) described this result as surprising, noting that sevoflurane use was recently found to be a risk factor for chronic pain after breast cancer surgery.

“An explanation for this discrepancy could be that the influence of sevoflurane on the development of CPMP depends on the other components of the anesthetic regimen,” the authors wrote, pointing out that the aforementioned study included the use of remifentanil in all patients, which can trigger acute opioid-induced hyperalgesia and chronic pain after surgery.

Apart from this effect, the authors said they did not see any impact from other analgesics – which included sufentanil, ketamine, clonidine, NSAIDs, and/or magnesium sulfate – on the risk of long-term chronic pain. However, patients treated with piritramide in the recovery room did have a significant 30% greater risk of chronic postoperative pain.

The study also found that patients who needed strong opioids in the postanesthesia care unit had a 30% higher risk of chronic long-term pain (95% CI, 1.11-1.53). “This was expected, as more intense acute postoperative pain is a known risk factor for developing chronic postsurgical pain, including CPMP,” the authors wrote.

Patients who had received adjuvant chemotherapy had a 32% higher incidence of chronic long-term pain, but there was no increase in risk associated with adjuvant radiotherapy. Both are known to cause neurotoxicity and therefore neuropathic pain, the authors commented.

No conflicts of interest were declared.

The use of halogenated agents for anesthetic during a mastectomy operation may be associated with a lower incidence of long-term chronic postmastectomy pain (CPMP), according to a paper published in the the Journal of Clinical Anesthesia.

The retrospective cross-sectional survey of 128 women who underwent mastectomy with axillary lymph node dissection set out to determine whether the anesthetic or analgesic regimen used perioperatively had any impact on the risk of long-term chronic postoperative pain.

Overall, 43.8% of the women reported chronic pain, and nearly half of these showed neuropathic characteristics with an ID Pain score greater than or equal to 2 (J Clin Anesthesia. 2016;33:20-25. doi: 10.1016/j.jclinane.2015.07.010).

Those who were given a halogenated agent for anesthesia during the operation – 64% of patients in the survey - had a significant 19% lower incidence of chronic long-term postoperative mastectomy pain (95% CI, 0.70-0.95; P = .012).

Arnaud Steyaert, MD, and colleagues at the Catholic University of Louvain (Belgium) described this result as surprising, noting that sevoflurane use was recently found to be a risk factor for chronic pain after breast cancer surgery.

“An explanation for this discrepancy could be that the influence of sevoflurane on the development of CPMP depends on the other components of the anesthetic regimen,” the authors wrote, pointing out that the aforementioned study included the use of remifentanil in all patients, which can trigger acute opioid-induced hyperalgesia and chronic pain after surgery.

Apart from this effect, the authors said they did not see any impact from other analgesics – which included sufentanil, ketamine, clonidine, NSAIDs, and/or magnesium sulfate – on the risk of long-term chronic pain. However, patients treated with piritramide in the recovery room did have a significant 30% greater risk of chronic postoperative pain.

The study also found that patients who needed strong opioids in the postanesthesia care unit had a 30% higher risk of chronic long-term pain (95% CI, 1.11-1.53). “This was expected, as more intense acute postoperative pain is a known risk factor for developing chronic postsurgical pain, including CPMP,” the authors wrote.

Patients who had received adjuvant chemotherapy had a 32% higher incidence of chronic long-term pain, but there was no increase in risk associated with adjuvant radiotherapy. Both are known to cause neurotoxicity and therefore neuropathic pain, the authors commented.

No conflicts of interest were declared.

A trastuzumab biosimilar drug has shown an equivalent response, compared with trastuzumab, in the treatment of ERBB2 (HER2)-positive metastatic breast cancer, according to the results of a randomized double-blind controlled trial.

The anti-ERBB2 humanized monoclonal antibody trastuzumab in combination with chemotherapy has been found in numerous trials to significantly improve progression-free survival and overall survival in women with ERBB2-positive metastatic breast, compared with chemotherapy alone.

A trastuzumab biosimilar drug has shown an equivalent response, compared with trastuzumab, in the treatment of ERBB2 (HER2)-positive metastatic breast cancer, according to the results of a randomized double-blind controlled trial.

The anti-ERBB2 humanized monoclonal antibody trastuzumab in combination with chemotherapy has been found in numerous trials to significantly improve progression-free survival and overall survival in women with ERBB2-positive metastatic breast, compared with chemotherapy alone.

A trastuzumab biosimilar drug has shown an equivalent response, compared with trastuzumab, in the treatment of ERBB2 (HER2)-positive metastatic breast cancer, according to the results of a randomized double-blind controlled trial.

The anti-ERBB2 humanized monoclonal antibody trastuzumab in combination with chemotherapy has been found in numerous trials to significantly improve progression-free survival and overall survival in women with ERBB2-positive metastatic breast, compared with chemotherapy alone.