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SLND after neoadjuvant chemo is feasible, but more study needed
SAN ANTONIO – Sentinel lymph node detection after neoadjuvant chemotherapy (NAC) is a safe and feasible strategy for preventing unnecessary systematic lymphadenectomy in patients with operable breast cancer and no clinical signs of cancer in the axillary lymph nodes prior to NAC, according to findings from the French prospective multicenter GANEA 2 trial.
However, further study is needed to assess the clinical impact of the 12% false negative rate associated with sentinel lymph node detection (SLND) in the current study, according to Jean-Marc Classe, MD, who reported the findings at the San Antonio Breast Cancer Symposium.
SLND was feasible in that it was achieved in 570 of 590 women (97%) with large operable breast tumors and negative findings on axillary sonography with fine needle cytology who were enrolled in the study, said Dr. Classe of Institut Cancerologie de l’Ouest Rene Gauducheau, Nantes, France.
Cancer cells were detected by SLND in 139 subjects after NAC and surgery, and all of those patients underwent axillary lymph node dissection. Another 418 had no sentinel node involvement after NAC and surgery, and had adequate follow-up; among those, overall 3-year survival was 97.8% and 3-year disease-free survival was 94.8%,
“In this group of patients ... we found only one axillary relapse,” he said.
These rates are comparable to historical survival rates among those without axillary involvement who undergo axillary lymph node dissection rather than sentinel lymph node detection, and the findings suggest that women with no clinical signs of axillary involvement could be spared systematic lymphadenectomy, he said.
“The standard surgical treatment after neoadjuvant chemotherapy is breast cancer surgery and lymphadenectomy level 1 and 2, but since the [National Surgical Adjuvant Breast and Bowel Project] B-27 trial, we all know that after neoadjuvant chemotherapy there are not any involved nodes in 50%-58% of patients,” he said, adding that about half of all lymphadenectomies in these patients are therefore unnecessary.
That percentage increases to more than 70% in “the very specific situation of patients treated for HER2+ breast cancer with cytologically proved axillary metastases after neoadjuvant chemotherapy,” he said.
“So we know that there is a place for sentinel lymph node biopsy after neoadjuvant chemotherapy in order to avoid unnecessary lymphadenectomy,” he said.
However, the high false negative rate associated with SLND in this and in prior studies, including the first GANEA trial, remains a concern. In fact, the most recent guidelines stated that the proof was too weak to strongly recommend sentinel lymph node biopsy after NAC, he noted.
The GANEA 2 trial was performed in response to a call in those guidelines for additional studies to assess the long-term risks of this strategy.
Study subjects included patients with FIGO stage T1-T3 infiltrating breast cancer who were enrolled from 15 French institutions between July 2010 and February 2014. Those with inflammatory cancer, local relapse, contraindications for NAC, or interrupted NAC due to progressive disease were excluded.
Follow-up included a medical visit with clinical assessment every 6 months and annual mammography.
The findings suggest that in patients with no proof of node involvement before treatment, SLND “seems to be safe within the limits of the short-term follow-up of this study,” Dr. Classe said, noting that given the concerns about the false negative rate and the uncertainty about the clinical impact of that, this approach “is not proved to be a safe procedure outside of trials.”
The strategy will be further evaluated, with a focus on eliminating false negative results, in the GANEA 3 trial, he said.
Dr. Classe reported having no disclosures.
SAN ANTONIO – Sentinel lymph node detection after neoadjuvant chemotherapy (NAC) is a safe and feasible strategy for preventing unnecessary systematic lymphadenectomy in patients with operable breast cancer and no clinical signs of cancer in the axillary lymph nodes prior to NAC, according to findings from the French prospective multicenter GANEA 2 trial.
However, further study is needed to assess the clinical impact of the 12% false negative rate associated with sentinel lymph node detection (SLND) in the current study, according to Jean-Marc Classe, MD, who reported the findings at the San Antonio Breast Cancer Symposium.
SLND was feasible in that it was achieved in 570 of 590 women (97%) with large operable breast tumors and negative findings on axillary sonography with fine needle cytology who were enrolled in the study, said Dr. Classe of Institut Cancerologie de l’Ouest Rene Gauducheau, Nantes, France.
Cancer cells were detected by SLND in 139 subjects after NAC and surgery, and all of those patients underwent axillary lymph node dissection. Another 418 had no sentinel node involvement after NAC and surgery, and had adequate follow-up; among those, overall 3-year survival was 97.8% and 3-year disease-free survival was 94.8%,
“In this group of patients ... we found only one axillary relapse,” he said.
These rates are comparable to historical survival rates among those without axillary involvement who undergo axillary lymph node dissection rather than sentinel lymph node detection, and the findings suggest that women with no clinical signs of axillary involvement could be spared systematic lymphadenectomy, he said.
“The standard surgical treatment after neoadjuvant chemotherapy is breast cancer surgery and lymphadenectomy level 1 and 2, but since the [National Surgical Adjuvant Breast and Bowel Project] B-27 trial, we all know that after neoadjuvant chemotherapy there are not any involved nodes in 50%-58% of patients,” he said, adding that about half of all lymphadenectomies in these patients are therefore unnecessary.
That percentage increases to more than 70% in “the very specific situation of patients treated for HER2+ breast cancer with cytologically proved axillary metastases after neoadjuvant chemotherapy,” he said.
“So we know that there is a place for sentinel lymph node biopsy after neoadjuvant chemotherapy in order to avoid unnecessary lymphadenectomy,” he said.
However, the high false negative rate associated with SLND in this and in prior studies, including the first GANEA trial, remains a concern. In fact, the most recent guidelines stated that the proof was too weak to strongly recommend sentinel lymph node biopsy after NAC, he noted.
The GANEA 2 trial was performed in response to a call in those guidelines for additional studies to assess the long-term risks of this strategy.
Study subjects included patients with FIGO stage T1-T3 infiltrating breast cancer who were enrolled from 15 French institutions between July 2010 and February 2014. Those with inflammatory cancer, local relapse, contraindications for NAC, or interrupted NAC due to progressive disease were excluded.
Follow-up included a medical visit with clinical assessment every 6 months and annual mammography.
The findings suggest that in patients with no proof of node involvement before treatment, SLND “seems to be safe within the limits of the short-term follow-up of this study,” Dr. Classe said, noting that given the concerns about the false negative rate and the uncertainty about the clinical impact of that, this approach “is not proved to be a safe procedure outside of trials.”
The strategy will be further evaluated, with a focus on eliminating false negative results, in the GANEA 3 trial, he said.
Dr. Classe reported having no disclosures.
SAN ANTONIO – Sentinel lymph node detection after neoadjuvant chemotherapy (NAC) is a safe and feasible strategy for preventing unnecessary systematic lymphadenectomy in patients with operable breast cancer and no clinical signs of cancer in the axillary lymph nodes prior to NAC, according to findings from the French prospective multicenter GANEA 2 trial.
However, further study is needed to assess the clinical impact of the 12% false negative rate associated with sentinel lymph node detection (SLND) in the current study, according to Jean-Marc Classe, MD, who reported the findings at the San Antonio Breast Cancer Symposium.
SLND was feasible in that it was achieved in 570 of 590 women (97%) with large operable breast tumors and negative findings on axillary sonography with fine needle cytology who were enrolled in the study, said Dr. Classe of Institut Cancerologie de l’Ouest Rene Gauducheau, Nantes, France.
Cancer cells were detected by SLND in 139 subjects after NAC and surgery, and all of those patients underwent axillary lymph node dissection. Another 418 had no sentinel node involvement after NAC and surgery, and had adequate follow-up; among those, overall 3-year survival was 97.8% and 3-year disease-free survival was 94.8%,
“In this group of patients ... we found only one axillary relapse,” he said.
These rates are comparable to historical survival rates among those without axillary involvement who undergo axillary lymph node dissection rather than sentinel lymph node detection, and the findings suggest that women with no clinical signs of axillary involvement could be spared systematic lymphadenectomy, he said.
“The standard surgical treatment after neoadjuvant chemotherapy is breast cancer surgery and lymphadenectomy level 1 and 2, but since the [National Surgical Adjuvant Breast and Bowel Project] B-27 trial, we all know that after neoadjuvant chemotherapy there are not any involved nodes in 50%-58% of patients,” he said, adding that about half of all lymphadenectomies in these patients are therefore unnecessary.
That percentage increases to more than 70% in “the very specific situation of patients treated for HER2+ breast cancer with cytologically proved axillary metastases after neoadjuvant chemotherapy,” he said.
“So we know that there is a place for sentinel lymph node biopsy after neoadjuvant chemotherapy in order to avoid unnecessary lymphadenectomy,” he said.
However, the high false negative rate associated with SLND in this and in prior studies, including the first GANEA trial, remains a concern. In fact, the most recent guidelines stated that the proof was too weak to strongly recommend sentinel lymph node biopsy after NAC, he noted.
The GANEA 2 trial was performed in response to a call in those guidelines for additional studies to assess the long-term risks of this strategy.
Study subjects included patients with FIGO stage T1-T3 infiltrating breast cancer who were enrolled from 15 French institutions between July 2010 and February 2014. Those with inflammatory cancer, local relapse, contraindications for NAC, or interrupted NAC due to progressive disease were excluded.
Follow-up included a medical visit with clinical assessment every 6 months and annual mammography.
The findings suggest that in patients with no proof of node involvement before treatment, SLND “seems to be safe within the limits of the short-term follow-up of this study,” Dr. Classe said, noting that given the concerns about the false negative rate and the uncertainty about the clinical impact of that, this approach “is not proved to be a safe procedure outside of trials.”
The strategy will be further evaluated, with a focus on eliminating false negative results, in the GANEA 3 trial, he said.
Dr. Classe reported having no disclosures.
AT SABCS 2016
Key clinical point:
Major finding: Overall 3-year survival was 97.8% and 3-year disease-free survival was 94.8% in 418 breast cancer patients who had no sentinel node involvement after NAC and surgery.
Data source: The prospective multicenter GANEA 2 trial of 590 patients.
Disclosures: Dr. Classe reported having no disclosures.
VIDEO: Watson helps oncologists sleuth out best options in breast cancer
SAN ANTONIO – Every day, practicing oncologists sort through mountains of data from treatment guidelines, clinical trials, protocols, and algorithms to make the best possible therapeutic decisions for their patients.
At Manipal Hospitals in Bangalore, India, those decisions are informed with the aid of Watson for Oncology (WFO), a software platform developed by IBM in concert with clinicians and investigators at Memorial Sloan Kettering Cancer Center in New York City.
In this video interview at the San Antonio Breast Cancer Symposium, S.P. Somashekhar, MBBS, MS, MCH, chairman of the Manipal Comprehensive Cancer Center, discusses how the system is used by the members of the center’s multidisciplinary tumor board to inform decision making. He also describes results of a study he presented at the symposium that shows a relatively high degree of concordance between clinician and WFO choices in the treatment of patients with local breast cancer but less agreement when it comes to the management of metastatic disease, for which there is no universal standard of care.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Every day, practicing oncologists sort through mountains of data from treatment guidelines, clinical trials, protocols, and algorithms to make the best possible therapeutic decisions for their patients.
At Manipal Hospitals in Bangalore, India, those decisions are informed with the aid of Watson for Oncology (WFO), a software platform developed by IBM in concert with clinicians and investigators at Memorial Sloan Kettering Cancer Center in New York City.
In this video interview at the San Antonio Breast Cancer Symposium, S.P. Somashekhar, MBBS, MS, MCH, chairman of the Manipal Comprehensive Cancer Center, discusses how the system is used by the members of the center’s multidisciplinary tumor board to inform decision making. He also describes results of a study he presented at the symposium that shows a relatively high degree of concordance between clinician and WFO choices in the treatment of patients with local breast cancer but less agreement when it comes to the management of metastatic disease, for which there is no universal standard of care.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Every day, practicing oncologists sort through mountains of data from treatment guidelines, clinical trials, protocols, and algorithms to make the best possible therapeutic decisions for their patients.
At Manipal Hospitals in Bangalore, India, those decisions are informed with the aid of Watson for Oncology (WFO), a software platform developed by IBM in concert with clinicians and investigators at Memorial Sloan Kettering Cancer Center in New York City.
In this video interview at the San Antonio Breast Cancer Symposium, S.P. Somashekhar, MBBS, MS, MCH, chairman of the Manipal Comprehensive Cancer Center, discusses how the system is used by the members of the center’s multidisciplinary tumor board to inform decision making. He also describes results of a study he presented at the symposium that shows a relatively high degree of concordance between clinician and WFO choices in the treatment of patients with local breast cancer but less agreement when it comes to the management of metastatic disease, for which there is no universal standard of care.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2016
PIK3 inhibitor gives slight PFS edge at high cost for HR+/HER2– advanced breast cancer
SAN ANTONIO – A combination of a PI3K inhibitor and selective estrogen receptor down-regulator (SERD) met its primary endpoint of 2.1 months better progression-free survival (PFS) in postmenopausal women with locally advanced or metastatic breast cancer who were quickly running out of other treatment options.
Yet the small gain in PFS came at a very high price in terms of toxicities, including mood disorders that may have led to patient suicide attempts, according to investigators.
The BELLE-3 trial looked at the combination of the SERD fulvestrant (Faslodex) and an experimental inhibitor of the PI3 kinase, buparlisib, in postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor–2 (HER2)-negative breast cancer treated with an aromatase inhibitor (AI) who experienced disease progression either on or after receiving therapy with an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1).
The combination of fulvestrant and buparlisib was associated with a median PFS of 3.9 months, compared with 1.8 months for fulvestrant and placebo (P less than .001), Angelo Di Leo, MD, of Ospedale Misericordia e Dolce in Prato, Italy, reported at the San Antonio Breast Cancer Symposium,
Objective response rates (ORR) were low, at 7.8% in the combination arm, and 2.1% in the fulvestrant-plus-placebo arm.
Although the PFS difference was statistically significant, “the higher rate of toxicity in patients receiving buparlisib and fulvestrant, including transaminase elevations and mood disorders, may represent a clinically relevant challenge for future development of this compound in this particular group of patients,” Dr. Di Leo said.
Blocks AKT pathway
The preclinical rationale for the use of a P13K inhibitor after disease progression on mTORC1 inhibitor is that current mTOR inhibitors such as everolimus have a feedback mechanism that activates the AKT pathway, and that the use of P13K inhibitors can “abrogate or attenuate this activation, potentially blocking that pathway,” explained coinvestigator Ruth O’Regan, MD, head of the division of hematology and oncology at the University of Wisconsin–Madison School of Medicine and Public Health. Dr. O’Regan discussed the BELLE-3 findings in a briefing prior to Dr. Di Leo’s presentation of the data in general session.
In BELLE-3, 432 postmenopausal women with HR+/HER2-, AI-pretreated, locally advanced or metastatic breast cancer that had progressed on or after treatment with an mTOR inhibitor as the last line of therapy were enrolled. The patients were stratified by the presence or absence of visceral disease and then randomized on a 2:1 basis to fulvestrant 500 mg daily plus either buparlisib 100 mg/day (289 patients), or placebo (143).
As noted, the primary endpoint of investigator-assessed PFS favored the addition of buparlisib, with a hazard ratio for progression of 0.67 (P less than .001). PFS results by independent central review were similar (HR 0.57, P less than .001).
The ORR for the buparlisib/fulvestrant combination, 7.6%, consisted of 0.3% complete responses, and 7.3% partial responses. The ORR for placebo/fulvestrant, 2.1%, was composed entirely of partial responses. The respective clinical benefit rates, defined as a combination of complete and partial responses and stable disease, were 24.6% and 15.4.
The benefit of buparlisib was evidently entirely among patients with visceral disease, with a PFS of 3.1 vs. 1.5 months. In contrast, PFS among patients with no visceral disease was 4.2 vs. 4.1 months, respectively, and was not significant.
In addition, the P13K inhibitor seemed to benefit patients with PIK3CA mutations detected in either the primary tumor or in circulating DNA samples, but not patients with wild-type PIK3CA.
Depression, anxiety with combination
Patients assigned to buparlisib/fulvestrant had substantially higher proportions of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations compared with patients on placebo fulvestrant, as well as more reported depression and anxiety. Three patients in the buparlisib arm attempted suicide. There were no reported suicide attempts in the placebo arm.
Dr. O’Regan said at the briefing that mood disorders are known adverse events associated with buparlisib, and that patients with psychiatric disorders were excluded from the trial.
Carlos Arteaga, MD, co-leader of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., who moderated the briefing, said in an interview that PI kinase mutations do not appear to be a good target, and that a pan-PIK3 inhibitor such as buparlisib may be hitting too many targets at once.
Inhibiting all of the PIK3 isoforms – alpha, beta, gamma, and delta – “may be a little too tough,” he said.
The trial should serve as impetus for developing agents that inhibit only the alpha isoform of PIK3 which mutates and appears to be the driver of some types of breast cancer, he said.
Following Dr. Di Leo’s presentation, perennial SABCS gadfly Steven Vogl, MD, New York, told the speaker that “you presented this very nicely, it’s very interesting biology. I don’t think you’d want to do this again to a human, right? Three month prolongation in PFS, miserable, with diarrhea, depression – you don’t want to do this again, is that correct?”
“I think buparlisib is probably not the best compound to be used in this particular setting of patients,” Dr. Di Leo said, but added that a better-tolerated PI3K inhibitor might be more effective.
“Actually, the study is raising an important question: Should we use the PI3K inhibitor in place of the mTOR inhibitor, or perhaps, as the study suggests, should we use the P13K inhibitors sequentially, after the mTOR inhibitor. This is an open question,” he replied.
Novartis sponsored the study. Dr. Di Leo disclosed consulting and lecture fees from the company, and Dr. O’Regan disclosed contracted research support. Dr. Arteaga reported no disclosures relevant to the study.
SAN ANTONIO – A combination of a PI3K inhibitor and selective estrogen receptor down-regulator (SERD) met its primary endpoint of 2.1 months better progression-free survival (PFS) in postmenopausal women with locally advanced or metastatic breast cancer who were quickly running out of other treatment options.
Yet the small gain in PFS came at a very high price in terms of toxicities, including mood disorders that may have led to patient suicide attempts, according to investigators.
The BELLE-3 trial looked at the combination of the SERD fulvestrant (Faslodex) and an experimental inhibitor of the PI3 kinase, buparlisib, in postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor–2 (HER2)-negative breast cancer treated with an aromatase inhibitor (AI) who experienced disease progression either on or after receiving therapy with an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1).
The combination of fulvestrant and buparlisib was associated with a median PFS of 3.9 months, compared with 1.8 months for fulvestrant and placebo (P less than .001), Angelo Di Leo, MD, of Ospedale Misericordia e Dolce in Prato, Italy, reported at the San Antonio Breast Cancer Symposium,
Objective response rates (ORR) were low, at 7.8% in the combination arm, and 2.1% in the fulvestrant-plus-placebo arm.
Although the PFS difference was statistically significant, “the higher rate of toxicity in patients receiving buparlisib and fulvestrant, including transaminase elevations and mood disorders, may represent a clinically relevant challenge for future development of this compound in this particular group of patients,” Dr. Di Leo said.
Blocks AKT pathway
The preclinical rationale for the use of a P13K inhibitor after disease progression on mTORC1 inhibitor is that current mTOR inhibitors such as everolimus have a feedback mechanism that activates the AKT pathway, and that the use of P13K inhibitors can “abrogate or attenuate this activation, potentially blocking that pathway,” explained coinvestigator Ruth O’Regan, MD, head of the division of hematology and oncology at the University of Wisconsin–Madison School of Medicine and Public Health. Dr. O’Regan discussed the BELLE-3 findings in a briefing prior to Dr. Di Leo’s presentation of the data in general session.
In BELLE-3, 432 postmenopausal women with HR+/HER2-, AI-pretreated, locally advanced or metastatic breast cancer that had progressed on or after treatment with an mTOR inhibitor as the last line of therapy were enrolled. The patients were stratified by the presence or absence of visceral disease and then randomized on a 2:1 basis to fulvestrant 500 mg daily plus either buparlisib 100 mg/day (289 patients), or placebo (143).
As noted, the primary endpoint of investigator-assessed PFS favored the addition of buparlisib, with a hazard ratio for progression of 0.67 (P less than .001). PFS results by independent central review were similar (HR 0.57, P less than .001).
The ORR for the buparlisib/fulvestrant combination, 7.6%, consisted of 0.3% complete responses, and 7.3% partial responses. The ORR for placebo/fulvestrant, 2.1%, was composed entirely of partial responses. The respective clinical benefit rates, defined as a combination of complete and partial responses and stable disease, were 24.6% and 15.4.
The benefit of buparlisib was evidently entirely among patients with visceral disease, with a PFS of 3.1 vs. 1.5 months. In contrast, PFS among patients with no visceral disease was 4.2 vs. 4.1 months, respectively, and was not significant.
In addition, the P13K inhibitor seemed to benefit patients with PIK3CA mutations detected in either the primary tumor or in circulating DNA samples, but not patients with wild-type PIK3CA.
Depression, anxiety with combination
Patients assigned to buparlisib/fulvestrant had substantially higher proportions of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations compared with patients on placebo fulvestrant, as well as more reported depression and anxiety. Three patients in the buparlisib arm attempted suicide. There were no reported suicide attempts in the placebo arm.
Dr. O’Regan said at the briefing that mood disorders are known adverse events associated with buparlisib, and that patients with psychiatric disorders were excluded from the trial.
Carlos Arteaga, MD, co-leader of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., who moderated the briefing, said in an interview that PI kinase mutations do not appear to be a good target, and that a pan-PIK3 inhibitor such as buparlisib may be hitting too many targets at once.
Inhibiting all of the PIK3 isoforms – alpha, beta, gamma, and delta – “may be a little too tough,” he said.
The trial should serve as impetus for developing agents that inhibit only the alpha isoform of PIK3 which mutates and appears to be the driver of some types of breast cancer, he said.
Following Dr. Di Leo’s presentation, perennial SABCS gadfly Steven Vogl, MD, New York, told the speaker that “you presented this very nicely, it’s very interesting biology. I don’t think you’d want to do this again to a human, right? Three month prolongation in PFS, miserable, with diarrhea, depression – you don’t want to do this again, is that correct?”
“I think buparlisib is probably not the best compound to be used in this particular setting of patients,” Dr. Di Leo said, but added that a better-tolerated PI3K inhibitor might be more effective.
“Actually, the study is raising an important question: Should we use the PI3K inhibitor in place of the mTOR inhibitor, or perhaps, as the study suggests, should we use the P13K inhibitors sequentially, after the mTOR inhibitor. This is an open question,” he replied.
Novartis sponsored the study. Dr. Di Leo disclosed consulting and lecture fees from the company, and Dr. O’Regan disclosed contracted research support. Dr. Arteaga reported no disclosures relevant to the study.
SAN ANTONIO – A combination of a PI3K inhibitor and selective estrogen receptor down-regulator (SERD) met its primary endpoint of 2.1 months better progression-free survival (PFS) in postmenopausal women with locally advanced or metastatic breast cancer who were quickly running out of other treatment options.
Yet the small gain in PFS came at a very high price in terms of toxicities, including mood disorders that may have led to patient suicide attempts, according to investigators.
The BELLE-3 trial looked at the combination of the SERD fulvestrant (Faslodex) and an experimental inhibitor of the PI3 kinase, buparlisib, in postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor–2 (HER2)-negative breast cancer treated with an aromatase inhibitor (AI) who experienced disease progression either on or after receiving therapy with an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1).
The combination of fulvestrant and buparlisib was associated with a median PFS of 3.9 months, compared with 1.8 months for fulvestrant and placebo (P less than .001), Angelo Di Leo, MD, of Ospedale Misericordia e Dolce in Prato, Italy, reported at the San Antonio Breast Cancer Symposium,
Objective response rates (ORR) were low, at 7.8% in the combination arm, and 2.1% in the fulvestrant-plus-placebo arm.
Although the PFS difference was statistically significant, “the higher rate of toxicity in patients receiving buparlisib and fulvestrant, including transaminase elevations and mood disorders, may represent a clinically relevant challenge for future development of this compound in this particular group of patients,” Dr. Di Leo said.
Blocks AKT pathway
The preclinical rationale for the use of a P13K inhibitor after disease progression on mTORC1 inhibitor is that current mTOR inhibitors such as everolimus have a feedback mechanism that activates the AKT pathway, and that the use of P13K inhibitors can “abrogate or attenuate this activation, potentially blocking that pathway,” explained coinvestigator Ruth O’Regan, MD, head of the division of hematology and oncology at the University of Wisconsin–Madison School of Medicine and Public Health. Dr. O’Regan discussed the BELLE-3 findings in a briefing prior to Dr. Di Leo’s presentation of the data in general session.
In BELLE-3, 432 postmenopausal women with HR+/HER2-, AI-pretreated, locally advanced or metastatic breast cancer that had progressed on or after treatment with an mTOR inhibitor as the last line of therapy were enrolled. The patients were stratified by the presence or absence of visceral disease and then randomized on a 2:1 basis to fulvestrant 500 mg daily plus either buparlisib 100 mg/day (289 patients), or placebo (143).
As noted, the primary endpoint of investigator-assessed PFS favored the addition of buparlisib, with a hazard ratio for progression of 0.67 (P less than .001). PFS results by independent central review were similar (HR 0.57, P less than .001).
The ORR for the buparlisib/fulvestrant combination, 7.6%, consisted of 0.3% complete responses, and 7.3% partial responses. The ORR for placebo/fulvestrant, 2.1%, was composed entirely of partial responses. The respective clinical benefit rates, defined as a combination of complete and partial responses and stable disease, were 24.6% and 15.4.
The benefit of buparlisib was evidently entirely among patients with visceral disease, with a PFS of 3.1 vs. 1.5 months. In contrast, PFS among patients with no visceral disease was 4.2 vs. 4.1 months, respectively, and was not significant.
In addition, the P13K inhibitor seemed to benefit patients with PIK3CA mutations detected in either the primary tumor or in circulating DNA samples, but not patients with wild-type PIK3CA.
Depression, anxiety with combination
Patients assigned to buparlisib/fulvestrant had substantially higher proportions of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations compared with patients on placebo fulvestrant, as well as more reported depression and anxiety. Three patients in the buparlisib arm attempted suicide. There were no reported suicide attempts in the placebo arm.
Dr. O’Regan said at the briefing that mood disorders are known adverse events associated with buparlisib, and that patients with psychiatric disorders were excluded from the trial.
Carlos Arteaga, MD, co-leader of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., who moderated the briefing, said in an interview that PI kinase mutations do not appear to be a good target, and that a pan-PIK3 inhibitor such as buparlisib may be hitting too many targets at once.
Inhibiting all of the PIK3 isoforms – alpha, beta, gamma, and delta – “may be a little too tough,” he said.
The trial should serve as impetus for developing agents that inhibit only the alpha isoform of PIK3 which mutates and appears to be the driver of some types of breast cancer, he said.
Following Dr. Di Leo’s presentation, perennial SABCS gadfly Steven Vogl, MD, New York, told the speaker that “you presented this very nicely, it’s very interesting biology. I don’t think you’d want to do this again to a human, right? Three month prolongation in PFS, miserable, with diarrhea, depression – you don’t want to do this again, is that correct?”
“I think buparlisib is probably not the best compound to be used in this particular setting of patients,” Dr. Di Leo said, but added that a better-tolerated PI3K inhibitor might be more effective.
“Actually, the study is raising an important question: Should we use the PI3K inhibitor in place of the mTOR inhibitor, or perhaps, as the study suggests, should we use the P13K inhibitors sequentially, after the mTOR inhibitor. This is an open question,” he replied.
Novartis sponsored the study. Dr. Di Leo disclosed consulting and lecture fees from the company, and Dr. O’Regan disclosed contracted research support. Dr. Arteaga reported no disclosures relevant to the study.
AT SABCS 2016
Key clinical point: The PI3K inhibitor buparlisib plus fulvestrant slightly prolonged progression-free survival of HR+/HER2– breast cancer pretreated with an aromatase inhibitor and mTOR inhibitor.
Major finding: The combination met its primary endpoint of better PFS than fulvestrant/placebo, but with high liver toxicity and mood disorders.
Data source: Randomized phase III trial of 432 women with hormone receptor–positive, HER2-negative, AI-pretreated breast cancer that progressed on or after mTOR inhibitor therapy.
Disclosures: Novartis sponsored the study. Dr. Di Leo disclosed consulting and lecture fees from the company, and Dr. O’Regan disclosed contracted research support. Dr. Arteaga reported no disclosures relevant to the study.
Cooling device reduces breast cancer–related alopecia during chemotherapy
SAN ANTONIO – About half of the women with stage 1 or 2 breast cancer who were treated using a scalp cooling device during chemotherapy retained their hair in the prospective, randomized Scalp Cooling Alopecia Prevention (SCALP) trial.
Of 229 women who were enrolled from seven U.S. sites between December 2013 and September 2016 and who planned to undergo at least four cycles of anthracycline- or taxane-based chemotherapy, 182 met eligibility criteria; 119 were randomized to undergo scalp cooling using the Orbis Paxman Hair Loss Prevention System (OPHLPS; Paxman Coolers) and 63 were assigned to a control group. Of those, 95 and 47, respectively, were evaluable and had completed four cycles of chemotherapy at the time of a preplanned interim analysis.
The study was stopped after the interim analysis because of the positive superiority in the treatment group, Dr. Nangia said.
Study subjects were women with early-stage breast cancer and planned neoadjuvant or adjuvant chemotherapy. Most (65%) received taxane-based chemotherapy and 35% received anthracycline-based chemotherapy; the latter has been shown to be associated with higher rates of hair loss.
The OPHLPS system involves the use of a “cold cap” that is cooled using a refrigeration system and fitted to a patient’s head during chemotherapy treatment. For the current study, subjects underwent scalp cooling for 30 minutes before chemotherapy, during chemotherapy, and for 90 minutes after.
Most subjects (39%-52%) reported that they were reasonably comfortable during use of the device during treatment cycles 1-4. Only 2.4% reported being very uncomfortable, and that was only during cycle 2.
An analysis based on type of therapy showed that 65.1% of those receiving a taxane experienced hair preservation, compared with 21.9% of those receiving an anthracycline.
Scalp cooling, which reduces blood flow and chemoexposure to the hair follicles and thereby reduces hair loss, is widely used in Europe and, despite a great deal of interest in the technology in the United States, the Food and Drug Administration has been slow to get on board because of concerns over the potential for scalp metastasis. However, long-term outcomes data from Europe demonstrate that scalp metastasis is “exceedingly rare” and has occurred only in those with metastasis throughout the body, Dr. Nangia said.
Those data opened the door to the current study – the first prospective randomized trial of scalp-cooling.
In response to questions about the effects of scalp cooling across additional chemotherapy cycles (for example, those who undergo eight cycles), Dr. Nangia said that all patients completed four cycles, and data for those with eight cycles planned will be included in a final analysis.
“In other countries, they do have success rates with eight cycles, which is standard for some women,” she said. SCALP trial subjects will also be followed for 5 years to monitor overall survival, recurrence of cancer, and potential metastasis to the scalp, she said.
Based on the findings of the study, the maker of the device is seeking FDA clearance. If approved, the OPHLPS would compete with the DigniCap (Dignitana), which has already received approval.
“Scalp cooling devices are highly effective and should become available to women with breast cancer receiving chemotherapy ... Further study should be done exploring the technology for other types of tumors and with other chemotherapy regimens. More study looking at the impact of chemotherapy-induced alopecia on psyche and body image should be performed as well,” Dr. Nangia concluded, noting that tailored quality-of-life tools are needed to evaluate the impact of alopecia on quality of life.
Dr. Nangia reported receiving research funding from Paxman, the sponsor of the study, to her institution.
SAN ANTONIO – About half of the women with stage 1 or 2 breast cancer who were treated using a scalp cooling device during chemotherapy retained their hair in the prospective, randomized Scalp Cooling Alopecia Prevention (SCALP) trial.
Of 229 women who were enrolled from seven U.S. sites between December 2013 and September 2016 and who planned to undergo at least four cycles of anthracycline- or taxane-based chemotherapy, 182 met eligibility criteria; 119 were randomized to undergo scalp cooling using the Orbis Paxman Hair Loss Prevention System (OPHLPS; Paxman Coolers) and 63 were assigned to a control group. Of those, 95 and 47, respectively, were evaluable and had completed four cycles of chemotherapy at the time of a preplanned interim analysis.
The study was stopped after the interim analysis because of the positive superiority in the treatment group, Dr. Nangia said.
Study subjects were women with early-stage breast cancer and planned neoadjuvant or adjuvant chemotherapy. Most (65%) received taxane-based chemotherapy and 35% received anthracycline-based chemotherapy; the latter has been shown to be associated with higher rates of hair loss.
The OPHLPS system involves the use of a “cold cap” that is cooled using a refrigeration system and fitted to a patient’s head during chemotherapy treatment. For the current study, subjects underwent scalp cooling for 30 minutes before chemotherapy, during chemotherapy, and for 90 minutes after.
Most subjects (39%-52%) reported that they were reasonably comfortable during use of the device during treatment cycles 1-4. Only 2.4% reported being very uncomfortable, and that was only during cycle 2.
An analysis based on type of therapy showed that 65.1% of those receiving a taxane experienced hair preservation, compared with 21.9% of those receiving an anthracycline.
Scalp cooling, which reduces blood flow and chemoexposure to the hair follicles and thereby reduces hair loss, is widely used in Europe and, despite a great deal of interest in the technology in the United States, the Food and Drug Administration has been slow to get on board because of concerns over the potential for scalp metastasis. However, long-term outcomes data from Europe demonstrate that scalp metastasis is “exceedingly rare” and has occurred only in those with metastasis throughout the body, Dr. Nangia said.
Those data opened the door to the current study – the first prospective randomized trial of scalp-cooling.
In response to questions about the effects of scalp cooling across additional chemotherapy cycles (for example, those who undergo eight cycles), Dr. Nangia said that all patients completed four cycles, and data for those with eight cycles planned will be included in a final analysis.
“In other countries, they do have success rates with eight cycles, which is standard for some women,” she said. SCALP trial subjects will also be followed for 5 years to monitor overall survival, recurrence of cancer, and potential metastasis to the scalp, she said.
Based on the findings of the study, the maker of the device is seeking FDA clearance. If approved, the OPHLPS would compete with the DigniCap (Dignitana), which has already received approval.
“Scalp cooling devices are highly effective and should become available to women with breast cancer receiving chemotherapy ... Further study should be done exploring the technology for other types of tumors and with other chemotherapy regimens. More study looking at the impact of chemotherapy-induced alopecia on psyche and body image should be performed as well,” Dr. Nangia concluded, noting that tailored quality-of-life tools are needed to evaluate the impact of alopecia on quality of life.
Dr. Nangia reported receiving research funding from Paxman, the sponsor of the study, to her institution.
SAN ANTONIO – About half of the women with stage 1 or 2 breast cancer who were treated using a scalp cooling device during chemotherapy retained their hair in the prospective, randomized Scalp Cooling Alopecia Prevention (SCALP) trial.
Of 229 women who were enrolled from seven U.S. sites between December 2013 and September 2016 and who planned to undergo at least four cycles of anthracycline- or taxane-based chemotherapy, 182 met eligibility criteria; 119 were randomized to undergo scalp cooling using the Orbis Paxman Hair Loss Prevention System (OPHLPS; Paxman Coolers) and 63 were assigned to a control group. Of those, 95 and 47, respectively, were evaluable and had completed four cycles of chemotherapy at the time of a preplanned interim analysis.
The study was stopped after the interim analysis because of the positive superiority in the treatment group, Dr. Nangia said.
Study subjects were women with early-stage breast cancer and planned neoadjuvant or adjuvant chemotherapy. Most (65%) received taxane-based chemotherapy and 35% received anthracycline-based chemotherapy; the latter has been shown to be associated with higher rates of hair loss.
The OPHLPS system involves the use of a “cold cap” that is cooled using a refrigeration system and fitted to a patient’s head during chemotherapy treatment. For the current study, subjects underwent scalp cooling for 30 minutes before chemotherapy, during chemotherapy, and for 90 minutes after.
Most subjects (39%-52%) reported that they were reasonably comfortable during use of the device during treatment cycles 1-4. Only 2.4% reported being very uncomfortable, and that was only during cycle 2.
An analysis based on type of therapy showed that 65.1% of those receiving a taxane experienced hair preservation, compared with 21.9% of those receiving an anthracycline.
Scalp cooling, which reduces blood flow and chemoexposure to the hair follicles and thereby reduces hair loss, is widely used in Europe and, despite a great deal of interest in the technology in the United States, the Food and Drug Administration has been slow to get on board because of concerns over the potential for scalp metastasis. However, long-term outcomes data from Europe demonstrate that scalp metastasis is “exceedingly rare” and has occurred only in those with metastasis throughout the body, Dr. Nangia said.
Those data opened the door to the current study – the first prospective randomized trial of scalp-cooling.
In response to questions about the effects of scalp cooling across additional chemotherapy cycles (for example, those who undergo eight cycles), Dr. Nangia said that all patients completed four cycles, and data for those with eight cycles planned will be included in a final analysis.
“In other countries, they do have success rates with eight cycles, which is standard for some women,” she said. SCALP trial subjects will also be followed for 5 years to monitor overall survival, recurrence of cancer, and potential metastasis to the scalp, she said.
Based on the findings of the study, the maker of the device is seeking FDA clearance. If approved, the OPHLPS would compete with the DigniCap (Dignitana), which has already received approval.
“Scalp cooling devices are highly effective and should become available to women with breast cancer receiving chemotherapy ... Further study should be done exploring the technology for other types of tumors and with other chemotherapy regimens. More study looking at the impact of chemotherapy-induced alopecia on psyche and body image should be performed as well,” Dr. Nangia concluded, noting that tailored quality-of-life tools are needed to evaluate the impact of alopecia on quality of life.
Dr. Nangia reported receiving research funding from Paxman, the sponsor of the study, to her institution.
AT SABCS 2016
Key clinical point:
Major finding: 50.5% of treated patients experienced no more than grade 1 alopecia (less than 50% hair loss), compared with 0% of control subjects.
Data source: The prospective, randomized SCALP trial involving 182 women.
Disclosures: Dr. Nangia reported receiving research funding from Paxman, sponsor of the study, to her institution.
VIDEO: AIs associated with endothelial dysfunction, a predictor of CVD
SAN ANTONIO – Aromatase inhibitors (AIs) appear to be associated with declines in vascular endothelial function, which in turn have been associated with the development of cardiovascular disease, suggests a small study presented at the San Antonio Breast Cancer Symposium.
In this video interview, Anne Blaes, MD, from the Masonic Cancer Center at the University of Minnesota in Minneapolis, talks about the study, which compared endothelial function between postmenopausal women with hormone receptor–positive breast cancers treated with AIs and healthy postmenopausal controls.
Those treated with AIs, independent of the duration of therapy, had significantly worse endothelial function than healthy postmenopausal controls, as measured by the EndoPAT ratio.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Aromatase inhibitors (AIs) appear to be associated with declines in vascular endothelial function, which in turn have been associated with the development of cardiovascular disease, suggests a small study presented at the San Antonio Breast Cancer Symposium.
In this video interview, Anne Blaes, MD, from the Masonic Cancer Center at the University of Minnesota in Minneapolis, talks about the study, which compared endothelial function between postmenopausal women with hormone receptor–positive breast cancers treated with AIs and healthy postmenopausal controls.
Those treated with AIs, independent of the duration of therapy, had significantly worse endothelial function than healthy postmenopausal controls, as measured by the EndoPAT ratio.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Aromatase inhibitors (AIs) appear to be associated with declines in vascular endothelial function, which in turn have been associated with the development of cardiovascular disease, suggests a small study presented at the San Antonio Breast Cancer Symposium.
In this video interview, Anne Blaes, MD, from the Masonic Cancer Center at the University of Minnesota in Minneapolis, talks about the study, which compared endothelial function between postmenopausal women with hormone receptor–positive breast cancers treated with AIs and healthy postmenopausal controls.
Those treated with AIs, independent of the duration of therapy, had significantly worse endothelial function than healthy postmenopausal controls, as measured by the EndoPAT ratio.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2016
It’s elementary: Watson aids in breast cancer decisions
SAN ANTONIO – When oncologists at Manipal Hospitals in Bangalore, India, need help with a breast cancer conundrum, they can make the electronic equivalent of the famous cry for help “Watson, come here, I want you!”
In this case, Watson is not the real-life sidekick of Alexander Graham Bell or the fictional companion of Sherlock Holmes, but Watson for Oncology (WFO), an IBM-created artificial intelligence platform being developed in the United States and used in clinical practice in India to help guide clinical decision making but not to replace clinicians’ judgment, explained S.P. Somashekhar, MBBS, MS, MCH, FRCS, chairman of the Manipal Comprehensive Cancer Center.
This is no game
WFO is the clinical cousin of the artificial intelligence platform, also named Watson, that beat all-time champion Ken Jennings on the television game show “Jeopardy!” The system was named after Thomas J. Watson, IBM’s first chief executive officer.
The version of Watson used in India was developed by physicians and investigators at Memorial Sloan Kettering Cancer Center (MSKCC) in New York and by IBM. Watson for Oncology is fed national treatment guidelines, more than 1,000 training cases, MSKCC internal guidelines, and medical literature curated by MSKCC; it then chews over the data and spits out evidence-based recommendations.
At Manipal Hospitals, the electronic medical record contains an “Ask Watson” button that allows clinicians to interrogate the artificial entity’s vast stores of medical data to offer recommendations that clinicians can then use, modify, or reject at their discretion.
The system analyzes more than 100 patient attributes and then offers options with a green label for “recommended,” amber label “for consideration,” or a red label for “not recommended.”
Concordance study
At SABCS, Dr. Somashekhar presented results of a study evaluating the concordance of treatment recommendations between WFO and the members of the Manipal Multidisciplinary Tumor Board (MTB).
They looked at data on 638 patients treated in their hospital system over the three prior years, assessing the MTBs initial, best joint decision at the time of the original treatment decision (T1), and compared it with WFO’s recommendation made in 2016 (T2) and with a blinded MTB re-review of nonconcordant cases, also made in 2016.
Evaluating concordance by stage, they found that, for 514 cases of nonmetastatic disease, there was 79% concordance between the original MTB decisions and WFO’s recommendations for therapies in the combined “for consideration” and “recommended” categories.
For 124 cases of metastatic disease, however, Watson and its human counterparts were more frequently at odds, with only a 46% concordance.
In a subset analysis by receptor status, the investigators found that Watson was best – that is, most highly concordant – in triple-negative disease, with a 67.9% concordance in regard to MTB choices. In contrast, for patients with metastatic disease negative for the human epidermal growth factor receptor-2 (HER2), the concordance rate was a low 35%.
Dr. Somashekhar commented that part of the explanation for the discordant concordance rates by tumor subtype can be attributed to the fact that patients with triple-negative breast cancers have fewer treatment options than patients with HER2 negative–only tumors, who have a much broader array of possibilities.
One area where WFO has its two-legged colleagues beaten hands down, however, is in the time it takes to capture and analyze data: humans took a mean of 20 minutes, Watson a median of 40 seconds.
The investigators acknowledged that WFO represents a further step toward personalized medicine, but emphasized that software will never replace the doctor-patient relationship or override the treating physician’s decisions.
‘This one would actually help’
At the briefing, moderator C. Kent Osborne, MD, from Baylor College of Medicine, Houston, commented, “I guess this not going to put us out of business as physicians – at least I hope not.”
Asked whether WFO could be a useful clinical tool or just another nuisance task added to an already overcrowded clinic schedule, Dr. Osborne responded, “I think this one would actually help.”
This study was investigative and received no external funding. Dr. Somashekhar, Dr. Osborne, and Dr. Blaes reported no conflicts of interest.
SAN ANTONIO – When oncologists at Manipal Hospitals in Bangalore, India, need help with a breast cancer conundrum, they can make the electronic equivalent of the famous cry for help “Watson, come here, I want you!”
In this case, Watson is not the real-life sidekick of Alexander Graham Bell or the fictional companion of Sherlock Holmes, but Watson for Oncology (WFO), an IBM-created artificial intelligence platform being developed in the United States and used in clinical practice in India to help guide clinical decision making but not to replace clinicians’ judgment, explained S.P. Somashekhar, MBBS, MS, MCH, FRCS, chairman of the Manipal Comprehensive Cancer Center.
This is no game
WFO is the clinical cousin of the artificial intelligence platform, also named Watson, that beat all-time champion Ken Jennings on the television game show “Jeopardy!” The system was named after Thomas J. Watson, IBM’s first chief executive officer.
The version of Watson used in India was developed by physicians and investigators at Memorial Sloan Kettering Cancer Center (MSKCC) in New York and by IBM. Watson for Oncology is fed national treatment guidelines, more than 1,000 training cases, MSKCC internal guidelines, and medical literature curated by MSKCC; it then chews over the data and spits out evidence-based recommendations.
At Manipal Hospitals, the electronic medical record contains an “Ask Watson” button that allows clinicians to interrogate the artificial entity’s vast stores of medical data to offer recommendations that clinicians can then use, modify, or reject at their discretion.
The system analyzes more than 100 patient attributes and then offers options with a green label for “recommended,” amber label “for consideration,” or a red label for “not recommended.”
Concordance study
At SABCS, Dr. Somashekhar presented results of a study evaluating the concordance of treatment recommendations between WFO and the members of the Manipal Multidisciplinary Tumor Board (MTB).
They looked at data on 638 patients treated in their hospital system over the three prior years, assessing the MTBs initial, best joint decision at the time of the original treatment decision (T1), and compared it with WFO’s recommendation made in 2016 (T2) and with a blinded MTB re-review of nonconcordant cases, also made in 2016.
Evaluating concordance by stage, they found that, for 514 cases of nonmetastatic disease, there was 79% concordance between the original MTB decisions and WFO’s recommendations for therapies in the combined “for consideration” and “recommended” categories.
For 124 cases of metastatic disease, however, Watson and its human counterparts were more frequently at odds, with only a 46% concordance.
In a subset analysis by receptor status, the investigators found that Watson was best – that is, most highly concordant – in triple-negative disease, with a 67.9% concordance in regard to MTB choices. In contrast, for patients with metastatic disease negative for the human epidermal growth factor receptor-2 (HER2), the concordance rate was a low 35%.
Dr. Somashekhar commented that part of the explanation for the discordant concordance rates by tumor subtype can be attributed to the fact that patients with triple-negative breast cancers have fewer treatment options than patients with HER2 negative–only tumors, who have a much broader array of possibilities.
One area where WFO has its two-legged colleagues beaten hands down, however, is in the time it takes to capture and analyze data: humans took a mean of 20 minutes, Watson a median of 40 seconds.
The investigators acknowledged that WFO represents a further step toward personalized medicine, but emphasized that software will never replace the doctor-patient relationship or override the treating physician’s decisions.
‘This one would actually help’
At the briefing, moderator C. Kent Osborne, MD, from Baylor College of Medicine, Houston, commented, “I guess this not going to put us out of business as physicians – at least I hope not.”
Asked whether WFO could be a useful clinical tool or just another nuisance task added to an already overcrowded clinic schedule, Dr. Osborne responded, “I think this one would actually help.”
This study was investigative and received no external funding. Dr. Somashekhar, Dr. Osborne, and Dr. Blaes reported no conflicts of interest.
SAN ANTONIO – When oncologists at Manipal Hospitals in Bangalore, India, need help with a breast cancer conundrum, they can make the electronic equivalent of the famous cry for help “Watson, come here, I want you!”
In this case, Watson is not the real-life sidekick of Alexander Graham Bell or the fictional companion of Sherlock Holmes, but Watson for Oncology (WFO), an IBM-created artificial intelligence platform being developed in the United States and used in clinical practice in India to help guide clinical decision making but not to replace clinicians’ judgment, explained S.P. Somashekhar, MBBS, MS, MCH, FRCS, chairman of the Manipal Comprehensive Cancer Center.
This is no game
WFO is the clinical cousin of the artificial intelligence platform, also named Watson, that beat all-time champion Ken Jennings on the television game show “Jeopardy!” The system was named after Thomas J. Watson, IBM’s first chief executive officer.
The version of Watson used in India was developed by physicians and investigators at Memorial Sloan Kettering Cancer Center (MSKCC) in New York and by IBM. Watson for Oncology is fed national treatment guidelines, more than 1,000 training cases, MSKCC internal guidelines, and medical literature curated by MSKCC; it then chews over the data and spits out evidence-based recommendations.
At Manipal Hospitals, the electronic medical record contains an “Ask Watson” button that allows clinicians to interrogate the artificial entity’s vast stores of medical data to offer recommendations that clinicians can then use, modify, or reject at their discretion.
The system analyzes more than 100 patient attributes and then offers options with a green label for “recommended,” amber label “for consideration,” or a red label for “not recommended.”
Concordance study
At SABCS, Dr. Somashekhar presented results of a study evaluating the concordance of treatment recommendations between WFO and the members of the Manipal Multidisciplinary Tumor Board (MTB).
They looked at data on 638 patients treated in their hospital system over the three prior years, assessing the MTBs initial, best joint decision at the time of the original treatment decision (T1), and compared it with WFO’s recommendation made in 2016 (T2) and with a blinded MTB re-review of nonconcordant cases, also made in 2016.
Evaluating concordance by stage, they found that, for 514 cases of nonmetastatic disease, there was 79% concordance between the original MTB decisions and WFO’s recommendations for therapies in the combined “for consideration” and “recommended” categories.
For 124 cases of metastatic disease, however, Watson and its human counterparts were more frequently at odds, with only a 46% concordance.
In a subset analysis by receptor status, the investigators found that Watson was best – that is, most highly concordant – in triple-negative disease, with a 67.9% concordance in regard to MTB choices. In contrast, for patients with metastatic disease negative for the human epidermal growth factor receptor-2 (HER2), the concordance rate was a low 35%.
Dr. Somashekhar commented that part of the explanation for the discordant concordance rates by tumor subtype can be attributed to the fact that patients with triple-negative breast cancers have fewer treatment options than patients with HER2 negative–only tumors, who have a much broader array of possibilities.
One area where WFO has its two-legged colleagues beaten hands down, however, is in the time it takes to capture and analyze data: humans took a mean of 20 minutes, Watson a median of 40 seconds.
The investigators acknowledged that WFO represents a further step toward personalized medicine, but emphasized that software will never replace the doctor-patient relationship or override the treating physician’s decisions.
‘This one would actually help’
At the briefing, moderator C. Kent Osborne, MD, from Baylor College of Medicine, Houston, commented, “I guess this not going to put us out of business as physicians – at least I hope not.”
Asked whether WFO could be a useful clinical tool or just another nuisance task added to an already overcrowded clinic schedule, Dr. Osborne responded, “I think this one would actually help.”
This study was investigative and received no external funding. Dr. Somashekhar, Dr. Osborne, and Dr. Blaes reported no conflicts of interest.
AT SABCS 2016
Key clinical point: There was good, if imperfect, concordance in breast cancer treatment decisions between the software platform Watson for Oncology and human tumor board members.
Major finding: Concordance on treatment decisions for nonmetastatic breast cancers was 79%; concordance for metastatic cancers was 46%.
Data source: Single-institution study comparing treatment-decision concordance rates between a computerized decision tool and human reviewers.
Disclosures: This study was investigative and received no external funding. Dr. Somashekhar, Dr. Osborne, and Dr. Blaes reported no conflicts of interest.
VIDEO: Watson for Oncology offers electronic curbside consults in breast cancer
SAN ANTONIO – Watson for Oncology or WFO, is the clinical cousin of the IBM-created cognitive computing system best known as the machine that defeated all-time champions on the TV quiz show “Jeopardy!”
WFO, however, has the much more important function of providing oncologists with evidence-based support for clinical decisions. Data being presented here at the San Antonio Breast Cancer Symposium show that in Bangalore, India, where WFO is used in a large hospital system, there is good concordance between tumor board recommendations and WFO’s recommendations about the treatment of breast cancer, although much more work needs to be done. The investigators emphasize that WFO is a highly useful tool that can augment but will not replace clinical judgment, and can never replace the physician-patient relationship.
In this video interview, Andrew Norden, MD, deputy chief health officer for the IBM Watson project, based in Cambridge, Mass., describes how Watson for Oncology works, and how different versions of the Watson platform are being used in medicine throughout the world.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Watson for Oncology or WFO, is the clinical cousin of the IBM-created cognitive computing system best known as the machine that defeated all-time champions on the TV quiz show “Jeopardy!”
WFO, however, has the much more important function of providing oncologists with evidence-based support for clinical decisions. Data being presented here at the San Antonio Breast Cancer Symposium show that in Bangalore, India, where WFO is used in a large hospital system, there is good concordance between tumor board recommendations and WFO’s recommendations about the treatment of breast cancer, although much more work needs to be done. The investigators emphasize that WFO is a highly useful tool that can augment but will not replace clinical judgment, and can never replace the physician-patient relationship.
In this video interview, Andrew Norden, MD, deputy chief health officer for the IBM Watson project, based in Cambridge, Mass., describes how Watson for Oncology works, and how different versions of the Watson platform are being used in medicine throughout the world.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Watson for Oncology or WFO, is the clinical cousin of the IBM-created cognitive computing system best known as the machine that defeated all-time champions on the TV quiz show “Jeopardy!”
WFO, however, has the much more important function of providing oncologists with evidence-based support for clinical decisions. Data being presented here at the San Antonio Breast Cancer Symposium show that in Bangalore, India, where WFO is used in a large hospital system, there is good concordance between tumor board recommendations and WFO’s recommendations about the treatment of breast cancer, although much more work needs to be done. The investigators emphasize that WFO is a highly useful tool that can augment but will not replace clinical judgment, and can never replace the physician-patient relationship.
In this video interview, Andrew Norden, MD, deputy chief health officer for the IBM Watson project, based in Cambridge, Mass., describes how Watson for Oncology works, and how different versions of the Watson platform are being used in medicine throughout the world.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2016
VIDEO: Abemaciclib reduces Ki67 expression in early HR+/HER2– breast cancer
SAN ANTONIO – Abemaciclib, both alone and in combination with anastrozole, significantly reduced Ki67 expression vs. anastrozole monotherapy after 2 weeks of treatment in the NeoMONARCH phase II neoadjuvant clinical trial of postmenopausal patients with hormone receptor–positive, HER2-negative early-stage breast cancer.
The findings, given that a change in Ki67 at 2 weeks in neoadjuvant studies appears to predict improved disease-free survival in adjuvant studies, support continued evaluation of the cyclin-dependent kinase-4 (CDK4) inhibitor for the treatment of patients with early-stage breast cancer, Sara Hurvitz, MD, reported at the San Antonio Breast Cancer Symposium.
“In hormone receptor–positive breast cancers, estrogen stimulates D-type cyclins, resulting in increased activity of CDK4 and CDK6, and then phosphorylate RB – the tumor suppressor protein retinoblastoma – which releases the E2F transcription factor,” explained Dr. Hurvitz of the University of California, Los Angeles.
This in turn ultimately leads to cell cycle progression from G1 to S.
“This increased rate of proliferation can be observed in tumor tissue samples by measuring the expression of Ki67. Blocking CDK4 and CDK6 should lead to a decrease in E2F expression, as well as a drop in the cell cycling and a drop in Ki67,” she said, adding that cell cycle arrest may induce senescence, which may also induce a phenotype that’s characterized by an immune cell infiltrate.
Indeed, in study subjects randomized to receive abemaciclib, treatment was shown to induce profound cell cycle arrest defined by decreased Ki67 and E2F targeted proliferation messenger RNAs, and reduction of expression of genes associated with senescence.
“Abemaciclib alone or in combination with anastrozole significantly reduced the Ki67 expression compared to anastrozole alone after 2 weeks of therapy, based on the geometric mean change and complete cell cycle arrest, and the study did meet its primary endpoint,” she said.
In a video interview, Dr. Hurvitz discussed the study methodology, results, and safety findings, as well as an intriguing observation regarding the effects of treatment on tumor differentiation and immune infiltrates over time.
This study was sponsored by Eli Lilly. Dr. Hurvitz has received renumeration for research and/or travel from Amgen, Bayer, BioMarin, Boehringer Ingelheim, Dignitana, Eli Lilly, Genentech, GSK, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, and Roche.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Abemaciclib, both alone and in combination with anastrozole, significantly reduced Ki67 expression vs. anastrozole monotherapy after 2 weeks of treatment in the NeoMONARCH phase II neoadjuvant clinical trial of postmenopausal patients with hormone receptor–positive, HER2-negative early-stage breast cancer.
The findings, given that a change in Ki67 at 2 weeks in neoadjuvant studies appears to predict improved disease-free survival in adjuvant studies, support continued evaluation of the cyclin-dependent kinase-4 (CDK4) inhibitor for the treatment of patients with early-stage breast cancer, Sara Hurvitz, MD, reported at the San Antonio Breast Cancer Symposium.
“In hormone receptor–positive breast cancers, estrogen stimulates D-type cyclins, resulting in increased activity of CDK4 and CDK6, and then phosphorylate RB – the tumor suppressor protein retinoblastoma – which releases the E2F transcription factor,” explained Dr. Hurvitz of the University of California, Los Angeles.
This in turn ultimately leads to cell cycle progression from G1 to S.
“This increased rate of proliferation can be observed in tumor tissue samples by measuring the expression of Ki67. Blocking CDK4 and CDK6 should lead to a decrease in E2F expression, as well as a drop in the cell cycling and a drop in Ki67,” she said, adding that cell cycle arrest may induce senescence, which may also induce a phenotype that’s characterized by an immune cell infiltrate.
Indeed, in study subjects randomized to receive abemaciclib, treatment was shown to induce profound cell cycle arrest defined by decreased Ki67 and E2F targeted proliferation messenger RNAs, and reduction of expression of genes associated with senescence.
“Abemaciclib alone or in combination with anastrozole significantly reduced the Ki67 expression compared to anastrozole alone after 2 weeks of therapy, based on the geometric mean change and complete cell cycle arrest, and the study did meet its primary endpoint,” she said.
In a video interview, Dr. Hurvitz discussed the study methodology, results, and safety findings, as well as an intriguing observation regarding the effects of treatment on tumor differentiation and immune infiltrates over time.
This study was sponsored by Eli Lilly. Dr. Hurvitz has received renumeration for research and/or travel from Amgen, Bayer, BioMarin, Boehringer Ingelheim, Dignitana, Eli Lilly, Genentech, GSK, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, and Roche.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Abemaciclib, both alone and in combination with anastrozole, significantly reduced Ki67 expression vs. anastrozole monotherapy after 2 weeks of treatment in the NeoMONARCH phase II neoadjuvant clinical trial of postmenopausal patients with hormone receptor–positive, HER2-negative early-stage breast cancer.
The findings, given that a change in Ki67 at 2 weeks in neoadjuvant studies appears to predict improved disease-free survival in adjuvant studies, support continued evaluation of the cyclin-dependent kinase-4 (CDK4) inhibitor for the treatment of patients with early-stage breast cancer, Sara Hurvitz, MD, reported at the San Antonio Breast Cancer Symposium.
“In hormone receptor–positive breast cancers, estrogen stimulates D-type cyclins, resulting in increased activity of CDK4 and CDK6, and then phosphorylate RB – the tumor suppressor protein retinoblastoma – which releases the E2F transcription factor,” explained Dr. Hurvitz of the University of California, Los Angeles.
This in turn ultimately leads to cell cycle progression from G1 to S.
“This increased rate of proliferation can be observed in tumor tissue samples by measuring the expression of Ki67. Blocking CDK4 and CDK6 should lead to a decrease in E2F expression, as well as a drop in the cell cycling and a drop in Ki67,” she said, adding that cell cycle arrest may induce senescence, which may also induce a phenotype that’s characterized by an immune cell infiltrate.
Indeed, in study subjects randomized to receive abemaciclib, treatment was shown to induce profound cell cycle arrest defined by decreased Ki67 and E2F targeted proliferation messenger RNAs, and reduction of expression of genes associated with senescence.
“Abemaciclib alone or in combination with anastrozole significantly reduced the Ki67 expression compared to anastrozole alone after 2 weeks of therapy, based on the geometric mean change and complete cell cycle arrest, and the study did meet its primary endpoint,” she said.
In a video interview, Dr. Hurvitz discussed the study methodology, results, and safety findings, as well as an intriguing observation regarding the effects of treatment on tumor differentiation and immune infiltrates over time.
This study was sponsored by Eli Lilly. Dr. Hurvitz has received renumeration for research and/or travel from Amgen, Bayer, BioMarin, Boehringer Ingelheim, Dignitana, Eli Lilly, Genentech, GSK, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, and Roche.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2016
Aromatase inhibitor effect on endothelial function may lead to CVD
SAN ANTONIO – Aromatase inhibitors, a mainstay of therapy in postmenopausal women with operable hormone receptor–positive breast cancers, are associated with reductions in endothelial function that could contribute to the development of cardiovascular disease, independent of the duration of therapy, investigators have found.
In a cross-sectional study examining endothelial function among postmenopausal women with locally advanced breast cancer on an aromatase inhibitor (AI), there were trends toward reduction in large and small artery elasticity and a significant decrement in vascular tone, compared with the vessels of healthy controls, reported Anne Blaes, MD, from the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“Other studies have suggested that the cardiac risk from aromatase inhibitors is increased further in those with a previous diagnosis of cardiovascular disease. In this study we did not include this patient population, but I really think further work needs to be done in this area,” she said at the San Antonio Breast Cancer Symposium.
Her group’s findings suggest that prospective breast cancer trials need biomarkers to predict cardiovascular risk for patients who are on chronic AI therapy, she said.
CV incidence modest, deaths lows
The incidence rates of cardiovascular disease in clinical trials of adjuvant AI therapy have ranged from 3% to 17%, although the incidence of death from cardiovascular disease was relatively low in these trials, on the order of 1%-2%. Data on cardiovascular risk factors, however, were inconsistently collected across the various studies, Dr. Blaes noted.
“More recently, a lot of discussion has gone on about both the use of prolonged endocrine therapy using aromatase inhibitors – whether to consider 5 or 10 years – and in addition, as our population is aging, competing risks for mortality, whether that’s breast cancer or cardiovascular risk,” she said.
The investigators examined endothelial function in 36 postmenopausal women with locally advanced, operable breast cancer treated with curative intent with adjuvant AI therapy, and compared results with those of 25 healthy postmenopausal volunteers, five of whom were excluded from the final analysis due to prior use of exogenous estrogen.
About half of the patients had received chemotherapy, and two-thirds had received radiation therapy. The AIs used for most patients were anastrozole (Arimidex) and letrozole (Femara). Seven of the 36 cases had previously received tamoxifen.
The authors measured endothelial function using the EndoPAT (Itamar Medical) system that measures peripheral arterial tone (PAT) to identify reactive hyperemia. Endothelial dysfunction measured this way has been associated with an increased risk of cardiac adverse events independent of the Framingham Risk Score, Dr. Blaes said.
The participants underwent biomarker analysis and pulse wave analysis using a cardiovascular profiling system, and pulse contour analysis using the Endo-PAT2000 system. The investigators then compared biomarkers and functional test markers between cases and controls using T-tests and Wilcoxon Rank-Sum tests.
Biomarkers included inflammatory markers (high-sensitivity C-reactive protein, white blood cell count, interleukin 6), markers of hemostasis (fibrinogen, d-dimer, plasminogen-activator inhibitor-1, tissue-type plasminogen activator), and endothelial function markers (von Willebrand factor, circulating endothelial cells, soluble vascular cell adhesion molecule-1, and others).
They measured large-artery elasticity (LAE), small-artery elasticity (SAE), and the EndoPAT ratio, or reactive hyperemia index (RHI), the post-to-pre occlusion PAT signal ratio in the occluded side, normalized to the control side and further corrected for baseline vascular tone. An RHI score above 1.67 is considered normal, and a score of 1.67 or below is considered abnormal.
They found that both LAE and SAE trended toward significantly worse vascular tone in cases, compared with controls, but the differences were not statistically significant. The EndoPAT ratio, however, was significantly worse among cases, at 0.8, compared with 2.6 for controls, a difference that remained significant after controlling for systolic blood pressure (P less than .0001).
Hemostatic and endothelial biomarkers were significantly elevated in cases, compared with controls, but there were no significant differences in inflammatory markers.
When the investigators looked at the association between vascular function and cancer treatment characteristics, they found no differences in the use of chemotherapy, radiation, or left vs. right breast treated.
The use of anastrozole was associated with a significant reduction in LAE, compared with either letrozole or exemestane (P = .03). There was no association between duration of AI therapy and EndoPAT ratio.
Estradiol levels implicated
Not surprisingly, women on endocrine therapy in the study had significantly lower levels of estradiol than controls. Estradiol appears to be important for regulating healthy endothelial function, commented Patricia A. Ganz, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was the invited discussant.
“I think these are very provocative, hypothesis-generating findings, and I think they really fit what we expect the physiology should be in terms of endothelial function, even within this postmenopausal group of women where we’re looking at two discrete groups in terms of the estradiol level,” she said.
The study was funded by Building Interdisciplinary Research Careers in Women’s Health and a Masonic Scholar Award. Dr. Blaes and Dr. Ganz reported no relevant conflicts of interest.
SAN ANTONIO – Aromatase inhibitors, a mainstay of therapy in postmenopausal women with operable hormone receptor–positive breast cancers, are associated with reductions in endothelial function that could contribute to the development of cardiovascular disease, independent of the duration of therapy, investigators have found.
In a cross-sectional study examining endothelial function among postmenopausal women with locally advanced breast cancer on an aromatase inhibitor (AI), there were trends toward reduction in large and small artery elasticity and a significant decrement in vascular tone, compared with the vessels of healthy controls, reported Anne Blaes, MD, from the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“Other studies have suggested that the cardiac risk from aromatase inhibitors is increased further in those with a previous diagnosis of cardiovascular disease. In this study we did not include this patient population, but I really think further work needs to be done in this area,” she said at the San Antonio Breast Cancer Symposium.
Her group’s findings suggest that prospective breast cancer trials need biomarkers to predict cardiovascular risk for patients who are on chronic AI therapy, she said.
CV incidence modest, deaths lows
The incidence rates of cardiovascular disease in clinical trials of adjuvant AI therapy have ranged from 3% to 17%, although the incidence of death from cardiovascular disease was relatively low in these trials, on the order of 1%-2%. Data on cardiovascular risk factors, however, were inconsistently collected across the various studies, Dr. Blaes noted.
“More recently, a lot of discussion has gone on about both the use of prolonged endocrine therapy using aromatase inhibitors – whether to consider 5 or 10 years – and in addition, as our population is aging, competing risks for mortality, whether that’s breast cancer or cardiovascular risk,” she said.
The investigators examined endothelial function in 36 postmenopausal women with locally advanced, operable breast cancer treated with curative intent with adjuvant AI therapy, and compared results with those of 25 healthy postmenopausal volunteers, five of whom were excluded from the final analysis due to prior use of exogenous estrogen.
About half of the patients had received chemotherapy, and two-thirds had received radiation therapy. The AIs used for most patients were anastrozole (Arimidex) and letrozole (Femara). Seven of the 36 cases had previously received tamoxifen.
The authors measured endothelial function using the EndoPAT (Itamar Medical) system that measures peripheral arterial tone (PAT) to identify reactive hyperemia. Endothelial dysfunction measured this way has been associated with an increased risk of cardiac adverse events independent of the Framingham Risk Score, Dr. Blaes said.
The participants underwent biomarker analysis and pulse wave analysis using a cardiovascular profiling system, and pulse contour analysis using the Endo-PAT2000 system. The investigators then compared biomarkers and functional test markers between cases and controls using T-tests and Wilcoxon Rank-Sum tests.
Biomarkers included inflammatory markers (high-sensitivity C-reactive protein, white blood cell count, interleukin 6), markers of hemostasis (fibrinogen, d-dimer, plasminogen-activator inhibitor-1, tissue-type plasminogen activator), and endothelial function markers (von Willebrand factor, circulating endothelial cells, soluble vascular cell adhesion molecule-1, and others).
They measured large-artery elasticity (LAE), small-artery elasticity (SAE), and the EndoPAT ratio, or reactive hyperemia index (RHI), the post-to-pre occlusion PAT signal ratio in the occluded side, normalized to the control side and further corrected for baseline vascular tone. An RHI score above 1.67 is considered normal, and a score of 1.67 or below is considered abnormal.
They found that both LAE and SAE trended toward significantly worse vascular tone in cases, compared with controls, but the differences were not statistically significant. The EndoPAT ratio, however, was significantly worse among cases, at 0.8, compared with 2.6 for controls, a difference that remained significant after controlling for systolic blood pressure (P less than .0001).
Hemostatic and endothelial biomarkers were significantly elevated in cases, compared with controls, but there were no significant differences in inflammatory markers.
When the investigators looked at the association between vascular function and cancer treatment characteristics, they found no differences in the use of chemotherapy, radiation, or left vs. right breast treated.
The use of anastrozole was associated with a significant reduction in LAE, compared with either letrozole or exemestane (P = .03). There was no association between duration of AI therapy and EndoPAT ratio.
Estradiol levels implicated
Not surprisingly, women on endocrine therapy in the study had significantly lower levels of estradiol than controls. Estradiol appears to be important for regulating healthy endothelial function, commented Patricia A. Ganz, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was the invited discussant.
“I think these are very provocative, hypothesis-generating findings, and I think they really fit what we expect the physiology should be in terms of endothelial function, even within this postmenopausal group of women where we’re looking at two discrete groups in terms of the estradiol level,” she said.
The study was funded by Building Interdisciplinary Research Careers in Women’s Health and a Masonic Scholar Award. Dr. Blaes and Dr. Ganz reported no relevant conflicts of interest.
SAN ANTONIO – Aromatase inhibitors, a mainstay of therapy in postmenopausal women with operable hormone receptor–positive breast cancers, are associated with reductions in endothelial function that could contribute to the development of cardiovascular disease, independent of the duration of therapy, investigators have found.
In a cross-sectional study examining endothelial function among postmenopausal women with locally advanced breast cancer on an aromatase inhibitor (AI), there were trends toward reduction in large and small artery elasticity and a significant decrement in vascular tone, compared with the vessels of healthy controls, reported Anne Blaes, MD, from the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“Other studies have suggested that the cardiac risk from aromatase inhibitors is increased further in those with a previous diagnosis of cardiovascular disease. In this study we did not include this patient population, but I really think further work needs to be done in this area,” she said at the San Antonio Breast Cancer Symposium.
Her group’s findings suggest that prospective breast cancer trials need biomarkers to predict cardiovascular risk for patients who are on chronic AI therapy, she said.
CV incidence modest, deaths lows
The incidence rates of cardiovascular disease in clinical trials of adjuvant AI therapy have ranged from 3% to 17%, although the incidence of death from cardiovascular disease was relatively low in these trials, on the order of 1%-2%. Data on cardiovascular risk factors, however, were inconsistently collected across the various studies, Dr. Blaes noted.
“More recently, a lot of discussion has gone on about both the use of prolonged endocrine therapy using aromatase inhibitors – whether to consider 5 or 10 years – and in addition, as our population is aging, competing risks for mortality, whether that’s breast cancer or cardiovascular risk,” she said.
The investigators examined endothelial function in 36 postmenopausal women with locally advanced, operable breast cancer treated with curative intent with adjuvant AI therapy, and compared results with those of 25 healthy postmenopausal volunteers, five of whom were excluded from the final analysis due to prior use of exogenous estrogen.
About half of the patients had received chemotherapy, and two-thirds had received radiation therapy. The AIs used for most patients were anastrozole (Arimidex) and letrozole (Femara). Seven of the 36 cases had previously received tamoxifen.
The authors measured endothelial function using the EndoPAT (Itamar Medical) system that measures peripheral arterial tone (PAT) to identify reactive hyperemia. Endothelial dysfunction measured this way has been associated with an increased risk of cardiac adverse events independent of the Framingham Risk Score, Dr. Blaes said.
The participants underwent biomarker analysis and pulse wave analysis using a cardiovascular profiling system, and pulse contour analysis using the Endo-PAT2000 system. The investigators then compared biomarkers and functional test markers between cases and controls using T-tests and Wilcoxon Rank-Sum tests.
Biomarkers included inflammatory markers (high-sensitivity C-reactive protein, white blood cell count, interleukin 6), markers of hemostasis (fibrinogen, d-dimer, plasminogen-activator inhibitor-1, tissue-type plasminogen activator), and endothelial function markers (von Willebrand factor, circulating endothelial cells, soluble vascular cell adhesion molecule-1, and others).
They measured large-artery elasticity (LAE), small-artery elasticity (SAE), and the EndoPAT ratio, or reactive hyperemia index (RHI), the post-to-pre occlusion PAT signal ratio in the occluded side, normalized to the control side and further corrected for baseline vascular tone. An RHI score above 1.67 is considered normal, and a score of 1.67 or below is considered abnormal.
They found that both LAE and SAE trended toward significantly worse vascular tone in cases, compared with controls, but the differences were not statistically significant. The EndoPAT ratio, however, was significantly worse among cases, at 0.8, compared with 2.6 for controls, a difference that remained significant after controlling for systolic blood pressure (P less than .0001).
Hemostatic and endothelial biomarkers were significantly elevated in cases, compared with controls, but there were no significant differences in inflammatory markers.
When the investigators looked at the association between vascular function and cancer treatment characteristics, they found no differences in the use of chemotherapy, radiation, or left vs. right breast treated.
The use of anastrozole was associated with a significant reduction in LAE, compared with either letrozole or exemestane (P = .03). There was no association between duration of AI therapy and EndoPAT ratio.
Estradiol levels implicated
Not surprisingly, women on endocrine therapy in the study had significantly lower levels of estradiol than controls. Estradiol appears to be important for regulating healthy endothelial function, commented Patricia A. Ganz, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was the invited discussant.
“I think these are very provocative, hypothesis-generating findings, and I think they really fit what we expect the physiology should be in terms of endothelial function, even within this postmenopausal group of women where we’re looking at two discrete groups in terms of the estradiol level,” she said.
The study was funded by Building Interdisciplinary Research Careers in Women’s Health and a Masonic Scholar Award. Dr. Blaes and Dr. Ganz reported no relevant conflicts of interest.
AT SABCS 2016
Key clinical point: Aromatase inhibitors appear to have a decremental effect on vascular endothelial function, which could contribute to cardiovascular disease.
Major finding: Postmenopausal breast cancer survivors had significantly worse endothelial function than healthy postmenopausal controls, as measured by the EndoPAT ratio.
Data source: Case-control study with 36 postmenopausal breast cancer survivors on aromatase inhibitors and 25 healthy controls.
Disclosures: The study was funded by Building Interdisciplinary Research Careers in Women’s Health and a Masonic Scholar Award. Dr. Blaes and Dr. Ganz reported no relevant conflicts of interest.
VIDEO: No effect of BRCA status on overall outcomes in early-onset breast cancer
SAN ANTONIO – No difference in outcomes was seen among young BRCA gene mutation carriers and noncarriers with early-stage invasive breast cancer in a large cohort in the United Kingdom, but a subgroup analysis of those with triple-negative breast cancer showed a clear survival advantage among BRCA mutation carriers.
The findings of the POSH (Prospective Study of Outcomes in Sporadic Versus Hereditary Breast Cancer) trial have important implications for treatment decision making – particularly with respect to surgery – for younger women with breast cancer, according to Diana M. Eccles, MD, of the University of Southampton (England) and University Hospital Southampton Foundation Trust.
The overall finding of no difference in outcomes – including for the primary endpoint of overall survival and secondary endpoints of overall and distant disease-free survival – was true in both univariate and multivariable analysis of data for 2,759 women (14% with BRCA mutations), aged 40 years and younger, who were enrolled over an 8-year period, beginning in 2000, from 126 oncology centers across the United Kingdom, and who were followed for a median of 8.2 years, Dr. Eccles reported at the San Antonio Breast Cancer Symposium.
“We looked at BRCA1 and BRCA2 separately, and we still could see absolutely no difference in survival between BRCA1 and BRCA2, and we were well powered to show a difference,” she said, noting that 99% of these patients were diagnosed based on symptomatic presentation and did not know they were BRCA mutation carriers.
The findings were different among 511 patients with triple-negative breast cancer, however,
“Here we did see a clear difference in survival in favor of BRCA gene carriers – 11% at 10 years. And what was interesting was this clear time-varying hazard of relapse, with the maximum benefit of surviving in the BRCA gene carriers observed in the first few years with a hazard for relapse at 5 years equivalent between the two groups,” she said.
The primary treatment approach in these patients was no different than that in the group as a whole, Dr. Eccles noted, explaining that those with and without triple-negative disease had similar usage of breast conserving vs. unilateral surgery and similar usage of anthracycline-based chemotherapy regimens, with taxane added in a small proportion, which was “very typical for treatment regimens at the time.”
A proportion of women with BRCA gene mutations that were found in the clinical setting had opted to have bilateral mastectomy (15% vs. 3% of noncarriers) “closely following or during their primary treatment diagnosis,” and a separate analysis showed an intriguing survival benefit among those who did not have bilateral mastectomy; survival was 2% better among those women at 5 and 10 years, again with a time-varying hazard, Dr. Eccles said, noting, however, that the study was not powered to show a difference in this measure.
“It’s intriguing that bilateral mastectomy after diagnosis does not seem to improve survival in these young gene carriers. These are very small numbers so we have to be careful, but this is good news for patients. Many patients believe that being a BRCA gene carrier, or even just having a family history is going to give them an adverse prognosis, and that’s clearly not true – and it’s also important that patients who are facing the difficult, difficult decisions around chemotherapy and breast cancer treatment don’t feel compelled to make a decision about bilateral mastectomy within that time shortly after their diagnosis and can reasonably reserve judgment about the extent of surgery until a later date,” she said.
She discussed her findings further in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – No difference in outcomes was seen among young BRCA gene mutation carriers and noncarriers with early-stage invasive breast cancer in a large cohort in the United Kingdom, but a subgroup analysis of those with triple-negative breast cancer showed a clear survival advantage among BRCA mutation carriers.
The findings of the POSH (Prospective Study of Outcomes in Sporadic Versus Hereditary Breast Cancer) trial have important implications for treatment decision making – particularly with respect to surgery – for younger women with breast cancer, according to Diana M. Eccles, MD, of the University of Southampton (England) and University Hospital Southampton Foundation Trust.
The overall finding of no difference in outcomes – including for the primary endpoint of overall survival and secondary endpoints of overall and distant disease-free survival – was true in both univariate and multivariable analysis of data for 2,759 women (14% with BRCA mutations), aged 40 years and younger, who were enrolled over an 8-year period, beginning in 2000, from 126 oncology centers across the United Kingdom, and who were followed for a median of 8.2 years, Dr. Eccles reported at the San Antonio Breast Cancer Symposium.
“We looked at BRCA1 and BRCA2 separately, and we still could see absolutely no difference in survival between BRCA1 and BRCA2, and we were well powered to show a difference,” she said, noting that 99% of these patients were diagnosed based on symptomatic presentation and did not know they were BRCA mutation carriers.
The findings were different among 511 patients with triple-negative breast cancer, however,
“Here we did see a clear difference in survival in favor of BRCA gene carriers – 11% at 10 years. And what was interesting was this clear time-varying hazard of relapse, with the maximum benefit of surviving in the BRCA gene carriers observed in the first few years with a hazard for relapse at 5 years equivalent between the two groups,” she said.
The primary treatment approach in these patients was no different than that in the group as a whole, Dr. Eccles noted, explaining that those with and without triple-negative disease had similar usage of breast conserving vs. unilateral surgery and similar usage of anthracycline-based chemotherapy regimens, with taxane added in a small proportion, which was “very typical for treatment regimens at the time.”
A proportion of women with BRCA gene mutations that were found in the clinical setting had opted to have bilateral mastectomy (15% vs. 3% of noncarriers) “closely following or during their primary treatment diagnosis,” and a separate analysis showed an intriguing survival benefit among those who did not have bilateral mastectomy; survival was 2% better among those women at 5 and 10 years, again with a time-varying hazard, Dr. Eccles said, noting, however, that the study was not powered to show a difference in this measure.
“It’s intriguing that bilateral mastectomy after diagnosis does not seem to improve survival in these young gene carriers. These are very small numbers so we have to be careful, but this is good news for patients. Many patients believe that being a BRCA gene carrier, or even just having a family history is going to give them an adverse prognosis, and that’s clearly not true – and it’s also important that patients who are facing the difficult, difficult decisions around chemotherapy and breast cancer treatment don’t feel compelled to make a decision about bilateral mastectomy within that time shortly after their diagnosis and can reasonably reserve judgment about the extent of surgery until a later date,” she said.
She discussed her findings further in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – No difference in outcomes was seen among young BRCA gene mutation carriers and noncarriers with early-stage invasive breast cancer in a large cohort in the United Kingdom, but a subgroup analysis of those with triple-negative breast cancer showed a clear survival advantage among BRCA mutation carriers.
The findings of the POSH (Prospective Study of Outcomes in Sporadic Versus Hereditary Breast Cancer) trial have important implications for treatment decision making – particularly with respect to surgery – for younger women with breast cancer, according to Diana M. Eccles, MD, of the University of Southampton (England) and University Hospital Southampton Foundation Trust.
The overall finding of no difference in outcomes – including for the primary endpoint of overall survival and secondary endpoints of overall and distant disease-free survival – was true in both univariate and multivariable analysis of data for 2,759 women (14% with BRCA mutations), aged 40 years and younger, who were enrolled over an 8-year period, beginning in 2000, from 126 oncology centers across the United Kingdom, and who were followed for a median of 8.2 years, Dr. Eccles reported at the San Antonio Breast Cancer Symposium.
“We looked at BRCA1 and BRCA2 separately, and we still could see absolutely no difference in survival between BRCA1 and BRCA2, and we were well powered to show a difference,” she said, noting that 99% of these patients were diagnosed based on symptomatic presentation and did not know they were BRCA mutation carriers.
The findings were different among 511 patients with triple-negative breast cancer, however,
“Here we did see a clear difference in survival in favor of BRCA gene carriers – 11% at 10 years. And what was interesting was this clear time-varying hazard of relapse, with the maximum benefit of surviving in the BRCA gene carriers observed in the first few years with a hazard for relapse at 5 years equivalent between the two groups,” she said.
The primary treatment approach in these patients was no different than that in the group as a whole, Dr. Eccles noted, explaining that those with and without triple-negative disease had similar usage of breast conserving vs. unilateral surgery and similar usage of anthracycline-based chemotherapy regimens, with taxane added in a small proportion, which was “very typical for treatment regimens at the time.”
A proportion of women with BRCA gene mutations that were found in the clinical setting had opted to have bilateral mastectomy (15% vs. 3% of noncarriers) “closely following or during their primary treatment diagnosis,” and a separate analysis showed an intriguing survival benefit among those who did not have bilateral mastectomy; survival was 2% better among those women at 5 and 10 years, again with a time-varying hazard, Dr. Eccles said, noting, however, that the study was not powered to show a difference in this measure.
“It’s intriguing that bilateral mastectomy after diagnosis does not seem to improve survival in these young gene carriers. These are very small numbers so we have to be careful, but this is good news for patients. Many patients believe that being a BRCA gene carrier, or even just having a family history is going to give them an adverse prognosis, and that’s clearly not true – and it’s also important that patients who are facing the difficult, difficult decisions around chemotherapy and breast cancer treatment don’t feel compelled to make a decision about bilateral mastectomy within that time shortly after their diagnosis and can reasonably reserve judgment about the extent of surgery until a later date,” she said.
She discussed her findings further in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SABCS 2016
Key clinical point:
Major finding: A significant 11% improvement in overall survival was seen among BRCA mutation carriers vs. noncarriers with triple-negative breast cancer.
Data source: The prospective POSH trial included 2,759 women with early-stage invasive breast cancer.
Disclosures: Dr. Eccles has been a consultant for AstraZeneca.
