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‘Fear and ignorance’ drive rise in bilateral mastectomy
SAN ANTONIO – The worldwide upsurge in bilateral mastectomy for unilateral breast cancer in the last decade came under withering fire from prominent breast surgeons at the San Antonio Breast Cancer Symposium.
“It seems crazy, doesn’t it, that we’re spending all this time trying to conserve the breast, yet we’re facing a tsunami of requests for bilateral mastectomy,” observed Dr. Fiona MacNeill, chairman of the education and training committee of the Royal College of Surgeons of England.
“A contralateral risk–reducing prophylactic mastectomy undoubtedly will reduce the risk of contralateral breast cancer, since you’re removing the breast, but this is overtreatment for the vast majority of women who request it. At 20 years we haven’t been able to demonstrate that it offers a significant survival advantage. I think a lot of what’s driving bilateral mastectomy is fear and ignorance, a failure to understand risk by patients and often by health professionals,” said Dr. MacNeill, a breast surgeon at Royal Marsden Hospital in London.
In an invited special lecture titled, “Less is more: minimizing breast cancer surgery,” Dr. MacNeill began by observing, “Only a surgeon could give this talk, because only a surgeon can tell you why we’re doing too much surgery.”
She stressed three main points: surgery is, as she put it, “a medieval treatment in a molecular era.” Overwhelming evidence shows that breast cancer outcomes are determined by disease biology, burden, and response to systemic therapy and not by the extent of surgery. And since there is no survival benefit for more aggressive surgery, the surgeon’s goal must be to optimize breast and axillary conservation.
In a separate presentation, Dr. Ismail Jatoi, professor and chief of surgical oncology at the University of Texas, San Antonio, outlined trends in surgical treatment of early-stage breast cancer as documented in a recent major retrospective study conducted in Tennessee of 1.2 million women treated at accredited U.S. breast cancer centers during 1998-2011.
The Tennessee investigators’ analysis points to a polarization in surgical therapy: The rate of unilateral mastectomy without reconstruction has dropped steadily since the beginning of the study period in 1998 among women eligible for breast-conserving surgery (BCS), while starting around 2006 the rate of bilateral mastectomy with reconstruction has surged. This increase in bilateral mastectomies with reconstruction resulted in an adjusted 34% jump in the overall mastectomy rate during 2004-2011 as compared with 1998-2003. As a result, in 2011 nearly 40% of women with early breast cancer underwent mastectomy. Meanwhile, the rate of BCS has been waning since 2006 (JAMA Surg. 2015 Jan;150[1]:9-16).
These disturbing trends have been fueled in part by at least eight published observational studies reporting improved survival with contralateral prophylactic mastectomy (CPM) as compared with unilateral mastectomy or BCS. But these were all observational studies and hence likely compromised by unmeasured confounders, according to Dr. Jatoi.
He presented highlights of his study of National Cancer Institute Surveillance, Epidemiology, and End Results data to support his recommendation that these observational studies be taken with a grain of salt.
His study included nearly 26,000 women who underwent CPM and more than 400,000 who did not. In a multivariate regression analysis adjusted for age, race, tumor stage, hormone receptor status, and histologic grade, CPM was associated with a statistically significant and impressive-sounding 16% reduction in the 5-year risk of breast cancer–specific mortality, a 17% reduction in overall mortality, and … a highly improbable 29% reduction in noncancer mortality (Breast Cancer Res Treat. 2014 Nov;148[2]:389-96).
“Obviously bilateral mastectomy is not going to reduce your risk of dying of heart attack or stroke or other noncancer causes. So even though we adjusted for everything possible in the SEER database, it suggests there were still unmeasured confounders. What this study shows is that it’s these unmeasured confounders that pose a threat to the validity of observational studies,” the surgeon said.
“Randomized data and observational studies consistently show that breast-conserving surgery is the optimal choice for most patients. It’s the safest choice, it’s cost effective, and it should remain in 2015 the optimal treatment for breast cancer,” he declared.
The cost-effectiveness of BCS was underscored during the symposium by means of a retrospective study presented by Dr. Benjamin D. Smith.
He and his coinvestigators analyzed costs and complication rates in the first 2 years following diagnosis of early-stage breast cancer in 44,344 patients under age 65 in the MarketScan database and almost 61,000 older women in the SEER-Medicare database.
The 2-year complication rate related to local therapy in younger breast cancer patients ranged from 30% for lumpectomy plus whole breast irradiation to 56% for mastectomy plus reconstruction. In older patients, the complication rates were 38% for lumpectomy plus whole breast irradiation and 69% for mastectomy plus reconstruction.
Adding together procedural and complication costs, the most expensive therapy in younger women was mastectomy with reconstruction, at an average of $89,140, which was $23,421 more than for lumpectomy plus whole breast irradiation, according to Dr. Smith, a radiation oncologist at MD Anderson Cancer Center in Houston.
“When oncologists offer all appropriate therapy options to patients, some women may choose to avoid radiation and opt for mastectomy and reconstruction instead. This study is helpful to such patients because it provides them with information regarding the trade-offs involved in this choice,” he explained.
Dr. MacNeill noted that in addition to the increased financial cost and physical complication rate entailed by mastectomy plus reconstruction for early breast cancer, this more aggressive surgery has another important unwelcome consequence: it delays the start of adjuvant therapy, which is the intervention that truly affects outcome.
Many women who opt for CPM do so because they can’t face the prospect of going through chemotherapy again should cancer arise in the contralateral breast. What’s often overlooked, she continued, is that the greatest risks of death or need for further systemic treatment due to relapse arise from the index cancer.
“We overestimate our patients’ contralateral risk, we underestimate the risk of dying from relapse of the index cancer, and we very often fail to consider other competing health risks from smoking, obesity, age, and other factors,” according to Dr. MacNeill.
“It’s not as if additional surgery is risk-free. A bilateral mastectomy carries bilateral complications. Our patients expect a perfect outcome because that’s what they see on television, but the reality is that for some women the results can be absolutely disastrous. Whilst women may not regret their choice for bilateral mastectomy with reconstruction because they think it’s lifesaving, the psychosexual impact is phenomenal,” she said.
That being said, Dr. MacNeill continued, “the elephant in the room” regarding BCS is that re-excision rates of up to 40% are common. This high rate of repeat surgery is a huge issue because of the resultant increased costs, morbidity, poor cosmesis, increased risk of mastectomy, and delay to adjuvant therapy.
High re-excision rates aren’t due to surgical incompetence, Dr. MacNeill stressed, but rather to the difficulty in defining microscopic disease intraoperatively. But help is on the way. Several novel approaches that facilitate lower re-excision rates and more breast conservation show considerable promise.
For example, investigators at Yale University have recently demonstrated in a randomized controlled trial that routine intraoperative cavity shave margins taken circumferentially halved the re-excision rate, from 21% to 10% (N Engl J Med. 2015 Aug 6;373[6]:503-10).
A meta-analysis of studies that included nearly 9,000 breast cancer patients who underwent BCS alone or BCS with oncoplastic breast conservation techniques concluded that the re-excision rate was just 4.3% in women who underwent oncoplastic breast conservation, compared with 14.6% with BCS alone (Ann Plast Surg. 2014 Feb;72[2]:145-9).
“This is going to be a driver for many breast cancer units to look at how they can use oncoplastic breast conservation to bring down their resection rates,” Dr. MacNeill predicted.
Neoadjuvant chemotherapy or endocrine therapy, a strategy in which surgery becomes adjuvant therapy, is likely to play an important role in facilitating breast conservation in the future. In the CALGB 40603 trial, for example, neoadjuvant chemotherapy in women with triple-negative breast cancer resulted in an absolute 14% increase in eligibility for BCS. Moreover, BCS was successful with no re-excision in 93% of treated patients (Ann Surg. 2015 Sep;262[3]:434-9).
The ‘less is more’ movement in breast cancer surgery may in the future mean no surgery at all in certain cases. Now underway in the United Kingdom is LORIS (the Low Risk DCIS Trial), in which women with low-risk DCIS are being randomized to surgery or 10 years of monitoring via annual mammograms.
“I’m suggesting that surgery may not exist in the longer term,” Dr. MacNeill said.
She, Dr. Jatoi, and Dr. Smith reported having no financial conflicts regarding their presentations. Dr. Smith’s study was supported by the Cancer Prevention and Research Institute of Texas, the Conquer Cancer Foundation, and the American Society for Radiation Oncology.
SAN ANTONIO – The worldwide upsurge in bilateral mastectomy for unilateral breast cancer in the last decade came under withering fire from prominent breast surgeons at the San Antonio Breast Cancer Symposium.
“It seems crazy, doesn’t it, that we’re spending all this time trying to conserve the breast, yet we’re facing a tsunami of requests for bilateral mastectomy,” observed Dr. Fiona MacNeill, chairman of the education and training committee of the Royal College of Surgeons of England.
“A contralateral risk–reducing prophylactic mastectomy undoubtedly will reduce the risk of contralateral breast cancer, since you’re removing the breast, but this is overtreatment for the vast majority of women who request it. At 20 years we haven’t been able to demonstrate that it offers a significant survival advantage. I think a lot of what’s driving bilateral mastectomy is fear and ignorance, a failure to understand risk by patients and often by health professionals,” said Dr. MacNeill, a breast surgeon at Royal Marsden Hospital in London.
In an invited special lecture titled, “Less is more: minimizing breast cancer surgery,” Dr. MacNeill began by observing, “Only a surgeon could give this talk, because only a surgeon can tell you why we’re doing too much surgery.”
She stressed three main points: surgery is, as she put it, “a medieval treatment in a molecular era.” Overwhelming evidence shows that breast cancer outcomes are determined by disease biology, burden, and response to systemic therapy and not by the extent of surgery. And since there is no survival benefit for more aggressive surgery, the surgeon’s goal must be to optimize breast and axillary conservation.
In a separate presentation, Dr. Ismail Jatoi, professor and chief of surgical oncology at the University of Texas, San Antonio, outlined trends in surgical treatment of early-stage breast cancer as documented in a recent major retrospective study conducted in Tennessee of 1.2 million women treated at accredited U.S. breast cancer centers during 1998-2011.
The Tennessee investigators’ analysis points to a polarization in surgical therapy: The rate of unilateral mastectomy without reconstruction has dropped steadily since the beginning of the study period in 1998 among women eligible for breast-conserving surgery (BCS), while starting around 2006 the rate of bilateral mastectomy with reconstruction has surged. This increase in bilateral mastectomies with reconstruction resulted in an adjusted 34% jump in the overall mastectomy rate during 2004-2011 as compared with 1998-2003. As a result, in 2011 nearly 40% of women with early breast cancer underwent mastectomy. Meanwhile, the rate of BCS has been waning since 2006 (JAMA Surg. 2015 Jan;150[1]:9-16).
These disturbing trends have been fueled in part by at least eight published observational studies reporting improved survival with contralateral prophylactic mastectomy (CPM) as compared with unilateral mastectomy or BCS. But these were all observational studies and hence likely compromised by unmeasured confounders, according to Dr. Jatoi.
He presented highlights of his study of National Cancer Institute Surveillance, Epidemiology, and End Results data to support his recommendation that these observational studies be taken with a grain of salt.
His study included nearly 26,000 women who underwent CPM and more than 400,000 who did not. In a multivariate regression analysis adjusted for age, race, tumor stage, hormone receptor status, and histologic grade, CPM was associated with a statistically significant and impressive-sounding 16% reduction in the 5-year risk of breast cancer–specific mortality, a 17% reduction in overall mortality, and … a highly improbable 29% reduction in noncancer mortality (Breast Cancer Res Treat. 2014 Nov;148[2]:389-96).
“Obviously bilateral mastectomy is not going to reduce your risk of dying of heart attack or stroke or other noncancer causes. So even though we adjusted for everything possible in the SEER database, it suggests there were still unmeasured confounders. What this study shows is that it’s these unmeasured confounders that pose a threat to the validity of observational studies,” the surgeon said.
“Randomized data and observational studies consistently show that breast-conserving surgery is the optimal choice for most patients. It’s the safest choice, it’s cost effective, and it should remain in 2015 the optimal treatment for breast cancer,” he declared.
The cost-effectiveness of BCS was underscored during the symposium by means of a retrospective study presented by Dr. Benjamin D. Smith.
He and his coinvestigators analyzed costs and complication rates in the first 2 years following diagnosis of early-stage breast cancer in 44,344 patients under age 65 in the MarketScan database and almost 61,000 older women in the SEER-Medicare database.
The 2-year complication rate related to local therapy in younger breast cancer patients ranged from 30% for lumpectomy plus whole breast irradiation to 56% for mastectomy plus reconstruction. In older patients, the complication rates were 38% for lumpectomy plus whole breast irradiation and 69% for mastectomy plus reconstruction.
Adding together procedural and complication costs, the most expensive therapy in younger women was mastectomy with reconstruction, at an average of $89,140, which was $23,421 more than for lumpectomy plus whole breast irradiation, according to Dr. Smith, a radiation oncologist at MD Anderson Cancer Center in Houston.
“When oncologists offer all appropriate therapy options to patients, some women may choose to avoid radiation and opt for mastectomy and reconstruction instead. This study is helpful to such patients because it provides them with information regarding the trade-offs involved in this choice,” he explained.
Dr. MacNeill noted that in addition to the increased financial cost and physical complication rate entailed by mastectomy plus reconstruction for early breast cancer, this more aggressive surgery has another important unwelcome consequence: it delays the start of adjuvant therapy, which is the intervention that truly affects outcome.
Many women who opt for CPM do so because they can’t face the prospect of going through chemotherapy again should cancer arise in the contralateral breast. What’s often overlooked, she continued, is that the greatest risks of death or need for further systemic treatment due to relapse arise from the index cancer.
“We overestimate our patients’ contralateral risk, we underestimate the risk of dying from relapse of the index cancer, and we very often fail to consider other competing health risks from smoking, obesity, age, and other factors,” according to Dr. MacNeill.
“It’s not as if additional surgery is risk-free. A bilateral mastectomy carries bilateral complications. Our patients expect a perfect outcome because that’s what they see on television, but the reality is that for some women the results can be absolutely disastrous. Whilst women may not regret their choice for bilateral mastectomy with reconstruction because they think it’s lifesaving, the psychosexual impact is phenomenal,” she said.
That being said, Dr. MacNeill continued, “the elephant in the room” regarding BCS is that re-excision rates of up to 40% are common. This high rate of repeat surgery is a huge issue because of the resultant increased costs, morbidity, poor cosmesis, increased risk of mastectomy, and delay to adjuvant therapy.
High re-excision rates aren’t due to surgical incompetence, Dr. MacNeill stressed, but rather to the difficulty in defining microscopic disease intraoperatively. But help is on the way. Several novel approaches that facilitate lower re-excision rates and more breast conservation show considerable promise.
For example, investigators at Yale University have recently demonstrated in a randomized controlled trial that routine intraoperative cavity shave margins taken circumferentially halved the re-excision rate, from 21% to 10% (N Engl J Med. 2015 Aug 6;373[6]:503-10).
A meta-analysis of studies that included nearly 9,000 breast cancer patients who underwent BCS alone or BCS with oncoplastic breast conservation techniques concluded that the re-excision rate was just 4.3% in women who underwent oncoplastic breast conservation, compared with 14.6% with BCS alone (Ann Plast Surg. 2014 Feb;72[2]:145-9).
“This is going to be a driver for many breast cancer units to look at how they can use oncoplastic breast conservation to bring down their resection rates,” Dr. MacNeill predicted.
Neoadjuvant chemotherapy or endocrine therapy, a strategy in which surgery becomes adjuvant therapy, is likely to play an important role in facilitating breast conservation in the future. In the CALGB 40603 trial, for example, neoadjuvant chemotherapy in women with triple-negative breast cancer resulted in an absolute 14% increase in eligibility for BCS. Moreover, BCS was successful with no re-excision in 93% of treated patients (Ann Surg. 2015 Sep;262[3]:434-9).
The ‘less is more’ movement in breast cancer surgery may in the future mean no surgery at all in certain cases. Now underway in the United Kingdom is LORIS (the Low Risk DCIS Trial), in which women with low-risk DCIS are being randomized to surgery or 10 years of monitoring via annual mammograms.
“I’m suggesting that surgery may not exist in the longer term,” Dr. MacNeill said.
She, Dr. Jatoi, and Dr. Smith reported having no financial conflicts regarding their presentations. Dr. Smith’s study was supported by the Cancer Prevention and Research Institute of Texas, the Conquer Cancer Foundation, and the American Society for Radiation Oncology.
SAN ANTONIO – The worldwide upsurge in bilateral mastectomy for unilateral breast cancer in the last decade came under withering fire from prominent breast surgeons at the San Antonio Breast Cancer Symposium.
“It seems crazy, doesn’t it, that we’re spending all this time trying to conserve the breast, yet we’re facing a tsunami of requests for bilateral mastectomy,” observed Dr. Fiona MacNeill, chairman of the education and training committee of the Royal College of Surgeons of England.
“A contralateral risk–reducing prophylactic mastectomy undoubtedly will reduce the risk of contralateral breast cancer, since you’re removing the breast, but this is overtreatment for the vast majority of women who request it. At 20 years we haven’t been able to demonstrate that it offers a significant survival advantage. I think a lot of what’s driving bilateral mastectomy is fear and ignorance, a failure to understand risk by patients and often by health professionals,” said Dr. MacNeill, a breast surgeon at Royal Marsden Hospital in London.
In an invited special lecture titled, “Less is more: minimizing breast cancer surgery,” Dr. MacNeill began by observing, “Only a surgeon could give this talk, because only a surgeon can tell you why we’re doing too much surgery.”
She stressed three main points: surgery is, as she put it, “a medieval treatment in a molecular era.” Overwhelming evidence shows that breast cancer outcomes are determined by disease biology, burden, and response to systemic therapy and not by the extent of surgery. And since there is no survival benefit for more aggressive surgery, the surgeon’s goal must be to optimize breast and axillary conservation.
In a separate presentation, Dr. Ismail Jatoi, professor and chief of surgical oncology at the University of Texas, San Antonio, outlined trends in surgical treatment of early-stage breast cancer as documented in a recent major retrospective study conducted in Tennessee of 1.2 million women treated at accredited U.S. breast cancer centers during 1998-2011.
The Tennessee investigators’ analysis points to a polarization in surgical therapy: The rate of unilateral mastectomy without reconstruction has dropped steadily since the beginning of the study period in 1998 among women eligible for breast-conserving surgery (BCS), while starting around 2006 the rate of bilateral mastectomy with reconstruction has surged. This increase in bilateral mastectomies with reconstruction resulted in an adjusted 34% jump in the overall mastectomy rate during 2004-2011 as compared with 1998-2003. As a result, in 2011 nearly 40% of women with early breast cancer underwent mastectomy. Meanwhile, the rate of BCS has been waning since 2006 (JAMA Surg. 2015 Jan;150[1]:9-16).
These disturbing trends have been fueled in part by at least eight published observational studies reporting improved survival with contralateral prophylactic mastectomy (CPM) as compared with unilateral mastectomy or BCS. But these were all observational studies and hence likely compromised by unmeasured confounders, according to Dr. Jatoi.
He presented highlights of his study of National Cancer Institute Surveillance, Epidemiology, and End Results data to support his recommendation that these observational studies be taken with a grain of salt.
His study included nearly 26,000 women who underwent CPM and more than 400,000 who did not. In a multivariate regression analysis adjusted for age, race, tumor stage, hormone receptor status, and histologic grade, CPM was associated with a statistically significant and impressive-sounding 16% reduction in the 5-year risk of breast cancer–specific mortality, a 17% reduction in overall mortality, and … a highly improbable 29% reduction in noncancer mortality (Breast Cancer Res Treat. 2014 Nov;148[2]:389-96).
“Obviously bilateral mastectomy is not going to reduce your risk of dying of heart attack or stroke or other noncancer causes. So even though we adjusted for everything possible in the SEER database, it suggests there were still unmeasured confounders. What this study shows is that it’s these unmeasured confounders that pose a threat to the validity of observational studies,” the surgeon said.
“Randomized data and observational studies consistently show that breast-conserving surgery is the optimal choice for most patients. It’s the safest choice, it’s cost effective, and it should remain in 2015 the optimal treatment for breast cancer,” he declared.
The cost-effectiveness of BCS was underscored during the symposium by means of a retrospective study presented by Dr. Benjamin D. Smith.
He and his coinvestigators analyzed costs and complication rates in the first 2 years following diagnosis of early-stage breast cancer in 44,344 patients under age 65 in the MarketScan database and almost 61,000 older women in the SEER-Medicare database.
The 2-year complication rate related to local therapy in younger breast cancer patients ranged from 30% for lumpectomy plus whole breast irradiation to 56% for mastectomy plus reconstruction. In older patients, the complication rates were 38% for lumpectomy plus whole breast irradiation and 69% for mastectomy plus reconstruction.
Adding together procedural and complication costs, the most expensive therapy in younger women was mastectomy with reconstruction, at an average of $89,140, which was $23,421 more than for lumpectomy plus whole breast irradiation, according to Dr. Smith, a radiation oncologist at MD Anderson Cancer Center in Houston.
“When oncologists offer all appropriate therapy options to patients, some women may choose to avoid radiation and opt for mastectomy and reconstruction instead. This study is helpful to such patients because it provides them with information regarding the trade-offs involved in this choice,” he explained.
Dr. MacNeill noted that in addition to the increased financial cost and physical complication rate entailed by mastectomy plus reconstruction for early breast cancer, this more aggressive surgery has another important unwelcome consequence: it delays the start of adjuvant therapy, which is the intervention that truly affects outcome.
Many women who opt for CPM do so because they can’t face the prospect of going through chemotherapy again should cancer arise in the contralateral breast. What’s often overlooked, she continued, is that the greatest risks of death or need for further systemic treatment due to relapse arise from the index cancer.
“We overestimate our patients’ contralateral risk, we underestimate the risk of dying from relapse of the index cancer, and we very often fail to consider other competing health risks from smoking, obesity, age, and other factors,” according to Dr. MacNeill.
“It’s not as if additional surgery is risk-free. A bilateral mastectomy carries bilateral complications. Our patients expect a perfect outcome because that’s what they see on television, but the reality is that for some women the results can be absolutely disastrous. Whilst women may not regret their choice for bilateral mastectomy with reconstruction because they think it’s lifesaving, the psychosexual impact is phenomenal,” she said.
That being said, Dr. MacNeill continued, “the elephant in the room” regarding BCS is that re-excision rates of up to 40% are common. This high rate of repeat surgery is a huge issue because of the resultant increased costs, morbidity, poor cosmesis, increased risk of mastectomy, and delay to adjuvant therapy.
High re-excision rates aren’t due to surgical incompetence, Dr. MacNeill stressed, but rather to the difficulty in defining microscopic disease intraoperatively. But help is on the way. Several novel approaches that facilitate lower re-excision rates and more breast conservation show considerable promise.
For example, investigators at Yale University have recently demonstrated in a randomized controlled trial that routine intraoperative cavity shave margins taken circumferentially halved the re-excision rate, from 21% to 10% (N Engl J Med. 2015 Aug 6;373[6]:503-10).
A meta-analysis of studies that included nearly 9,000 breast cancer patients who underwent BCS alone or BCS with oncoplastic breast conservation techniques concluded that the re-excision rate was just 4.3% in women who underwent oncoplastic breast conservation, compared with 14.6% with BCS alone (Ann Plast Surg. 2014 Feb;72[2]:145-9).
“This is going to be a driver for many breast cancer units to look at how they can use oncoplastic breast conservation to bring down their resection rates,” Dr. MacNeill predicted.
Neoadjuvant chemotherapy or endocrine therapy, a strategy in which surgery becomes adjuvant therapy, is likely to play an important role in facilitating breast conservation in the future. In the CALGB 40603 trial, for example, neoadjuvant chemotherapy in women with triple-negative breast cancer resulted in an absolute 14% increase in eligibility for BCS. Moreover, BCS was successful with no re-excision in 93% of treated patients (Ann Surg. 2015 Sep;262[3]:434-9).
The ‘less is more’ movement in breast cancer surgery may in the future mean no surgery at all in certain cases. Now underway in the United Kingdom is LORIS (the Low Risk DCIS Trial), in which women with low-risk DCIS are being randomized to surgery or 10 years of monitoring via annual mammograms.
“I’m suggesting that surgery may not exist in the longer term,” Dr. MacNeill said.
She, Dr. Jatoi, and Dr. Smith reported having no financial conflicts regarding their presentations. Dr. Smith’s study was supported by the Cancer Prevention and Research Institute of Texas, the Conquer Cancer Foundation, and the American Society for Radiation Oncology.
EXPERT ANALYSIS FROM SABCS 2015
Treatment failure reduced in Barrett’s esophagus with endoscopic mucosal resection
The use of endoscopic mucosal resection (EMR) before radiofrequency ablation significantly reduced the risk for treatment failure among patients with Barrett’s esophagus–associated intramucosal adenocarcinoma (IMC) and dysplasia, according to new data published in the American Journal of Surgical Pathology.
Complete eradication of IMC/dysplasia on the first follow-up endoscopy after treatment was achieved in 86% of patients, while durable eradication, defined as a complete recurrence that persisted until the last follow-up, was achieved in 78% of patients. However, there was significant variation between the different study sites (P = .03) and outcomes were significantly impacted by the baseline extent of IMC and the use of EMR prior to radiofrequency ablation (RFA) therapy.
In addition, almost a quarter of all patients developed treatment-related strictures, usually in the setting of multiple EMRs, and recurrence occurred as a malignant stricture in one patient.
Radiofrequency ablation used with or without EMR, is a safe, effective, and durable treatment option for the treatment of dysplasia associated with Barrett’s esophagus. However, studies that have assessed the predictors of treatment failure in Barrett’s esophagus-associated intramucosal adenocarcinoma (IMC) are limited.
In this study, Dr. Agoston T. Agoston of the department of pathology at Brigham and Women’s Hospital, Boston, and his colleagues investigated the rate of Barrett’s esophagus–associated IMC eradication when using RFA, with or without EMR, in a multicenter setting. In addition, they attempted to identify clinical and pathologic predictors of treatment failure.
“We anticipate that these data will have significant implications for a personalized treatment approach to patients with BE [Barrett’s esophagus]–associated IMC,” wrote the authors.
They conducted a retrospective review of medical records from four tertiary care academic medical centers, and identified 78 patients who underwent RFA with or without EMR as the primary treatment for biopsy-proven IMC.
Some notable baseline differences were observed in patient characteristics at the different study sites, including baseline Barrett’s esophagus segment length (P = .06), baseline nodularity (P = .08), and percentage of tissue involved by IMC at pretreatment endoscopy and biopsy (P = .01).
Over a mean follow-up time of 26.4 months (range, 2-116 months), 86% of patients achieved complete eradication and 78% durable eradication of IMC/dysplasia.
Within the cohort, 11 patients failed to achieve complete eradication, and of the 67 patients who initially did, 6 patients (9.0%) had a subsequent recurrence of neoplasia (3.91 recurrences per 100 patient-years). This extrapolated to an overall rate of 22% for treatment failure (17/78 patients). Of the 17 patients who failed the treatment, 3 subsequently underwent esophagectomy, 1 received palliative measures in the setting of advanced neurological disease, and 1 patient is currently undergoing a repeat ablation procedure with curative intent.
Dr. Agoston and his team also identified 2 clinicopathologic factors that were significantly associated with treatment failure, and both remained significant on univariate and multivariate analysis. The first was that the use of EMR prior to RFA was associated with a significantly reduced risk for treatment failure (hazard ratio, 0.15; 95% confidence interval, 0.05-0.48; P = .001), and the second was that the extent of IMC involving at least 50% of the columnar metaplastic area was associated with a significantly increased risk for treatment failure (HR, 4.24; 95% CI, 1.53-11.7; P = .005).
They also observed similar results when the analysis of extent of IMC as a predictor was restricted to a subset of 43 cases in which the diagnosis of IMC was made on EMR specimens only (HR, 10.8; 95% CI, 2.30-50.8; P = .003).
“In conclusion, we have identified endoscopic and pathologic factors associated with treatment success in patients with BE-associated IMC treated with RFA with or without EMR,” they wrote. “Utilization of these predictors can help in identifying patients with a high probability of success and also those patients with a higher risk for treatment failure for whom a more aggressive initial approach may be justified” (Am J Surg Pathol. 2015 Dec 5. doi: 10.1097/PAS.0000000000000566).
Dr. Rothstein and Dr. Abrams have received research support previously from Barrx/ Covidien and C2 Therapeutics/Covidien, respectively. None of the other authors reported significant conflicts of interest.
The use of endoscopic mucosal resection (EMR) before radiofrequency ablation significantly reduced the risk for treatment failure among patients with Barrett’s esophagus–associated intramucosal adenocarcinoma (IMC) and dysplasia, according to new data published in the American Journal of Surgical Pathology.
Complete eradication of IMC/dysplasia on the first follow-up endoscopy after treatment was achieved in 86% of patients, while durable eradication, defined as a complete recurrence that persisted until the last follow-up, was achieved in 78% of patients. However, there was significant variation between the different study sites (P = .03) and outcomes were significantly impacted by the baseline extent of IMC and the use of EMR prior to radiofrequency ablation (RFA) therapy.
In addition, almost a quarter of all patients developed treatment-related strictures, usually in the setting of multiple EMRs, and recurrence occurred as a malignant stricture in one patient.
Radiofrequency ablation used with or without EMR, is a safe, effective, and durable treatment option for the treatment of dysplasia associated with Barrett’s esophagus. However, studies that have assessed the predictors of treatment failure in Barrett’s esophagus-associated intramucosal adenocarcinoma (IMC) are limited.
In this study, Dr. Agoston T. Agoston of the department of pathology at Brigham and Women’s Hospital, Boston, and his colleagues investigated the rate of Barrett’s esophagus–associated IMC eradication when using RFA, with or without EMR, in a multicenter setting. In addition, they attempted to identify clinical and pathologic predictors of treatment failure.
“We anticipate that these data will have significant implications for a personalized treatment approach to patients with BE [Barrett’s esophagus]–associated IMC,” wrote the authors.
They conducted a retrospective review of medical records from four tertiary care academic medical centers, and identified 78 patients who underwent RFA with or without EMR as the primary treatment for biopsy-proven IMC.
Some notable baseline differences were observed in patient characteristics at the different study sites, including baseline Barrett’s esophagus segment length (P = .06), baseline nodularity (P = .08), and percentage of tissue involved by IMC at pretreatment endoscopy and biopsy (P = .01).
Over a mean follow-up time of 26.4 months (range, 2-116 months), 86% of patients achieved complete eradication and 78% durable eradication of IMC/dysplasia.
Within the cohort, 11 patients failed to achieve complete eradication, and of the 67 patients who initially did, 6 patients (9.0%) had a subsequent recurrence of neoplasia (3.91 recurrences per 100 patient-years). This extrapolated to an overall rate of 22% for treatment failure (17/78 patients). Of the 17 patients who failed the treatment, 3 subsequently underwent esophagectomy, 1 received palliative measures in the setting of advanced neurological disease, and 1 patient is currently undergoing a repeat ablation procedure with curative intent.
Dr. Agoston and his team also identified 2 clinicopathologic factors that were significantly associated with treatment failure, and both remained significant on univariate and multivariate analysis. The first was that the use of EMR prior to RFA was associated with a significantly reduced risk for treatment failure (hazard ratio, 0.15; 95% confidence interval, 0.05-0.48; P = .001), and the second was that the extent of IMC involving at least 50% of the columnar metaplastic area was associated with a significantly increased risk for treatment failure (HR, 4.24; 95% CI, 1.53-11.7; P = .005).
They also observed similar results when the analysis of extent of IMC as a predictor was restricted to a subset of 43 cases in which the diagnosis of IMC was made on EMR specimens only (HR, 10.8; 95% CI, 2.30-50.8; P = .003).
“In conclusion, we have identified endoscopic and pathologic factors associated with treatment success in patients with BE-associated IMC treated with RFA with or without EMR,” they wrote. “Utilization of these predictors can help in identifying patients with a high probability of success and also those patients with a higher risk for treatment failure for whom a more aggressive initial approach may be justified” (Am J Surg Pathol. 2015 Dec 5. doi: 10.1097/PAS.0000000000000566).
Dr. Rothstein and Dr. Abrams have received research support previously from Barrx/ Covidien and C2 Therapeutics/Covidien, respectively. None of the other authors reported significant conflicts of interest.
The use of endoscopic mucosal resection (EMR) before radiofrequency ablation significantly reduced the risk for treatment failure among patients with Barrett’s esophagus–associated intramucosal adenocarcinoma (IMC) and dysplasia, according to new data published in the American Journal of Surgical Pathology.
Complete eradication of IMC/dysplasia on the first follow-up endoscopy after treatment was achieved in 86% of patients, while durable eradication, defined as a complete recurrence that persisted until the last follow-up, was achieved in 78% of patients. However, there was significant variation between the different study sites (P = .03) and outcomes were significantly impacted by the baseline extent of IMC and the use of EMR prior to radiofrequency ablation (RFA) therapy.
In addition, almost a quarter of all patients developed treatment-related strictures, usually in the setting of multiple EMRs, and recurrence occurred as a malignant stricture in one patient.
Radiofrequency ablation used with or without EMR, is a safe, effective, and durable treatment option for the treatment of dysplasia associated with Barrett’s esophagus. However, studies that have assessed the predictors of treatment failure in Barrett’s esophagus-associated intramucosal adenocarcinoma (IMC) are limited.
In this study, Dr. Agoston T. Agoston of the department of pathology at Brigham and Women’s Hospital, Boston, and his colleagues investigated the rate of Barrett’s esophagus–associated IMC eradication when using RFA, with or without EMR, in a multicenter setting. In addition, they attempted to identify clinical and pathologic predictors of treatment failure.
“We anticipate that these data will have significant implications for a personalized treatment approach to patients with BE [Barrett’s esophagus]–associated IMC,” wrote the authors.
They conducted a retrospective review of medical records from four tertiary care academic medical centers, and identified 78 patients who underwent RFA with or without EMR as the primary treatment for biopsy-proven IMC.
Some notable baseline differences were observed in patient characteristics at the different study sites, including baseline Barrett’s esophagus segment length (P = .06), baseline nodularity (P = .08), and percentage of tissue involved by IMC at pretreatment endoscopy and biopsy (P = .01).
Over a mean follow-up time of 26.4 months (range, 2-116 months), 86% of patients achieved complete eradication and 78% durable eradication of IMC/dysplasia.
Within the cohort, 11 patients failed to achieve complete eradication, and of the 67 patients who initially did, 6 patients (9.0%) had a subsequent recurrence of neoplasia (3.91 recurrences per 100 patient-years). This extrapolated to an overall rate of 22% for treatment failure (17/78 patients). Of the 17 patients who failed the treatment, 3 subsequently underwent esophagectomy, 1 received palliative measures in the setting of advanced neurological disease, and 1 patient is currently undergoing a repeat ablation procedure with curative intent.
Dr. Agoston and his team also identified 2 clinicopathologic factors that were significantly associated with treatment failure, and both remained significant on univariate and multivariate analysis. The first was that the use of EMR prior to RFA was associated with a significantly reduced risk for treatment failure (hazard ratio, 0.15; 95% confidence interval, 0.05-0.48; P = .001), and the second was that the extent of IMC involving at least 50% of the columnar metaplastic area was associated with a significantly increased risk for treatment failure (HR, 4.24; 95% CI, 1.53-11.7; P = .005).
They also observed similar results when the analysis of extent of IMC as a predictor was restricted to a subset of 43 cases in which the diagnosis of IMC was made on EMR specimens only (HR, 10.8; 95% CI, 2.30-50.8; P = .003).
“In conclusion, we have identified endoscopic and pathologic factors associated with treatment success in patients with BE-associated IMC treated with RFA with or without EMR,” they wrote. “Utilization of these predictors can help in identifying patients with a high probability of success and also those patients with a higher risk for treatment failure for whom a more aggressive initial approach may be justified” (Am J Surg Pathol. 2015 Dec 5. doi: 10.1097/PAS.0000000000000566).
Dr. Rothstein and Dr. Abrams have received research support previously from Barrx/ Covidien and C2 Therapeutics/Covidien, respectively. None of the other authors reported significant conflicts of interest.
FROM THE AMERICAN JOURNAL OF SURGICAL PATHOLOGY
Key clinical point: The use of EMR before radiofrequency ablation significantly reduced the risk for treatment failure for IMC associated with Barrett’s esophagus.
Major finding: The overall rate of complete and durable IMC eradication in Barrett’s esophagus was 86% and 78%, respectively, during a mean follow-up of about 2 years, but was significantly impacted by the baseline extent of IMC and the use of EMR.
Data source: A retrospective review of data from four tertiary care academic medical centers that included 78 patients and was conducted to determine the rate of IMC eradication when using RFA and EMR.
Disclosures: Dr. Rothstein and Dr. Abrams have received research support previously from Barrx/ Covidien and C2 Therapeutics/Covidien, respectively. None of the other authors reported significant conflicts of interest.
ESR1 mutations linked with poorer survival from ER-positive breast cancer
SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.
Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.
Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.
Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.
“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.
Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.
There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.
In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.
“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.
The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.
Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”
Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.
BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.
Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.
In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).
Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).
In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).
Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.
Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.
SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.
Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.
Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.
Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.
“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.
Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.
There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.
In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.
“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.
The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.
Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”
Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.
BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.
Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.
In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).
Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).
In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).
Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.
Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.
SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.
Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.
Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.
Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.
“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.
Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.
There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.
In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.
“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.
The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.
Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”
Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.
BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.
Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.
In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).
Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).
In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).
Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.
Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.
AT SABCS 2015
Key clinical point: Women with estrogen receptor–positive advanced breast cancer who have an ESR1 mutation are at increased risk for death.
Major finding: Median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both mutations.
Data source: An exploratory analysis of plasma cell–free DNA from 541 patients in a phase III trial evaluating everolimus plus exemestane (BOLERO-2 trial).
Disclosures: Dr. Chandarlapaty disclosed that he receives consulting fees from Chugai, Foresite Capital, and Oncothyreon, and receives grant support from Novartis. The study was supported by Novartis and the Memorial Sloan Kettering Cancer Center’s Center for Metastasis Research.
Neratinib shows consistent breast cancer benefit at 3 years
SAN ANTONIO – The investigational oral tyrosine kinase inhibitor neratinib showed continued benefit in terms of reduced invasive disease-free survival at 3 years of follow-up in women with early-stage HER2-positive breast cancer in the randomized, double-blind ExteNET trial, Dr. Arlene Chan reported at the San Antonio Breast Cancer Symposium.
The 3-year analysis was not prespecified. It was performed because she and her coinvestigators were concerned that the previously reported benefit seen at 2 years might be lost with longer follow-up, as has occurred with trastuzumab (Herceptin) in the landmark HERA (HERceptin Adjuvant) trial. Reassuringly, however, the absolute 2.3% benefit for neratinib compared to placebo seen at 2 years in ExteNET was maintained at 3 years in the updated analysis, where the absolute difference remained essentially unchanged at 2.1%, according to Dr. Chan, vice chair of the Breast Cancer Research Center of Western Australia in Perth.
Moreover, most patients have reached the 4-year mark in follow-up, where the invasive disease-free survival benefit has remained significant in favor of neratinib at 90.5% versus 88.6% with placebo, she added.
ExteNET was a large international trial of 2,840 women with stage II-IIIc HER2-positive breast cancer with node-positive disease who were randomized to oral neratinib at 240 mg/day or placebo for 1 year beginning an average of 4.4 months after completing adjuvant chemotherapy and 1 year of trastuzumab.
The impetus for ExteNET was the well-established observation that relapse occurs in up to 26% of trastuzumab-treated patients at 8-plus years of follow-up. The study hypothesis is that neratinib, a tyrosine kinase inhibitor of HER1, –2, and –4, will prevent or delay disease recurrence because it attacks the cancer through a mechanism of action different from that of trastuzumab.
At 2 years of follow-up post neratinib, the invasive disease-free survival rate was 93.9% with active therapy and 91.6% with placebo, as previously reported by Dr. Chan. At 3 years in the roughly 85% of patients who remained in the study, which changed sponsors in the interim, the rates were 92% and 89.9%.
The 3-year outcomes were most robust in patients who began neratinib less than 1 year after completing trastuzumab and who were hormone receptor positive. In this subgroup, the 3-year invasive disease-free survival rate was 93.3% with neratinib versus 88.6% with placebo. That, Dr. Chan said, is the scenario where delayed adjuvant neratinib might prove beneficial in clinical practice.
Patients with hormone receptor–negative disease didn’t benefit from neratinib.
Forty percent of patients on neratinib developed grade 3 diarrhea, the agent’s major side effect and one that is a class effect with the tyrosine kinase inhibitors. Most cases occurred within the first 30 days of treatment and lasted for a median of 5 days, with 1.4% of neratinib-treated patients being hospitalized for this complication.
Dr. Chan noted that the study protocol precluded prophylaxis with loperamide during the first month of neratinib, which has been shown by other investigators to markedly reduce the frequency and severity of diarrhea.
Another ExteNET follow-up is planned at the 5-year mark.
Audience members asked how the Food and Drug Administration’s approval of pertuzumab (Perjeta) with indications for neoadjuvant treatment of HER2-positive breast cancer as well as for metastatic disease will change the prospects for neratinib.
Dr. Chan replied that, like other medical oncologists, she’s eagerly awaiting the results of the APHINITY trial, which is testing adjuvant pertuzumab versus placebo on top of chemotherapy plus trastuzumab in women with HER2-positive disease.
“I would suspect that even if APHINITY is positive, there will be patients who will still have a risk of relapse, so we still won’t be curing all HER2-positive patients,” she said, adding that a new clinical trial would be required in order to establish that neratinib is of benefit in such individuals.
SAN ANTONIO – The investigational oral tyrosine kinase inhibitor neratinib showed continued benefit in terms of reduced invasive disease-free survival at 3 years of follow-up in women with early-stage HER2-positive breast cancer in the randomized, double-blind ExteNET trial, Dr. Arlene Chan reported at the San Antonio Breast Cancer Symposium.
The 3-year analysis was not prespecified. It was performed because she and her coinvestigators were concerned that the previously reported benefit seen at 2 years might be lost with longer follow-up, as has occurred with trastuzumab (Herceptin) in the landmark HERA (HERceptin Adjuvant) trial. Reassuringly, however, the absolute 2.3% benefit for neratinib compared to placebo seen at 2 years in ExteNET was maintained at 3 years in the updated analysis, where the absolute difference remained essentially unchanged at 2.1%, according to Dr. Chan, vice chair of the Breast Cancer Research Center of Western Australia in Perth.
Moreover, most patients have reached the 4-year mark in follow-up, where the invasive disease-free survival benefit has remained significant in favor of neratinib at 90.5% versus 88.6% with placebo, she added.
ExteNET was a large international trial of 2,840 women with stage II-IIIc HER2-positive breast cancer with node-positive disease who were randomized to oral neratinib at 240 mg/day or placebo for 1 year beginning an average of 4.4 months after completing adjuvant chemotherapy and 1 year of trastuzumab.
The impetus for ExteNET was the well-established observation that relapse occurs in up to 26% of trastuzumab-treated patients at 8-plus years of follow-up. The study hypothesis is that neratinib, a tyrosine kinase inhibitor of HER1, –2, and –4, will prevent or delay disease recurrence because it attacks the cancer through a mechanism of action different from that of trastuzumab.
At 2 years of follow-up post neratinib, the invasive disease-free survival rate was 93.9% with active therapy and 91.6% with placebo, as previously reported by Dr. Chan. At 3 years in the roughly 85% of patients who remained in the study, which changed sponsors in the interim, the rates were 92% and 89.9%.
The 3-year outcomes were most robust in patients who began neratinib less than 1 year after completing trastuzumab and who were hormone receptor positive. In this subgroup, the 3-year invasive disease-free survival rate was 93.3% with neratinib versus 88.6% with placebo. That, Dr. Chan said, is the scenario where delayed adjuvant neratinib might prove beneficial in clinical practice.
Patients with hormone receptor–negative disease didn’t benefit from neratinib.
Forty percent of patients on neratinib developed grade 3 diarrhea, the agent’s major side effect and one that is a class effect with the tyrosine kinase inhibitors. Most cases occurred within the first 30 days of treatment and lasted for a median of 5 days, with 1.4% of neratinib-treated patients being hospitalized for this complication.
Dr. Chan noted that the study protocol precluded prophylaxis with loperamide during the first month of neratinib, which has been shown by other investigators to markedly reduce the frequency and severity of diarrhea.
Another ExteNET follow-up is planned at the 5-year mark.
Audience members asked how the Food and Drug Administration’s approval of pertuzumab (Perjeta) with indications for neoadjuvant treatment of HER2-positive breast cancer as well as for metastatic disease will change the prospects for neratinib.
Dr. Chan replied that, like other medical oncologists, she’s eagerly awaiting the results of the APHINITY trial, which is testing adjuvant pertuzumab versus placebo on top of chemotherapy plus trastuzumab in women with HER2-positive disease.
“I would suspect that even if APHINITY is positive, there will be patients who will still have a risk of relapse, so we still won’t be curing all HER2-positive patients,” she said, adding that a new clinical trial would be required in order to establish that neratinib is of benefit in such individuals.
SAN ANTONIO – The investigational oral tyrosine kinase inhibitor neratinib showed continued benefit in terms of reduced invasive disease-free survival at 3 years of follow-up in women with early-stage HER2-positive breast cancer in the randomized, double-blind ExteNET trial, Dr. Arlene Chan reported at the San Antonio Breast Cancer Symposium.
The 3-year analysis was not prespecified. It was performed because she and her coinvestigators were concerned that the previously reported benefit seen at 2 years might be lost with longer follow-up, as has occurred with trastuzumab (Herceptin) in the landmark HERA (HERceptin Adjuvant) trial. Reassuringly, however, the absolute 2.3% benefit for neratinib compared to placebo seen at 2 years in ExteNET was maintained at 3 years in the updated analysis, where the absolute difference remained essentially unchanged at 2.1%, according to Dr. Chan, vice chair of the Breast Cancer Research Center of Western Australia in Perth.
Moreover, most patients have reached the 4-year mark in follow-up, where the invasive disease-free survival benefit has remained significant in favor of neratinib at 90.5% versus 88.6% with placebo, she added.
ExteNET was a large international trial of 2,840 women with stage II-IIIc HER2-positive breast cancer with node-positive disease who were randomized to oral neratinib at 240 mg/day or placebo for 1 year beginning an average of 4.4 months after completing adjuvant chemotherapy and 1 year of trastuzumab.
The impetus for ExteNET was the well-established observation that relapse occurs in up to 26% of trastuzumab-treated patients at 8-plus years of follow-up. The study hypothesis is that neratinib, a tyrosine kinase inhibitor of HER1, –2, and –4, will prevent or delay disease recurrence because it attacks the cancer through a mechanism of action different from that of trastuzumab.
At 2 years of follow-up post neratinib, the invasive disease-free survival rate was 93.9% with active therapy and 91.6% with placebo, as previously reported by Dr. Chan. At 3 years in the roughly 85% of patients who remained in the study, which changed sponsors in the interim, the rates were 92% and 89.9%.
The 3-year outcomes were most robust in patients who began neratinib less than 1 year after completing trastuzumab and who were hormone receptor positive. In this subgroup, the 3-year invasive disease-free survival rate was 93.3% with neratinib versus 88.6% with placebo. That, Dr. Chan said, is the scenario where delayed adjuvant neratinib might prove beneficial in clinical practice.
Patients with hormone receptor–negative disease didn’t benefit from neratinib.
Forty percent of patients on neratinib developed grade 3 diarrhea, the agent’s major side effect and one that is a class effect with the tyrosine kinase inhibitors. Most cases occurred within the first 30 days of treatment and lasted for a median of 5 days, with 1.4% of neratinib-treated patients being hospitalized for this complication.
Dr. Chan noted that the study protocol precluded prophylaxis with loperamide during the first month of neratinib, which has been shown by other investigators to markedly reduce the frequency and severity of diarrhea.
Another ExteNET follow-up is planned at the 5-year mark.
Audience members asked how the Food and Drug Administration’s approval of pertuzumab (Perjeta) with indications for neoadjuvant treatment of HER2-positive breast cancer as well as for metastatic disease will change the prospects for neratinib.
Dr. Chan replied that, like other medical oncologists, she’s eagerly awaiting the results of the APHINITY trial, which is testing adjuvant pertuzumab versus placebo on top of chemotherapy plus trastuzumab in women with HER2-positive disease.
“I would suspect that even if APHINITY is positive, there will be patients who will still have a risk of relapse, so we still won’t be curing all HER2-positive patients,” she said, adding that a new clinical trial would be required in order to establish that neratinib is of benefit in such individuals.
AT SABCS 2015
Key clinical point: The significant benefit of delayed adjuvant neratinib following chemotherapy and trastuzumab remains unabated at 3 years’ follow-up in women with HER2-positive breast cancer.
Major finding: At 3 years of follow-up in a large randomized trial in women with HER2-positive breast cancer, the invasive disease-free survival rate remained significantly higher with delayed adjuvant neratinib than with placebo by a margin of 92% versus 89.1%.
Data source: ExteNET, a double-blind clinical trial of 2,840 women with stage II-IIIc HER2-positive breast cancer with node-positive disease who were randomized to oral neratinib at 240 mg/day or placebo for 1 year following completion of adjuvant chemotherapy and 1 year of trastuzumab.
Disclosures: Puma Biotechnology sponsored the trial. The presenter reported serving as a consultant to Pfizer, Amgen, and Eisai.
TH3RESA: T-DM1 prolongs survival in heavily pretreated HER2-positive breast cancer
SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.
“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.
T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.
“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.
Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”
About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.
“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”
The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.
The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.
The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).
“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.
The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).
Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.
The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.
Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.
“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”
SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.
“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.
T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.
“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.
Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”
About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.
“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”
The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.
The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.
The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).
“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.
The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).
Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.
The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.
Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.
“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”
SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.
“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.
T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.
“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.
Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”
About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.
“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”
The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.
The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.
The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).
“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.
The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).
Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.
The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.
Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.
“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”
AT SABCS 2015
Key clinical point: T-DM1 is safe and efficacious for treating heavily pretreated HER2-positive breast cancer.
Major finding: The median overall survival was 22.7 months with T-DM1 vs. 15.8 months with the treatment of a physician’s choice.
Data source: A randomized phase III trial in 602 patients with heavily pretreated HER2-positive breast cancer (TH3RESA trial).
Disclosures: Dr. Wildiers disclosed that his institution has received compensation from Roche for lectures he has presented at national meetings and for consulting work, as well as an unrestricted research grant for academic research. The trial was supported by Roche.
Beta-blocker prevents trastuzumab-related LVEF drop
SAN ANTONIO – Prophylactic beta-blockade with bisoprolol during adjuvant trastuzumab therapy for HER2-positive breast cancer prevented trastuzumab-induced decline in left ventricular ejection fraction in MANTICORE, a randomized trial presented at the San Antonio Breast Cancer Symposium.
“MANTICORE provides the first intervention proven in a randomized, double-blind, placebo-controlled, multicenter way to be an effective means of preventing trastuzumab-associated left ventricular dysfunction,” said Edith Pituskin, Ph.D., of the University of Alberta, Edmonton.
MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) randomized 99 patients with HER2-positive early breast cancer and a normal-range left ventricular ejection fraction (LVEF) at baseline to bisoprolol (Zebeta), the ACE inhibitor perindopril (Aceon), or placebo shortly before starting a planned 1-year course of adjuvant trastuzumab (Herceptin). The patients had low background levels of cardiovascular risk factors. Roughly three-quarters of subjects were able to titrate up to the target dose of 10 mg once daily for bisoprolol or 8 mg once daily for perindopril.
Cardiac MRI assessments at baseline, 3, and 12 months – the point when trastuzumab and the cardioprotective medications were stopped – showed that neither bisoprolol nor perindopril prevented trastuzumab-related left ventricular remodeling, which was a disappointment, given that this was the prespecified primary endpoint.
“Our results hint that, potentially, trastuzumab exposure–related left ventricular remodeling is not reversible,” Dr. Pituskin said.
The average reduction from baseline in LVEF over the course of a year of adjuvant trastuzumab therapy was 5% with placebo, 3% with perindopril, and 1% with bisoprolol, with the differences between bisoprolol and the other two study arms being highly statistically significant.
On the plus side, both of the once-daily cardiac medications displayed an important side benefit in MANTICORE: an eightfold reduction in the number of interruptions of trastuzumab therapy mandated by a significant drop in LVEF. There were eight such interruptions in the control group versus one each in the bisoprolol and perindopril arms. That’s of practical value in terms of patient convenience, cost of care, and possibly even the efficacy of the adjuvant cancer regimen, she noted.
Audience members raised several questions: what’s the clinical significance of the asymptomatic reduction in LVEF seen in the control group in MANTICORE? Does it place affected patients at risk for overt heart failure as time passes? And since LVEF is just one aspect of cardiac function, isn’t it possible that the cardiac medications were simply propping up LVEF while the underlying cardiotoxic effects of trastuzumab remained unchecked, such that the LVEF will drop once patients are off therapy?
Dr. Pituskin replied that these are good questions, the answers to which may be forthcoming at the planned follow-up cardiac MRI to be conducted at 24 months, a full year after discontinuation of the therapies.
Asked to compare the MANTICORE findings with those of the PRADA trial presented at this year’s annual meeting of the American Heart Association, in which an LVEF drop in breast cancer patients on adjuvant anthracycline and trastuzumab was prevented by prophylactic use of the angiotensin receptor blocker candesartan (Atacand) but not the beta-blocker metoprolol, Dr. Pituskin said she can’t make a definitive comparison until PRADA is published, but that it’s her understanding PRADA was a single-center trial without serial cardiac MRIs, and it included many more participants on an anthracycline-containing regimen, long recognized as a major hazard in terms of cardiotoxicity, and one thought to have a different cardiotoxic mechanism than trastuzumab.
By way of background, she noted that roughly 20% of women with breast cancer have HER2 receptor–overexpressing tumors. In such patients it’s well established that trastuzumab reduces mortality by one-third. However, it’s also well established that one in five patients on trastuzumab experience left ventricular dysfunction, and 1%-5% of patients develop heart failure, an “extremely devastating” complication carrying a 50% 5-year mortality. Beta-blockers and ACE inhibitors or angiotensin receptor blockers are standard, guideline-recommended treatments for patients with established heart failure.
SAN ANTONIO – Prophylactic beta-blockade with bisoprolol during adjuvant trastuzumab therapy for HER2-positive breast cancer prevented trastuzumab-induced decline in left ventricular ejection fraction in MANTICORE, a randomized trial presented at the San Antonio Breast Cancer Symposium.
“MANTICORE provides the first intervention proven in a randomized, double-blind, placebo-controlled, multicenter way to be an effective means of preventing trastuzumab-associated left ventricular dysfunction,” said Edith Pituskin, Ph.D., of the University of Alberta, Edmonton.
MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) randomized 99 patients with HER2-positive early breast cancer and a normal-range left ventricular ejection fraction (LVEF) at baseline to bisoprolol (Zebeta), the ACE inhibitor perindopril (Aceon), or placebo shortly before starting a planned 1-year course of adjuvant trastuzumab (Herceptin). The patients had low background levels of cardiovascular risk factors. Roughly three-quarters of subjects were able to titrate up to the target dose of 10 mg once daily for bisoprolol or 8 mg once daily for perindopril.
Cardiac MRI assessments at baseline, 3, and 12 months – the point when trastuzumab and the cardioprotective medications were stopped – showed that neither bisoprolol nor perindopril prevented trastuzumab-related left ventricular remodeling, which was a disappointment, given that this was the prespecified primary endpoint.
“Our results hint that, potentially, trastuzumab exposure–related left ventricular remodeling is not reversible,” Dr. Pituskin said.
The average reduction from baseline in LVEF over the course of a year of adjuvant trastuzumab therapy was 5% with placebo, 3% with perindopril, and 1% with bisoprolol, with the differences between bisoprolol and the other two study arms being highly statistically significant.
On the plus side, both of the once-daily cardiac medications displayed an important side benefit in MANTICORE: an eightfold reduction in the number of interruptions of trastuzumab therapy mandated by a significant drop in LVEF. There were eight such interruptions in the control group versus one each in the bisoprolol and perindopril arms. That’s of practical value in terms of patient convenience, cost of care, and possibly even the efficacy of the adjuvant cancer regimen, she noted.
Audience members raised several questions: what’s the clinical significance of the asymptomatic reduction in LVEF seen in the control group in MANTICORE? Does it place affected patients at risk for overt heart failure as time passes? And since LVEF is just one aspect of cardiac function, isn’t it possible that the cardiac medications were simply propping up LVEF while the underlying cardiotoxic effects of trastuzumab remained unchecked, such that the LVEF will drop once patients are off therapy?
Dr. Pituskin replied that these are good questions, the answers to which may be forthcoming at the planned follow-up cardiac MRI to be conducted at 24 months, a full year after discontinuation of the therapies.
Asked to compare the MANTICORE findings with those of the PRADA trial presented at this year’s annual meeting of the American Heart Association, in which an LVEF drop in breast cancer patients on adjuvant anthracycline and trastuzumab was prevented by prophylactic use of the angiotensin receptor blocker candesartan (Atacand) but not the beta-blocker metoprolol, Dr. Pituskin said she can’t make a definitive comparison until PRADA is published, but that it’s her understanding PRADA was a single-center trial without serial cardiac MRIs, and it included many more participants on an anthracycline-containing regimen, long recognized as a major hazard in terms of cardiotoxicity, and one thought to have a different cardiotoxic mechanism than trastuzumab.
By way of background, she noted that roughly 20% of women with breast cancer have HER2 receptor–overexpressing tumors. In such patients it’s well established that trastuzumab reduces mortality by one-third. However, it’s also well established that one in five patients on trastuzumab experience left ventricular dysfunction, and 1%-5% of patients develop heart failure, an “extremely devastating” complication carrying a 50% 5-year mortality. Beta-blockers and ACE inhibitors or angiotensin receptor blockers are standard, guideline-recommended treatments for patients with established heart failure.
SAN ANTONIO – Prophylactic beta-blockade with bisoprolol during adjuvant trastuzumab therapy for HER2-positive breast cancer prevented trastuzumab-induced decline in left ventricular ejection fraction in MANTICORE, a randomized trial presented at the San Antonio Breast Cancer Symposium.
“MANTICORE provides the first intervention proven in a randomized, double-blind, placebo-controlled, multicenter way to be an effective means of preventing trastuzumab-associated left ventricular dysfunction,” said Edith Pituskin, Ph.D., of the University of Alberta, Edmonton.
MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) randomized 99 patients with HER2-positive early breast cancer and a normal-range left ventricular ejection fraction (LVEF) at baseline to bisoprolol (Zebeta), the ACE inhibitor perindopril (Aceon), or placebo shortly before starting a planned 1-year course of adjuvant trastuzumab (Herceptin). The patients had low background levels of cardiovascular risk factors. Roughly three-quarters of subjects were able to titrate up to the target dose of 10 mg once daily for bisoprolol or 8 mg once daily for perindopril.
Cardiac MRI assessments at baseline, 3, and 12 months – the point when trastuzumab and the cardioprotective medications were stopped – showed that neither bisoprolol nor perindopril prevented trastuzumab-related left ventricular remodeling, which was a disappointment, given that this was the prespecified primary endpoint.
“Our results hint that, potentially, trastuzumab exposure–related left ventricular remodeling is not reversible,” Dr. Pituskin said.
The average reduction from baseline in LVEF over the course of a year of adjuvant trastuzumab therapy was 5% with placebo, 3% with perindopril, and 1% with bisoprolol, with the differences between bisoprolol and the other two study arms being highly statistically significant.
On the plus side, both of the once-daily cardiac medications displayed an important side benefit in MANTICORE: an eightfold reduction in the number of interruptions of trastuzumab therapy mandated by a significant drop in LVEF. There were eight such interruptions in the control group versus one each in the bisoprolol and perindopril arms. That’s of practical value in terms of patient convenience, cost of care, and possibly even the efficacy of the adjuvant cancer regimen, she noted.
Audience members raised several questions: what’s the clinical significance of the asymptomatic reduction in LVEF seen in the control group in MANTICORE? Does it place affected patients at risk for overt heart failure as time passes? And since LVEF is just one aspect of cardiac function, isn’t it possible that the cardiac medications were simply propping up LVEF while the underlying cardiotoxic effects of trastuzumab remained unchecked, such that the LVEF will drop once patients are off therapy?
Dr. Pituskin replied that these are good questions, the answers to which may be forthcoming at the planned follow-up cardiac MRI to be conducted at 24 months, a full year after discontinuation of the therapies.
Asked to compare the MANTICORE findings with those of the PRADA trial presented at this year’s annual meeting of the American Heart Association, in which an LVEF drop in breast cancer patients on adjuvant anthracycline and trastuzumab was prevented by prophylactic use of the angiotensin receptor blocker candesartan (Atacand) but not the beta-blocker metoprolol, Dr. Pituskin said she can’t make a definitive comparison until PRADA is published, but that it’s her understanding PRADA was a single-center trial without serial cardiac MRIs, and it included many more participants on an anthracycline-containing regimen, long recognized as a major hazard in terms of cardiotoxicity, and one thought to have a different cardiotoxic mechanism than trastuzumab.
By way of background, she noted that roughly 20% of women with breast cancer have HER2 receptor–overexpressing tumors. In such patients it’s well established that trastuzumab reduces mortality by one-third. However, it’s also well established that one in five patients on trastuzumab experience left ventricular dysfunction, and 1%-5% of patients develop heart failure, an “extremely devastating” complication carrying a 50% 5-year mortality. Beta-blockers and ACE inhibitors or angiotensin receptor blockers are standard, guideline-recommended treatments for patients with established heart failure.
AT SABCS 2015
Key clinical point: Bisoprolol prevents the trastuzumab-related decline in left ventricular ejection fraction in breast cancer patients.
Major finding: The average reduction from baseline in LVEF over the course of a year of adjuvant trastuzumab therapy was 5% with placebo, 3% with perindopril, and 1% with bisoprolol, with the differences between bisoprolol and the other two study arms being highly statistically significant. .
Data source: MANTICORE was a randomized, double-blind, multicenter study in which 99 patients with HER2-positive breast cancer were placed on prophylactic bisoprolol, perindopril, or placebo before starting adjuvant trastuzumab.
Disclosures: MANTICORE was funded by the Canadian Institutes for Health Research and the Alberta Cancer Foundation. The study presenter reported having no financial conflicts of interest.
‘Clinical equipoise’ surrounds neoadjuvant carboplatin for TNBC
SAN ANTONIO – Should carboplatin be considered a routine part of neoadjuvant therapy in early stage triple negative breast cancer?
Not yet, Dr. Angela M. DeMichele declared at the San Antonio Breast Cancer Symposium.
“I would say it’s still an individualized decision. The hazard ratios suggest benefit, but currently there’s not enough data to be conclusive,” according to Dr. DeMichele, who served as discussant for two clinical trials with discordant results – GeparSixto and CALGB/Alliance 40603 – presented at the symposium.
She also addressed a second issue raised by the two studies: is a pathologic complete response a valid surrogate for event-free survival?
“I would say a qualified yes,” commented Dr. DeMichele, professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia.
In GeparSixto, the addition of weekly carboplatin to a neoadjuvant chemotherapy backbone comprised of an anthracycline, taxane, and bevacizumab in patients with triple negative breast cancer (TNBC) boosted the 3-year disease-free survival rate significantly, from 76.1% to 85.5%. This result prompted GeparSixto presenter Dr. Gunter von Minckwitz, president of the German Breast Group, to declare that the study supports incorporation of carboplatin as part of standard neoadjuvant therapy in TNBC.
In contrast, in CALGB/Alliance 40603, adding carboplatin to neoadjuvant chemotherapy didn’t result in a significant improvement in 3-year event-free or overall survival.
Dr. DeMichele noted that with just 3 years of followup to date in these trials, there isn’t any information yet about carboplatin’s added potential long-term bone marrow toxicity. That’s an important unanswered question. Nor is any quality of life data available from the two trials. These issues need clarification before broader use of carboplatin.
One possible explanation for the disparate results in the two studies lies in differences in the chemotherapy and carboplatin doses and treatment schedules used. Patients in GeparSixto received greater cumulative amounts of anthracycline and taxane, given over a longer time period. And if patients were randomized to receive carboplatin, they got it at area under the curve 1.5 or 2 weekly for the duration of chemotherapy, as compared to carboplatin dosed just four times at area under the curve 6 every 3 weeks in CALGB/Alliance 40603.
“Could the weekly carboplatin in GeparSixto have provided less time for DNA repair in the tumor?,” she speculated.
Dr. William M. Sikov, who presented the CALGB/Alliance 40603 findings, found this quite plausible.
“We know treatment schedule and dose are important with anthracyclines, they’re important with taxanes, and it’s certainly not far fetched to propose that they may be important for carboplatin as well. Might that have made a difference? Can’t say,” observed Dr. Sikov of Women and Infants Hospital of Rhode Island in Providence.
In any case, Dr. DeMichele said neither GeparSixto, with its 315 patients with TNBC, nor CALGB/Alliance 40603, with 443, was adequately powered to prove or disprove a therapeutic advantage for the addition of neoadjuvant carboplatin.
“This is the 50th anniversary of the discovery of carboplatin. Yet despite all of our advancements in breast cancer, we’re still trying to figure out the role of platinum-containing agents in our armamentarium for breast cancer,” she observed.
During this period of what she termed clinical equipoise regarding carboplatin, she said it’s reasonable to consider using the agent outside of a clinical trial in selected circumstances: namely, when it’s important to gain rapid control of locoregional disease in order to improve operability or reduce morbidity, or in patients at the highest risk of relapse, mainly those who are very young or have stage III disease.
The issue of the validity of pathologic complete response (pCR) as a surrogate endpoint for event-free survival was raised by the GeparSixto and CALGB/Alliance 40603 investigators. In CALGB/Alliance 40603 only 9% of patients who had a pCR developed a distant recurrence and 3-year mortality was just 6%, compared with a 27% distant recurrence rate and 25% mortality in those without a pCR. Patients with a pCR had a 70% improvement in event-free survival and an 80% improvement in overall survival compared to those without a pCR, Dr. Sikov reported.
Similarly, in GeparSixto disease relapse occurred in only 5 of 129 TNBC patients with a pCR, compared with 50 of 162 without a pCR.
Dr. DeMichele said that while these are encouraging results, neither trial was designed to evaluate pCR as a predictor of improved event-free survival in accord with the Food and Drug Administration’s formal written guidance for attaining recognition of pCR as a surrogate endpoint. The studies were underpowered for this purpose. And a pooled analysis of 12 international trials totaling nearly 12,000 patients that was led by FDA investigators concluded that the data couldn’t validate pCR as a surrogate endpoint for event-free and overall survival (Lancet. 2014 Jul 12;384[9938]:164-72).
However, four studies adequately powered to detect improvement in event-free survival in conjunction with a carboplatin-induced benefit in terms of pCR are underway, including the NRG-BR-003 trial in the U.S. and the BrighTNess study in China.
In addition, a study with an innovative post-neoadjuvant design for platinum-based therapy is underway. The ECOG-ACRIN 1131 study is a Phase III randomized postoperative trial of four rounds of carboplatin or cisplatin versus observation in patients with residual TNBC following an anthracycline-based neoadjuvant regimen. This strategy limits exposure to the toxicities of platinum-based compounds to those patients in need of additional therapy. The planned 558-patient trial is powered to detect a 33% improvement in event-free survival.
SAN ANTONIO – Should carboplatin be considered a routine part of neoadjuvant therapy in early stage triple negative breast cancer?
Not yet, Dr. Angela M. DeMichele declared at the San Antonio Breast Cancer Symposium.
“I would say it’s still an individualized decision. The hazard ratios suggest benefit, but currently there’s not enough data to be conclusive,” according to Dr. DeMichele, who served as discussant for two clinical trials with discordant results – GeparSixto and CALGB/Alliance 40603 – presented at the symposium.
She also addressed a second issue raised by the two studies: is a pathologic complete response a valid surrogate for event-free survival?
“I would say a qualified yes,” commented Dr. DeMichele, professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia.
In GeparSixto, the addition of weekly carboplatin to a neoadjuvant chemotherapy backbone comprised of an anthracycline, taxane, and bevacizumab in patients with triple negative breast cancer (TNBC) boosted the 3-year disease-free survival rate significantly, from 76.1% to 85.5%. This result prompted GeparSixto presenter Dr. Gunter von Minckwitz, president of the German Breast Group, to declare that the study supports incorporation of carboplatin as part of standard neoadjuvant therapy in TNBC.
In contrast, in CALGB/Alliance 40603, adding carboplatin to neoadjuvant chemotherapy didn’t result in a significant improvement in 3-year event-free or overall survival.
Dr. DeMichele noted that with just 3 years of followup to date in these trials, there isn’t any information yet about carboplatin’s added potential long-term bone marrow toxicity. That’s an important unanswered question. Nor is any quality of life data available from the two trials. These issues need clarification before broader use of carboplatin.
One possible explanation for the disparate results in the two studies lies in differences in the chemotherapy and carboplatin doses and treatment schedules used. Patients in GeparSixto received greater cumulative amounts of anthracycline and taxane, given over a longer time period. And if patients were randomized to receive carboplatin, they got it at area under the curve 1.5 or 2 weekly for the duration of chemotherapy, as compared to carboplatin dosed just four times at area under the curve 6 every 3 weeks in CALGB/Alliance 40603.
“Could the weekly carboplatin in GeparSixto have provided less time for DNA repair in the tumor?,” she speculated.
Dr. William M. Sikov, who presented the CALGB/Alliance 40603 findings, found this quite plausible.
“We know treatment schedule and dose are important with anthracyclines, they’re important with taxanes, and it’s certainly not far fetched to propose that they may be important for carboplatin as well. Might that have made a difference? Can’t say,” observed Dr. Sikov of Women and Infants Hospital of Rhode Island in Providence.
In any case, Dr. DeMichele said neither GeparSixto, with its 315 patients with TNBC, nor CALGB/Alliance 40603, with 443, was adequately powered to prove or disprove a therapeutic advantage for the addition of neoadjuvant carboplatin.
“This is the 50th anniversary of the discovery of carboplatin. Yet despite all of our advancements in breast cancer, we’re still trying to figure out the role of platinum-containing agents in our armamentarium for breast cancer,” she observed.
During this period of what she termed clinical equipoise regarding carboplatin, she said it’s reasonable to consider using the agent outside of a clinical trial in selected circumstances: namely, when it’s important to gain rapid control of locoregional disease in order to improve operability or reduce morbidity, or in patients at the highest risk of relapse, mainly those who are very young or have stage III disease.
The issue of the validity of pathologic complete response (pCR) as a surrogate endpoint for event-free survival was raised by the GeparSixto and CALGB/Alliance 40603 investigators. In CALGB/Alliance 40603 only 9% of patients who had a pCR developed a distant recurrence and 3-year mortality was just 6%, compared with a 27% distant recurrence rate and 25% mortality in those without a pCR. Patients with a pCR had a 70% improvement in event-free survival and an 80% improvement in overall survival compared to those without a pCR, Dr. Sikov reported.
Similarly, in GeparSixto disease relapse occurred in only 5 of 129 TNBC patients with a pCR, compared with 50 of 162 without a pCR.
Dr. DeMichele said that while these are encouraging results, neither trial was designed to evaluate pCR as a predictor of improved event-free survival in accord with the Food and Drug Administration’s formal written guidance for attaining recognition of pCR as a surrogate endpoint. The studies were underpowered for this purpose. And a pooled analysis of 12 international trials totaling nearly 12,000 patients that was led by FDA investigators concluded that the data couldn’t validate pCR as a surrogate endpoint for event-free and overall survival (Lancet. 2014 Jul 12;384[9938]:164-72).
However, four studies adequately powered to detect improvement in event-free survival in conjunction with a carboplatin-induced benefit in terms of pCR are underway, including the NRG-BR-003 trial in the U.S. and the BrighTNess study in China.
In addition, a study with an innovative post-neoadjuvant design for platinum-based therapy is underway. The ECOG-ACRIN 1131 study is a Phase III randomized postoperative trial of four rounds of carboplatin or cisplatin versus observation in patients with residual TNBC following an anthracycline-based neoadjuvant regimen. This strategy limits exposure to the toxicities of platinum-based compounds to those patients in need of additional therapy. The planned 558-patient trial is powered to detect a 33% improvement in event-free survival.
SAN ANTONIO – Should carboplatin be considered a routine part of neoadjuvant therapy in early stage triple negative breast cancer?
Not yet, Dr. Angela M. DeMichele declared at the San Antonio Breast Cancer Symposium.
“I would say it’s still an individualized decision. The hazard ratios suggest benefit, but currently there’s not enough data to be conclusive,” according to Dr. DeMichele, who served as discussant for two clinical trials with discordant results – GeparSixto and CALGB/Alliance 40603 – presented at the symposium.
She also addressed a second issue raised by the two studies: is a pathologic complete response a valid surrogate for event-free survival?
“I would say a qualified yes,” commented Dr. DeMichele, professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia.
In GeparSixto, the addition of weekly carboplatin to a neoadjuvant chemotherapy backbone comprised of an anthracycline, taxane, and bevacizumab in patients with triple negative breast cancer (TNBC) boosted the 3-year disease-free survival rate significantly, from 76.1% to 85.5%. This result prompted GeparSixto presenter Dr. Gunter von Minckwitz, president of the German Breast Group, to declare that the study supports incorporation of carboplatin as part of standard neoadjuvant therapy in TNBC.
In contrast, in CALGB/Alliance 40603, adding carboplatin to neoadjuvant chemotherapy didn’t result in a significant improvement in 3-year event-free or overall survival.
Dr. DeMichele noted that with just 3 years of followup to date in these trials, there isn’t any information yet about carboplatin’s added potential long-term bone marrow toxicity. That’s an important unanswered question. Nor is any quality of life data available from the two trials. These issues need clarification before broader use of carboplatin.
One possible explanation for the disparate results in the two studies lies in differences in the chemotherapy and carboplatin doses and treatment schedules used. Patients in GeparSixto received greater cumulative amounts of anthracycline and taxane, given over a longer time period. And if patients were randomized to receive carboplatin, they got it at area under the curve 1.5 or 2 weekly for the duration of chemotherapy, as compared to carboplatin dosed just four times at area under the curve 6 every 3 weeks in CALGB/Alliance 40603.
“Could the weekly carboplatin in GeparSixto have provided less time for DNA repair in the tumor?,” she speculated.
Dr. William M. Sikov, who presented the CALGB/Alliance 40603 findings, found this quite plausible.
“We know treatment schedule and dose are important with anthracyclines, they’re important with taxanes, and it’s certainly not far fetched to propose that they may be important for carboplatin as well. Might that have made a difference? Can’t say,” observed Dr. Sikov of Women and Infants Hospital of Rhode Island in Providence.
In any case, Dr. DeMichele said neither GeparSixto, with its 315 patients with TNBC, nor CALGB/Alliance 40603, with 443, was adequately powered to prove or disprove a therapeutic advantage for the addition of neoadjuvant carboplatin.
“This is the 50th anniversary of the discovery of carboplatin. Yet despite all of our advancements in breast cancer, we’re still trying to figure out the role of platinum-containing agents in our armamentarium for breast cancer,” she observed.
During this period of what she termed clinical equipoise regarding carboplatin, she said it’s reasonable to consider using the agent outside of a clinical trial in selected circumstances: namely, when it’s important to gain rapid control of locoregional disease in order to improve operability or reduce morbidity, or in patients at the highest risk of relapse, mainly those who are very young or have stage III disease.
The issue of the validity of pathologic complete response (pCR) as a surrogate endpoint for event-free survival was raised by the GeparSixto and CALGB/Alliance 40603 investigators. In CALGB/Alliance 40603 only 9% of patients who had a pCR developed a distant recurrence and 3-year mortality was just 6%, compared with a 27% distant recurrence rate and 25% mortality in those without a pCR. Patients with a pCR had a 70% improvement in event-free survival and an 80% improvement in overall survival compared to those without a pCR, Dr. Sikov reported.
Similarly, in GeparSixto disease relapse occurred in only 5 of 129 TNBC patients with a pCR, compared with 50 of 162 without a pCR.
Dr. DeMichele said that while these are encouraging results, neither trial was designed to evaluate pCR as a predictor of improved event-free survival in accord with the Food and Drug Administration’s formal written guidance for attaining recognition of pCR as a surrogate endpoint. The studies were underpowered for this purpose. And a pooled analysis of 12 international trials totaling nearly 12,000 patients that was led by FDA investigators concluded that the data couldn’t validate pCR as a surrogate endpoint for event-free and overall survival (Lancet. 2014 Jul 12;384[9938]:164-72).
However, four studies adequately powered to detect improvement in event-free survival in conjunction with a carboplatin-induced benefit in terms of pCR are underway, including the NRG-BR-003 trial in the U.S. and the BrighTNess study in China.
In addition, a study with an innovative post-neoadjuvant design for platinum-based therapy is underway. The ECOG-ACRIN 1131 study is a Phase III randomized postoperative trial of four rounds of carboplatin or cisplatin versus observation in patients with residual TNBC following an anthracycline-based neoadjuvant regimen. This strategy limits exposure to the toxicities of platinum-based compounds to those patients in need of additional therapy. The planned 558-patient trial is powered to detect a 33% improvement in event-free survival.
EXPERT ANALYSIS FROM SABCS 2015
VIDEO: Cleveland Clinic experts provide SABCS take-home messages
SAN ANTONIO –The San Antonio Breast Cancer Symposium had a lot to offer clinicians. Cleveland Clinic breast cancer experts Dr. Jame Abraham, Dr. Holly Pederson, and Dr. Alberto Montero outline take-home messages from research presented at the San Antonio Breast Cancer Symposium. The panel agreed that some findings were practice-changing – particularly results showing adjuvant denosumab not only reduces fracture risk for women but also improves breast cancer outcomes – while findings for other treatments, including immunotherapy for breast cancer, have a long way to go before arriving in the clinic.
Dr. Pederson highlighted presentations on prevention, including findings linking aspirin with lower breast density. She also said presentations confirmed for her that gene panels are here to stay in helping identify and manage women at high risk of breast cancer.
The panelists also discussed the clinical relevance of studies on neoadjuvant carboplatin and on using capecitabine for cleanup of residual disease after neoadjuvant therapy.
The three panelists had no financial disclosures related to these studies.
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 –The San Antonio Breast Cancer Symposium had a lot to offer clinicians. Cleveland Clinic breast cancer experts Dr. Jame Abraham, Dr. Holly Pederson, and Dr. Alberto Montero outline take-home messages from research presented at the San Antonio Breast Cancer Symposium. The panel agreed that some findings were practice-changing – particularly results showing adjuvant denosumab not only reduces fracture risk for women but also improves breast cancer outcomes – while findings for other treatments, including immunotherapy for breast cancer, have a long way to go before arriving in the clinic.
Dr. Pederson highlighted presentations on prevention, including findings linking aspirin with lower breast density. She also said presentations confirmed for her that gene panels are here to stay in helping identify and manage women at high risk of breast cancer.
The panelists also discussed the clinical relevance of studies on neoadjuvant carboplatin and on using capecitabine for cleanup of residual disease after neoadjuvant therapy.
The three panelists had no financial disclosures related to these studies.
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 –The San Antonio Breast Cancer Symposium had a lot to offer clinicians. Cleveland Clinic breast cancer experts Dr. Jame Abraham, Dr. Holly Pederson, and Dr. Alberto Montero outline take-home messages from research presented at the San Antonio Breast Cancer Symposium. The panel agreed that some findings were practice-changing – particularly results showing adjuvant denosumab not only reduces fracture risk for women but also improves breast cancer outcomes – while findings for other treatments, including immunotherapy for breast cancer, have a long way to go before arriving in the clinic.
Dr. Pederson highlighted presentations on prevention, including findings linking aspirin with lower breast density. She also said presentations confirmed for her that gene panels are here to stay in helping identify and manage women at high risk of breast cancer.
The panelists also discussed the clinical relevance of studies on neoadjuvant carboplatin and on using capecitabine for cleanup of residual disease after neoadjuvant therapy.
The three panelists had no financial disclosures related to these studies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
EXPERT ANALYSIS FROM SABCS 2015
Die not yet cast for lymphazurin and methylene blue dye
CHICAGO – Two commonly used dyes produced mixed results in sentinel lymph node mapping of early stage breast cancer in what was described as the highest-powered study to date.
The average number of sentinel lymph nodes identified per person was significantly higher with 1% methylene blue dye than with 1% lymphazurin (2.89 vs. 2.22; P less than .001).
Although there is extensive support for methylene blue as a safe and efficacious alternative to lymphazurin, this finding on the number of sentinel nodes identified is not replicated in any other study, Dr. Vaishali Patel said at the annual clinical congress of the American College of Surgeons. The study was conducted at the McLaren Flint (Mich.) Medical Center. Dr. Sukamal Saha was principal investigator.
On the other hand, lymphazurin identified significantly more additional lymph nodes than methylene blue (mean 4.48 vs. 2.84; P less than .001).
Nodal positivity was also significantly higher with lymphazurin than methylene blue (14.93% vs. 8.85%; P less than .001), which also has not been reported in other trials.
“We think this does offer a true comparison between the two dyes,” Dr. Patel of Detroit Medical Center Sinai-Grace Hospital said. “The volume of dye and technique were consistent for all 651 patients. … with one surgeon performing the injections and one surgeon performing the procedures.” The 651 consecutive patients were randomly assigned based on agent availability to a preoperative injection of lymphazurin (half intraparenchymal and half subareolar in the upper outer quadrant) or an intraoperative injection of methylene blue over 5 minutes (3 ccs intraparenchymal, 1 cc subareolar, and 1 cc intradermal).
The lymphazurin and methylene blue groups were also similar in number (298 patients vs. 353 patients), age (mean 61.6 years vs. 63.5 years), and T stage (in situ 12% vs. 17.8%; T1 64% vs. 65%; T2 23% vs. 17.5%).
In contrast, three smaller, well-established studies that came to different conclusions used four different surgeons and novel techniques to inject their radiocolloid and supervised residents for lymphatic mapping, she noted.
The radiocolloid lymphazurin first demonstrated superiority over methylene blue in 1990, but alternatives continue to be investigated due to frequent nonavailability and a host of adverse events including blue hives, blue discoloration or tattooing, and anaphylaxis.
Lymphazurin also costs 10-12 times more than methylene blue, which was reflected in the study in an average per patient cost of $815 vs. $75 for methylene blue, Dr. Patel said.
The American Society of Breast Surgeons, however, recommends dual-agent mapping using blue dye and a radioisotope in breast cancer to further improve the success in identifying the sentinel lymph nodes. The improvement is likely because of the dual mechanism at play: radiocolloids become entrapped within the lymph node, whereas certain blue dyes bind to interstitial albumin and are taken up by lymphatics, she explained.
The higher number of sentinel lymph nodes in the methylene blue group may be due to its particle size, which is smaller, weighs less, and diffused faster, Dr. Patel suggested.
The higher number of additional lymph nodes captured with lymphazurin may be because of the higher frequency of nodal dissection in this group than in the methylene blue group (25% vs. 16%).
The finding of greater nodal positivity in the lymphazurin group may be related to mechanism of action or the high percentage of patients with T1 disease enrolled in the study. Still, nodal positivity was higher with lymphazurin than methylene blue regardless of T stage, she said.
The lymphazurin group had higher rates than the methylene blue group of pseudohypoxemia (10% vs. 0%; P less than .0001), but blue hives (1.34% vs. 0%; P = .043) and anaphylaxis (.67% vs. 0%; P = .20) were kept in check. Patients were premedicated and early in the series, the surgeon began excising the area of injected blue skin during the primary surgery, Dr. Patel observed.
Despite being diluted, methylene blue was associated with higher rates of seroma (3.4% vs. 1.7%; P = .005) and skin necrosis (2.55% vs. 9%; P = .005).
Discussant Dr. Alyssa Throckmorton of Baptist Memorial Health Care in Memphis pointed out that more recent data show radiocolloid mapping alone is comparable to dual-agent mapping, suggesting that blue dye may not be needed. That said, there have been national shortages of methylene blue as well as lymphazurin.
“I think in surgeons who are going to use blue dye, with the way drug shortages have become in the last few years, you are going to have to be facile and familiar with both types of dye if you are going to use that as part of your clinical practice,” she said.
CHICAGO – Two commonly used dyes produced mixed results in sentinel lymph node mapping of early stage breast cancer in what was described as the highest-powered study to date.
The average number of sentinel lymph nodes identified per person was significantly higher with 1% methylene blue dye than with 1% lymphazurin (2.89 vs. 2.22; P less than .001).
Although there is extensive support for methylene blue as a safe and efficacious alternative to lymphazurin, this finding on the number of sentinel nodes identified is not replicated in any other study, Dr. Vaishali Patel said at the annual clinical congress of the American College of Surgeons. The study was conducted at the McLaren Flint (Mich.) Medical Center. Dr. Sukamal Saha was principal investigator.
On the other hand, lymphazurin identified significantly more additional lymph nodes than methylene blue (mean 4.48 vs. 2.84; P less than .001).
Nodal positivity was also significantly higher with lymphazurin than methylene blue (14.93% vs. 8.85%; P less than .001), which also has not been reported in other trials.
“We think this does offer a true comparison between the two dyes,” Dr. Patel of Detroit Medical Center Sinai-Grace Hospital said. “The volume of dye and technique were consistent for all 651 patients. … with one surgeon performing the injections and one surgeon performing the procedures.” The 651 consecutive patients were randomly assigned based on agent availability to a preoperative injection of lymphazurin (half intraparenchymal and half subareolar in the upper outer quadrant) or an intraoperative injection of methylene blue over 5 minutes (3 ccs intraparenchymal, 1 cc subareolar, and 1 cc intradermal).
The lymphazurin and methylene blue groups were also similar in number (298 patients vs. 353 patients), age (mean 61.6 years vs. 63.5 years), and T stage (in situ 12% vs. 17.8%; T1 64% vs. 65%; T2 23% vs. 17.5%).
In contrast, three smaller, well-established studies that came to different conclusions used four different surgeons and novel techniques to inject their radiocolloid and supervised residents for lymphatic mapping, she noted.
The radiocolloid lymphazurin first demonstrated superiority over methylene blue in 1990, but alternatives continue to be investigated due to frequent nonavailability and a host of adverse events including blue hives, blue discoloration or tattooing, and anaphylaxis.
Lymphazurin also costs 10-12 times more than methylene blue, which was reflected in the study in an average per patient cost of $815 vs. $75 for methylene blue, Dr. Patel said.
The American Society of Breast Surgeons, however, recommends dual-agent mapping using blue dye and a radioisotope in breast cancer to further improve the success in identifying the sentinel lymph nodes. The improvement is likely because of the dual mechanism at play: radiocolloids become entrapped within the lymph node, whereas certain blue dyes bind to interstitial albumin and are taken up by lymphatics, she explained.
The higher number of sentinel lymph nodes in the methylene blue group may be due to its particle size, which is smaller, weighs less, and diffused faster, Dr. Patel suggested.
The higher number of additional lymph nodes captured with lymphazurin may be because of the higher frequency of nodal dissection in this group than in the methylene blue group (25% vs. 16%).
The finding of greater nodal positivity in the lymphazurin group may be related to mechanism of action or the high percentage of patients with T1 disease enrolled in the study. Still, nodal positivity was higher with lymphazurin than methylene blue regardless of T stage, she said.
The lymphazurin group had higher rates than the methylene blue group of pseudohypoxemia (10% vs. 0%; P less than .0001), but blue hives (1.34% vs. 0%; P = .043) and anaphylaxis (.67% vs. 0%; P = .20) were kept in check. Patients were premedicated and early in the series, the surgeon began excising the area of injected blue skin during the primary surgery, Dr. Patel observed.
Despite being diluted, methylene blue was associated with higher rates of seroma (3.4% vs. 1.7%; P = .005) and skin necrosis (2.55% vs. 9%; P = .005).
Discussant Dr. Alyssa Throckmorton of Baptist Memorial Health Care in Memphis pointed out that more recent data show radiocolloid mapping alone is comparable to dual-agent mapping, suggesting that blue dye may not be needed. That said, there have been national shortages of methylene blue as well as lymphazurin.
“I think in surgeons who are going to use blue dye, with the way drug shortages have become in the last few years, you are going to have to be facile and familiar with both types of dye if you are going to use that as part of your clinical practice,” she said.
CHICAGO – Two commonly used dyes produced mixed results in sentinel lymph node mapping of early stage breast cancer in what was described as the highest-powered study to date.
The average number of sentinel lymph nodes identified per person was significantly higher with 1% methylene blue dye than with 1% lymphazurin (2.89 vs. 2.22; P less than .001).
Although there is extensive support for methylene blue as a safe and efficacious alternative to lymphazurin, this finding on the number of sentinel nodes identified is not replicated in any other study, Dr. Vaishali Patel said at the annual clinical congress of the American College of Surgeons. The study was conducted at the McLaren Flint (Mich.) Medical Center. Dr. Sukamal Saha was principal investigator.
On the other hand, lymphazurin identified significantly more additional lymph nodes than methylene blue (mean 4.48 vs. 2.84; P less than .001).
Nodal positivity was also significantly higher with lymphazurin than methylene blue (14.93% vs. 8.85%; P less than .001), which also has not been reported in other trials.
“We think this does offer a true comparison between the two dyes,” Dr. Patel of Detroit Medical Center Sinai-Grace Hospital said. “The volume of dye and technique were consistent for all 651 patients. … with one surgeon performing the injections and one surgeon performing the procedures.” The 651 consecutive patients were randomly assigned based on agent availability to a preoperative injection of lymphazurin (half intraparenchymal and half subareolar in the upper outer quadrant) or an intraoperative injection of methylene blue over 5 minutes (3 ccs intraparenchymal, 1 cc subareolar, and 1 cc intradermal).
The lymphazurin and methylene blue groups were also similar in number (298 patients vs. 353 patients), age (mean 61.6 years vs. 63.5 years), and T stage (in situ 12% vs. 17.8%; T1 64% vs. 65%; T2 23% vs. 17.5%).
In contrast, three smaller, well-established studies that came to different conclusions used four different surgeons and novel techniques to inject their radiocolloid and supervised residents for lymphatic mapping, she noted.
The radiocolloid lymphazurin first demonstrated superiority over methylene blue in 1990, but alternatives continue to be investigated due to frequent nonavailability and a host of adverse events including blue hives, blue discoloration or tattooing, and anaphylaxis.
Lymphazurin also costs 10-12 times more than methylene blue, which was reflected in the study in an average per patient cost of $815 vs. $75 for methylene blue, Dr. Patel said.
The American Society of Breast Surgeons, however, recommends dual-agent mapping using blue dye and a radioisotope in breast cancer to further improve the success in identifying the sentinel lymph nodes. The improvement is likely because of the dual mechanism at play: radiocolloids become entrapped within the lymph node, whereas certain blue dyes bind to interstitial albumin and are taken up by lymphatics, she explained.
The higher number of sentinel lymph nodes in the methylene blue group may be due to its particle size, which is smaller, weighs less, and diffused faster, Dr. Patel suggested.
The higher number of additional lymph nodes captured with lymphazurin may be because of the higher frequency of nodal dissection in this group than in the methylene blue group (25% vs. 16%).
The finding of greater nodal positivity in the lymphazurin group may be related to mechanism of action or the high percentage of patients with T1 disease enrolled in the study. Still, nodal positivity was higher with lymphazurin than methylene blue regardless of T stage, she said.
The lymphazurin group had higher rates than the methylene blue group of pseudohypoxemia (10% vs. 0%; P less than .0001), but blue hives (1.34% vs. 0%; P = .043) and anaphylaxis (.67% vs. 0%; P = .20) were kept in check. Patients were premedicated and early in the series, the surgeon began excising the area of injected blue skin during the primary surgery, Dr. Patel observed.
Despite being diluted, methylene blue was associated with higher rates of seroma (3.4% vs. 1.7%; P = .005) and skin necrosis (2.55% vs. 9%; P = .005).
Discussant Dr. Alyssa Throckmorton of Baptist Memorial Health Care in Memphis pointed out that more recent data show radiocolloid mapping alone is comparable to dual-agent mapping, suggesting that blue dye may not be needed. That said, there have been national shortages of methylene blue as well as lymphazurin.
“I think in surgeons who are going to use blue dye, with the way drug shortages have become in the last few years, you are going to have to be facile and familiar with both types of dye if you are going to use that as part of your clinical practice,” she said.
AT THE ACS CLINICAL CONGRESS
Key clinical point: Contrary to prior studies, lymph node positivity was higher with lymphazurin than methylene blue in patients with early breast cancer.
Major finding: Nodal positivity was 14.93% with lymphazurin vs. 8.85% with methylene blue (P less than .001).
Data source: Prospective study in 651 patients undergoing lymphatic mapping for breast cancer.
Disclosures: Dr. Patel and Dr. Throckmorton reported having no relevant conflicts.
Readmission after esophagectomy raises mortality
About one in five patients who have surgery to remove part or all of the esophagus return to the hospital for complications within 30 days, and when they do their chance of death increases fivefold, compared with those who don’t return to the hospital, investigators at the University of Virginia Health System reported in the Journal of Thoracic and Cardiovascular Surgery (2015;150:1254-60).
“Early recognition of life-threatening readmission diagnoses is essential in order to provide optimal care,” said lead author Dr. Yinin Hu and colleagues. Esophageal cancer is the fastest-growing cancer in the United States, so the study investigators set out to closely examine the reasons for readmissions and death after surgery.
The study identified 1,688 patients in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database aged 66 or older who had surgery for esophageal cancer from 2000 to 2009. The overall 30-day mortality was 6.9%, and the 90-day mortality was 13.9%.
After excluding in-hospital deaths, the investigators’ readmission analysis included 1,543 patients. In this group, overall 90-day mortality following discharge was 6.4%, and the readmission rate within 30 days of discharge was 20.7%
The 90-day mortality for patients who were readmitted was more than four times that for those who were not readmitted, 16.3% vs. 3.8%; their in-hospital mortality was 8.8%. About one-third of readmissions were to facilities different from where patients had the index esophagectomy, and those patients were about seven times more likely to be transferred after readmission than patients admitted to the same facility, 15% vs. 1.9%. Risk-adjusted mortality did not vary significantly across providers.
The most frequent reasons for readmission were pneumonia (11.8%), malnutrition/dehydration (8.1%), pleural effusion (97.5%), and aspiration pneumonitis (6.8%). “Notably, more than one in five patients readmitted with a pulmonary diagnosis subsequently died within 90 days of the operation,” Dr. Hu and coauthors said, indicating that readmissions for pulmonary complications carried the worst prognosis.
This is the first study to demonstrate the gravity of pulmonary readmissions within 30 days of discharge, Dr. Hu and coauthors said. “Patients with nonspecific dyspneic symptoms or small pleural effusions should receive aggressive care upon readmission, as more than 20% will not survive the next few months,” Dr. Hu and coauthors said. “These results reinforce the notion that a fairly benign readmitting diagnosis is often an indicator of a much more severe root process.”
Among nonpulmonary reasons for readmission, dehydration and malnutrition carried the highest risk for death. “While there are many interventions that can promote postoperative nutrition, a readmission due to poor dietary tolerance often indicates other complications such as infection, stenosis, or anastomotic leak,” Dr. Hu and coauthors said. They suggested a thorough root-cause analysis should be part of every readmission.
The study also analyzed the hospital length of stay (LOS) as a predictor for readmission. The median LOS was 13 days, but the most common LOS was 9 days. “In general, the probability of readmission increases with increasing postoperative LOS,” Dr. Hu and colleagues said.
The authors reported no disclosures. Dr. Yinin Hu received funding from the National Institutes of Health and coauthor Dr. Benjamin Kozower received funding from the Agency for Healthcare Research and Quality.
The findings of this study may indicate that patients who stay in the hospital longer have underlying issues that did not surface during their admission for the operation, Dr. Anthony W. Kim of Yale University, New Haven, Conn., said in his invited commentary (J Thorac Cardiovasc Surg. 2015;150:1030-1). “Therefore, rather than employing a prevention of a failure-to-rescue strategy during a readmission, it may be worthwhile to enact a prevention-of-readmission strategy triggered by a longer than typical [length of stay],” Dr. Kim said. He suggested the root-cause analysis should begin in the hospital on the day after the patient exceeds the median length of stay.
 |
Dr. Anthony W. Kim |
But citing the law of unintended consequences, Dr. Kim warns against using readmission as a quality metric as well a instrument to dictate reimbursement. “The law of unintended consequences dictates that when a readmission is taken out of context, using this measure raises the potential conflict of interest between doing what is right for the patient and achieving a specific milestone that may not be in the best interest of an individual patient,” he said. “Discharging a patient early perhaps to the exclusion of adequately addressing inpatient issues for the purposes of achieving a target [length of stay] is perhaps the prime example of these conflicting interests.”
Because of the difficult recovery course after esophagectomy, some readmissions are “necessary, beneficial and, unequivocally, the right decision,” Dr. Kim said. “Ironically, one of the unintended consequences of this article may be that it exposes the fact that until a better system of recording and scrutinizing readmissions exists, governing organizations should exercise considerable caution when assessing a surgeon, hospital, or system and their readmissions,” he said.
To paraphrase the sociologist Robert K. Merton, who devised the law of unintended consequences, the existing state of knowledge limits one’s ability to anticipate the consequences of action. The authors of this study “have added immensely to a body of knowledge that is still growing and deserves ongoing study if policy is to be based upon it,” Dr. Kim said.
Dr. Kim had no disclosures.
The findings of this study may indicate that patients who stay in the hospital longer have underlying issues that did not surface during their admission for the operation, Dr. Anthony W. Kim of Yale University, New Haven, Conn., said in his invited commentary (J Thorac Cardiovasc Surg. 2015;150:1030-1). “Therefore, rather than employing a prevention of a failure-to-rescue strategy during a readmission, it may be worthwhile to enact a prevention-of-readmission strategy triggered by a longer than typical [length of stay],” Dr. Kim said. He suggested the root-cause analysis should begin in the hospital on the day after the patient exceeds the median length of stay.
|
Dr. Anthony W. Kim |
But citing the law of unintended consequences, Dr. Kim warns against using readmission as a quality metric as well a instrument to dictate reimbursement. “The law of unintended consequences dictates that when a readmission is taken out of context, using this measure raises the potential conflict of interest between doing what is right for the patient and achieving a specific milestone that may not be in the best interest of an individual patient,” he said. “Discharging a patient early perhaps to the exclusion of adequately addressing inpatient issues for the purposes of achieving a target [length of stay] is perhaps the prime example of these conflicting interests.”
Because of the difficult recovery course after esophagectomy, some readmissions are “necessary, beneficial and, unequivocally, the right decision,” Dr. Kim said. “Ironically, one of the unintended consequences of this article may be that it exposes the fact that until a better system of recording and scrutinizing readmissions exists, governing organizations should exercise considerable caution when assessing a surgeon, hospital, or system and their readmissions,” he said.
To paraphrase the sociologist Robert K. Merton, who devised the law of unintended consequences, the existing state of knowledge limits one’s ability to anticipate the consequences of action. The authors of this study “have added immensely to a body of knowledge that is still growing and deserves ongoing study if policy is to be based upon it,” Dr. Kim said.
Dr. Kim had no disclosures.
The findings of this study may indicate that patients who stay in the hospital longer have underlying issues that did not surface during their admission for the operation, Dr. Anthony W. Kim of Yale University, New Haven, Conn., said in his invited commentary (J Thorac Cardiovasc Surg. 2015;150:1030-1). “Therefore, rather than employing a prevention of a failure-to-rescue strategy during a readmission, it may be worthwhile to enact a prevention-of-readmission strategy triggered by a longer than typical [length of stay],” Dr. Kim said. He suggested the root-cause analysis should begin in the hospital on the day after the patient exceeds the median length of stay.
|
Dr. Anthony W. Kim |
But citing the law of unintended consequences, Dr. Kim warns against using readmission as a quality metric as well a instrument to dictate reimbursement. “The law of unintended consequences dictates that when a readmission is taken out of context, using this measure raises the potential conflict of interest between doing what is right for the patient and achieving a specific milestone that may not be in the best interest of an individual patient,” he said. “Discharging a patient early perhaps to the exclusion of adequately addressing inpatient issues for the purposes of achieving a target [length of stay] is perhaps the prime example of these conflicting interests.”
Because of the difficult recovery course after esophagectomy, some readmissions are “necessary, beneficial and, unequivocally, the right decision,” Dr. Kim said. “Ironically, one of the unintended consequences of this article may be that it exposes the fact that until a better system of recording and scrutinizing readmissions exists, governing organizations should exercise considerable caution when assessing a surgeon, hospital, or system and their readmissions,” he said.
To paraphrase the sociologist Robert K. Merton, who devised the law of unintended consequences, the existing state of knowledge limits one’s ability to anticipate the consequences of action. The authors of this study “have added immensely to a body of knowledge that is still growing and deserves ongoing study if policy is to be based upon it,” Dr. Kim said.
Dr. Kim had no disclosures.
About one in five patients who have surgery to remove part or all of the esophagus return to the hospital for complications within 30 days, and when they do their chance of death increases fivefold, compared with those who don’t return to the hospital, investigators at the University of Virginia Health System reported in the Journal of Thoracic and Cardiovascular Surgery (2015;150:1254-60).
“Early recognition of life-threatening readmission diagnoses is essential in order to provide optimal care,” said lead author Dr. Yinin Hu and colleagues. Esophageal cancer is the fastest-growing cancer in the United States, so the study investigators set out to closely examine the reasons for readmissions and death after surgery.
The study identified 1,688 patients in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database aged 66 or older who had surgery for esophageal cancer from 2000 to 2009. The overall 30-day mortality was 6.9%, and the 90-day mortality was 13.9%.
After excluding in-hospital deaths, the investigators’ readmission analysis included 1,543 patients. In this group, overall 90-day mortality following discharge was 6.4%, and the readmission rate within 30 days of discharge was 20.7%
The 90-day mortality for patients who were readmitted was more than four times that for those who were not readmitted, 16.3% vs. 3.8%; their in-hospital mortality was 8.8%. About one-third of readmissions were to facilities different from where patients had the index esophagectomy, and those patients were about seven times more likely to be transferred after readmission than patients admitted to the same facility, 15% vs. 1.9%. Risk-adjusted mortality did not vary significantly across providers.
The most frequent reasons for readmission were pneumonia (11.8%), malnutrition/dehydration (8.1%), pleural effusion (97.5%), and aspiration pneumonitis (6.8%). “Notably, more than one in five patients readmitted with a pulmonary diagnosis subsequently died within 90 days of the operation,” Dr. Hu and coauthors said, indicating that readmissions for pulmonary complications carried the worst prognosis.
This is the first study to demonstrate the gravity of pulmonary readmissions within 30 days of discharge, Dr. Hu and coauthors said. “Patients with nonspecific dyspneic symptoms or small pleural effusions should receive aggressive care upon readmission, as more than 20% will not survive the next few months,” Dr. Hu and coauthors said. “These results reinforce the notion that a fairly benign readmitting diagnosis is often an indicator of a much more severe root process.”
Among nonpulmonary reasons for readmission, dehydration and malnutrition carried the highest risk for death. “While there are many interventions that can promote postoperative nutrition, a readmission due to poor dietary tolerance often indicates other complications such as infection, stenosis, or anastomotic leak,” Dr. Hu and coauthors said. They suggested a thorough root-cause analysis should be part of every readmission.
The study also analyzed the hospital length of stay (LOS) as a predictor for readmission. The median LOS was 13 days, but the most common LOS was 9 days. “In general, the probability of readmission increases with increasing postoperative LOS,” Dr. Hu and colleagues said.
The authors reported no disclosures. Dr. Yinin Hu received funding from the National Institutes of Health and coauthor Dr. Benjamin Kozower received funding from the Agency for Healthcare Research and Quality.
About one in five patients who have surgery to remove part or all of the esophagus return to the hospital for complications within 30 days, and when they do their chance of death increases fivefold, compared with those who don’t return to the hospital, investigators at the University of Virginia Health System reported in the Journal of Thoracic and Cardiovascular Surgery (2015;150:1254-60).
“Early recognition of life-threatening readmission diagnoses is essential in order to provide optimal care,” said lead author Dr. Yinin Hu and colleagues. Esophageal cancer is the fastest-growing cancer in the United States, so the study investigators set out to closely examine the reasons for readmissions and death after surgery.
The study identified 1,688 patients in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database aged 66 or older who had surgery for esophageal cancer from 2000 to 2009. The overall 30-day mortality was 6.9%, and the 90-day mortality was 13.9%.
After excluding in-hospital deaths, the investigators’ readmission analysis included 1,543 patients. In this group, overall 90-day mortality following discharge was 6.4%, and the readmission rate within 30 days of discharge was 20.7%
The 90-day mortality for patients who were readmitted was more than four times that for those who were not readmitted, 16.3% vs. 3.8%; their in-hospital mortality was 8.8%. About one-third of readmissions were to facilities different from where patients had the index esophagectomy, and those patients were about seven times more likely to be transferred after readmission than patients admitted to the same facility, 15% vs. 1.9%. Risk-adjusted mortality did not vary significantly across providers.
The most frequent reasons for readmission were pneumonia (11.8%), malnutrition/dehydration (8.1%), pleural effusion (97.5%), and aspiration pneumonitis (6.8%). “Notably, more than one in five patients readmitted with a pulmonary diagnosis subsequently died within 90 days of the operation,” Dr. Hu and coauthors said, indicating that readmissions for pulmonary complications carried the worst prognosis.
This is the first study to demonstrate the gravity of pulmonary readmissions within 30 days of discharge, Dr. Hu and coauthors said. “Patients with nonspecific dyspneic symptoms or small pleural effusions should receive aggressive care upon readmission, as more than 20% will not survive the next few months,” Dr. Hu and coauthors said. “These results reinforce the notion that a fairly benign readmitting diagnosis is often an indicator of a much more severe root process.”
Among nonpulmonary reasons for readmission, dehydration and malnutrition carried the highest risk for death. “While there are many interventions that can promote postoperative nutrition, a readmission due to poor dietary tolerance often indicates other complications such as infection, stenosis, or anastomotic leak,” Dr. Hu and coauthors said. They suggested a thorough root-cause analysis should be part of every readmission.
The study also analyzed the hospital length of stay (LOS) as a predictor for readmission. The median LOS was 13 days, but the most common LOS was 9 days. “In general, the probability of readmission increases with increasing postoperative LOS,” Dr. Hu and colleagues said.
The authors reported no disclosures. Dr. Yinin Hu received funding from the National Institutes of Health and coauthor Dr. Benjamin Kozower received funding from the Agency for Healthcare Research and Quality.
Key clinical point: Patients readmitted after esophagectomy are at a greater than fourfold higher risk of death than patients who do not need readmission.
Major finding: The 90-day mortality for patients who were readmitted was greater than four times that for those who were not readmitted, 16.3% vs. 3.8%.
Data source: Analysis of 1,688 patients in the SEER-Medicare database aged 66 or older who had surgery for esophageal cancer from 2000 to 2009.
Disclosures: The authors had no disclosures. Lead author Dr. Yinin Hu received funding from the National Institutes of Health and coauthor Dr. Benjamin Kozower received funding from the Agency for Healthcare Research and Quality.
