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EndoPredict results reflected tumor response to neoadjuvant therapy
SAN ANTONIO – The results of the EndoPredict test appear to predict tumor response in patients with early hormone receptor–positive, HER2-negative breast cancer given neoadjuvant therapy, based on results of a study conducted by the Austrian Breast & Colorectal Cancer Study Group (ABCSG).
“Very good tumor shrinkage in estrogen receptor–positive, HER2-negative disease is going to happen only in a minority of patients, and biomarkers that would predict excellent tumor shrinkage are an unmet medical need,” commented lead investigator Peter Dubsky, MD, PhD, who is head of the Breast Center at Hirslanden Klinik St. Anna, Lucerne, Switzerland. “As a surgeon, that would help me to predict breast conservation at diagnosis, but as a surgical oncologist, I would also recognize that tumor response is an important component of future survival.”
The ABCSG findings suggest expanded utility for EndoPredict. The test’s molecular score is currently used along with tumor size and nodal status to predict the 10-year distant recurrence rate, and whether patients may safely forgo chemotherapy or are at high risk and may need adjuvant chemotherapy in addition to endocrine therapy.
Dr. Dubsky and his coinvestigators assessed performance of the EndoPredict test among 217 patients treated on ABCSG 34, a randomized phase 2 neoadjuvant trial. Findings showed that among patients given neoadjuvant endocrine therapy because they had less aggressive disease features, an EndoPredict high-risk result was associated with poor response (negative predictive value of 92%), defined as a residual cancer burden (RCB) of II or III, he reported at the San Antonio Breast Cancer Symposium.
On the other hand, among patients given neoadjuvant chemotherapy because they had more aggressive disease features, a low-risk result was associated with poor response (negative predictive value of 100%).
“Clinicians really gave us two distinct cohorts within ABCSG 34. In the luminal A–type patients who were treated with neoendocrine therapy, a high EndoPredict score predicted a low chance of tumor shrinkage. In the more aggressive ER-positive tumors, so-called luminal B type, treated with neoadjuvant chemotherapy, there was absolutely no excellent response in the low-risk group,” Dr. Dubsky summarized. “We believe that this molecular score may contribute to patient selection for biomarker-driven studies, especially in the neoadjuvant setting.”
Session attendee Steven Vogl, MD, a medical oncologist with the Montefiore Medical Center in New York, commented, “I have trouble correlating an RCB of 0 or I with what you as a surgeon do for the patient, because you are talking about pathologic complete response or just a few cells there. That’s not what determines how much breast you take off: It’s determined by the total size of the tumor and the size of the breast. So if it’s less than a few centimeters, I’m sure you can do a lumpectomy in every patient. Tell me why I should care that you are getting an RCB of 0 or I in these endocrine patients.”
“Because it’s more likely that these patients will have a smaller tumor and better tumor shrinkage,” Dr. Dubsky replied. “You are of course right, RCB 0 or I was not designed to help surgeons. But it helps me as a translational scientist to have a surrogate and an exact classification for good tumor shrinkage. That’s how I used it.”
C. Kent Osborne, MD, codirector of SABCS and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, asked, “We see it in the clinic, and I’m sure you have as well, patients whose tumor doesn’t shrink very much, but the Ki-67 really drops. And that may or may not be a better factor than the actual tumor shrinkage. So how many patients who had tumors that didn’t shrink, which was your endpoint, had a reduction in Ki-67 that was, say, 5%?”
“We haven’t looked at that specifically, but we will do so as we carry on with the follow-up of these patients. Then we can learn more about the prognosis,” Dr. Dubsky replied.
Study details
ABCSG 34 was a randomized phase 2 trial testing addition of the cancer vaccine tecemotide (Stimuvax) to neoadjuvant standard of care among patients with HER2-negative early breast cancer.
Dr. Dubsky and coinvestigators restricted analyses to patients with hormone receptor–positive disease who, depending on clinical and pathologic factors, received neoadjuvant chemotherapy (eight cycles of epirubicin-cyclophosphamide and docetaxel) or neoadjuvant endocrine therapy (6 months of letrozole [Femara]) as standard of care. They were then randomized to additionally receive tecemotide or not before undergoing surgery.
Overall, 25% of the 134 patients in the neoadjuvant chemotherapy group had a good tumor response, defined as pathologic complete response in both breast and nodes (RCB of 0) or minimal residual disease (RCB of I).
Higher EndoPredict score was associated with greater likelihood of good response to chemotherapy. EndoPredict risk group (high vs. low) had a negative predictive value of 100%, a positive predictive value of 26.4%, a true-positive rate of 100%, and a true-negative rate of 8.9% for predicting response (P = .112).
Area under the receiver operating characteristic curve was 0.736.
In a multivariate model, EndoPredict score as a continuous variable was not an independent predictor of response. “The good response was largely driven by covariates that included cell proliferation, and it was Ki-67 that was significant,” Dr. Dubsky noted.
Overall, 18% of the 83 patients in the neoadjuvant endocrine therapy group had a good tumor response (RCB of 0 or I). Here, lower EndoPredict score was associated with greater likelihood of good response. EndoPredict risk group (high vs. low) had a negative predictive value of 92.3%, a positive predictive value of 27.3%, a true-positive rate of 80.0%, and a true-negative rate of 52.9% for predicting response (P = .024). Area under the curve was 0.726.
In a multivariate model here, EndoPredict score as a continuous variable, its estrogen receptor–signaling/differentiation component, and Ki-67 did not independently predict response. “It was maybe a bit surprising that T stage was the strongest factor, possibly indicating that we should have simply treated those women longer than 6 months,” Dr. Dubsky commented. The EndoPredict proliferation component was also a significant predictor.
“Possibly, the very narrow distribution of Ki-67 [among patients given neoendocrine therapy] may have prevented this factor from playing a bigger role in this particular model,” he speculated.
Dr. Dubsky disclosed that he receives consulting fees from Myriad, the maker of EndoPredict, and from Cepheid, Nanostring, and Amgen.
SOURCE: Dubsky P et al. SABCS 2017 Abstract GS6-04.
SAN ANTONIO – The results of the EndoPredict test appear to predict tumor response in patients with early hormone receptor–positive, HER2-negative breast cancer given neoadjuvant therapy, based on results of a study conducted by the Austrian Breast & Colorectal Cancer Study Group (ABCSG).
“Very good tumor shrinkage in estrogen receptor–positive, HER2-negative disease is going to happen only in a minority of patients, and biomarkers that would predict excellent tumor shrinkage are an unmet medical need,” commented lead investigator Peter Dubsky, MD, PhD, who is head of the Breast Center at Hirslanden Klinik St. Anna, Lucerne, Switzerland. “As a surgeon, that would help me to predict breast conservation at diagnosis, but as a surgical oncologist, I would also recognize that tumor response is an important component of future survival.”
The ABCSG findings suggest expanded utility for EndoPredict. The test’s molecular score is currently used along with tumor size and nodal status to predict the 10-year distant recurrence rate, and whether patients may safely forgo chemotherapy or are at high risk and may need adjuvant chemotherapy in addition to endocrine therapy.
Dr. Dubsky and his coinvestigators assessed performance of the EndoPredict test among 217 patients treated on ABCSG 34, a randomized phase 2 neoadjuvant trial. Findings showed that among patients given neoadjuvant endocrine therapy because they had less aggressive disease features, an EndoPredict high-risk result was associated with poor response (negative predictive value of 92%), defined as a residual cancer burden (RCB) of II or III, he reported at the San Antonio Breast Cancer Symposium.
On the other hand, among patients given neoadjuvant chemotherapy because they had more aggressive disease features, a low-risk result was associated with poor response (negative predictive value of 100%).
“Clinicians really gave us two distinct cohorts within ABCSG 34. In the luminal A–type patients who were treated with neoendocrine therapy, a high EndoPredict score predicted a low chance of tumor shrinkage. In the more aggressive ER-positive tumors, so-called luminal B type, treated with neoadjuvant chemotherapy, there was absolutely no excellent response in the low-risk group,” Dr. Dubsky summarized. “We believe that this molecular score may contribute to patient selection for biomarker-driven studies, especially in the neoadjuvant setting.”
Session attendee Steven Vogl, MD, a medical oncologist with the Montefiore Medical Center in New York, commented, “I have trouble correlating an RCB of 0 or I with what you as a surgeon do for the patient, because you are talking about pathologic complete response or just a few cells there. That’s not what determines how much breast you take off: It’s determined by the total size of the tumor and the size of the breast. So if it’s less than a few centimeters, I’m sure you can do a lumpectomy in every patient. Tell me why I should care that you are getting an RCB of 0 or I in these endocrine patients.”
“Because it’s more likely that these patients will have a smaller tumor and better tumor shrinkage,” Dr. Dubsky replied. “You are of course right, RCB 0 or I was not designed to help surgeons. But it helps me as a translational scientist to have a surrogate and an exact classification for good tumor shrinkage. That’s how I used it.”
C. Kent Osborne, MD, codirector of SABCS and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, asked, “We see it in the clinic, and I’m sure you have as well, patients whose tumor doesn’t shrink very much, but the Ki-67 really drops. And that may or may not be a better factor than the actual tumor shrinkage. So how many patients who had tumors that didn’t shrink, which was your endpoint, had a reduction in Ki-67 that was, say, 5%?”
“We haven’t looked at that specifically, but we will do so as we carry on with the follow-up of these patients. Then we can learn more about the prognosis,” Dr. Dubsky replied.
Study details
ABCSG 34 was a randomized phase 2 trial testing addition of the cancer vaccine tecemotide (Stimuvax) to neoadjuvant standard of care among patients with HER2-negative early breast cancer.
Dr. Dubsky and coinvestigators restricted analyses to patients with hormone receptor–positive disease who, depending on clinical and pathologic factors, received neoadjuvant chemotherapy (eight cycles of epirubicin-cyclophosphamide and docetaxel) or neoadjuvant endocrine therapy (6 months of letrozole [Femara]) as standard of care. They were then randomized to additionally receive tecemotide or not before undergoing surgery.
Overall, 25% of the 134 patients in the neoadjuvant chemotherapy group had a good tumor response, defined as pathologic complete response in both breast and nodes (RCB of 0) or minimal residual disease (RCB of I).
Higher EndoPredict score was associated with greater likelihood of good response to chemotherapy. EndoPredict risk group (high vs. low) had a negative predictive value of 100%, a positive predictive value of 26.4%, a true-positive rate of 100%, and a true-negative rate of 8.9% for predicting response (P = .112).
Area under the receiver operating characteristic curve was 0.736.
In a multivariate model, EndoPredict score as a continuous variable was not an independent predictor of response. “The good response was largely driven by covariates that included cell proliferation, and it was Ki-67 that was significant,” Dr. Dubsky noted.
Overall, 18% of the 83 patients in the neoadjuvant endocrine therapy group had a good tumor response (RCB of 0 or I). Here, lower EndoPredict score was associated with greater likelihood of good response. EndoPredict risk group (high vs. low) had a negative predictive value of 92.3%, a positive predictive value of 27.3%, a true-positive rate of 80.0%, and a true-negative rate of 52.9% for predicting response (P = .024). Area under the curve was 0.726.
In a multivariate model here, EndoPredict score as a continuous variable, its estrogen receptor–signaling/differentiation component, and Ki-67 did not independently predict response. “It was maybe a bit surprising that T stage was the strongest factor, possibly indicating that we should have simply treated those women longer than 6 months,” Dr. Dubsky commented. The EndoPredict proliferation component was also a significant predictor.
“Possibly, the very narrow distribution of Ki-67 [among patients given neoendocrine therapy] may have prevented this factor from playing a bigger role in this particular model,” he speculated.
Dr. Dubsky disclosed that he receives consulting fees from Myriad, the maker of EndoPredict, and from Cepheid, Nanostring, and Amgen.
SOURCE: Dubsky P et al. SABCS 2017 Abstract GS6-04.
SAN ANTONIO – The results of the EndoPredict test appear to predict tumor response in patients with early hormone receptor–positive, HER2-negative breast cancer given neoadjuvant therapy, based on results of a study conducted by the Austrian Breast & Colorectal Cancer Study Group (ABCSG).
“Very good tumor shrinkage in estrogen receptor–positive, HER2-negative disease is going to happen only in a minority of patients, and biomarkers that would predict excellent tumor shrinkage are an unmet medical need,” commented lead investigator Peter Dubsky, MD, PhD, who is head of the Breast Center at Hirslanden Klinik St. Anna, Lucerne, Switzerland. “As a surgeon, that would help me to predict breast conservation at diagnosis, but as a surgical oncologist, I would also recognize that tumor response is an important component of future survival.”
The ABCSG findings suggest expanded utility for EndoPredict. The test’s molecular score is currently used along with tumor size and nodal status to predict the 10-year distant recurrence rate, and whether patients may safely forgo chemotherapy or are at high risk and may need adjuvant chemotherapy in addition to endocrine therapy.
Dr. Dubsky and his coinvestigators assessed performance of the EndoPredict test among 217 patients treated on ABCSG 34, a randomized phase 2 neoadjuvant trial. Findings showed that among patients given neoadjuvant endocrine therapy because they had less aggressive disease features, an EndoPredict high-risk result was associated with poor response (negative predictive value of 92%), defined as a residual cancer burden (RCB) of II or III, he reported at the San Antonio Breast Cancer Symposium.
On the other hand, among patients given neoadjuvant chemotherapy because they had more aggressive disease features, a low-risk result was associated with poor response (negative predictive value of 100%).
“Clinicians really gave us two distinct cohorts within ABCSG 34. In the luminal A–type patients who were treated with neoendocrine therapy, a high EndoPredict score predicted a low chance of tumor shrinkage. In the more aggressive ER-positive tumors, so-called luminal B type, treated with neoadjuvant chemotherapy, there was absolutely no excellent response in the low-risk group,” Dr. Dubsky summarized. “We believe that this molecular score may contribute to patient selection for biomarker-driven studies, especially in the neoadjuvant setting.”
Session attendee Steven Vogl, MD, a medical oncologist with the Montefiore Medical Center in New York, commented, “I have trouble correlating an RCB of 0 or I with what you as a surgeon do for the patient, because you are talking about pathologic complete response or just a few cells there. That’s not what determines how much breast you take off: It’s determined by the total size of the tumor and the size of the breast. So if it’s less than a few centimeters, I’m sure you can do a lumpectomy in every patient. Tell me why I should care that you are getting an RCB of 0 or I in these endocrine patients.”
“Because it’s more likely that these patients will have a smaller tumor and better tumor shrinkage,” Dr. Dubsky replied. “You are of course right, RCB 0 or I was not designed to help surgeons. But it helps me as a translational scientist to have a surrogate and an exact classification for good tumor shrinkage. That’s how I used it.”
C. Kent Osborne, MD, codirector of SABCS and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, asked, “We see it in the clinic, and I’m sure you have as well, patients whose tumor doesn’t shrink very much, but the Ki-67 really drops. And that may or may not be a better factor than the actual tumor shrinkage. So how many patients who had tumors that didn’t shrink, which was your endpoint, had a reduction in Ki-67 that was, say, 5%?”
“We haven’t looked at that specifically, but we will do so as we carry on with the follow-up of these patients. Then we can learn more about the prognosis,” Dr. Dubsky replied.
Study details
ABCSG 34 was a randomized phase 2 trial testing addition of the cancer vaccine tecemotide (Stimuvax) to neoadjuvant standard of care among patients with HER2-negative early breast cancer.
Dr. Dubsky and coinvestigators restricted analyses to patients with hormone receptor–positive disease who, depending on clinical and pathologic factors, received neoadjuvant chemotherapy (eight cycles of epirubicin-cyclophosphamide and docetaxel) or neoadjuvant endocrine therapy (6 months of letrozole [Femara]) as standard of care. They were then randomized to additionally receive tecemotide or not before undergoing surgery.
Overall, 25% of the 134 patients in the neoadjuvant chemotherapy group had a good tumor response, defined as pathologic complete response in both breast and nodes (RCB of 0) or minimal residual disease (RCB of I).
Higher EndoPredict score was associated with greater likelihood of good response to chemotherapy. EndoPredict risk group (high vs. low) had a negative predictive value of 100%, a positive predictive value of 26.4%, a true-positive rate of 100%, and a true-negative rate of 8.9% for predicting response (P = .112).
Area under the receiver operating characteristic curve was 0.736.
In a multivariate model, EndoPredict score as a continuous variable was not an independent predictor of response. “The good response was largely driven by covariates that included cell proliferation, and it was Ki-67 that was significant,” Dr. Dubsky noted.
Overall, 18% of the 83 patients in the neoadjuvant endocrine therapy group had a good tumor response (RCB of 0 or I). Here, lower EndoPredict score was associated with greater likelihood of good response. EndoPredict risk group (high vs. low) had a negative predictive value of 92.3%, a positive predictive value of 27.3%, a true-positive rate of 80.0%, and a true-negative rate of 52.9% for predicting response (P = .024). Area under the curve was 0.726.
In a multivariate model here, EndoPredict score as a continuous variable, its estrogen receptor–signaling/differentiation component, and Ki-67 did not independently predict response. “It was maybe a bit surprising that T stage was the strongest factor, possibly indicating that we should have simply treated those women longer than 6 months,” Dr. Dubsky commented. The EndoPredict proliferation component was also a significant predictor.
“Possibly, the very narrow distribution of Ki-67 [among patients given neoendocrine therapy] may have prevented this factor from playing a bigger role in this particular model,” he speculated.
Dr. Dubsky disclosed that he receives consulting fees from Myriad, the maker of EndoPredict, and from Cepheid, Nanostring, and Amgen.
SOURCE: Dubsky P et al. SABCS 2017 Abstract GS6-04.
REPORTING FROM SABCS 2017
Key clinical point:
Major finding: EndoPredict predicted poor tumor shrinkage in patients given neoadjuvant endocrine therapy (high-risk test result NPV, 92%) or neoadjuvant chemotherapy (low-risk test result NPV, 100%).
Data source: A cohort study of 217 patients with HR–positive, HER2-negative breast cancer enrolled in a phase 2 trial of neoadjuvant therapy (ABCSG 34).
Disclosures: Dr. Dubsky disclosed that he receives consulting fees from Cepheid, Myriad, Nanostring, and Amgen.
Wider margins may reduce recurrence risk in early breast cancer
SAN ANTONIO – A margin width beyond ‘no tumor on ink’ may reduce local recurrence in certain subsets of patients undergoing breast-conserving treatment for early-stage breast cancer, according to findings from a meta-analysis.
“Further prospective studies are required to validate the appropriate margin width,” study author Frank A. Vicini, MD, of 21st Century Oncology/Michigan Healthcare Professionals in Farmington Hills, Michigan, said at the San Antonio Breast Cancer Symposium.
Dr. Vicini pointed out that the medical community has been addressing the question of “what is the appropriate margin for breast conserving therapy” for about 3 or 4 decades. A meta-analysis of 33 studies (Ann Surg Oncol. 2014 Mar;21[3]:717-30. doi: 10.1245/s10434-014-3480-5) showed that wider margins are unlikely to have a substantial benefit over “no tumor on ink.”
The results of the meta-analysis led to guidelines published by the Society of Surgical Oncology–American Society for Radiation Oncology that supported those conclusions.
“So the question now is that with additional patients and additional modeling, is this conclusion still correct?” Dr. Vicini said.
The 2014 meta-analysis had significant limitations, and to address them, Dr. Vicini and his colleagues conducted an updated analysis of all available data that included 31 of the initial studies. However, stricter criteria were used for inclusion into their review. The authors reviewed all studies published between 1995 and 2016 that had a minimum follow-up of 50 months, and that included explicit pathologic definitions of margin status and local recurrence in relation to margin status.
The final meta-analysis included 55,302 patients (74% T1 tumors; 72% node-negative disease) from a total of 38 studies, and the median follow up was 7.2 years.
The analysis used three generalized linear mixed models for the outcome of local recurrence, and random effects for study and fixed effects for various patient and study characteristics.
In model 1, all patients with at or equal margin width were compared with those who had wider margins. Model 2 examined the impact of margin width “range” as opposed to a set margin width of 0 mm to 2 mm, 2 mm to 5 mm, or greater than 5 mm. Model 3 divided margin distance by cut points of –1 mm, 2 mm, and 5 mm.
The crude rate of local recurrence was 10.3% for patients with positive margins versus 3.8% for those with negative margins that were defined as no tumor on ink or wider (P less than .001). Local recurrence rates declined as the margin distance increased: 7.2% for patients with margins 0-2 mm, 3.6% for margins of 2-5 mm, and 3.2% for margins wider than 5 mm (P less than .001 for each). The use of endocrine therapy and increasing median study year were associated with decreased rates of local recurrence in univariate models but not in multivariable analyses.
For local recurrence in model 1, a benefit for wider margins was observed, with the greatest benefit seen at 1 mm. The odds ratio (OR) for local recurrence for negative vs. close/positive margins was 0.46 (95% confidence interval, 0.4-0.53) for margins larger than 0 mm, 0.43 (95% CI, 0.36-0.51) for those greater than 1 mm, 0.49 (95% CI, 0.42-0.55) for those larger than 2 mm, and 0.53 (95% CI, 0.43-0.66) for greater than 5 mm. Upon multivariate analysis, the only significant predictive variable was margin status.
For model 2, margin width turned out to be the significant variable, and only wider margins were associated with a decrease in local recurrence.
Finally, in model 3, both margin status and margin width were significantly associated with local recurrence. When modeling as negative, close, or positive margins, the lowest rates were at 2 mm (negative, 3.6%; close, 5.5%; positive, 9.5%) and 5 mm (negative, 2.9%; close, 4.1%; positive, 12.8%).
“So the initial question is the same – should we achieve a 1- to 2-mm margin for our patients as compared to a no tumor on ink, taking into account the potential for local control benefits versus morbidity and time, and cost?” said Dr. Vicini.
“The real question in my mind, is which patients with no tumor on ink require additional surgery,” he concluded. “In my opinion, it may not only be related to the margin status itself, but to the volume of disease near the margin but these meta-analyses were not designed to look at that point.”
SOURCE: Vicini et al. SABCS Abstract GS5-01
SAN ANTONIO – A margin width beyond ‘no tumor on ink’ may reduce local recurrence in certain subsets of patients undergoing breast-conserving treatment for early-stage breast cancer, according to findings from a meta-analysis.
“Further prospective studies are required to validate the appropriate margin width,” study author Frank A. Vicini, MD, of 21st Century Oncology/Michigan Healthcare Professionals in Farmington Hills, Michigan, said at the San Antonio Breast Cancer Symposium.
Dr. Vicini pointed out that the medical community has been addressing the question of “what is the appropriate margin for breast conserving therapy” for about 3 or 4 decades. A meta-analysis of 33 studies (Ann Surg Oncol. 2014 Mar;21[3]:717-30. doi: 10.1245/s10434-014-3480-5) showed that wider margins are unlikely to have a substantial benefit over “no tumor on ink.”
The results of the meta-analysis led to guidelines published by the Society of Surgical Oncology–American Society for Radiation Oncology that supported those conclusions.
“So the question now is that with additional patients and additional modeling, is this conclusion still correct?” Dr. Vicini said.
The 2014 meta-analysis had significant limitations, and to address them, Dr. Vicini and his colleagues conducted an updated analysis of all available data that included 31 of the initial studies. However, stricter criteria were used for inclusion into their review. The authors reviewed all studies published between 1995 and 2016 that had a minimum follow-up of 50 months, and that included explicit pathologic definitions of margin status and local recurrence in relation to margin status.
The final meta-analysis included 55,302 patients (74% T1 tumors; 72% node-negative disease) from a total of 38 studies, and the median follow up was 7.2 years.
The analysis used three generalized linear mixed models for the outcome of local recurrence, and random effects for study and fixed effects for various patient and study characteristics.
In model 1, all patients with at or equal margin width were compared with those who had wider margins. Model 2 examined the impact of margin width “range” as opposed to a set margin width of 0 mm to 2 mm, 2 mm to 5 mm, or greater than 5 mm. Model 3 divided margin distance by cut points of –1 mm, 2 mm, and 5 mm.
The crude rate of local recurrence was 10.3% for patients with positive margins versus 3.8% for those with negative margins that were defined as no tumor on ink or wider (P less than .001). Local recurrence rates declined as the margin distance increased: 7.2% for patients with margins 0-2 mm, 3.6% for margins of 2-5 mm, and 3.2% for margins wider than 5 mm (P less than .001 for each). The use of endocrine therapy and increasing median study year were associated with decreased rates of local recurrence in univariate models but not in multivariable analyses.
For local recurrence in model 1, a benefit for wider margins was observed, with the greatest benefit seen at 1 mm. The odds ratio (OR) for local recurrence for negative vs. close/positive margins was 0.46 (95% confidence interval, 0.4-0.53) for margins larger than 0 mm, 0.43 (95% CI, 0.36-0.51) for those greater than 1 mm, 0.49 (95% CI, 0.42-0.55) for those larger than 2 mm, and 0.53 (95% CI, 0.43-0.66) for greater than 5 mm. Upon multivariate analysis, the only significant predictive variable was margin status.
For model 2, margin width turned out to be the significant variable, and only wider margins were associated with a decrease in local recurrence.
Finally, in model 3, both margin status and margin width were significantly associated with local recurrence. When modeling as negative, close, or positive margins, the lowest rates were at 2 mm (negative, 3.6%; close, 5.5%; positive, 9.5%) and 5 mm (negative, 2.9%; close, 4.1%; positive, 12.8%).
“So the initial question is the same – should we achieve a 1- to 2-mm margin for our patients as compared to a no tumor on ink, taking into account the potential for local control benefits versus morbidity and time, and cost?” said Dr. Vicini.
“The real question in my mind, is which patients with no tumor on ink require additional surgery,” he concluded. “In my opinion, it may not only be related to the margin status itself, but to the volume of disease near the margin but these meta-analyses were not designed to look at that point.”
SOURCE: Vicini et al. SABCS Abstract GS5-01
SAN ANTONIO – A margin width beyond ‘no tumor on ink’ may reduce local recurrence in certain subsets of patients undergoing breast-conserving treatment for early-stage breast cancer, according to findings from a meta-analysis.
“Further prospective studies are required to validate the appropriate margin width,” study author Frank A. Vicini, MD, of 21st Century Oncology/Michigan Healthcare Professionals in Farmington Hills, Michigan, said at the San Antonio Breast Cancer Symposium.
Dr. Vicini pointed out that the medical community has been addressing the question of “what is the appropriate margin for breast conserving therapy” for about 3 or 4 decades. A meta-analysis of 33 studies (Ann Surg Oncol. 2014 Mar;21[3]:717-30. doi: 10.1245/s10434-014-3480-5) showed that wider margins are unlikely to have a substantial benefit over “no tumor on ink.”
The results of the meta-analysis led to guidelines published by the Society of Surgical Oncology–American Society for Radiation Oncology that supported those conclusions.
“So the question now is that with additional patients and additional modeling, is this conclusion still correct?” Dr. Vicini said.
The 2014 meta-analysis had significant limitations, and to address them, Dr. Vicini and his colleagues conducted an updated analysis of all available data that included 31 of the initial studies. However, stricter criteria were used for inclusion into their review. The authors reviewed all studies published between 1995 and 2016 that had a minimum follow-up of 50 months, and that included explicit pathologic definitions of margin status and local recurrence in relation to margin status.
The final meta-analysis included 55,302 patients (74% T1 tumors; 72% node-negative disease) from a total of 38 studies, and the median follow up was 7.2 years.
The analysis used three generalized linear mixed models for the outcome of local recurrence, and random effects for study and fixed effects for various patient and study characteristics.
In model 1, all patients with at or equal margin width were compared with those who had wider margins. Model 2 examined the impact of margin width “range” as opposed to a set margin width of 0 mm to 2 mm, 2 mm to 5 mm, or greater than 5 mm. Model 3 divided margin distance by cut points of –1 mm, 2 mm, and 5 mm.
The crude rate of local recurrence was 10.3% for patients with positive margins versus 3.8% for those with negative margins that were defined as no tumor on ink or wider (P less than .001). Local recurrence rates declined as the margin distance increased: 7.2% for patients with margins 0-2 mm, 3.6% for margins of 2-5 mm, and 3.2% for margins wider than 5 mm (P less than .001 for each). The use of endocrine therapy and increasing median study year were associated with decreased rates of local recurrence in univariate models but not in multivariable analyses.
For local recurrence in model 1, a benefit for wider margins was observed, with the greatest benefit seen at 1 mm. The odds ratio (OR) for local recurrence for negative vs. close/positive margins was 0.46 (95% confidence interval, 0.4-0.53) for margins larger than 0 mm, 0.43 (95% CI, 0.36-0.51) for those greater than 1 mm, 0.49 (95% CI, 0.42-0.55) for those larger than 2 mm, and 0.53 (95% CI, 0.43-0.66) for greater than 5 mm. Upon multivariate analysis, the only significant predictive variable was margin status.
For model 2, margin width turned out to be the significant variable, and only wider margins were associated with a decrease in local recurrence.
Finally, in model 3, both margin status and margin width were significantly associated with local recurrence. When modeling as negative, close, or positive margins, the lowest rates were at 2 mm (negative, 3.6%; close, 5.5%; positive, 9.5%) and 5 mm (negative, 2.9%; close, 4.1%; positive, 12.8%).
“So the initial question is the same – should we achieve a 1- to 2-mm margin for our patients as compared to a no tumor on ink, taking into account the potential for local control benefits versus morbidity and time, and cost?” said Dr. Vicini.
“The real question in my mind, is which patients with no tumor on ink require additional surgery,” he concluded. “In my opinion, it may not only be related to the margin status itself, but to the volume of disease near the margin but these meta-analyses were not designed to look at that point.”
SOURCE: Vicini et al. SABCS Abstract GS5-01
REPORTING FROM SABCS 2017
Key clinical point: Margin widths of at least 2 mm are associated with a reduced risk of ipsilateral breast tumor recurrence versus narrower but uninvolved margins.
Major finding: Crude rates of local recurrence decreased as the margin distance increased: 7.2% for patients with margins 0-2 mm, 3.6% for margins of 2-5 mm, and 3.2% for margins wider than 5 mm (P less than .001 for each).
Data source: Meta-analysis of 38 studies with a total cohort of 55,302 patients treated during 1968-2010.
Disclosures: Study funding was not disclosed. The authors have no relevant disclosures.
Source: Vicini et al. SABCS Abstract GS5-01
Enzalutamide plus exemestane improves PFS in HR+ breast cancer subset
SAN ANTONIO – Enzalutamide added to exemestane improved progression-free survival (PFS) in patients with hormone receptor (HR)-positive advanced breast cancer, investigators reported.
Specifically, it improved outcomes in patients who had not received any prior endocrine therapy and who were positive for a gene signature-based biomarker indicating androgen receptor (AR) signaling.
Patients in this subset who were treated with combination enzalutamide and exemestane achieved a median PFS of 16.5 months, which was significantly higher than the 4 months observed with placebo and exemestane.
However, the addition of enzalutamide had no effect on PFS in the overall cohort or among patients who were biomarker positive but who had received prior endocrine therapy.
“The study met its primary endpoint in improving PFS in the enzalutamide plus exemestane-treated patients who were biomarker positive and HR positive with no prior endocrine therapy for advanced disease as compared [with] exemestane alone,” Denise A. Yardley, MD, of Tennessee Oncology, Nashville, said at the San Antonio Breast Cancer Symposium.
“The role of the AR in HR-positive breast cancer and the predictive value of the identified biomarker are still unclear and will require further studies and validation,” said Dr. Yardley.
Targeting AR is an active area of breast cancer research, as a majority of HR-positive tumors express the AR, as do a moderate number of HER2-positive tumors and almost a third of triple-negative breast cancers. AR signaling has also been associated with resistance to endocrine therapy. Aromatase inhibitors divert estrogen precursors to androgens and data from preclinical models have shown that enzalutamide blocked both estrogen- and androgen-mediated growth of HR+ cells.
Enzalutamide is an inhibitor of AR signaling that is currently used to treat patients with castration-resistant prostate cancer, and has demonstrated clinical activity and was well tolerated in patients with AR-positive advanced triple negative breast cancer, explained Dr. Yardley.
In this study, Dr. Yardley and her colleagues conducted a placebo-controlled phase 2 randomized trial that included 247 patients with HR+/HER2-normal advanced/metastatic breast cancer who were assigned to either 25 mg exemestane plus placebo or 50 mg exemestane and 160 mg enzalutamide daily.
The patients were divided into two parallel cohorts: those with no prior endocrine therapy (C1; n = 127) or those who had received one prior endocrine therapy for metastatic disease (C2; n = 120).
The primary endpoint was PFS in the intent-to-treat population and in the biomarker subgroup of each cohort. Secondary endpoints included the clinical benefit rate at 24 weeks, best overall response, and safety.
The authors found that the PFS in the intent-to-treat population did not significantly differ between those randomized to enzalutamide or placebo in either cohort. In cohort 1, the median PFS was 11.8 months in the enzalutamide arm and 5.8 months in the placebo arm (hazard ratio, 0.82; P = .3631), and in cohort 2, 3.6 months and 3.9 months, respectively (HR, 1.02; P = .9212).
However, statistically significant improvements in median PFS and clinical benefit rate at 24 weeks were observed only in the group with a positive biomarker who had not received any prior endocrine therapy. In cohort 1, the median PFS was 16.5 months in the enzalutamide arm vs. 4.3 months in the placebo arm (HR, 0.44, P = .0335). In cohort 2, median PFS did not significantly differ between groups (6.0 vs. 5.3 months; HR, 0.55; P = .1936).
The clinical response rate in cohort 1 of the biomarker positive group was 83% in the enzalutamide arm versus 38% in the placebo arm (P = .0012).
Adverse events with enzalutamide was similar to those previously reported, and the most common were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Dose interruptions due to adverse events occurred in 21.0% and 25.0% of patients randomized to enzalutamide in cohorts 1 and 2 vs. 20.6% and 15.0% in the placebo group.
Dr. Yardley explained that the biomarker used in the study was identified on PAM50. “It was exploratory and proprietary,” she noted, adding that she is unable to share any further information about it at this time.
SOURCE: Yardley et al. SABCS Abstract GS4-07
SAN ANTONIO – Enzalutamide added to exemestane improved progression-free survival (PFS) in patients with hormone receptor (HR)-positive advanced breast cancer, investigators reported.
Specifically, it improved outcomes in patients who had not received any prior endocrine therapy and who were positive for a gene signature-based biomarker indicating androgen receptor (AR) signaling.
Patients in this subset who were treated with combination enzalutamide and exemestane achieved a median PFS of 16.5 months, which was significantly higher than the 4 months observed with placebo and exemestane.
However, the addition of enzalutamide had no effect on PFS in the overall cohort or among patients who were biomarker positive but who had received prior endocrine therapy.
“The study met its primary endpoint in improving PFS in the enzalutamide plus exemestane-treated patients who were biomarker positive and HR positive with no prior endocrine therapy for advanced disease as compared [with] exemestane alone,” Denise A. Yardley, MD, of Tennessee Oncology, Nashville, said at the San Antonio Breast Cancer Symposium.
“The role of the AR in HR-positive breast cancer and the predictive value of the identified biomarker are still unclear and will require further studies and validation,” said Dr. Yardley.
Targeting AR is an active area of breast cancer research, as a majority of HR-positive tumors express the AR, as do a moderate number of HER2-positive tumors and almost a third of triple-negative breast cancers. AR signaling has also been associated with resistance to endocrine therapy. Aromatase inhibitors divert estrogen precursors to androgens and data from preclinical models have shown that enzalutamide blocked both estrogen- and androgen-mediated growth of HR+ cells.
Enzalutamide is an inhibitor of AR signaling that is currently used to treat patients with castration-resistant prostate cancer, and has demonstrated clinical activity and was well tolerated in patients with AR-positive advanced triple negative breast cancer, explained Dr. Yardley.
In this study, Dr. Yardley and her colleagues conducted a placebo-controlled phase 2 randomized trial that included 247 patients with HR+/HER2-normal advanced/metastatic breast cancer who were assigned to either 25 mg exemestane plus placebo or 50 mg exemestane and 160 mg enzalutamide daily.
The patients were divided into two parallel cohorts: those with no prior endocrine therapy (C1; n = 127) or those who had received one prior endocrine therapy for metastatic disease (C2; n = 120).
The primary endpoint was PFS in the intent-to-treat population and in the biomarker subgroup of each cohort. Secondary endpoints included the clinical benefit rate at 24 weeks, best overall response, and safety.
The authors found that the PFS in the intent-to-treat population did not significantly differ between those randomized to enzalutamide or placebo in either cohort. In cohort 1, the median PFS was 11.8 months in the enzalutamide arm and 5.8 months in the placebo arm (hazard ratio, 0.82; P = .3631), and in cohort 2, 3.6 months and 3.9 months, respectively (HR, 1.02; P = .9212).
However, statistically significant improvements in median PFS and clinical benefit rate at 24 weeks were observed only in the group with a positive biomarker who had not received any prior endocrine therapy. In cohort 1, the median PFS was 16.5 months in the enzalutamide arm vs. 4.3 months in the placebo arm (HR, 0.44, P = .0335). In cohort 2, median PFS did not significantly differ between groups (6.0 vs. 5.3 months; HR, 0.55; P = .1936).
The clinical response rate in cohort 1 of the biomarker positive group was 83% in the enzalutamide arm versus 38% in the placebo arm (P = .0012).
Adverse events with enzalutamide was similar to those previously reported, and the most common were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Dose interruptions due to adverse events occurred in 21.0% and 25.0% of patients randomized to enzalutamide in cohorts 1 and 2 vs. 20.6% and 15.0% in the placebo group.
Dr. Yardley explained that the biomarker used in the study was identified on PAM50. “It was exploratory and proprietary,” she noted, adding that she is unable to share any further information about it at this time.
SOURCE: Yardley et al. SABCS Abstract GS4-07
SAN ANTONIO – Enzalutamide added to exemestane improved progression-free survival (PFS) in patients with hormone receptor (HR)-positive advanced breast cancer, investigators reported.
Specifically, it improved outcomes in patients who had not received any prior endocrine therapy and who were positive for a gene signature-based biomarker indicating androgen receptor (AR) signaling.
Patients in this subset who were treated with combination enzalutamide and exemestane achieved a median PFS of 16.5 months, which was significantly higher than the 4 months observed with placebo and exemestane.
However, the addition of enzalutamide had no effect on PFS in the overall cohort or among patients who were biomarker positive but who had received prior endocrine therapy.
“The study met its primary endpoint in improving PFS in the enzalutamide plus exemestane-treated patients who were biomarker positive and HR positive with no prior endocrine therapy for advanced disease as compared [with] exemestane alone,” Denise A. Yardley, MD, of Tennessee Oncology, Nashville, said at the San Antonio Breast Cancer Symposium.
“The role of the AR in HR-positive breast cancer and the predictive value of the identified biomarker are still unclear and will require further studies and validation,” said Dr. Yardley.
Targeting AR is an active area of breast cancer research, as a majority of HR-positive tumors express the AR, as do a moderate number of HER2-positive tumors and almost a third of triple-negative breast cancers. AR signaling has also been associated with resistance to endocrine therapy. Aromatase inhibitors divert estrogen precursors to androgens and data from preclinical models have shown that enzalutamide blocked both estrogen- and androgen-mediated growth of HR+ cells.
Enzalutamide is an inhibitor of AR signaling that is currently used to treat patients with castration-resistant prostate cancer, and has demonstrated clinical activity and was well tolerated in patients with AR-positive advanced triple negative breast cancer, explained Dr. Yardley.
In this study, Dr. Yardley and her colleagues conducted a placebo-controlled phase 2 randomized trial that included 247 patients with HR+/HER2-normal advanced/metastatic breast cancer who were assigned to either 25 mg exemestane plus placebo or 50 mg exemestane and 160 mg enzalutamide daily.
The patients were divided into two parallel cohorts: those with no prior endocrine therapy (C1; n = 127) or those who had received one prior endocrine therapy for metastatic disease (C2; n = 120).
The primary endpoint was PFS in the intent-to-treat population and in the biomarker subgroup of each cohort. Secondary endpoints included the clinical benefit rate at 24 weeks, best overall response, and safety.
The authors found that the PFS in the intent-to-treat population did not significantly differ between those randomized to enzalutamide or placebo in either cohort. In cohort 1, the median PFS was 11.8 months in the enzalutamide arm and 5.8 months in the placebo arm (hazard ratio, 0.82; P = .3631), and in cohort 2, 3.6 months and 3.9 months, respectively (HR, 1.02; P = .9212).
However, statistically significant improvements in median PFS and clinical benefit rate at 24 weeks were observed only in the group with a positive biomarker who had not received any prior endocrine therapy. In cohort 1, the median PFS was 16.5 months in the enzalutamide arm vs. 4.3 months in the placebo arm (HR, 0.44, P = .0335). In cohort 2, median PFS did not significantly differ between groups (6.0 vs. 5.3 months; HR, 0.55; P = .1936).
The clinical response rate in cohort 1 of the biomarker positive group was 83% in the enzalutamide arm versus 38% in the placebo arm (P = .0012).
Adverse events with enzalutamide was similar to those previously reported, and the most common were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Dose interruptions due to adverse events occurred in 21.0% and 25.0% of patients randomized to enzalutamide in cohorts 1 and 2 vs. 20.6% and 15.0% in the placebo group.
Dr. Yardley explained that the biomarker used in the study was identified on PAM50. “It was exploratory and proprietary,” she noted, adding that she is unable to share any further information about it at this time.
SOURCE: Yardley et al. SABCS Abstract GS4-07
REPORTING FROM SABCS 2017
Key clinical point: Enzalutamide added to exemestane improves progression-free survival in hormone receptor–positive advanced breast cancer patients with a biomarker indicating androgen receptor signaling.
Major finding: In this subset of patients, combination therapy improved PFS: 16.5 months vs. 4.3 months for the placebo arm (HR 0.44, P = .0335).
Data source: A placebo-controlled phase 2 randomized trial comprising 247 patients with HR+/HER2-normal advanced/metastatic breast cancer.
Disclosures: Study funding was not disclosed.
Source: Yardley et al. SABCS Abstract GS4-07.
Pertuzumab approved for HER2-positive breast cancer
, according to the Food and Drug Administration.
The approval was based on results from the APHINITY trial, which included 4,804 patients who had HER2-positive early breast cancers that were excised prior to the study. After a median follow-up period of 45.4 months, an invasive disease event occurred in 7.1% of all patients who received pertuzumab (Perjeta) and in 8.7% of patients who received placebo. In patients with hormone receptor–negative disease, invasive events occurred in 8.2% of the pertuzumab group and in 10.6% of the placebo group. In patients with node-positive disease, the invasive event rate was 9.2% in the pertuzumab group and 12.1% in the placebo group.
“The initial pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30- to 60-minute intravenous infusion,” the FDA said in the statement.
Find the full statement on the FDA website.
, according to the Food and Drug Administration.
The approval was based on results from the APHINITY trial, which included 4,804 patients who had HER2-positive early breast cancers that were excised prior to the study. After a median follow-up period of 45.4 months, an invasive disease event occurred in 7.1% of all patients who received pertuzumab (Perjeta) and in 8.7% of patients who received placebo. In patients with hormone receptor–negative disease, invasive events occurred in 8.2% of the pertuzumab group and in 10.6% of the placebo group. In patients with node-positive disease, the invasive event rate was 9.2% in the pertuzumab group and 12.1% in the placebo group.
“The initial pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30- to 60-minute intravenous infusion,” the FDA said in the statement.
Find the full statement on the FDA website.
, according to the Food and Drug Administration.
The approval was based on results from the APHINITY trial, which included 4,804 patients who had HER2-positive early breast cancers that were excised prior to the study. After a median follow-up period of 45.4 months, an invasive disease event occurred in 7.1% of all patients who received pertuzumab (Perjeta) and in 8.7% of patients who received placebo. In patients with hormone receptor–negative disease, invasive events occurred in 8.2% of the pertuzumab group and in 10.6% of the placebo group. In patients with node-positive disease, the invasive event rate was 9.2% in the pertuzumab group and 12.1% in the placebo group.
“The initial pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30- to 60-minute intravenous infusion,” the FDA said in the statement.
Find the full statement on the FDA website.
Lapatinib plus trastuzumab improves outcomes in HER2+ breast cancer
SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.
EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).
“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.
As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.
However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.
Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.
But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.
The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.
Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.
A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.
“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).
EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).
In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).
Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.
When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.
Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).
“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.
SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.
SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.
EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).
“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.
As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.
However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.
Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.
But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.
The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.
Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.
A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.
“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).
EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).
In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).
Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.
When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.
Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).
“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.
SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.
SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.
EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).
“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.
As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.
However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.
Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.
But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.
The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.
Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.
A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.
“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).
EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).
In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).
Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.
When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.
Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).
“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.
SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.
REPORTING FROM SABCS 2017
Key clinical point: In contrast to previous trials,
Major finding: Event-free survival was significantly longer in the dual HER2 blockade arm versus trastuzumab alone (HR, 0.35; 95% CI, 0.15-0.84; P = .013).
Data source: Phase 3 randomized trial that included 305 women with HER2+ breast cancer.
Disclosures: The study was sponsored by the Alliance for Clinical Trials in Oncology. Dr. Krop reports relationships with Genentech/Roche and MacroGenics.
Source: Krop IE et al. SABCS 2017 Abstract GS3-02.
Axillary node dissection can be avoided with limited SLN involvement
SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.
Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.
“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.
In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.
“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.
For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.
The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.
At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).
The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).
The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).
There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.
In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.
“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”
The study received no outside funding and the authors had no disclosures.
SOURCE: Galimberti et al. SABCS Abstract GS5-02
SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.
Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.
“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.
In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.
“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.
For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.
The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.
At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).
The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).
The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).
There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.
In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.
“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”
The study received no outside funding and the authors had no disclosures.
SOURCE: Galimberti et al. SABCS Abstract GS5-02
SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.
Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.
“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.
In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.
“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.
For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.
The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.
At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).
The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).
The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).
There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.
In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.
“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”
The study received no outside funding and the authors had no disclosures.
SOURCE: Galimberti et al. SABCS Abstract GS5-02
REPORTING FROM SABCS 2017
Key clinical point: Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement.
Major finding: At 10 years the disease-free rates were 77% for the no–axillary dissection group and 75% for the axillary dissection group (HR [no-AD vs. AD], 0.85; 95% CI, 0.65-1.11; log-rank P = .23; noninferiority P = .002).
Data source: Updated results of the phase 3 IBCSG 23-01 study, a multicenter, randomized, noninferiority trial that included 934 participants.
Disclosures: The study received no outside funding and the authors had no disclosures.
Source: Galimberti et al. SABCS Abstract GS5-02.
ERBB2 expression predicts pCR in HER2+ breast cancer
SAN ANTONIO – Among patients receiving trastuzumab plus lapatinib neoadjuvant therapy for HER2-positive early breast cancer, amplification of ERBB2 was predictive of a pathologic complete response (pCR), according to findings presented at the San Antonio Breast Cancer Symposium.
However, ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pCR, said lead study author Cristos Sotiriou, MD, of the Breast Cancer Translational Research Laboratory at the Institut Jules Bordet in Belgium
High genomic instability was associated with a higher pCR rate in patients with estrogen receptor–positive tumors, but copy number alterations (CNAs) were not associated with event-free survival (EFS).
In the large phase 3 NeoALTTO trial, lapatinib combined with trastuzumab in the neoadjuvant setting nearly doubled the pCR rate as compared with either agent used alone. The 3-year EFS was also improved with dual HER2 blockage versus single HER2 therapy (84% for the combination, hazard ratio, 0.78; P = .33 vs. 78% for lapatinib alone and 76% for trastuzumab alone, HR, 1.06; P = .81 for both).
The researchers of this trial also found that pCR was a surrogate for long-term outcome.
“Expression of ERBB2, ESR1, and immune signatures were the main drivers of pCR,” said Dr. Sotiriou.
The main goal of the current study was to investigate the relevance of CNAs for pCR and EFS in this population. A total of 455 patients were enrolled in the NeoALTTO study, and of this cohort, 270 had tumor content that was sufficient to assay for CNAs. Tumor-infiltrating lymphocytes and gene expression were also obtained and the genome instability index was calculated, and 184 samples were included in the final analysis.
Of the cancer genes, only ERBB2 was predictive of pCR.
A total of 159 recurrent CNA regions were identified. ERBB2 amplification was associated with high pCR (P = .0007), but less than ERBB2 expression, and it lost its significance after correcting for ERBB2 expression.
The genome instability index (GII) was defined as the “median absolute deviation of the normalized copy number” and independent of ERBB2 amplification, the pCR rate increased with the GII (P = .03.
Amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087). One of the segments harbored 39 genes, some with an expression level that was also predictive of pCR. The 6q23-24 segment was associated with pCR in estrogen receptor–positive tumors only (interaction test P = .04).
After multiple testing correction, there were no amplified regions or genes found to be predictive of EFS.
“A novel amplified region on 6q23-24 was shown to be predictive of pCR, in particular for estrogen receptor–positive tumors,” said Dr. Sotiriou. “This may warrant further investigation.”
SOURCE: Sotiriou et al. SABCS Abstract GS1-04
SAN ANTONIO – Among patients receiving trastuzumab plus lapatinib neoadjuvant therapy for HER2-positive early breast cancer, amplification of ERBB2 was predictive of a pathologic complete response (pCR), according to findings presented at the San Antonio Breast Cancer Symposium.
However, ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pCR, said lead study author Cristos Sotiriou, MD, of the Breast Cancer Translational Research Laboratory at the Institut Jules Bordet in Belgium
High genomic instability was associated with a higher pCR rate in patients with estrogen receptor–positive tumors, but copy number alterations (CNAs) were not associated with event-free survival (EFS).
In the large phase 3 NeoALTTO trial, lapatinib combined with trastuzumab in the neoadjuvant setting nearly doubled the pCR rate as compared with either agent used alone. The 3-year EFS was also improved with dual HER2 blockage versus single HER2 therapy (84% for the combination, hazard ratio, 0.78; P = .33 vs. 78% for lapatinib alone and 76% for trastuzumab alone, HR, 1.06; P = .81 for both).
The researchers of this trial also found that pCR was a surrogate for long-term outcome.
“Expression of ERBB2, ESR1, and immune signatures were the main drivers of pCR,” said Dr. Sotiriou.
The main goal of the current study was to investigate the relevance of CNAs for pCR and EFS in this population. A total of 455 patients were enrolled in the NeoALTTO study, and of this cohort, 270 had tumor content that was sufficient to assay for CNAs. Tumor-infiltrating lymphocytes and gene expression were also obtained and the genome instability index was calculated, and 184 samples were included in the final analysis.
Of the cancer genes, only ERBB2 was predictive of pCR.
A total of 159 recurrent CNA regions were identified. ERBB2 amplification was associated with high pCR (P = .0007), but less than ERBB2 expression, and it lost its significance after correcting for ERBB2 expression.
The genome instability index (GII) was defined as the “median absolute deviation of the normalized copy number” and independent of ERBB2 amplification, the pCR rate increased with the GII (P = .03.
Amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087). One of the segments harbored 39 genes, some with an expression level that was also predictive of pCR. The 6q23-24 segment was associated with pCR in estrogen receptor–positive tumors only (interaction test P = .04).
After multiple testing correction, there were no amplified regions or genes found to be predictive of EFS.
“A novel amplified region on 6q23-24 was shown to be predictive of pCR, in particular for estrogen receptor–positive tumors,” said Dr. Sotiriou. “This may warrant further investigation.”
SOURCE: Sotiriou et al. SABCS Abstract GS1-04
SAN ANTONIO – Among patients receiving trastuzumab plus lapatinib neoadjuvant therapy for HER2-positive early breast cancer, amplification of ERBB2 was predictive of a pathologic complete response (pCR), according to findings presented at the San Antonio Breast Cancer Symposium.
However, ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pCR, said lead study author Cristos Sotiriou, MD, of the Breast Cancer Translational Research Laboratory at the Institut Jules Bordet in Belgium
High genomic instability was associated with a higher pCR rate in patients with estrogen receptor–positive tumors, but copy number alterations (CNAs) were not associated with event-free survival (EFS).
In the large phase 3 NeoALTTO trial, lapatinib combined with trastuzumab in the neoadjuvant setting nearly doubled the pCR rate as compared with either agent used alone. The 3-year EFS was also improved with dual HER2 blockage versus single HER2 therapy (84% for the combination, hazard ratio, 0.78; P = .33 vs. 78% for lapatinib alone and 76% for trastuzumab alone, HR, 1.06; P = .81 for both).
The researchers of this trial also found that pCR was a surrogate for long-term outcome.
“Expression of ERBB2, ESR1, and immune signatures were the main drivers of pCR,” said Dr. Sotiriou.
The main goal of the current study was to investigate the relevance of CNAs for pCR and EFS in this population. A total of 455 patients were enrolled in the NeoALTTO study, and of this cohort, 270 had tumor content that was sufficient to assay for CNAs. Tumor-infiltrating lymphocytes and gene expression were also obtained and the genome instability index was calculated, and 184 samples were included in the final analysis.
Of the cancer genes, only ERBB2 was predictive of pCR.
A total of 159 recurrent CNA regions were identified. ERBB2 amplification was associated with high pCR (P = .0007), but less than ERBB2 expression, and it lost its significance after correcting for ERBB2 expression.
The genome instability index (GII) was defined as the “median absolute deviation of the normalized copy number” and independent of ERBB2 amplification, the pCR rate increased with the GII (P = .03.
Amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087). One of the segments harbored 39 genes, some with an expression level that was also predictive of pCR. The 6q23-24 segment was associated with pCR in estrogen receptor–positive tumors only (interaction test P = .04).
After multiple testing correction, there were no amplified regions or genes found to be predictive of EFS.
“A novel amplified region on 6q23-24 was shown to be predictive of pCR, in particular for estrogen receptor–positive tumors,” said Dr. Sotiriou. “This may warrant further investigation.”
SOURCE: Sotiriou et al. SABCS Abstract GS1-04
REPORTING FROM SABCS 2017
Key clinical point: ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pathologic complete response than did EEBB2 amplification.
Major finding: Of the cancer genes, only ERBB2 was predictive of pCR, and amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087).
Data source: An analysis of the large phase 3 NeoALTTO trial, in which lapatinib was combined with trastuzumab in the neoadjuvant setting to investigate the relevance of copy number alterations on outcome.
Disclosures: The NeoALTTO trial was funded by GlaxoSmithKline. Dr. Sotiriou did not make any disclosures.
Source: Sotiriou et al. SABCS Abstract GS1-04
DCIS risk signature is validated in SweDCIS population
SAN ANTONIO – A biological risk signature can help guide decisions about use of adjuvant radiation therapy in patients with ductal carcinoma in situ (DCIS), suggests a validation study reported at the San Antonio Breast Cancer Symposium.
Radiation therapy reduces the 10-year risk of any ipsilateral recurrence in this population by about 50% as established in a large overview of trials (J Natl Cancer Inst Monogr. 2010;2010:162-77), noted lead investigator Fredrik Wärnberg, MD, PhD, of Uppsala Academic Hospital, Uppsala University, Sweden. But factors such as tumor size, grade, and margins have not been helpful in identifying patients most likely to benefit.
The risk signature incorporates four clinicopathologic factors and seven immunohistochemically assessed biomarkers of hormone receptor status, HER2 status, stress response, and proliferation. Possible scores range from 0 to 10, and are split into categories of low risk (0 to 3) and elevated risk (greater than 3). “To me, the magic of this signature is that it is nonlinear. Each factor can be dependent on the value of other factors in the model,” Dr. Wärnberg said.
Results of the validation study showed that among the 506 patients who had clear margins after surgery, radiation therapy significantly reduced the 10-year risk of invasive recurrence in those with an elevated risk score by more than three-fourths, but not in those with a low risk score.
“The biologic risk signature … correlated to risk. It’s prognostic, that’s nothing new,” he summarized. “More interestingly, it was also predictive for radiotherapy benefit. Not all patient groups had the same benefit from radiation therapy. In the low-risk group, there wasn’t any significant benefit from radiation therapy for invasive recurrences. But in the elevated risk group, the radiation therapy benefit was twice as high as expected – about a 76% relative risk reduction with radiotherapy for invasive recurrences.”
Study details
Main results from the SweDCIS trial, previously reported (J Clin Oncol. 2014;32:3613-8), showed that adjuvant radiation therapy reduced recurrences, yielding a 12% absolute reduction in risk of ipsilateral recurrence (10% for in situ recurrences and 2% for invasive recurrences).
For the validation study, Dr. Wärnberg and his colleagues were able to obtain tissue and biological signature results, blinded to patient outcome, for 56% of the original trial population. About half of patients each were determined to have low risk scores and elevated risk scores.
Among the 506 patients with clear margins, the score, analyzed as a continuous variable, was associated with risk of any (in situ or invasive) ipsilateral recurrence during follow-up (hazard ratio, 1.49 per 5-unit increase; P = .038).
In a multivariate model, receipt of radiation therapy was associated with a 52% relative reduction in 10-year risk of any ipsilateral recurrence for those with a low-risk score (HR, 0.48; P = .04) and a greater 69% relative reduction for those with an elevated risk score (HR, 0.31; P less than .001).
Radiation therapy did not significantly reduce the risk of ipsilateral invasive recurrence in the low risk group (HR, 0.84; P = .70), but it did in the elevated risk group (HR, 0.24; P = .012).
These findings essentially mirrored those of a 2015 validation study in a separate cohort of 526 patients from Uppsala University Hospital and the University of Massachusetts, according to Dr. Wärnberg. “We found highly consistent data with these two different sets,” he said.
Analyses additionally showed that radiation therapy reduced the 10-year risk of an invasive breast cancer recurrence by an absolute 1% for patients with low risk scores (not significant) but by an absolute 9% for patients with elevated risk scores (P = .012).
Dr. Wärnberg disclosed that he had no relevant conflicts of interest. The study was funded in part by PreludeDx.
SOURCE: Warnberg et al., SABCS Abstract GS5-08
SAN ANTONIO – A biological risk signature can help guide decisions about use of adjuvant radiation therapy in patients with ductal carcinoma in situ (DCIS), suggests a validation study reported at the San Antonio Breast Cancer Symposium.
Radiation therapy reduces the 10-year risk of any ipsilateral recurrence in this population by about 50% as established in a large overview of trials (J Natl Cancer Inst Monogr. 2010;2010:162-77), noted lead investigator Fredrik Wärnberg, MD, PhD, of Uppsala Academic Hospital, Uppsala University, Sweden. But factors such as tumor size, grade, and margins have not been helpful in identifying patients most likely to benefit.
The risk signature incorporates four clinicopathologic factors and seven immunohistochemically assessed biomarkers of hormone receptor status, HER2 status, stress response, and proliferation. Possible scores range from 0 to 10, and are split into categories of low risk (0 to 3) and elevated risk (greater than 3). “To me, the magic of this signature is that it is nonlinear. Each factor can be dependent on the value of other factors in the model,” Dr. Wärnberg said.
Results of the validation study showed that among the 506 patients who had clear margins after surgery, radiation therapy significantly reduced the 10-year risk of invasive recurrence in those with an elevated risk score by more than three-fourths, but not in those with a low risk score.
“The biologic risk signature … correlated to risk. It’s prognostic, that’s nothing new,” he summarized. “More interestingly, it was also predictive for radiotherapy benefit. Not all patient groups had the same benefit from radiation therapy. In the low-risk group, there wasn’t any significant benefit from radiation therapy for invasive recurrences. But in the elevated risk group, the radiation therapy benefit was twice as high as expected – about a 76% relative risk reduction with radiotherapy for invasive recurrences.”
Study details
Main results from the SweDCIS trial, previously reported (J Clin Oncol. 2014;32:3613-8), showed that adjuvant radiation therapy reduced recurrences, yielding a 12% absolute reduction in risk of ipsilateral recurrence (10% for in situ recurrences and 2% for invasive recurrences).
For the validation study, Dr. Wärnberg and his colleagues were able to obtain tissue and biological signature results, blinded to patient outcome, for 56% of the original trial population. About half of patients each were determined to have low risk scores and elevated risk scores.
Among the 506 patients with clear margins, the score, analyzed as a continuous variable, was associated with risk of any (in situ or invasive) ipsilateral recurrence during follow-up (hazard ratio, 1.49 per 5-unit increase; P = .038).
In a multivariate model, receipt of radiation therapy was associated with a 52% relative reduction in 10-year risk of any ipsilateral recurrence for those with a low-risk score (HR, 0.48; P = .04) and a greater 69% relative reduction for those with an elevated risk score (HR, 0.31; P less than .001).
Radiation therapy did not significantly reduce the risk of ipsilateral invasive recurrence in the low risk group (HR, 0.84; P = .70), but it did in the elevated risk group (HR, 0.24; P = .012).
These findings essentially mirrored those of a 2015 validation study in a separate cohort of 526 patients from Uppsala University Hospital and the University of Massachusetts, according to Dr. Wärnberg. “We found highly consistent data with these two different sets,” he said.
Analyses additionally showed that radiation therapy reduced the 10-year risk of an invasive breast cancer recurrence by an absolute 1% for patients with low risk scores (not significant) but by an absolute 9% for patients with elevated risk scores (P = .012).
Dr. Wärnberg disclosed that he had no relevant conflicts of interest. The study was funded in part by PreludeDx.
SOURCE: Warnberg et al., SABCS Abstract GS5-08
SAN ANTONIO – A biological risk signature can help guide decisions about use of adjuvant radiation therapy in patients with ductal carcinoma in situ (DCIS), suggests a validation study reported at the San Antonio Breast Cancer Symposium.
Radiation therapy reduces the 10-year risk of any ipsilateral recurrence in this population by about 50% as established in a large overview of trials (J Natl Cancer Inst Monogr. 2010;2010:162-77), noted lead investigator Fredrik Wärnberg, MD, PhD, of Uppsala Academic Hospital, Uppsala University, Sweden. But factors such as tumor size, grade, and margins have not been helpful in identifying patients most likely to benefit.
The risk signature incorporates four clinicopathologic factors and seven immunohistochemically assessed biomarkers of hormone receptor status, HER2 status, stress response, and proliferation. Possible scores range from 0 to 10, and are split into categories of low risk (0 to 3) and elevated risk (greater than 3). “To me, the magic of this signature is that it is nonlinear. Each factor can be dependent on the value of other factors in the model,” Dr. Wärnberg said.
Results of the validation study showed that among the 506 patients who had clear margins after surgery, radiation therapy significantly reduced the 10-year risk of invasive recurrence in those with an elevated risk score by more than three-fourths, but not in those with a low risk score.
“The biologic risk signature … correlated to risk. It’s prognostic, that’s nothing new,” he summarized. “More interestingly, it was also predictive for radiotherapy benefit. Not all patient groups had the same benefit from radiation therapy. In the low-risk group, there wasn’t any significant benefit from radiation therapy for invasive recurrences. But in the elevated risk group, the radiation therapy benefit was twice as high as expected – about a 76% relative risk reduction with radiotherapy for invasive recurrences.”
Study details
Main results from the SweDCIS trial, previously reported (J Clin Oncol. 2014;32:3613-8), showed that adjuvant radiation therapy reduced recurrences, yielding a 12% absolute reduction in risk of ipsilateral recurrence (10% for in situ recurrences and 2% for invasive recurrences).
For the validation study, Dr. Wärnberg and his colleagues were able to obtain tissue and biological signature results, blinded to patient outcome, for 56% of the original trial population. About half of patients each were determined to have low risk scores and elevated risk scores.
Among the 506 patients with clear margins, the score, analyzed as a continuous variable, was associated with risk of any (in situ or invasive) ipsilateral recurrence during follow-up (hazard ratio, 1.49 per 5-unit increase; P = .038).
In a multivariate model, receipt of radiation therapy was associated with a 52% relative reduction in 10-year risk of any ipsilateral recurrence for those with a low-risk score (HR, 0.48; P = .04) and a greater 69% relative reduction for those with an elevated risk score (HR, 0.31; P less than .001).
Radiation therapy did not significantly reduce the risk of ipsilateral invasive recurrence in the low risk group (HR, 0.84; P = .70), but it did in the elevated risk group (HR, 0.24; P = .012).
These findings essentially mirrored those of a 2015 validation study in a separate cohort of 526 patients from Uppsala University Hospital and the University of Massachusetts, according to Dr. Wärnberg. “We found highly consistent data with these two different sets,” he said.
Analyses additionally showed that radiation therapy reduced the 10-year risk of an invasive breast cancer recurrence by an absolute 1% for patients with low risk scores (not significant) but by an absolute 9% for patients with elevated risk scores (P = .012).
Dr. Wärnberg disclosed that he had no relevant conflicts of interest. The study was funded in part by PreludeDx.
SOURCE: Warnberg et al., SABCS Abstract GS5-08
REPORTING FROM SABCS 2017
Key clinical point:
Major finding: Among patients with clear margins, radiation therapy significantly reduced 10-year risk of invasive recurrence in those with an elevated risk score (hazard ratio, 0.24; P = .012) but not in those with a low risk score (HR, 0.84; P = .70).
Data source: A validation study in 584 patients with DCIS from a randomized trial of radiation therapy (SweDCIS).
Disclosures: Dr. Wärnberg disclosed that he had no relevant conflicts of interest. The study was funded in part by PreludeDx.
Source: Warnberg et al., SABCS Abstract GS5-08
Path CR signals good outcomes in treated high-risk breast cancers
REPORTING FROM SABCS 2017
SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.
Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.
He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.
I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.
As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10, and 0.14, P less than .001 for each).
However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.
The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”
I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.
SOURCE: Yee, D et al. SABCS Abstract GS3-08.
REPORTING FROM SABCS 2017
SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.
Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.
He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.
I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.
As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10, and 0.14, P less than .001 for each).
However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.
The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”
I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.
SOURCE: Yee, D et al. SABCS Abstract GS3-08.
REPORTING FROM SABCS 2017
SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.
Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.
He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.
I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.
As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10, and 0.14, P less than .001 for each).
However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.
The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”
I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.
SOURCE: Yee, D et al. SABCS Abstract GS3-08.
Postmenopausal women who shed pounds see lower breast cancer risk
SAN ANTONIO – Postmenopausal women may be able to lower their risk of invasive breast cancer by simply losing some weight, according to an analysis of the large prospective Women’s Health Initiative Observational Study.
“While obesity is an established risk factor for postmenopausal breast cancer, studies of weight loss and breast cancer provide inconsistent results. It’s been very, very difficult to show that losing weight changes breast cancer incidence,” said lead investigator Rowan T. Chlebowski, MD, PhD, research professor in the department of medical oncology and therapeutics research at City of Hope in Duarte, Calif. “Consequently, the current public health message is limited to ‘avoid body fatness’ [N Engl J Med. 2016;375:794-8]. That’s not a very strong public health message.”
Results showed that compared with peers whose weight remained stable, women who lost at least 5% of their body weight (an average of about 17-20 pounds) had a significant 12% reduction in breast cancer risk, Dr. Chlebowski reported in a session and press briefing at the San Antonio Breast Cancer Symposium. Benefit was similar whether the weight loss was intentional or not, and whether women were normal weight, overweight, or obese at baseline.
“These findings suggest that interventions in postmenopausal women designed to generate weight loss may reduce breast cancer risk. I feel these are very optimistic findings in that they provide a lesson to postmenopausal women that even a moderate degree of weight loss may be associated with health benefits,” he said. “This is a relatively new finding, and I think it should have public health implications.”
Parsing the findings
“I hope that you can present this to general doctors rather than oncologists because those are the ones seeing healthy women, by and large,” said press briefing moderator C. Kent Osborne, MD, codirector of SABCS and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston. “But in my patients, I’ve always suggested that they lose weight. Most of them with breast cancer are overweight, it seems. And I always had to do it because of diabetes and other factors. Now we can do it because we have a breast cancer endpoint that also suggests that losing weight will help with that as well.”
Additional results from the study showed that women who experienced a weight gain of at least 5% did not have a significantly elevated risk of breast cancer overall.
“Do you think that the women who gained a little bit of weight didn’t have an increase in incidence because they were already overweight?” Dr. Osborne asked.
“When we go over all these very complex mechanisms and the different drivers, there’s probably a threshold. So obesity’s association with inflammatory factors, I think that’s a driver to a certain degree. But then something else takes over, or maybe the main driver takes over,” Dr. Chlebowski replied. “We don’t have enough data to decide exactly what that threshold is, but that’s the ongoing hypothesis.”
In the session, attendee Daniel McGrail, PhD, of the MD Anderson Cancer Center, Houston, asked, “Since this [risk reduction with weight loss] occurred regardless of initial [body mass index], and you have all these covariates accounted for, does that imply that actually caloric deficits or decreasing caloric intake could be preventing breast cancer risk regardless of initial weight or any other parameters?”
“In all these western diseases, what we take for normal is probably less normal than it might have been 250 years ago or thousands of years ago when we were eating berries and being chased by animals,” Dr. Chlebowski replied. “So this raises a question as to whether the normal weight cutoff should be an ideal weight for western cancer prevention.”
Study details
The Women’s Health Initiative Observational Study recruited 93,676 postmenopausal women aged 50-79 years from 40 U.S. clinical centers during 1993-1998. The women had measurements taken of height and weight at baseline and at year 3 for calculation of BMI, and were asked about intentionality of any weight loss during that period.
Analyses were based on 61,335 women who had normal or higher body weight and were cancer free at baseline, survived at least 3 years, and had adequate data.
Overall, about 13.3% of women lost at least 5% of their body weight between baseline and year 3; 7.9% did so intentionally, losing an average of 19.6 pounds, and 5.5% did so unintentionally, losing an average of 16.9 pounds.
“We used the 5% decrease because this level has been shown to change some biochemical markers potentially associated with cancer. And it has been shown in a different study population, a randomized trial, to reduce the frequency of diabetes,” Dr. Chlebowski noted.
“There was nothing that the study did to induce the weight loss. And based on a partial look at the data, it doesn’t look like many of the women went to some kind of program to lose weight. So it was probably self-directed weight loss,” he noted. “Interestingly, the body mass index of this group was 29.9, so they were on the verge of going into obesity. We wondered in retrospect whether that was a motivating factor for them.”
In multivariate analysis, relative to peers having a stable weight over time, the women losing at least 5% of their weight had a lower risk of breast cancer (hazard ratio, 0.88; 95% confidence interval, 0.78-0.98; P = .02).
Findings were unchanged after further adjustment for mammography frequency. In addition, risk reduction was statistically indistinguishable whether the weight loss was intentional or not (P = .2 for interaction), and whether women were normal weight, overweight, or obese at baseline (P = .4 for interaction).
The 19.6% of women who had a weight gain of at least 5% did not have a significantly elevated risk of breast cancer overall, but they did have a significantly elevated risk of triple-negative breast cancer (HR, 1.54; 95% CI, 1.16-2.05). “We really don’t have a good explanation for this,” Dr. Chlebowski said.
Tackling the global obesity epidemic by conventional means to reduce cancer risk is an uphill battle, he concluded. “We are going to be looking for possible mediating factors. If you can find the mediating factors, pharmacologic intervention would have a much greater chance of success.”
Dr. Chlebowski disclosed that he had no relevant conflicts of interest. Research was supported by the National Heart, Lung and Blood Institute; National Institutes of Health; Department of Health and Human Services; and American Institute for Cancer Research.
SOURCE: Chlebowski et al., SABCS 2017 Abstract GS5-07
SAN ANTONIO – Postmenopausal women may be able to lower their risk of invasive breast cancer by simply losing some weight, according to an analysis of the large prospective Women’s Health Initiative Observational Study.
“While obesity is an established risk factor for postmenopausal breast cancer, studies of weight loss and breast cancer provide inconsistent results. It’s been very, very difficult to show that losing weight changes breast cancer incidence,” said lead investigator Rowan T. Chlebowski, MD, PhD, research professor in the department of medical oncology and therapeutics research at City of Hope in Duarte, Calif. “Consequently, the current public health message is limited to ‘avoid body fatness’ [N Engl J Med. 2016;375:794-8]. That’s not a very strong public health message.”
Results showed that compared with peers whose weight remained stable, women who lost at least 5% of their body weight (an average of about 17-20 pounds) had a significant 12% reduction in breast cancer risk, Dr. Chlebowski reported in a session and press briefing at the San Antonio Breast Cancer Symposium. Benefit was similar whether the weight loss was intentional or not, and whether women were normal weight, overweight, or obese at baseline.
“These findings suggest that interventions in postmenopausal women designed to generate weight loss may reduce breast cancer risk. I feel these are very optimistic findings in that they provide a lesson to postmenopausal women that even a moderate degree of weight loss may be associated with health benefits,” he said. “This is a relatively new finding, and I think it should have public health implications.”
Parsing the findings
“I hope that you can present this to general doctors rather than oncologists because those are the ones seeing healthy women, by and large,” said press briefing moderator C. Kent Osborne, MD, codirector of SABCS and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston. “But in my patients, I’ve always suggested that they lose weight. Most of them with breast cancer are overweight, it seems. And I always had to do it because of diabetes and other factors. Now we can do it because we have a breast cancer endpoint that also suggests that losing weight will help with that as well.”
Additional results from the study showed that women who experienced a weight gain of at least 5% did not have a significantly elevated risk of breast cancer overall.
“Do you think that the women who gained a little bit of weight didn’t have an increase in incidence because they were already overweight?” Dr. Osborne asked.
“When we go over all these very complex mechanisms and the different drivers, there’s probably a threshold. So obesity’s association with inflammatory factors, I think that’s a driver to a certain degree. But then something else takes over, or maybe the main driver takes over,” Dr. Chlebowski replied. “We don’t have enough data to decide exactly what that threshold is, but that’s the ongoing hypothesis.”
In the session, attendee Daniel McGrail, PhD, of the MD Anderson Cancer Center, Houston, asked, “Since this [risk reduction with weight loss] occurred regardless of initial [body mass index], and you have all these covariates accounted for, does that imply that actually caloric deficits or decreasing caloric intake could be preventing breast cancer risk regardless of initial weight or any other parameters?”
“In all these western diseases, what we take for normal is probably less normal than it might have been 250 years ago or thousands of years ago when we were eating berries and being chased by animals,” Dr. Chlebowski replied. “So this raises a question as to whether the normal weight cutoff should be an ideal weight for western cancer prevention.”
Study details
The Women’s Health Initiative Observational Study recruited 93,676 postmenopausal women aged 50-79 years from 40 U.S. clinical centers during 1993-1998. The women had measurements taken of height and weight at baseline and at year 3 for calculation of BMI, and were asked about intentionality of any weight loss during that period.
Analyses were based on 61,335 women who had normal or higher body weight and were cancer free at baseline, survived at least 3 years, and had adequate data.
Overall, about 13.3% of women lost at least 5% of their body weight between baseline and year 3; 7.9% did so intentionally, losing an average of 19.6 pounds, and 5.5% did so unintentionally, losing an average of 16.9 pounds.
“We used the 5% decrease because this level has been shown to change some biochemical markers potentially associated with cancer. And it has been shown in a different study population, a randomized trial, to reduce the frequency of diabetes,” Dr. Chlebowski noted.
“There was nothing that the study did to induce the weight loss. And based on a partial look at the data, it doesn’t look like many of the women went to some kind of program to lose weight. So it was probably self-directed weight loss,” he noted. “Interestingly, the body mass index of this group was 29.9, so they were on the verge of going into obesity. We wondered in retrospect whether that was a motivating factor for them.”
In multivariate analysis, relative to peers having a stable weight over time, the women losing at least 5% of their weight had a lower risk of breast cancer (hazard ratio, 0.88; 95% confidence interval, 0.78-0.98; P = .02).
Findings were unchanged after further adjustment for mammography frequency. In addition, risk reduction was statistically indistinguishable whether the weight loss was intentional or not (P = .2 for interaction), and whether women were normal weight, overweight, or obese at baseline (P = .4 for interaction).
The 19.6% of women who had a weight gain of at least 5% did not have a significantly elevated risk of breast cancer overall, but they did have a significantly elevated risk of triple-negative breast cancer (HR, 1.54; 95% CI, 1.16-2.05). “We really don’t have a good explanation for this,” Dr. Chlebowski said.
Tackling the global obesity epidemic by conventional means to reduce cancer risk is an uphill battle, he concluded. “We are going to be looking for possible mediating factors. If you can find the mediating factors, pharmacologic intervention would have a much greater chance of success.”
Dr. Chlebowski disclosed that he had no relevant conflicts of interest. Research was supported by the National Heart, Lung and Blood Institute; National Institutes of Health; Department of Health and Human Services; and American Institute for Cancer Research.
SOURCE: Chlebowski et al., SABCS 2017 Abstract GS5-07
SAN ANTONIO – Postmenopausal women may be able to lower their risk of invasive breast cancer by simply losing some weight, according to an analysis of the large prospective Women’s Health Initiative Observational Study.
“While obesity is an established risk factor for postmenopausal breast cancer, studies of weight loss and breast cancer provide inconsistent results. It’s been very, very difficult to show that losing weight changes breast cancer incidence,” said lead investigator Rowan T. Chlebowski, MD, PhD, research professor in the department of medical oncology and therapeutics research at City of Hope in Duarte, Calif. “Consequently, the current public health message is limited to ‘avoid body fatness’ [N Engl J Med. 2016;375:794-8]. That’s not a very strong public health message.”
Results showed that compared with peers whose weight remained stable, women who lost at least 5% of their body weight (an average of about 17-20 pounds) had a significant 12% reduction in breast cancer risk, Dr. Chlebowski reported in a session and press briefing at the San Antonio Breast Cancer Symposium. Benefit was similar whether the weight loss was intentional or not, and whether women were normal weight, overweight, or obese at baseline.
“These findings suggest that interventions in postmenopausal women designed to generate weight loss may reduce breast cancer risk. I feel these are very optimistic findings in that they provide a lesson to postmenopausal women that even a moderate degree of weight loss may be associated with health benefits,” he said. “This is a relatively new finding, and I think it should have public health implications.”
Parsing the findings
“I hope that you can present this to general doctors rather than oncologists because those are the ones seeing healthy women, by and large,” said press briefing moderator C. Kent Osborne, MD, codirector of SABCS and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston. “But in my patients, I’ve always suggested that they lose weight. Most of them with breast cancer are overweight, it seems. And I always had to do it because of diabetes and other factors. Now we can do it because we have a breast cancer endpoint that also suggests that losing weight will help with that as well.”
Additional results from the study showed that women who experienced a weight gain of at least 5% did not have a significantly elevated risk of breast cancer overall.
“Do you think that the women who gained a little bit of weight didn’t have an increase in incidence because they were already overweight?” Dr. Osborne asked.
“When we go over all these very complex mechanisms and the different drivers, there’s probably a threshold. So obesity’s association with inflammatory factors, I think that’s a driver to a certain degree. But then something else takes over, or maybe the main driver takes over,” Dr. Chlebowski replied. “We don’t have enough data to decide exactly what that threshold is, but that’s the ongoing hypothesis.”
In the session, attendee Daniel McGrail, PhD, of the MD Anderson Cancer Center, Houston, asked, “Since this [risk reduction with weight loss] occurred regardless of initial [body mass index], and you have all these covariates accounted for, does that imply that actually caloric deficits or decreasing caloric intake could be preventing breast cancer risk regardless of initial weight or any other parameters?”
“In all these western diseases, what we take for normal is probably less normal than it might have been 250 years ago or thousands of years ago when we were eating berries and being chased by animals,” Dr. Chlebowski replied. “So this raises a question as to whether the normal weight cutoff should be an ideal weight for western cancer prevention.”
Study details
The Women’s Health Initiative Observational Study recruited 93,676 postmenopausal women aged 50-79 years from 40 U.S. clinical centers during 1993-1998. The women had measurements taken of height and weight at baseline and at year 3 for calculation of BMI, and were asked about intentionality of any weight loss during that period.
Analyses were based on 61,335 women who had normal or higher body weight and were cancer free at baseline, survived at least 3 years, and had adequate data.
Overall, about 13.3% of women lost at least 5% of their body weight between baseline and year 3; 7.9% did so intentionally, losing an average of 19.6 pounds, and 5.5% did so unintentionally, losing an average of 16.9 pounds.
“We used the 5% decrease because this level has been shown to change some biochemical markers potentially associated with cancer. And it has been shown in a different study population, a randomized trial, to reduce the frequency of diabetes,” Dr. Chlebowski noted.
“There was nothing that the study did to induce the weight loss. And based on a partial look at the data, it doesn’t look like many of the women went to some kind of program to lose weight. So it was probably self-directed weight loss,” he noted. “Interestingly, the body mass index of this group was 29.9, so they were on the verge of going into obesity. We wondered in retrospect whether that was a motivating factor for them.”
In multivariate analysis, relative to peers having a stable weight over time, the women losing at least 5% of their weight had a lower risk of breast cancer (hazard ratio, 0.88; 95% confidence interval, 0.78-0.98; P = .02).
Findings were unchanged after further adjustment for mammography frequency. In addition, risk reduction was statistically indistinguishable whether the weight loss was intentional or not (P = .2 for interaction), and whether women were normal weight, overweight, or obese at baseline (P = .4 for interaction).
The 19.6% of women who had a weight gain of at least 5% did not have a significantly elevated risk of breast cancer overall, but they did have a significantly elevated risk of triple-negative breast cancer (HR, 1.54; 95% CI, 1.16-2.05). “We really don’t have a good explanation for this,” Dr. Chlebowski said.
Tackling the global obesity epidemic by conventional means to reduce cancer risk is an uphill battle, he concluded. “We are going to be looking for possible mediating factors. If you can find the mediating factors, pharmacologic intervention would have a much greater chance of success.”
Dr. Chlebowski disclosed that he had no relevant conflicts of interest. Research was supported by the National Heart, Lung and Blood Institute; National Institutes of Health; Department of Health and Human Services; and American Institute for Cancer Research.
SOURCE: Chlebowski et al., SABCS 2017 Abstract GS5-07
REPORTING FROM SABCS 2017
Key clinical point:
Major finding: Compared with peers who had stable weight, women who lost at least 5% of their body weight had a lower risk of invasive breast cancer (hazard ratio, 0.88; P = .02).
Data source: A prospective cohort study of 93,676 postmenopausal women from the Women’s Health Initiative Observational Study.
Disclosures: Dr. Chlebowski disclosed that he had no relevant conflicts of interest. Research was supported by the National Heart, Lung, and Blood Institute; National Institutes of Health; Department of Health and Human Services; and American Institute for Cancer Research.
Source: Chlebowski et al. SABCS 2017 Abstract GS5-07.