Breast Cancer

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

sworcester@mdedge.com

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

sworcester@mdedge.com

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

sworcester@mdedge.com

A model that crunches data from routine blood tests can accurately identify cancer patients who will develop acute kidney injury (AKI) up to a month before it happens, according to a cohort study.

The algorithm spotted nearly 74% of the patients who went on to develop AKI within 30 days, providing a window for intervention and possibly prevention, according to investigators.

These results were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (abstract PR-11).

“Cancer patients are a high-risk population for AKI due to the nature of their treatment and illness,” said presenter Lauren A. Scanlon, PhD, a data scientist at The Christie NHS Foundation Trust in Huddersfield, England. “AKI causes a huge disruption in treatment and distress for the patient, so it would be amazing if we could, say, predict the AKI before it occurs and prevent it from even happening.”

U.K. health care providers are already using an algorithm to monitor patients’ creatinine levels, comparing new values against historic ones, Dr. Scanlon explained. When that algorithm detects AKI, it issues an alert that triggers implementation of an AKI care bundle, including measures such as fluid monitoring and medication review, within 24 hours.

Taking this concept further, Dr. Scanlon and colleagues developed a random forest model, a type of machine learning algorithm, that incorporates other markers from blood tests routinely obtained for all patients, with the aim of predicting AKI up to 30 days in advance.

“Using routinely collected blood test results will ensure that the model is applicable to all our patients and can be implemented in an automated manner,” Dr. Scanlon noted.

The investigators developed and trained the model using 597,403 blood test results from 48,865 patients undergoing cancer treatment between January 2017 and May 2020.

The model assigns patients to five categories of risk for AKI in the next 30 days: very low, low, medium, high, and very high.

“We wanted the model to output in this way so that it could be used by clinicians alongside their own insight and knowledge on a case-by-case basis,” Dr. Scanlon explained.

The investigators then prospectively validated the model and its risk categories in another 9,913 patients who underwent cancer treatment between June and August 2020.

Using a model threshold of medium risk or higher, the model correctly predicted AKI in 330 (73.8%) of the 447 patients in the validation cohort who ultimately developed AKI.

“This is pretty amazing and shows that this model really is working and can correctly detect these AKIs up to 30 days before they occur, giving a huge window to put in place preventive strategies,” Dr. Scanlon said.

Among the 154 patients in whom the model incorrectly predicted AKI, 9 patients had only a single follow-up blood test and 17 patients did not have any, leaving their actual outcomes unclear.

“Given that AKI detection uses blood tests, an AKI in these patients was never confirmed,” Dr. Scanlon noted. “So this could give a potential benefit of the model that we never intended: It could reduce undiagnosed AKI by flagging those who are at risk.”

“Our next steps are to test the model through a technology clinical trial to see if putting intervention strategies in place does prevent these AKIs from taking place,” Dr. Scanlon concluded. “We are also going to move to ongoing monitoring of the model performance.”

Dr. Scanlon disclosed no conflicts of interest. The study did not receive specific funding.

A model that crunches data from routine blood tests can accurately identify cancer patients who will develop acute kidney injury (AKI) up to a month before it happens, according to a cohort study.

The algorithm spotted nearly 74% of the patients who went on to develop AKI within 30 days, providing a window for intervention and possibly prevention, according to investigators.

These results were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (abstract PR-11).

“Cancer patients are a high-risk population for AKI due to the nature of their treatment and illness,” said presenter Lauren A. Scanlon, PhD, a data scientist at The Christie NHS Foundation Trust in Huddersfield, England. “AKI causes a huge disruption in treatment and distress for the patient, so it would be amazing if we could, say, predict the AKI before it occurs and prevent it from even happening.”

U.K. health care providers are already using an algorithm to monitor patients’ creatinine levels, comparing new values against historic ones, Dr. Scanlon explained. When that algorithm detects AKI, it issues an alert that triggers implementation of an AKI care bundle, including measures such as fluid monitoring and medication review, within 24 hours.

Taking this concept further, Dr. Scanlon and colleagues developed a random forest model, a type of machine learning algorithm, that incorporates other markers from blood tests routinely obtained for all patients, with the aim of predicting AKI up to 30 days in advance.

“Using routinely collected blood test results will ensure that the model is applicable to all our patients and can be implemented in an automated manner,” Dr. Scanlon noted.

The investigators developed and trained the model using 597,403 blood test results from 48,865 patients undergoing cancer treatment between January 2017 and May 2020.

The model assigns patients to five categories of risk for AKI in the next 30 days: very low, low, medium, high, and very high.

“We wanted the model to output in this way so that it could be used by clinicians alongside their own insight and knowledge on a case-by-case basis,” Dr. Scanlon explained.

The investigators then prospectively validated the model and its risk categories in another 9,913 patients who underwent cancer treatment between June and August 2020.

Using a model threshold of medium risk or higher, the model correctly predicted AKI in 330 (73.8%) of the 447 patients in the validation cohort who ultimately developed AKI.

“This is pretty amazing and shows that this model really is working and can correctly detect these AKIs up to 30 days before they occur, giving a huge window to put in place preventive strategies,” Dr. Scanlon said.

Among the 154 patients in whom the model incorrectly predicted AKI, 9 patients had only a single follow-up blood test and 17 patients did not have any, leaving their actual outcomes unclear.

“Given that AKI detection uses blood tests, an AKI in these patients was never confirmed,” Dr. Scanlon noted. “So this could give a potential benefit of the model that we never intended: It could reduce undiagnosed AKI by flagging those who are at risk.”

“Our next steps are to test the model through a technology clinical trial to see if putting intervention strategies in place does prevent these AKIs from taking place,” Dr. Scanlon concluded. “We are also going to move to ongoing monitoring of the model performance.”

Dr. Scanlon disclosed no conflicts of interest. The study did not receive specific funding.

A model that crunches data from routine blood tests can accurately identify cancer patients who will develop acute kidney injury (AKI) up to a month before it happens, according to a cohort study.

The algorithm spotted nearly 74% of the patients who went on to develop AKI within 30 days, providing a window for intervention and possibly prevention, according to investigators.

These results were reported at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (abstract PR-11).

“Cancer patients are a high-risk population for AKI due to the nature of their treatment and illness,” said presenter Lauren A. Scanlon, PhD, a data scientist at The Christie NHS Foundation Trust in Huddersfield, England. “AKI causes a huge disruption in treatment and distress for the patient, so it would be amazing if we could, say, predict the AKI before it occurs and prevent it from even happening.”

U.K. health care providers are already using an algorithm to monitor patients’ creatinine levels, comparing new values against historic ones, Dr. Scanlon explained. When that algorithm detects AKI, it issues an alert that triggers implementation of an AKI care bundle, including measures such as fluid monitoring and medication review, within 24 hours.

Taking this concept further, Dr. Scanlon and colleagues developed a random forest model, a type of machine learning algorithm, that incorporates other markers from blood tests routinely obtained for all patients, with the aim of predicting AKI up to 30 days in advance.

“Using routinely collected blood test results will ensure that the model is applicable to all our patients and can be implemented in an automated manner,” Dr. Scanlon noted.

The investigators developed and trained the model using 597,403 blood test results from 48,865 patients undergoing cancer treatment between January 2017 and May 2020.

The model assigns patients to five categories of risk for AKI in the next 30 days: very low, low, medium, high, and very high.

“We wanted the model to output in this way so that it could be used by clinicians alongside their own insight and knowledge on a case-by-case basis,” Dr. Scanlon explained.

The investigators then prospectively validated the model and its risk categories in another 9,913 patients who underwent cancer treatment between June and August 2020.

Using a model threshold of medium risk or higher, the model correctly predicted AKI in 330 (73.8%) of the 447 patients in the validation cohort who ultimately developed AKI.

“This is pretty amazing and shows that this model really is working and can correctly detect these AKIs up to 30 days before they occur, giving a huge window to put in place preventive strategies,” Dr. Scanlon said.

Among the 154 patients in whom the model incorrectly predicted AKI, 9 patients had only a single follow-up blood test and 17 patients did not have any, leaving their actual outcomes unclear.

“Given that AKI detection uses blood tests, an AKI in these patients was never confirmed,” Dr. Scanlon noted. “So this could give a potential benefit of the model that we never intended: It could reduce undiagnosed AKI by flagging those who are at risk.”

“Our next steps are to test the model through a technology clinical trial to see if putting intervention strategies in place does prevent these AKIs from taking place,” Dr. Scanlon concluded. “We are also going to move to ongoing monitoring of the model performance.”

Dr. Scanlon disclosed no conflicts of interest. The study did not receive specific funding.

The first guidelines ever released for screening mammography for older survivors of breast cancer (>75 years) recommend that routine mammography be discontinued for women whose life expectancy is less than 5 years but that screening continue for those whose life expectancy is more than 10 years.

For women who have a life expectancy of 5-10 years, the guidelines recommend that consideration be given to discontinuing mammography.

Overall, the guidelines encourage shared decision-making that is individualized for each woman after weighing the benefits and harms associated with surveillance mammography and patient preferences.

The panel also recommended that patients with clinical findings and symptoms receive ongoing clinical breast examinations and diagnostic mammography and that patients be reassured that these practices will continue.

Guidelines on breast cancer screening for healthy women already “acknowledge the limitations of mammograms and the need to consider one’s health status and preferences when making decisions on how and when to stop routine mammograms,” said the article’s first author, Rachel A. Freedman, MD, MPH, of the Dana-Farber Cancer Institute, Boston.

However, “we don’t have this kind of consensus for women with a history of breast cancer,” she continued. “Current follow-up care guidelines simply state that women with a history of breast cancer with intact breasts should have annual mammography without any guidance.

“In practice, the use of mammograms is highly variable, with less than 50% of breast cancer survivors who have limited life expectancy having annual mammograms, according to survey data we have from prior work,” Dr. Freedman said in an interview.

The guidelines were published online Jan. 28 in JAMA Oncology.
 

Clinicians discuss how to have these discussions

As part of the process of developing these expert consensus guidelines, the researchers held several clinical focus groups that involved primary care physicians from Brigham and Women’s Hospital and oncology clinicians (including breast surgeons and medical oncologists) from the Dana-Farber Cancer Institute.

All clinicians felt that having expert guidelines and talking points to guide discussions would be helpful, the researchers report.

“However, some oncology clinicians felt that 75 years is often ‘too young’ to stop surveillance mammography and that 80 years may be a more comfortable age to stop routine testing,” they write. “Most clinicians felt that estimations of life expectancy, more than age, should inform the timing of this discussion.”

In contrast to primary and geriatric care clinicians, oncology clinicians reported discomfort with such discussions. They appreciated having the information but “felt it was easier to communicate findings indirectly, without specifically revealing life expectancy to patients. One oncology clinician, however, felt it would be ‘sneaky’ to calculate life expectancy without communicating this to patients, supporting more open discussions,” the authors report.

“All clinicians acknowledged that framing the conversation around patients’ low risk for in-breast cancer events and how mammography will not benefit them was more appealing than discussing life expectancy,” the researchers continue. Their literature review found that the risk of these individuals developing second breast cancers was similar to that of a healthy woman developing a first breast cancer, leading one clinician to comment: “If their risk is really equivalent to the general population – that is very powerful.”

“Some clinicians reported that they ‘focus on the risks’ or frame such discussions by asking: ‘If you were to find something on [a] mammogram, would you do anything about it?’ If a patient answered no, clinicians felt this was a signal to stop mammography,” they noted.
 

Literature review finds very low risk

Dr. Freedman and colleagues conducted a literature review of the risk for ipsilateral and contralateral breast cancer events among survivors and of the harms and benefits associated with mammography. Following the literature review, a multidisciplinary expert panel, which included patients and patient advocates, was convened to develop consensus guidelines.

The literature review confirmed that there was a low risk for in-breast cancer events in this population and that the risk was particularly low among patients who undergo treatment with endocrine therapy. Among those who did not receive systemic therapy for ERBB2-positive or triple-negative cancers, the rates of ipsilateral recurrence were estimated to be higher.

On the basis of the literature review, the estimated 10-year risk for in-breast cancer events ranged from 1% to 15% for ipsilateral breast cancers and from 1% to 5% for contralateral cancers. Among women in the same age group who did not have a history of breast cancer, the 5-year risk of developing the disease (average risk) was 2.2%.

The authors note that these findings mirror their estimates for new breast cancers among survivors who had low-risk disease. The findings are also similar to those cited in a large-scale mammography study, in which breast cancer survivors aged 70-80 years had a 1.1% annual risk for in-breast cancers. The risk was 0.7%-0.9% for similarly aged patients who did not have a history of breast cancer.

The benefits associated with mammography for older women are not well defined, but the literature suggests that mammography offers little to modest clinical benefit for patients in this age group. The limited benefits are likely because of the more than 10-year time lag that is needed to detect the small improvements in breast cancer mortality; slow-growing tumors generally do not affect the life expectancy of older women, they point out.

“Through our expert consensus process and after iterative feedback from clinicians, we created guidelines to support patients and clinicians in making individualized decisions on how and when to stop mammography,” said Dr. Freedman. “These guidelines are based on the risk of a breast cancer returning in the breast, one’s underlying health, and one’s preferences.”

The guidelines are also intended to provide information to patients on the benefits and harms of mammography in this setting, in addition to “how much we anticipate a mammogram may or may not continue to help a woman over time,” she said.

A companion guide for patients on these guidelines will be published in the coming months.

Dr. Freedman has received institutional clinical trial funding from Eisai and Puma Biotechnology outside the submitted work.

A version of this article first appeared on Medscape.com.

The first guidelines ever released for screening mammography for older survivors of breast cancer (>75 years) recommend that routine mammography be discontinued for women whose life expectancy is less than 5 years but that screening continue for those whose life expectancy is more than 10 years.

For women who have a life expectancy of 5-10 years, the guidelines recommend that consideration be given to discontinuing mammography.

Overall, the guidelines encourage shared decision-making that is individualized for each woman after weighing the benefits and harms associated with surveillance mammography and patient preferences.

The panel also recommended that patients with clinical findings and symptoms receive ongoing clinical breast examinations and diagnostic mammography and that patients be reassured that these practices will continue.

Guidelines on breast cancer screening for healthy women already “acknowledge the limitations of mammograms and the need to consider one’s health status and preferences when making decisions on how and when to stop routine mammograms,” said the article’s first author, Rachel A. Freedman, MD, MPH, of the Dana-Farber Cancer Institute, Boston.

However, “we don’t have this kind of consensus for women with a history of breast cancer,” she continued. “Current follow-up care guidelines simply state that women with a history of breast cancer with intact breasts should have annual mammography without any guidance.

“In practice, the use of mammograms is highly variable, with less than 50% of breast cancer survivors who have limited life expectancy having annual mammograms, according to survey data we have from prior work,” Dr. Freedman said in an interview.

The guidelines were published online Jan. 28 in JAMA Oncology.
 

Clinicians discuss how to have these discussions

As part of the process of developing these expert consensus guidelines, the researchers held several clinical focus groups that involved primary care physicians from Brigham and Women’s Hospital and oncology clinicians (including breast surgeons and medical oncologists) from the Dana-Farber Cancer Institute.

All clinicians felt that having expert guidelines and talking points to guide discussions would be helpful, the researchers report.

“However, some oncology clinicians felt that 75 years is often ‘too young’ to stop surveillance mammography and that 80 years may be a more comfortable age to stop routine testing,” they write. “Most clinicians felt that estimations of life expectancy, more than age, should inform the timing of this discussion.”

In contrast to primary and geriatric care clinicians, oncology clinicians reported discomfort with such discussions. They appreciated having the information but “felt it was easier to communicate findings indirectly, without specifically revealing life expectancy to patients. One oncology clinician, however, felt it would be ‘sneaky’ to calculate life expectancy without communicating this to patients, supporting more open discussions,” the authors report.

“All clinicians acknowledged that framing the conversation around patients’ low risk for in-breast cancer events and how mammography will not benefit them was more appealing than discussing life expectancy,” the researchers continue. Their literature review found that the risk of these individuals developing second breast cancers was similar to that of a healthy woman developing a first breast cancer, leading one clinician to comment: “If their risk is really equivalent to the general population – that is very powerful.”

“Some clinicians reported that they ‘focus on the risks’ or frame such discussions by asking: ‘If you were to find something on [a] mammogram, would you do anything about it?’ If a patient answered no, clinicians felt this was a signal to stop mammography,” they noted.
 

Literature review finds very low risk

Dr. Freedman and colleagues conducted a literature review of the risk for ipsilateral and contralateral breast cancer events among survivors and of the harms and benefits associated with mammography. Following the literature review, a multidisciplinary expert panel, which included patients and patient advocates, was convened to develop consensus guidelines.

The literature review confirmed that there was a low risk for in-breast cancer events in this population and that the risk was particularly low among patients who undergo treatment with endocrine therapy. Among those who did not receive systemic therapy for ERBB2-positive or triple-negative cancers, the rates of ipsilateral recurrence were estimated to be higher.

On the basis of the literature review, the estimated 10-year risk for in-breast cancer events ranged from 1% to 15% for ipsilateral breast cancers and from 1% to 5% for contralateral cancers. Among women in the same age group who did not have a history of breast cancer, the 5-year risk of developing the disease (average risk) was 2.2%.

The authors note that these findings mirror their estimates for new breast cancers among survivors who had low-risk disease. The findings are also similar to those cited in a large-scale mammography study, in which breast cancer survivors aged 70-80 years had a 1.1% annual risk for in-breast cancers. The risk was 0.7%-0.9% for similarly aged patients who did not have a history of breast cancer.

The benefits associated with mammography for older women are not well defined, but the literature suggests that mammography offers little to modest clinical benefit for patients in this age group. The limited benefits are likely because of the more than 10-year time lag that is needed to detect the small improvements in breast cancer mortality; slow-growing tumors generally do not affect the life expectancy of older women, they point out.

“Through our expert consensus process and after iterative feedback from clinicians, we created guidelines to support patients and clinicians in making individualized decisions on how and when to stop mammography,” said Dr. Freedman. “These guidelines are based on the risk of a breast cancer returning in the breast, one’s underlying health, and one’s preferences.”

The guidelines are also intended to provide information to patients on the benefits and harms of mammography in this setting, in addition to “how much we anticipate a mammogram may or may not continue to help a woman over time,” she said.

A companion guide for patients on these guidelines will be published in the coming months.

Dr. Freedman has received institutional clinical trial funding from Eisai and Puma Biotechnology outside the submitted work.

A version of this article first appeared on Medscape.com.

The first guidelines ever released for screening mammography for older survivors of breast cancer (>75 years) recommend that routine mammography be discontinued for women whose life expectancy is less than 5 years but that screening continue for those whose life expectancy is more than 10 years.

For women who have a life expectancy of 5-10 years, the guidelines recommend that consideration be given to discontinuing mammography.

Overall, the guidelines encourage shared decision-making that is individualized for each woman after weighing the benefits and harms associated with surveillance mammography and patient preferences.

The panel also recommended that patients with clinical findings and symptoms receive ongoing clinical breast examinations and diagnostic mammography and that patients be reassured that these practices will continue.

Guidelines on breast cancer screening for healthy women already “acknowledge the limitations of mammograms and the need to consider one’s health status and preferences when making decisions on how and when to stop routine mammograms,” said the article’s first author, Rachel A. Freedman, MD, MPH, of the Dana-Farber Cancer Institute, Boston.

However, “we don’t have this kind of consensus for women with a history of breast cancer,” she continued. “Current follow-up care guidelines simply state that women with a history of breast cancer with intact breasts should have annual mammography without any guidance.

“In practice, the use of mammograms is highly variable, with less than 50% of breast cancer survivors who have limited life expectancy having annual mammograms, according to survey data we have from prior work,” Dr. Freedman said in an interview.

The guidelines were published online Jan. 28 in JAMA Oncology.
 

Clinicians discuss how to have these discussions

As part of the process of developing these expert consensus guidelines, the researchers held several clinical focus groups that involved primary care physicians from Brigham and Women’s Hospital and oncology clinicians (including breast surgeons and medical oncologists) from the Dana-Farber Cancer Institute.

All clinicians felt that having expert guidelines and talking points to guide discussions would be helpful, the researchers report.

“However, some oncology clinicians felt that 75 years is often ‘too young’ to stop surveillance mammography and that 80 years may be a more comfortable age to stop routine testing,” they write. “Most clinicians felt that estimations of life expectancy, more than age, should inform the timing of this discussion.”

In contrast to primary and geriatric care clinicians, oncology clinicians reported discomfort with such discussions. They appreciated having the information but “felt it was easier to communicate findings indirectly, without specifically revealing life expectancy to patients. One oncology clinician, however, felt it would be ‘sneaky’ to calculate life expectancy without communicating this to patients, supporting more open discussions,” the authors report.

“All clinicians acknowledged that framing the conversation around patients’ low risk for in-breast cancer events and how mammography will not benefit them was more appealing than discussing life expectancy,” the researchers continue. Their literature review found that the risk of these individuals developing second breast cancers was similar to that of a healthy woman developing a first breast cancer, leading one clinician to comment: “If their risk is really equivalent to the general population – that is very powerful.”

“Some clinicians reported that they ‘focus on the risks’ or frame such discussions by asking: ‘If you were to find something on [a] mammogram, would you do anything about it?’ If a patient answered no, clinicians felt this was a signal to stop mammography,” they noted.
 

Literature review finds very low risk

Dr. Freedman and colleagues conducted a literature review of the risk for ipsilateral and contralateral breast cancer events among survivors and of the harms and benefits associated with mammography. Following the literature review, a multidisciplinary expert panel, which included patients and patient advocates, was convened to develop consensus guidelines.

The literature review confirmed that there was a low risk for in-breast cancer events in this population and that the risk was particularly low among patients who undergo treatment with endocrine therapy. Among those who did not receive systemic therapy for ERBB2-positive or triple-negative cancers, the rates of ipsilateral recurrence were estimated to be higher.

On the basis of the literature review, the estimated 10-year risk for in-breast cancer events ranged from 1% to 15% for ipsilateral breast cancers and from 1% to 5% for contralateral cancers. Among women in the same age group who did not have a history of breast cancer, the 5-year risk of developing the disease (average risk) was 2.2%.

The authors note that these findings mirror their estimates for new breast cancers among survivors who had low-risk disease. The findings are also similar to those cited in a large-scale mammography study, in which breast cancer survivors aged 70-80 years had a 1.1% annual risk for in-breast cancers. The risk was 0.7%-0.9% for similarly aged patients who did not have a history of breast cancer.

The benefits associated with mammography for older women are not well defined, but the literature suggests that mammography offers little to modest clinical benefit for patients in this age group. The limited benefits are likely because of the more than 10-year time lag that is needed to detect the small improvements in breast cancer mortality; slow-growing tumors generally do not affect the life expectancy of older women, they point out.

“Through our expert consensus process and after iterative feedback from clinicians, we created guidelines to support patients and clinicians in making individualized decisions on how and when to stop mammography,” said Dr. Freedman. “These guidelines are based on the risk of a breast cancer returning in the breast, one’s underlying health, and one’s preferences.”

The guidelines are also intended to provide information to patients on the benefits and harms of mammography in this setting, in addition to “how much we anticipate a mammogram may or may not continue to help a woman over time,” she said.

A companion guide for patients on these guidelines will be published in the coming months.

Dr. Freedman has received institutional clinical trial funding from Eisai and Puma Biotechnology outside the submitted work.

A version of this article first appeared on Medscape.com.

The combination of liothyronine (LT₃) with levothyroxine (LT₄) for the treatment of hypothyroidism shows no evidence of any increased risk of breast cancer in a large, long-term study, contrary to concerns raised in some prior trials.

“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online Jan. 5 in Thyroid.

“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.

Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.

“The findings of these [prior] studies were concerning as they suggested an association between T₃ and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T₃ on the estrogen receptor,” Dr. Nguyen of the division of endocrinology, diabetes & metabolism at Keck Medical Center of University of Southern California, Los Angeles, told this news organization.

“Therefore, the findings of this paper provide some reassurance, which is important because, as the paper states, the use of T₃ is becoming increasingly common.”
 

Many patients with hypothyroidism opt to add liothyronine

Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T₄) to high-normal levels, it may potentially lower triiodothyronine (T₃) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.

To offset the effect, some add liothyronine (a synthetic version of T₃) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.

To further investigate, Dr. Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.

Among the individuals, 11,147 had made at least three purchases of LT₃, including combinations with LT₄. LT₄-only users were an average age of 54.4 years, and the average age of those who also took LT₃ was 44.7 years.

Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT₃ plus LT₄ versus LT₄ alone (hazard ratio, 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.

Further evaluation of women as well as men showed those treated with LT₃ also had no increased incidence of any cancer (HR, 0.97).

In dose-adjusted models, LT₃ treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.

However, the implications of these latter results remain uncertain, first author Dr. Planck said in an interview.

“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.

 

LT3 treatment still considered ‘experimental’

Despite the dramatic increase in LT₃ prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT₄ alone in terms of hypothyroid symptoms, quality of life, or patient preference.

As a result, many international guidelines still consider the combination-treatment approach to be experimental.

Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T₃ levels to breast cancer in postmenopausal women.

As for the mechanism, some small experimental studies have suggested an estrogenlike effect whereby T₃ could enhance the proliferation of breast cancer cells.

On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.

However, the current findings should lay some of those concerns to rest, Dr. Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”

“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT₃ and LT₄ treatment.”

The authors and Nguyen have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The combination of liothyronine (LT₃) with levothyroxine (LT₄) for the treatment of hypothyroidism shows no evidence of any increased risk of breast cancer in a large, long-term study, contrary to concerns raised in some prior trials.

“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online Jan. 5 in Thyroid.

“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.

Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.

“The findings of these [prior] studies were concerning as they suggested an association between T₃ and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T₃ on the estrogen receptor,” Dr. Nguyen of the division of endocrinology, diabetes & metabolism at Keck Medical Center of University of Southern California, Los Angeles, told this news organization.

“Therefore, the findings of this paper provide some reassurance, which is important because, as the paper states, the use of T₃ is becoming increasingly common.”
 

Many patients with hypothyroidism opt to add liothyronine

Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T₄) to high-normal levels, it may potentially lower triiodothyronine (T₃) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.

To offset the effect, some add liothyronine (a synthetic version of T₃) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.

To further investigate, Dr. Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.

Among the individuals, 11,147 had made at least three purchases of LT₃, including combinations with LT₄. LT₄-only users were an average age of 54.4 years, and the average age of those who also took LT₃ was 44.7 years.

Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT₃ plus LT₄ versus LT₄ alone (hazard ratio, 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.

Further evaluation of women as well as men showed those treated with LT₃ also had no increased incidence of any cancer (HR, 0.97).

In dose-adjusted models, LT₃ treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.

However, the implications of these latter results remain uncertain, first author Dr. Planck said in an interview.

“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.

 

LT3 treatment still considered ‘experimental’

Despite the dramatic increase in LT₃ prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT₄ alone in terms of hypothyroid symptoms, quality of life, or patient preference.

As a result, many international guidelines still consider the combination-treatment approach to be experimental.

Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T₃ levels to breast cancer in postmenopausal women.

As for the mechanism, some small experimental studies have suggested an estrogenlike effect whereby T₃ could enhance the proliferation of breast cancer cells.

On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.

However, the current findings should lay some of those concerns to rest, Dr. Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”

“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT₃ and LT₄ treatment.”

The authors and Nguyen have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The combination of liothyronine (LT₃) with levothyroxine (LT₄) for the treatment of hypothyroidism shows no evidence of any increased risk of breast cancer in a large, long-term study, contrary to concerns raised in some prior trials.

“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online Jan. 5 in Thyroid.

“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.

Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.

“The findings of these [prior] studies were concerning as they suggested an association between T₃ and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T₃ on the estrogen receptor,” Dr. Nguyen of the division of endocrinology, diabetes & metabolism at Keck Medical Center of University of Southern California, Los Angeles, told this news organization.

“Therefore, the findings of this paper provide some reassurance, which is important because, as the paper states, the use of T₃ is becoming increasingly common.”
 

Many patients with hypothyroidism opt to add liothyronine

Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T₄) to high-normal levels, it may potentially lower triiodothyronine (T₃) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.

To offset the effect, some add liothyronine (a synthetic version of T₃) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.

To further investigate, Dr. Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.

Among the individuals, 11,147 had made at least three purchases of LT₃, including combinations with LT₄. LT₄-only users were an average age of 54.4 years, and the average age of those who also took LT₃ was 44.7 years.

Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT₃ plus LT₄ versus LT₄ alone (hazard ratio, 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.

Further evaluation of women as well as men showed those treated with LT₃ also had no increased incidence of any cancer (HR, 0.97).

In dose-adjusted models, LT₃ treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.

However, the implications of these latter results remain uncertain, first author Dr. Planck said in an interview.

“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.

 

LT3 treatment still considered ‘experimental’

Despite the dramatic increase in LT₃ prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT₄ alone in terms of hypothyroid symptoms, quality of life, or patient preference.

As a result, many international guidelines still consider the combination-treatment approach to be experimental.

Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T₃ levels to breast cancer in postmenopausal women.

As for the mechanism, some small experimental studies have suggested an estrogenlike effect whereby T₃ could enhance the proliferation of breast cancer cells.

On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.

However, the current findings should lay some of those concerns to rest, Dr. Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”

“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT₃ and LT₄ treatment.”

The authors and Nguyen have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new tool for predicting the risk of severe chemotherapy toxicity in older adults with early-stage breast cancer outperforms existing models and should help older patients and physicians make treatment decisions with more confidence, according to investigators.

They devised and tested the tool, called the Cancer and Aging Research Group–Breast Cancer (CARG-BC) score, in two cohorts of patients aged 65 years or older with stage I-III breast cancer.

The area under the curve for predicting grade 3-5 toxicity was 0.75 in the development cohort and 0.69 in the validation cohort, for a combined AUC of 0.73.

The CARG-BC score outperformed both Karnofsky performance status (AUC, 0.50) and the Cancer and Aging Research Group Chemotherapy Toxicity Tool (AUC, 0.56).

CARG-BC risk groups were also associated with hospitalizations, dose modifications, and early termination of treatment.

Allison Magnuson, DO, of the University of Rochester (N.Y.), and colleagues described these results in the Journal of Clinical Oncology.
 

About CARG-BC

To calculate a patient’s CARG-BC score, the researchers added up points assigned to eight independent predictors of grade 3-5 chemotherapy toxicity:

• Planned anthracycline use (1 point)
• Stage II or III disease (3 points)
• Planned treatment duration longer than 3 months (4 points)
• Abnormal liver function (3 points)
• Low hemoglobin level (3 points)
• A fall in the previous 6 months (4 points)
• Limited ability to walk more than 1 mile (3 points)
• Lack of social support (3 points)

Patients with scores of 0-5 have a low risk, those with scores of 6-11 have an intermediate risk, and those with scores of 12 or above have a high risk of grade 3-5 toxicity.
 

Patient characteristics and results

There were 283 patients in the development cohort and 190 in the validation cohort. There were no significant demographic, disease, or treatment differences between the cohorts.

All patients had a mean age of 70.5 years, 36.2% had stage I disease, 42.9% had stage II, and 20.9% had stage III disease. Three-quarters of patients were non-Hispanic White, and 99.4% were women. Roughly a third of patients had received an anthracycline-based regimen.

Overall, about a quarter of patients had an unplanned dose reduction (24%), dose delay (26%), stopped treatment early (24%), or were hospitalized during treatment (23%). All of these occurrences were more likely in intermediate- and high-risk patients versus low-risk patients (P < .001).

In the development cohort, 19% of low-risk patients, 54% of intermediate-risk patients, and 87% of high-risk patients developed grade 3-5 chemotherapy toxicity.

Compared with the 93 patients in the low-risk group, the odds of toxicity was almost 5 times greater for the 159 intermediate-risk subjects, and 28 times greater for the 30 high-risk subjects.

In the validation cohort, grade 3-5 toxicity rates were 27% in the low-risk group, 45% in the intermediate-risk group, and 76% in the high-risk group.

This study had its limitations, including that a majority of subjects (72.2%) had a college education, and the validation cohort was accrued from the same 16 institutions as the development cohort.

“Further validation in a more diverse population should be considered,” the investigators wrote.
 

A ‘useful’ tool for guiding therapy

The investigators noted that chemotherapy is a complex decision for older adults with stage I-III breast cancer. While it may be indicated, chemotherapy is underused often because of the higher risk of severe toxicity in older people.

“Unfortunately, older adults aged 65 and over, who comprise about half of all breast cancer diagnoses, are significantly less likely to be offered chemotherapy compared to younger patients – sometimes because their doctors fear they won’t be able to tolerate it,” investigator Mina Sedrak, MD, of City of Hope National Medical Center in Duarte, Calif., said in a press release.

The CARG-BC score may be useful to direct therapy in older adults with early-stage breast cancer, the investigators wrote. They noted that intensifying supportive care and developing modified treatment regimens may be appropriate for patients at higher risk for toxicity.

“Although this score should not be used as the only factor in deciding whether to administer and/or alter the dose or schedule of chemotherapy, the CARG-BC score can be used to facilitate this complex decision-making process, along with clinical judgment and patient preferences,” they wrote.

“I think this is a great tool. [It] will be helpful to me to have a more accurate conversation with geriatric patients about the actual risk/benefit ratio for chemotherapy in early breast cancer,” said Amy Tiersten, MD, of Mount Sinai Hospital in New York, when asked for comment.

“If routinely implemented, it may help reduce age bias and also identify older patients who may look well but may be vulnerable and quickly decompensate while undergoing treatment,” said Lidia Schapira, MD, of Stanford (Calif.) University. “Importantly, it can be used to guide conversations about trade-offs and to start a frank conversation about an older patient’s fears and concerns about treatment.”

This research was funded by the National Institute on Aging, the Breast Cancer Research Foundation, and the Center for Cancer and Aging at City of Hope. The investigators, Dr. Schapira, and Dr. Tiersten had no relevant disclosures.

aotto@mdedge.com

A new tool for predicting the risk of severe chemotherapy toxicity in older adults with early-stage breast cancer outperforms existing models and should help older patients and physicians make treatment decisions with more confidence, according to investigators.

They devised and tested the tool, called the Cancer and Aging Research Group–Breast Cancer (CARG-BC) score, in two cohorts of patients aged 65 years or older with stage I-III breast cancer.

The area under the curve for predicting grade 3-5 toxicity was 0.75 in the development cohort and 0.69 in the validation cohort, for a combined AUC of 0.73.

The CARG-BC score outperformed both Karnofsky performance status (AUC, 0.50) and the Cancer and Aging Research Group Chemotherapy Toxicity Tool (AUC, 0.56).

CARG-BC risk groups were also associated with hospitalizations, dose modifications, and early termination of treatment.

Allison Magnuson, DO, of the University of Rochester (N.Y.), and colleagues described these results in the Journal of Clinical Oncology.
 

About CARG-BC

To calculate a patient’s CARG-BC score, the researchers added up points assigned to eight independent predictors of grade 3-5 chemotherapy toxicity:

• Planned anthracycline use (1 point)
• Stage II or III disease (3 points)
• Planned treatment duration longer than 3 months (4 points)
• Abnormal liver function (3 points)
• Low hemoglobin level (3 points)
• A fall in the previous 6 months (4 points)
• Limited ability to walk more than 1 mile (3 points)
• Lack of social support (3 points)

Patients with scores of 0-5 have a low risk, those with scores of 6-11 have an intermediate risk, and those with scores of 12 or above have a high risk of grade 3-5 toxicity.
 

Patient characteristics and results

There were 283 patients in the development cohort and 190 in the validation cohort. There were no significant demographic, disease, or treatment differences between the cohorts.

All patients had a mean age of 70.5 years, 36.2% had stage I disease, 42.9% had stage II, and 20.9% had stage III disease. Three-quarters of patients were non-Hispanic White, and 99.4% were women. Roughly a third of patients had received an anthracycline-based regimen.

Overall, about a quarter of patients had an unplanned dose reduction (24%), dose delay (26%), stopped treatment early (24%), or were hospitalized during treatment (23%). All of these occurrences were more likely in intermediate- and high-risk patients versus low-risk patients (P < .001).

In the development cohort, 19% of low-risk patients, 54% of intermediate-risk patients, and 87% of high-risk patients developed grade 3-5 chemotherapy toxicity.

Compared with the 93 patients in the low-risk group, the odds of toxicity was almost 5 times greater for the 159 intermediate-risk subjects, and 28 times greater for the 30 high-risk subjects.

In the validation cohort, grade 3-5 toxicity rates were 27% in the low-risk group, 45% in the intermediate-risk group, and 76% in the high-risk group.

This study had its limitations, including that a majority of subjects (72.2%) had a college education, and the validation cohort was accrued from the same 16 institutions as the development cohort.

“Further validation in a more diverse population should be considered,” the investigators wrote.
 

A ‘useful’ tool for guiding therapy

The investigators noted that chemotherapy is a complex decision for older adults with stage I-III breast cancer. While it may be indicated, chemotherapy is underused often because of the higher risk of severe toxicity in older people.

“Unfortunately, older adults aged 65 and over, who comprise about half of all breast cancer diagnoses, are significantly less likely to be offered chemotherapy compared to younger patients – sometimes because their doctors fear they won’t be able to tolerate it,” investigator Mina Sedrak, MD, of City of Hope National Medical Center in Duarte, Calif., said in a press release.

The CARG-BC score may be useful to direct therapy in older adults with early-stage breast cancer, the investigators wrote. They noted that intensifying supportive care and developing modified treatment regimens may be appropriate for patients at higher risk for toxicity.

“Although this score should not be used as the only factor in deciding whether to administer and/or alter the dose or schedule of chemotherapy, the CARG-BC score can be used to facilitate this complex decision-making process, along with clinical judgment and patient preferences,” they wrote.

“I think this is a great tool. [It] will be helpful to me to have a more accurate conversation with geriatric patients about the actual risk/benefit ratio for chemotherapy in early breast cancer,” said Amy Tiersten, MD, of Mount Sinai Hospital in New York, when asked for comment.

“If routinely implemented, it may help reduce age bias and also identify older patients who may look well but may be vulnerable and quickly decompensate while undergoing treatment,” said Lidia Schapira, MD, of Stanford (Calif.) University. “Importantly, it can be used to guide conversations about trade-offs and to start a frank conversation about an older patient’s fears and concerns about treatment.”

This research was funded by the National Institute on Aging, the Breast Cancer Research Foundation, and the Center for Cancer and Aging at City of Hope. The investigators, Dr. Schapira, and Dr. Tiersten had no relevant disclosures.

aotto@mdedge.com

A new tool for predicting the risk of severe chemotherapy toxicity in older adults with early-stage breast cancer outperforms existing models and should help older patients and physicians make treatment decisions with more confidence, according to investigators.

They devised and tested the tool, called the Cancer and Aging Research Group–Breast Cancer (CARG-BC) score, in two cohorts of patients aged 65 years or older with stage I-III breast cancer.

The area under the curve for predicting grade 3-5 toxicity was 0.75 in the development cohort and 0.69 in the validation cohort, for a combined AUC of 0.73.

The CARG-BC score outperformed both Karnofsky performance status (AUC, 0.50) and the Cancer and Aging Research Group Chemotherapy Toxicity Tool (AUC, 0.56).

CARG-BC risk groups were also associated with hospitalizations, dose modifications, and early termination of treatment.

Allison Magnuson, DO, of the University of Rochester (N.Y.), and colleagues described these results in the Journal of Clinical Oncology.
 

About CARG-BC

To calculate a patient’s CARG-BC score, the researchers added up points assigned to eight independent predictors of grade 3-5 chemotherapy toxicity:

• Planned anthracycline use (1 point)
• Stage II or III disease (3 points)
• Planned treatment duration longer than 3 months (4 points)
• Abnormal liver function (3 points)
• Low hemoglobin level (3 points)
• A fall in the previous 6 months (4 points)
• Limited ability to walk more than 1 mile (3 points)
• Lack of social support (3 points)

Patients with scores of 0-5 have a low risk, those with scores of 6-11 have an intermediate risk, and those with scores of 12 or above have a high risk of grade 3-5 toxicity.
 

Patient characteristics and results

There were 283 patients in the development cohort and 190 in the validation cohort. There were no significant demographic, disease, or treatment differences between the cohorts.

All patients had a mean age of 70.5 years, 36.2% had stage I disease, 42.9% had stage II, and 20.9% had stage III disease. Three-quarters of patients were non-Hispanic White, and 99.4% were women. Roughly a third of patients had received an anthracycline-based regimen.

Overall, about a quarter of patients had an unplanned dose reduction (24%), dose delay (26%), stopped treatment early (24%), or were hospitalized during treatment (23%). All of these occurrences were more likely in intermediate- and high-risk patients versus low-risk patients (P < .001).

In the development cohort, 19% of low-risk patients, 54% of intermediate-risk patients, and 87% of high-risk patients developed grade 3-5 chemotherapy toxicity.

Compared with the 93 patients in the low-risk group, the odds of toxicity was almost 5 times greater for the 159 intermediate-risk subjects, and 28 times greater for the 30 high-risk subjects.

In the validation cohort, grade 3-5 toxicity rates were 27% in the low-risk group, 45% in the intermediate-risk group, and 76% in the high-risk group.

This study had its limitations, including that a majority of subjects (72.2%) had a college education, and the validation cohort was accrued from the same 16 institutions as the development cohort.

“Further validation in a more diverse population should be considered,” the investigators wrote.
 

A ‘useful’ tool for guiding therapy

The investigators noted that chemotherapy is a complex decision for older adults with stage I-III breast cancer. While it may be indicated, chemotherapy is underused often because of the higher risk of severe toxicity in older people.

“Unfortunately, older adults aged 65 and over, who comprise about half of all breast cancer diagnoses, are significantly less likely to be offered chemotherapy compared to younger patients – sometimes because their doctors fear they won’t be able to tolerate it,” investigator Mina Sedrak, MD, of City of Hope National Medical Center in Duarte, Calif., said in a press release.

The CARG-BC score may be useful to direct therapy in older adults with early-stage breast cancer, the investigators wrote. They noted that intensifying supportive care and developing modified treatment regimens may be appropriate for patients at higher risk for toxicity.

“Although this score should not be used as the only factor in deciding whether to administer and/or alter the dose or schedule of chemotherapy, the CARG-BC score can be used to facilitate this complex decision-making process, along with clinical judgment and patient preferences,” they wrote.

“I think this is a great tool. [It] will be helpful to me to have a more accurate conversation with geriatric patients about the actual risk/benefit ratio for chemotherapy in early breast cancer,” said Amy Tiersten, MD, of Mount Sinai Hospital in New York, when asked for comment.

“If routinely implemented, it may help reduce age bias and also identify older patients who may look well but may be vulnerable and quickly decompensate while undergoing treatment,” said Lidia Schapira, MD, of Stanford (Calif.) University. “Importantly, it can be used to guide conversations about trade-offs and to start a frank conversation about an older patient’s fears and concerns about treatment.”

This research was funded by the National Institute on Aging, the Breast Cancer Research Foundation, and the Center for Cancer and Aging at City of Hope. The investigators, Dr. Schapira, and Dr. Tiersten had no relevant disclosures.

aotto@mdedge.com

For patients with intermediate- or high-risk ductal carcinoma in situ (DCIS) treated with conservative surgery and whole breast irradiation (WBI), adding a boost dose to the tumor bed significantly reduced the risk of recurrence, regardless of WBI fractionation, in the BIG-3-07/TROG 07.01 trial.

Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.

Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.

Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.

The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:

• WBI at 50 Gy in 25 fractions
• WBI at 42.5 Gy in 16 fractions
• WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
• WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.

In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.

All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
 

Giving a boost to better outcomes

The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.

There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).

The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).

The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).

There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).

Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
 

Reduce the boost dose?

A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.

“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.

“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.

Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.

Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.

The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.

For patients with intermediate- or high-risk ductal carcinoma in situ (DCIS) treated with conservative surgery and whole breast irradiation (WBI), adding a boost dose to the tumor bed significantly reduced the risk of recurrence, regardless of WBI fractionation, in the BIG-3-07/TROG 07.01 trial.

Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.

Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.

Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.

The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:

• WBI at 50 Gy in 25 fractions
• WBI at 42.5 Gy in 16 fractions
• WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
• WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.

In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.

All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
 

Giving a boost to better outcomes

The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.

There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).

The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).

The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).

There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).

Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
 

Reduce the boost dose?

A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.

“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.

“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.

Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.

Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.

The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.

For patients with intermediate- or high-risk ductal carcinoma in situ (DCIS) treated with conservative surgery and whole breast irradiation (WBI), adding a boost dose to the tumor bed significantly reduced the risk of recurrence, regardless of WBI fractionation, in the BIG-3-07/TROG 07.01 trial.

Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.

Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.

Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.

The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:

• WBI at 50 Gy in 25 fractions
• WBI at 42.5 Gy in 16 fractions
• WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
• WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.

In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.

All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
 

Giving a boost to better outcomes

The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.

There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).

The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).

The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).

There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).

Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
 

Reduce the boost dose?

A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.

“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.

“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.

Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.

Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.

The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.

For the second year in a row, mortality from cancer has fallen in the United States, driven largely by reductions in the incidence of, and death from, non–small cell lung cancer (NSCLC) in men and women, according to a new report from the American Cancer Society.

The study was published online Jan. 12 in CA: A Cancer Journal for Clinicians.

“Mortality rates are a better indicator of progress against cancer than incidence or survival because they are less affected by biases resulting from changes in detection practices,” wrote the authors, led by Rebecca Siegel, MPH, American Cancer Society, Atlanta.  

“The overall drop of 31% as of 2018 [since the early 1990s] translates to an estimated 3,188,500 fewer cancer deaths (2,170,700 in men and 1,017,800 in women) than what would have occurred if mortality rates had remained at their peak,” the researchers added.

Lung cancer accounted for 46% of the total decline in cancer mortality in the past 5 years, with a record, single-year drop of 2.4% between 2017 and 2018.

The recent and rapid reductions in lung cancer mortality reflect better treatments for NSCLC, the authors suggested. For example, survival rates at 2 years have increased from 34% for patients diagnosed with NSCLC between 2009 and 2010 to 42% for those diagnosed during 2015 and 2016 – an absolute gain of 5%-6% in survival odds for every stage of diagnosis.

On a more somber note, the authors warned that COVID-19 is predicted to have a negative impact on both the diagnosis and outcomes of patients with cancer in the near future.  

“We anticipate that disruptions in access to cancer care in 2020 will lead to downstream increases in advanced stage diagnoses that may impede progress in reducing cancer mortality rates in the years to come,” Ms. Siegel said in a statement.
 

New cancer cases

The report provides an estimated number of new cancer cases and deaths in 2021 in the United States (nationally and state-by-state) based on the most current population-based data for cancer incidence through 2017 and for mortality through 2018. “An estimated 608,570 Americans will die from cancer in 2021, corresponding to more than 1600 deaths per day,” Ms. Siegel and colleagues reported.

The greatest number of deaths are predicted to be from the most common cancers: Lung, prostate, and colorectal cancer in men and lung, breast, and colorectal cancer in women, they added. However, the mortality rates for all four cancers are continuing to fall.

As of 2018, the death rate from lung cancer had dropped by 54% among males and by 30% among females over the past few decades, the investigators noted.

Mortality from female breast cancer has dropped by 41% since 1989; by 52% for prostate cancer since 1993; and by 53% and 59% for colorectal cancer for men (since 1980) and women (since 1969), respectively.

“However, in recent years, mortality declines have slowed for breast cancer and [colorectal cancer] and have halted for prostate cancer,” the researchers noted.

In contrast, the pace of the annual decline in lung cancer mortality doubled among men from 3.1% between 2009 and 2013 to 5.5% between 2014 and 2018, and from 1.8% to 4.4% among women during the same time intervals.
 

Increase in incidence at common sites

Despite the steady progress in mortality for most cancers, “rates continue to increase for some common sites,” Ms. Siegel and colleagues reported.

For example, death rates from uterine corpus cancer have accelerated from the late 1990s at twice the pace of the increase in its incidence. Death rates also have increased for cancers of the oral cavity and pharynx – although in this cancer, increases in mortality parallel an increase in its incidence. 

“Pancreatic cancer death rates [in turn] continued to increase slowly in men ... but remained stable in women, despite incidence [rates] rising by about 1% per year in both sexes,” the authors observed.

Meanwhile, the incidence of cervical cancer, although declining for decades overall, is increasing for patients who present with more distant-stage disease as well as cervical adenocarcinoma, both of which are often undetected by cytology.

“These findings underscore the need for more targeted efforts to increase both HPV [human papillomavirus] vaccination among all individuals aged [26 and younger] and primary HPV testing or HPV/cytology co-testing every 5 years among women beginning at age 25,” the authors emphasized.

On a more positive note, the long-term increase in mortality from liver cancer has recently slowed among women and has stabilized among men, they added.

Once again, disparities in both cancer occurrence and outcomes varied considerably between racial and ethnic groups. For example, cancer is the leading cause of death in people who are Hispanic, Asian American, and Alaska Native. Survival rates at 5 years for almost all cancers are still higher for White patients than for Black patients, although the disparity in cancer mortality between Black persons and White persons has declined to 13% from a peak of 33% in 1993.

Geographic disparities in cancer mortality rates still prevail; the rates are largest for preventable cancers such as lung and cervical cancer, for which mortality varies by as much as fivefold across states.

And although cancer remains the second most common cause of death among children, death rates from cancer have continuously declined over time among both children and adolescents, largely the result of dramatic declines in death rates from leukemia in both age groups.

The study authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For the second year in a row, mortality from cancer has fallen in the United States, driven largely by reductions in the incidence of, and death from, non–small cell lung cancer (NSCLC) in men and women, according to a new report from the American Cancer Society.

The study was published online Jan. 12 in CA: A Cancer Journal for Clinicians.

“Mortality rates are a better indicator of progress against cancer than incidence or survival because they are less affected by biases resulting from changes in detection practices,” wrote the authors, led by Rebecca Siegel, MPH, American Cancer Society, Atlanta.  

“The overall drop of 31% as of 2018 [since the early 1990s] translates to an estimated 3,188,500 fewer cancer deaths (2,170,700 in men and 1,017,800 in women) than what would have occurred if mortality rates had remained at their peak,” the researchers added.

Lung cancer accounted for 46% of the total decline in cancer mortality in the past 5 years, with a record, single-year drop of 2.4% between 2017 and 2018.

The recent and rapid reductions in lung cancer mortality reflect better treatments for NSCLC, the authors suggested. For example, survival rates at 2 years have increased from 34% for patients diagnosed with NSCLC between 2009 and 2010 to 42% for those diagnosed during 2015 and 2016 – an absolute gain of 5%-6% in survival odds for every stage of diagnosis.

On a more somber note, the authors warned that COVID-19 is predicted to have a negative impact on both the diagnosis and outcomes of patients with cancer in the near future.  

“We anticipate that disruptions in access to cancer care in 2020 will lead to downstream increases in advanced stage diagnoses that may impede progress in reducing cancer mortality rates in the years to come,” Ms. Siegel said in a statement.
 

New cancer cases

The report provides an estimated number of new cancer cases and deaths in 2021 in the United States (nationally and state-by-state) based on the most current population-based data for cancer incidence through 2017 and for mortality through 2018. “An estimated 608,570 Americans will die from cancer in 2021, corresponding to more than 1600 deaths per day,” Ms. Siegel and colleagues reported.

The greatest number of deaths are predicted to be from the most common cancers: Lung, prostate, and colorectal cancer in men and lung, breast, and colorectal cancer in women, they added. However, the mortality rates for all four cancers are continuing to fall.

As of 2018, the death rate from lung cancer had dropped by 54% among males and by 30% among females over the past few decades, the investigators noted.

Mortality from female breast cancer has dropped by 41% since 1989; by 52% for prostate cancer since 1993; and by 53% and 59% for colorectal cancer for men (since 1980) and women (since 1969), respectively.

“However, in recent years, mortality declines have slowed for breast cancer and [colorectal cancer] and have halted for prostate cancer,” the researchers noted.

In contrast, the pace of the annual decline in lung cancer mortality doubled among men from 3.1% between 2009 and 2013 to 5.5% between 2014 and 2018, and from 1.8% to 4.4% among women during the same time intervals.
 

Increase in incidence at common sites

Despite the steady progress in mortality for most cancers, “rates continue to increase for some common sites,” Ms. Siegel and colleagues reported.

For example, death rates from uterine corpus cancer have accelerated from the late 1990s at twice the pace of the increase in its incidence. Death rates also have increased for cancers of the oral cavity and pharynx – although in this cancer, increases in mortality parallel an increase in its incidence. 

“Pancreatic cancer death rates [in turn] continued to increase slowly in men ... but remained stable in women, despite incidence [rates] rising by about 1% per year in both sexes,” the authors observed.

Meanwhile, the incidence of cervical cancer, although declining for decades overall, is increasing for patients who present with more distant-stage disease as well as cervical adenocarcinoma, both of which are often undetected by cytology.

“These findings underscore the need for more targeted efforts to increase both HPV [human papillomavirus] vaccination among all individuals aged [26 and younger] and primary HPV testing or HPV/cytology co-testing every 5 years among women beginning at age 25,” the authors emphasized.

On a more positive note, the long-term increase in mortality from liver cancer has recently slowed among women and has stabilized among men, they added.

Once again, disparities in both cancer occurrence and outcomes varied considerably between racial and ethnic groups. For example, cancer is the leading cause of death in people who are Hispanic, Asian American, and Alaska Native. Survival rates at 5 years for almost all cancers are still higher for White patients than for Black patients, although the disparity in cancer mortality between Black persons and White persons has declined to 13% from a peak of 33% in 1993.

Geographic disparities in cancer mortality rates still prevail; the rates are largest for preventable cancers such as lung and cervical cancer, for which mortality varies by as much as fivefold across states.

And although cancer remains the second most common cause of death among children, death rates from cancer have continuously declined over time among both children and adolescents, largely the result of dramatic declines in death rates from leukemia in both age groups.

The study authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For the second year in a row, mortality from cancer has fallen in the United States, driven largely by reductions in the incidence of, and death from, non–small cell lung cancer (NSCLC) in men and women, according to a new report from the American Cancer Society.

The study was published online Jan. 12 in CA: A Cancer Journal for Clinicians.

“Mortality rates are a better indicator of progress against cancer than incidence or survival because they are less affected by biases resulting from changes in detection practices,” wrote the authors, led by Rebecca Siegel, MPH, American Cancer Society, Atlanta.  

“The overall drop of 31% as of 2018 [since the early 1990s] translates to an estimated 3,188,500 fewer cancer deaths (2,170,700 in men and 1,017,800 in women) than what would have occurred if mortality rates had remained at their peak,” the researchers added.

Lung cancer accounted for 46% of the total decline in cancer mortality in the past 5 years, with a record, single-year drop of 2.4% between 2017 and 2018.

The recent and rapid reductions in lung cancer mortality reflect better treatments for NSCLC, the authors suggested. For example, survival rates at 2 years have increased from 34% for patients diagnosed with NSCLC between 2009 and 2010 to 42% for those diagnosed during 2015 and 2016 – an absolute gain of 5%-6% in survival odds for every stage of diagnosis.

On a more somber note, the authors warned that COVID-19 is predicted to have a negative impact on both the diagnosis and outcomes of patients with cancer in the near future.  

“We anticipate that disruptions in access to cancer care in 2020 will lead to downstream increases in advanced stage diagnoses that may impede progress in reducing cancer mortality rates in the years to come,” Ms. Siegel said in a statement.
 

New cancer cases

The report provides an estimated number of new cancer cases and deaths in 2021 in the United States (nationally and state-by-state) based on the most current population-based data for cancer incidence through 2017 and for mortality through 2018. “An estimated 608,570 Americans will die from cancer in 2021, corresponding to more than 1600 deaths per day,” Ms. Siegel and colleagues reported.

The greatest number of deaths are predicted to be from the most common cancers: Lung, prostate, and colorectal cancer in men and lung, breast, and colorectal cancer in women, they added. However, the mortality rates for all four cancers are continuing to fall.

As of 2018, the death rate from lung cancer had dropped by 54% among males and by 30% among females over the past few decades, the investigators noted.

Mortality from female breast cancer has dropped by 41% since 1989; by 52% for prostate cancer since 1993; and by 53% and 59% for colorectal cancer for men (since 1980) and women (since 1969), respectively.

“However, in recent years, mortality declines have slowed for breast cancer and [colorectal cancer] and have halted for prostate cancer,” the researchers noted.

In contrast, the pace of the annual decline in lung cancer mortality doubled among men from 3.1% between 2009 and 2013 to 5.5% between 2014 and 2018, and from 1.8% to 4.4% among women during the same time intervals.
 

Increase in incidence at common sites

Despite the steady progress in mortality for most cancers, “rates continue to increase for some common sites,” Ms. Siegel and colleagues reported.

For example, death rates from uterine corpus cancer have accelerated from the late 1990s at twice the pace of the increase in its incidence. Death rates also have increased for cancers of the oral cavity and pharynx – although in this cancer, increases in mortality parallel an increase in its incidence. 

“Pancreatic cancer death rates [in turn] continued to increase slowly in men ... but remained stable in women, despite incidence [rates] rising by about 1% per year in both sexes,” the authors observed.

Meanwhile, the incidence of cervical cancer, although declining for decades overall, is increasing for patients who present with more distant-stage disease as well as cervical adenocarcinoma, both of which are often undetected by cytology.

“These findings underscore the need for more targeted efforts to increase both HPV [human papillomavirus] vaccination among all individuals aged [26 and younger] and primary HPV testing or HPV/cytology co-testing every 5 years among women beginning at age 25,” the authors emphasized.

On a more positive note, the long-term increase in mortality from liver cancer has recently slowed among women and has stabilized among men, they added.

Once again, disparities in both cancer occurrence and outcomes varied considerably between racial and ethnic groups. For example, cancer is the leading cause of death in people who are Hispanic, Asian American, and Alaska Native. Survival rates at 5 years for almost all cancers are still higher for White patients than for Black patients, although the disparity in cancer mortality between Black persons and White persons has declined to 13% from a peak of 33% in 1993.

Geographic disparities in cancer mortality rates still prevail; the rates are largest for preventable cancers such as lung and cervical cancer, for which mortality varies by as much as fivefold across states.

And although cancer remains the second most common cause of death among children, death rates from cancer have continuously declined over time among both children and adolescents, largely the result of dramatic declines in death rates from leukemia in both age groups.

The study authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

When results of the TAILORx trial were presented at ASCO 2018, many oncologists thought it seemed too simple that a single number from a genomic assay could separate patients who would and would not benefit from adjuvant postoperative chemotherapy.

Those oncologists were right to be skeptical. Subsequent data indicated that better predictive tools were needed.

A new tool called “RSClin” may fit the bill. RSClin integrates the prognostic and predictive value of the 21-gene Oncotype DX recurrence score (RS) with the additional prognostic information conveyed by patient age, tumor grade, and tumor size.

RSClin provides individualized estimates of distant relapse risk for women with node-negative, endocrine sensitive, HER2/neu oncogene-negative early breast cancer – and a quantification of the additive freedom from distant relapse if that patient receives adjuvant chemotherapy. The tool is now available via a tab on the professional portal at https://online.genomichealth.com/.

Details on RSClin, including how the tool was developed and validated, were presented at the 2020 San Antonio Breast Cancer Symposium by Joseph A. Sparano, MD, of Albert Einstein College of Medicine in New York.
 

Beyond the initial publication of TAILORx

Results from the TAILORx trial published in The New England Journal of Medicine in 2018 offered the potential for genomic risk assessment to guide the choice of postoperative therapy for many women with the most common type of primary breast cancer. The relative risk reduction with chemotherapy increased with increasing RS result.

Subsequent analyses of the TAILORx dataset, published in The New England Journal of Medicine and JAMA Oncology in 2019, examined the added effect of parameters of clinical risk (tumor size and grade) and patient age for patients with known genomic risk.

In these analyses, clinical risk was prognostic for recurrence but did not predict the absolute magnitude of chemotherapy benefit, regardless of age. There was a trend toward chemotherapy benefit in women who were younger than 50 years of age who had RS 21-15, but it was irrespective of clinical risk.
 

The development of RSClin

RSClin was derived from a patient-specific meta-analysis of 10,004 women with hormone receptor–positive, HER2-negative, node-negative breast cancer, of whom 9,427 participated in the TAILORx trial.

In TAILORx, which ran from 2006 to 2015, women with RS 0-11 received contemporary hormone therapy alone. Women with RS 12-25 were randomized to receive hormone therapy alone or with conventional combination chemotherapy. Women with RS above 26 received chemotherapy plus endocrine therapy.

The other patients in the meta-analysis participated in NSABP studies B-14 (tamoxifen versus placebo) and B-20 (tamoxifen versus chemotherapy plus tamoxifen).

Cox regression models were fit separately to each study with covariates of the continuous variables of RS result, tumor size, and patient age and the discrete variable of histologic tumor grade (assessed centrally in B-14 and in local laboratories in TAILORx). The prespecified endpoint was time to first distant recurrence.

RSClin estimates of distant recurrence risk were generated using baseline risk with TAILORx event rates to reflect current medical practice.

Model estimates were calculated for specified endocrine therapy with tamoxifen or aromatase inhibitors utilizing the treatment effect hazard ratio from an Early Breast Cancer Trialists’ Collaborative Group meta-analysis.

Patient-specific absolute benefit of chemotherapy was estimated by combining patient-specific meta-analysis risk estimates for distant recurrence and for relative chemotherapy benefit using the B-20 and TAILORx trials.
 

RSClin results and external validation

Among all patients in the meta-analysis cohort, RSClin provided a significantly more accurate prediction of distant recurrence events, in comparison with RS alone or clinical-pathologic factors alone.

External validation was performed using data from real-world outcomes from the 1,098 evaluable node-negative patients in the Clalit Health Services registry, of whom 876 received endocrine therapy alone and 222 received endocrine therapy plus chemotherapy.

RSClin estimates of distant recurrence closely approximated the observed risk in the registry (standardized hazard ratio, 1.73; 95% confidence interval, 1.40-2.15; P < .001). Within each RSClin risk quintile, the average 10-year risk estimate approached the observed Kaplan-Meier estimates in the cohort (Lin concordance correlation = 0.962).
 

Shared decision-making

For many years, the dilemma of whether to recommend adjuvant chemotherapy to a patient with early breast cancer has prompted the generation of tools to quantify a patient’s risk of recurrence and the magnitude of benefit for endocrine therapy and/or chemotherapy.

When the original Adjuvant! Online program was developed, genomic risk profiling was in its infancy. Genomic tools such as the 21-gene RS have subsequently demonstrated that they can help optimize the adjuvant treatment we recommend.

The RSClin tool provides more precise, individualized information than does clinical-pathological or genomic data alone. It prognosticates the risk of distant recurrence of breast cancer, which patients and providers fervently wish to minimize.

RSClin estimates the incremental benefit of contemporary adjuvant chemotherapy over modern endocrine therapy alone, in absolute values, for individual patients. This transparent, discrete, easily explained information is vital for counseling patients.

However, as highlighted in an editorial published in the Journal of Clinical Oncology, RSClin is not without its potential drawbacks. These include:

• Tumor heterogeneity leading to misleading results.
• Variable patient adherence to endocrine therapy or chemotherapy.
• The influence of comorbid conditions on the risk/benefit ratio.
• The potential of ovarian function suppression in young women to approach the magnitude of benefit associated with chemotherapy.

Accordingly, RSClin may be the latest and best available tool, but it will not be the last.

For patients with RS above 26, for older women with intermediate RS, and for younger women with a low RS and low clinical-pathologic features, RSClin may not influence treatment recommendations.

However, for the common scenario of an intermediate-risk RS and a mix of pathologic features, the accurate prognostication for distant recurrence risk and estimate of absolute benefit from chemotherapy will be terrifically helpful to oncology caregivers.

Dr. Sparano disclosed funding from the National Cancer Institute and travel support from Rhenium.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

When results of the TAILORx trial were presented at ASCO 2018, many oncologists thought it seemed too simple that a single number from a genomic assay could separate patients who would and would not benefit from adjuvant postoperative chemotherapy.

Those oncologists were right to be skeptical. Subsequent data indicated that better predictive tools were needed.

A new tool called “RSClin” may fit the bill. RSClin integrates the prognostic and predictive value of the 21-gene Oncotype DX recurrence score (RS) with the additional prognostic information conveyed by patient age, tumor grade, and tumor size.

RSClin provides individualized estimates of distant relapse risk for women with node-negative, endocrine sensitive, HER2/neu oncogene-negative early breast cancer – and a quantification of the additive freedom from distant relapse if that patient receives adjuvant chemotherapy. The tool is now available via a tab on the professional portal at https://online.genomichealth.com/.

Details on RSClin, including how the tool was developed and validated, were presented at the 2020 San Antonio Breast Cancer Symposium by Joseph A. Sparano, MD, of Albert Einstein College of Medicine in New York.
 

Beyond the initial publication of TAILORx

Results from the TAILORx trial published in The New England Journal of Medicine in 2018 offered the potential for genomic risk assessment to guide the choice of postoperative therapy for many women with the most common type of primary breast cancer. The relative risk reduction with chemotherapy increased with increasing RS result.

Subsequent analyses of the TAILORx dataset, published in The New England Journal of Medicine and JAMA Oncology in 2019, examined the added effect of parameters of clinical risk (tumor size and grade) and patient age for patients with known genomic risk.

In these analyses, clinical risk was prognostic for recurrence but did not predict the absolute magnitude of chemotherapy benefit, regardless of age. There was a trend toward chemotherapy benefit in women who were younger than 50 years of age who had RS 21-15, but it was irrespective of clinical risk.
 

The development of RSClin

RSClin was derived from a patient-specific meta-analysis of 10,004 women with hormone receptor–positive, HER2-negative, node-negative breast cancer, of whom 9,427 participated in the TAILORx trial.

In TAILORx, which ran from 2006 to 2015, women with RS 0-11 received contemporary hormone therapy alone. Women with RS 12-25 were randomized to receive hormone therapy alone or with conventional combination chemotherapy. Women with RS above 26 received chemotherapy plus endocrine therapy.

The other patients in the meta-analysis participated in NSABP studies B-14 (tamoxifen versus placebo) and B-20 (tamoxifen versus chemotherapy plus tamoxifen).

Cox regression models were fit separately to each study with covariates of the continuous variables of RS result, tumor size, and patient age and the discrete variable of histologic tumor grade (assessed centrally in B-14 and in local laboratories in TAILORx). The prespecified endpoint was time to first distant recurrence.

RSClin estimates of distant recurrence risk were generated using baseline risk with TAILORx event rates to reflect current medical practice.

Model estimates were calculated for specified endocrine therapy with tamoxifen or aromatase inhibitors utilizing the treatment effect hazard ratio from an Early Breast Cancer Trialists’ Collaborative Group meta-analysis.

Patient-specific absolute benefit of chemotherapy was estimated by combining patient-specific meta-analysis risk estimates for distant recurrence and for relative chemotherapy benefit using the B-20 and TAILORx trials.
 

RSClin results and external validation

Among all patients in the meta-analysis cohort, RSClin provided a significantly more accurate prediction of distant recurrence events, in comparison with RS alone or clinical-pathologic factors alone.

External validation was performed using data from real-world outcomes from the 1,098 evaluable node-negative patients in the Clalit Health Services registry, of whom 876 received endocrine therapy alone and 222 received endocrine therapy plus chemotherapy.

RSClin estimates of distant recurrence closely approximated the observed risk in the registry (standardized hazard ratio, 1.73; 95% confidence interval, 1.40-2.15; P < .001). Within each RSClin risk quintile, the average 10-year risk estimate approached the observed Kaplan-Meier estimates in the cohort (Lin concordance correlation = 0.962).
 

Shared decision-making

For many years, the dilemma of whether to recommend adjuvant chemotherapy to a patient with early breast cancer has prompted the generation of tools to quantify a patient’s risk of recurrence and the magnitude of benefit for endocrine therapy and/or chemotherapy.

When the original Adjuvant! Online program was developed, genomic risk profiling was in its infancy. Genomic tools such as the 21-gene RS have subsequently demonstrated that they can help optimize the adjuvant treatment we recommend.

The RSClin tool provides more precise, individualized information than does clinical-pathological or genomic data alone. It prognosticates the risk of distant recurrence of breast cancer, which patients and providers fervently wish to minimize.

RSClin estimates the incremental benefit of contemporary adjuvant chemotherapy over modern endocrine therapy alone, in absolute values, for individual patients. This transparent, discrete, easily explained information is vital for counseling patients.

However, as highlighted in an editorial published in the Journal of Clinical Oncology, RSClin is not without its potential drawbacks. These include:

• Tumor heterogeneity leading to misleading results.
• Variable patient adherence to endocrine therapy or chemotherapy.
• The influence of comorbid conditions on the risk/benefit ratio.
• The potential of ovarian function suppression in young women to approach the magnitude of benefit associated with chemotherapy.

Accordingly, RSClin may be the latest and best available tool, but it will not be the last.

For patients with RS above 26, for older women with intermediate RS, and for younger women with a low RS and low clinical-pathologic features, RSClin may not influence treatment recommendations.

However, for the common scenario of an intermediate-risk RS and a mix of pathologic features, the accurate prognostication for distant recurrence risk and estimate of absolute benefit from chemotherapy will be terrifically helpful to oncology caregivers.

Dr. Sparano disclosed funding from the National Cancer Institute and travel support from Rhenium.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

When results of the TAILORx trial were presented at ASCO 2018, many oncologists thought it seemed too simple that a single number from a genomic assay could separate patients who would and would not benefit from adjuvant postoperative chemotherapy.

Those oncologists were right to be skeptical. Subsequent data indicated that better predictive tools were needed.

A new tool called “RSClin” may fit the bill. RSClin integrates the prognostic and predictive value of the 21-gene Oncotype DX recurrence score (RS) with the additional prognostic information conveyed by patient age, tumor grade, and tumor size.

RSClin provides individualized estimates of distant relapse risk for women with node-negative, endocrine sensitive, HER2/neu oncogene-negative early breast cancer – and a quantification of the additive freedom from distant relapse if that patient receives adjuvant chemotherapy. The tool is now available via a tab on the professional portal at https://online.genomichealth.com/.

Details on RSClin, including how the tool was developed and validated, were presented at the 2020 San Antonio Breast Cancer Symposium by Joseph A. Sparano, MD, of Albert Einstein College of Medicine in New York.
 

Beyond the initial publication of TAILORx

Results from the TAILORx trial published in The New England Journal of Medicine in 2018 offered the potential for genomic risk assessment to guide the choice of postoperative therapy for many women with the most common type of primary breast cancer. The relative risk reduction with chemotherapy increased with increasing RS result.

Subsequent analyses of the TAILORx dataset, published in The New England Journal of Medicine and JAMA Oncology in 2019, examined the added effect of parameters of clinical risk (tumor size and grade) and patient age for patients with known genomic risk.

In these analyses, clinical risk was prognostic for recurrence but did not predict the absolute magnitude of chemotherapy benefit, regardless of age. There was a trend toward chemotherapy benefit in women who were younger than 50 years of age who had RS 21-15, but it was irrespective of clinical risk.
 

The development of RSClin

RSClin was derived from a patient-specific meta-analysis of 10,004 women with hormone receptor–positive, HER2-negative, node-negative breast cancer, of whom 9,427 participated in the TAILORx trial.

In TAILORx, which ran from 2006 to 2015, women with RS 0-11 received contemporary hormone therapy alone. Women with RS 12-25 were randomized to receive hormone therapy alone or with conventional combination chemotherapy. Women with RS above 26 received chemotherapy plus endocrine therapy.

The other patients in the meta-analysis participated in NSABP studies B-14 (tamoxifen versus placebo) and B-20 (tamoxifen versus chemotherapy plus tamoxifen).

Cox regression models were fit separately to each study with covariates of the continuous variables of RS result, tumor size, and patient age and the discrete variable of histologic tumor grade (assessed centrally in B-14 and in local laboratories in TAILORx). The prespecified endpoint was time to first distant recurrence.

RSClin estimates of distant recurrence risk were generated using baseline risk with TAILORx event rates to reflect current medical practice.

Model estimates were calculated for specified endocrine therapy with tamoxifen or aromatase inhibitors utilizing the treatment effect hazard ratio from an Early Breast Cancer Trialists’ Collaborative Group meta-analysis.

Patient-specific absolute benefit of chemotherapy was estimated by combining patient-specific meta-analysis risk estimates for distant recurrence and for relative chemotherapy benefit using the B-20 and TAILORx trials.
 

RSClin results and external validation

Among all patients in the meta-analysis cohort, RSClin provided a significantly more accurate prediction of distant recurrence events, in comparison with RS alone or clinical-pathologic factors alone.

External validation was performed using data from real-world outcomes from the 1,098 evaluable node-negative patients in the Clalit Health Services registry, of whom 876 received endocrine therapy alone and 222 received endocrine therapy plus chemotherapy.

RSClin estimates of distant recurrence closely approximated the observed risk in the registry (standardized hazard ratio, 1.73; 95% confidence interval, 1.40-2.15; P < .001). Within each RSClin risk quintile, the average 10-year risk estimate approached the observed Kaplan-Meier estimates in the cohort (Lin concordance correlation = 0.962).
 

Shared decision-making

For many years, the dilemma of whether to recommend adjuvant chemotherapy to a patient with early breast cancer has prompted the generation of tools to quantify a patient’s risk of recurrence and the magnitude of benefit for endocrine therapy and/or chemotherapy.

When the original Adjuvant! Online program was developed, genomic risk profiling was in its infancy. Genomic tools such as the 21-gene RS have subsequently demonstrated that they can help optimize the adjuvant treatment we recommend.

The RSClin tool provides more precise, individualized information than does clinical-pathological or genomic data alone. It prognosticates the risk of distant recurrence of breast cancer, which patients and providers fervently wish to minimize.

RSClin estimates the incremental benefit of contemporary adjuvant chemotherapy over modern endocrine therapy alone, in absolute values, for individual patients. This transparent, discrete, easily explained information is vital for counseling patients.

However, as highlighted in an editorial published in the Journal of Clinical Oncology, RSClin is not without its potential drawbacks. These include:

• Tumor heterogeneity leading to misleading results.
• Variable patient adherence to endocrine therapy or chemotherapy.
• The influence of comorbid conditions on the risk/benefit ratio.
• The potential of ovarian function suppression in young women to approach the magnitude of benefit associated with chemotherapy.

Accordingly, RSClin may be the latest and best available tool, but it will not be the last.

For patients with RS above 26, for older women with intermediate RS, and for younger women with a low RS and low clinical-pathologic features, RSClin may not influence treatment recommendations.

However, for the common scenario of an intermediate-risk RS and a mix of pathologic features, the accurate prognostication for distant recurrence risk and estimate of absolute benefit from chemotherapy will be terrifically helpful to oncology caregivers.

Dr. Sparano disclosed funding from the National Cancer Institute and travel support from Rhenium.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

A combination of biomarkers identifies patients with luminal early breast cancer who can safely skip chemotherapy after surgery, results from the ADAPT HR+/HER2– trial suggest.

The findings were reported at the 2020 San Antonio Breast Cancer Symposium.

“In early luminal breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in patients with one to three involved lymph nodes, is still unclear,” noted principal investigator Nadia Harbeck, MD, PhD, of the University of Munich.

Successive trials have used nodal status, genomic risk scores, and response to preoperative therapy to home in on subsets of women for whom this practice is safe.

The ADAPT HR+/HER2– trial is a phase 3 trial that enrolled 5,625 patients with luminal (hormone receptor–positive, HER2-negative) early breast cancer who were candidates for adjuvant chemotherapy based on conventional criteria.

The trial combined a static biomarker – Oncotype Dx recurrence score (RS) in the baseline core biopsy – and a dynamic biomarker – Ki-67 response to a 3-week course of preoperative endocrine therapy – to personalize adjuvant therapy.

At SABCS 2020, Dr. Harbeck reported results for 2,290 patients having zero to three involved lymph nodes: 868 patients with RS 0-11 and 1,422 patients with RS 12-25 who had a response to brief preoperative endocrine therapy (a Ki-67 fraction ≤10% at surgery). All were treated with endocrine therapy alone as adjuvant therapy.
 

Similar outcomes

The median follow-up was 60 months. The 5-year rate of invasive disease–free survival was 93.9% for the group with RS 0-11 and 92.6% for the group with RS 12-25 and a response to the preoperative endocrine therapy.

The study met its primary endpoint, as the lower limit of the 95% confidence interval for the difference between groups of –3.3% fell just within the predefined margin of –3.3% or less for noninferiority (P = .05).

The groups also had similarly “excellent” distant disease–free survival (96.3% for RS 0-11 and 95.6% for RS 12-25; P = .247) and overall survival (98.0% for RS 0-11 and 97.3% for RS 12-25; P = .160), Dr. Harbeck reported.

The similar distant disease–free survival was consistent regardless of whether women were younger or older than 50 years and regardless of whether women had involved nodes or not.

In multivariate analysis, women had greater risk of distant disease–free survival events if they had three positive lymph nodes versus zero to two (hazard ratio, 3.40) or a pathologic T stage of 2-4 versus 0-1 (HR, 2.24), whereas risk fell with increasing baseline progesterone receptor expression (HR, 0.92).

“Neither patient age nor study arm were prognostic factors for patient outcome,” Dr. Harbeck noted.

In stratified analysis, the negative impact of having three positive nodes was seen only in the group with RS 12-25 and response to preoperative endocrine therapy, suggesting this subgroup may not be good candidates for omission of chemotherapy, she said.
 

Applying results to practice

“In luminal early breast cancer, the following patients – irrespective of their age – can safely be treated by endocrine therapy alone: patients with zero to three involved lymph nodes and recurrence score 0-11, and those with limited nodal burden (zero to two lymph nodes), recurrence score 12-25, and endocrine response after short preoperative endocrine therapy,” Dr. Harbeck summarized.

“Oncotype Dx testing can spare chemotherapy for the majority of patients with up to three involved lymph nodes. Dynamic Ki-67 response testing is feasible in clinical routine and complements baseline risk assessment to define patient selection for therapy deescalation or escalation,” she added.

The investigators have used the trial’s data to develop an algorithm for predicting the probability of response to short-course preoperative endocrine therapy that is available free of charge online (www.enrep.info).

“This may support everyday clinical decision-making in luminal early breast cancer; for example, whether to start a short period of preoperative endocrine therapy at all, and whether to rely on adjuvant endocrine therapy alone, but also in times like these, whether it’s safe to delay surgery by putting patients on prolonged preoperative endocrine therapy if surgical resources are scarce,” Dr. Harbeck commented.

Her clinic is now recruiting patients for the ADAPT Cycle trial, which is testing an endocrine-based approach with a CDK4/6 inhibitor versus chemotherapy in patients who are not candidates for adjuvant endocrine therapy alone. Therefore, all eligible patients receive the short course of endocrine therapy up front as the standard.

“But if you don’t have a trial, what are you going to do on Monday morning? Please let your patient know whether her tumor is endocrine responsive by doing this 3-week preoperative endocrine therapy,” Dr. Harbeck recommended. “It’s easy to do, you can schedule your surgeries better, and in patients with up to three lymph nodes, it helps with your decision-making, not just in the postmenopausal patients but also in the premenopausal patients, regarding whether they can forgo chemotherapy.”

Findings in context

More than 75% of ADAPT patients with RS 12-25 had a response to short-course endocrine therapy, noted invited discussant Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Conn.

“This implies that the endocrine challenge is not informative for most patients,” he said, adding that a related question is whether the 25% of patients who did not have a response and were therefore given chemotherapy benefited from that therapy.

Dr. Pusztai cautioned that, among patients in the group with RS 12-25 who had a response to preoperative endocrine therapy, certain subgroups were fairly or very small: those aged 50 years or younger (330 patients) and those with two or three positive nodes (75 and 22 patients, respectively).

And collective findings of the similar but much larger TAILORx trial and RxPONDER trial (also reported at SABCS 2020) do suggest a benefit of chemotherapy in younger women, regardless of the number of positive nodes.

“Selection of [estrogen receptor]–positive patients with zero to three lymph nodes for adjuvant chemotherapy currently should be based on age and baseline recurrence score or a similar validated molecular assay,” Dr. Pusztai recommended. “TAILORx results guide us in regard to the use of the recurrence score in node-negative patients with a recurrence score of less than 26, and the recently presented RxPONDER results provide evidence for the use of recurrence score in patients with one to three positive nodes with a recurrence score in the range of 0-26. Both of these trials showed benefit in younger women from adjuvant chemotherapy.”

The ADAPT trial was sponsored by Roche, Genomic Health/Exact Sciences, Celgene, Bayer, Teva, and Amgen. Dr. Harbeck disclosed relationships with Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Samsung, Sandoz, and Seattle Genetics. Dr. Pusztai disclosed relationships with AstraZeneca, Athenex, Almac, Bristol-Myers Squibb, Biotheranostics, Clovis, Daiichi, Eisai, Genentech, H2Bio, H3 Biomedicine, Immunomedics, Merck, Novartis, Pfizer, Pieris, Radius Health, Syndax, and Seattle Genetics,.

A combination of biomarkers identifies patients with luminal early breast cancer who can safely skip chemotherapy after surgery, results from the ADAPT HR+/HER2– trial suggest.

The findings were reported at the 2020 San Antonio Breast Cancer Symposium.

“In early luminal breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in patients with one to three involved lymph nodes, is still unclear,” noted principal investigator Nadia Harbeck, MD, PhD, of the University of Munich.

Successive trials have used nodal status, genomic risk scores, and response to preoperative therapy to home in on subsets of women for whom this practice is safe.

The ADAPT HR+/HER2– trial is a phase 3 trial that enrolled 5,625 patients with luminal (hormone receptor–positive, HER2-negative) early breast cancer who were candidates for adjuvant chemotherapy based on conventional criteria.

The trial combined a static biomarker – Oncotype Dx recurrence score (RS) in the baseline core biopsy – and a dynamic biomarker – Ki-67 response to a 3-week course of preoperative endocrine therapy – to personalize adjuvant therapy.

At SABCS 2020, Dr. Harbeck reported results for 2,290 patients having zero to three involved lymph nodes: 868 patients with RS 0-11 and 1,422 patients with RS 12-25 who had a response to brief preoperative endocrine therapy (a Ki-67 fraction ≤10% at surgery). All were treated with endocrine therapy alone as adjuvant therapy.
 

Similar outcomes

The median follow-up was 60 months. The 5-year rate of invasive disease–free survival was 93.9% for the group with RS 0-11 and 92.6% for the group with RS 12-25 and a response to the preoperative endocrine therapy.

The study met its primary endpoint, as the lower limit of the 95% confidence interval for the difference between groups of –3.3% fell just within the predefined margin of –3.3% or less for noninferiority (P = .05).

The groups also had similarly “excellent” distant disease–free survival (96.3% for RS 0-11 and 95.6% for RS 12-25; P = .247) and overall survival (98.0% for RS 0-11 and 97.3% for RS 12-25; P = .160), Dr. Harbeck reported.

The similar distant disease–free survival was consistent regardless of whether women were younger or older than 50 years and regardless of whether women had involved nodes or not.

In multivariate analysis, women had greater risk of distant disease–free survival events if they had three positive lymph nodes versus zero to two (hazard ratio, 3.40) or a pathologic T stage of 2-4 versus 0-1 (HR, 2.24), whereas risk fell with increasing baseline progesterone receptor expression (HR, 0.92).

“Neither patient age nor study arm were prognostic factors for patient outcome,” Dr. Harbeck noted.

In stratified analysis, the negative impact of having three positive nodes was seen only in the group with RS 12-25 and response to preoperative endocrine therapy, suggesting this subgroup may not be good candidates for omission of chemotherapy, she said.
 

Applying results to practice

“In luminal early breast cancer, the following patients – irrespective of their age – can safely be treated by endocrine therapy alone: patients with zero to three involved lymph nodes and recurrence score 0-11, and those with limited nodal burden (zero to two lymph nodes), recurrence score 12-25, and endocrine response after short preoperative endocrine therapy,” Dr. Harbeck summarized.

“Oncotype Dx testing can spare chemotherapy for the majority of patients with up to three involved lymph nodes. Dynamic Ki-67 response testing is feasible in clinical routine and complements baseline risk assessment to define patient selection for therapy deescalation or escalation,” she added.

The investigators have used the trial’s data to develop an algorithm for predicting the probability of response to short-course preoperative endocrine therapy that is available free of charge online (www.enrep.info).

“This may support everyday clinical decision-making in luminal early breast cancer; for example, whether to start a short period of preoperative endocrine therapy at all, and whether to rely on adjuvant endocrine therapy alone, but also in times like these, whether it’s safe to delay surgery by putting patients on prolonged preoperative endocrine therapy if surgical resources are scarce,” Dr. Harbeck commented.

Her clinic is now recruiting patients for the ADAPT Cycle trial, which is testing an endocrine-based approach with a CDK4/6 inhibitor versus chemotherapy in patients who are not candidates for adjuvant endocrine therapy alone. Therefore, all eligible patients receive the short course of endocrine therapy up front as the standard.

“But if you don’t have a trial, what are you going to do on Monday morning? Please let your patient know whether her tumor is endocrine responsive by doing this 3-week preoperative endocrine therapy,” Dr. Harbeck recommended. “It’s easy to do, you can schedule your surgeries better, and in patients with up to three lymph nodes, it helps with your decision-making, not just in the postmenopausal patients but also in the premenopausal patients, regarding whether they can forgo chemotherapy.”

Findings in context

More than 75% of ADAPT patients with RS 12-25 had a response to short-course endocrine therapy, noted invited discussant Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Conn.

“This implies that the endocrine challenge is not informative for most patients,” he said, adding that a related question is whether the 25% of patients who did not have a response and were therefore given chemotherapy benefited from that therapy.

Dr. Pusztai cautioned that, among patients in the group with RS 12-25 who had a response to preoperative endocrine therapy, certain subgroups were fairly or very small: those aged 50 years or younger (330 patients) and those with two or three positive nodes (75 and 22 patients, respectively).

And collective findings of the similar but much larger TAILORx trial and RxPONDER trial (also reported at SABCS 2020) do suggest a benefit of chemotherapy in younger women, regardless of the number of positive nodes.

“Selection of [estrogen receptor]–positive patients with zero to three lymph nodes for adjuvant chemotherapy currently should be based on age and baseline recurrence score or a similar validated molecular assay,” Dr. Pusztai recommended. “TAILORx results guide us in regard to the use of the recurrence score in node-negative patients with a recurrence score of less than 26, and the recently presented RxPONDER results provide evidence for the use of recurrence score in patients with one to three positive nodes with a recurrence score in the range of 0-26. Both of these trials showed benefit in younger women from adjuvant chemotherapy.”

The ADAPT trial was sponsored by Roche, Genomic Health/Exact Sciences, Celgene, Bayer, Teva, and Amgen. Dr. Harbeck disclosed relationships with Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Samsung, Sandoz, and Seattle Genetics. Dr. Pusztai disclosed relationships with AstraZeneca, Athenex, Almac, Bristol-Myers Squibb, Biotheranostics, Clovis, Daiichi, Eisai, Genentech, H2Bio, H3 Biomedicine, Immunomedics, Merck, Novartis, Pfizer, Pieris, Radius Health, Syndax, and Seattle Genetics,.

A combination of biomarkers identifies patients with luminal early breast cancer who can safely skip chemotherapy after surgery, results from the ADAPT HR+/HER2– trial suggest.

The findings were reported at the 2020 San Antonio Breast Cancer Symposium.

“In early luminal breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in patients with one to three involved lymph nodes, is still unclear,” noted principal investigator Nadia Harbeck, MD, PhD, of the University of Munich.

Successive trials have used nodal status, genomic risk scores, and response to preoperative therapy to home in on subsets of women for whom this practice is safe.

The ADAPT HR+/HER2– trial is a phase 3 trial that enrolled 5,625 patients with luminal (hormone receptor–positive, HER2-negative) early breast cancer who were candidates for adjuvant chemotherapy based on conventional criteria.

The trial combined a static biomarker – Oncotype Dx recurrence score (RS) in the baseline core biopsy – and a dynamic biomarker – Ki-67 response to a 3-week course of preoperative endocrine therapy – to personalize adjuvant therapy.

At SABCS 2020, Dr. Harbeck reported results for 2,290 patients having zero to three involved lymph nodes: 868 patients with RS 0-11 and 1,422 patients with RS 12-25 who had a response to brief preoperative endocrine therapy (a Ki-67 fraction ≤10% at surgery). All were treated with endocrine therapy alone as adjuvant therapy.
 

Similar outcomes

The median follow-up was 60 months. The 5-year rate of invasive disease–free survival was 93.9% for the group with RS 0-11 and 92.6% for the group with RS 12-25 and a response to the preoperative endocrine therapy.

The study met its primary endpoint, as the lower limit of the 95% confidence interval for the difference between groups of –3.3% fell just within the predefined margin of –3.3% or less for noninferiority (P = .05).

The groups also had similarly “excellent” distant disease–free survival (96.3% for RS 0-11 and 95.6% for RS 12-25; P = .247) and overall survival (98.0% for RS 0-11 and 97.3% for RS 12-25; P = .160), Dr. Harbeck reported.

The similar distant disease–free survival was consistent regardless of whether women were younger or older than 50 years and regardless of whether women had involved nodes or not.

In multivariate analysis, women had greater risk of distant disease–free survival events if they had three positive lymph nodes versus zero to two (hazard ratio, 3.40) or a pathologic T stage of 2-4 versus 0-1 (HR, 2.24), whereas risk fell with increasing baseline progesterone receptor expression (HR, 0.92).

“Neither patient age nor study arm were prognostic factors for patient outcome,” Dr. Harbeck noted.

In stratified analysis, the negative impact of having three positive nodes was seen only in the group with RS 12-25 and response to preoperative endocrine therapy, suggesting this subgroup may not be good candidates for omission of chemotherapy, she said.
 

Applying results to practice

“In luminal early breast cancer, the following patients – irrespective of their age – can safely be treated by endocrine therapy alone: patients with zero to three involved lymph nodes and recurrence score 0-11, and those with limited nodal burden (zero to two lymph nodes), recurrence score 12-25, and endocrine response after short preoperative endocrine therapy,” Dr. Harbeck summarized.

“Oncotype Dx testing can spare chemotherapy for the majority of patients with up to three involved lymph nodes. Dynamic Ki-67 response testing is feasible in clinical routine and complements baseline risk assessment to define patient selection for therapy deescalation or escalation,” she added.

The investigators have used the trial’s data to develop an algorithm for predicting the probability of response to short-course preoperative endocrine therapy that is available free of charge online (www.enrep.info).

“This may support everyday clinical decision-making in luminal early breast cancer; for example, whether to start a short period of preoperative endocrine therapy at all, and whether to rely on adjuvant endocrine therapy alone, but also in times like these, whether it’s safe to delay surgery by putting patients on prolonged preoperative endocrine therapy if surgical resources are scarce,” Dr. Harbeck commented.

Her clinic is now recruiting patients for the ADAPT Cycle trial, which is testing an endocrine-based approach with a CDK4/6 inhibitor versus chemotherapy in patients who are not candidates for adjuvant endocrine therapy alone. Therefore, all eligible patients receive the short course of endocrine therapy up front as the standard.

“But if you don’t have a trial, what are you going to do on Monday morning? Please let your patient know whether her tumor is endocrine responsive by doing this 3-week preoperative endocrine therapy,” Dr. Harbeck recommended. “It’s easy to do, you can schedule your surgeries better, and in patients with up to three lymph nodes, it helps with your decision-making, not just in the postmenopausal patients but also in the premenopausal patients, regarding whether they can forgo chemotherapy.”

Findings in context

More than 75% of ADAPT patients with RS 12-25 had a response to short-course endocrine therapy, noted invited discussant Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Conn.

“This implies that the endocrine challenge is not informative for most patients,” he said, adding that a related question is whether the 25% of patients who did not have a response and were therefore given chemotherapy benefited from that therapy.

Dr. Pusztai cautioned that, among patients in the group with RS 12-25 who had a response to preoperative endocrine therapy, certain subgroups were fairly or very small: those aged 50 years or younger (330 patients) and those with two or three positive nodes (75 and 22 patients, respectively).

And collective findings of the similar but much larger TAILORx trial and RxPONDER trial (also reported at SABCS 2020) do suggest a benefit of chemotherapy in younger women, regardless of the number of positive nodes.

“Selection of [estrogen receptor]–positive patients with zero to three lymph nodes for adjuvant chemotherapy currently should be based on age and baseline recurrence score or a similar validated molecular assay,” Dr. Pusztai recommended. “TAILORx results guide us in regard to the use of the recurrence score in node-negative patients with a recurrence score of less than 26, and the recently presented RxPONDER results provide evidence for the use of recurrence score in patients with one to three positive nodes with a recurrence score in the range of 0-26. Both of these trials showed benefit in younger women from adjuvant chemotherapy.”

The ADAPT trial was sponsored by Roche, Genomic Health/Exact Sciences, Celgene, Bayer, Teva, and Amgen. Dr. Harbeck disclosed relationships with Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Samsung, Sandoz, and Seattle Genetics. Dr. Pusztai disclosed relationships with AstraZeneca, Athenex, Almac, Bristol-Myers Squibb, Biotheranostics, Clovis, Daiichi, Eisai, Genentech, H2Bio, H3 Biomedicine, Immunomedics, Merck, Novartis, Pfizer, Pieris, Radius Health, Syndax, and Seattle Genetics,.

The histone deacetylase (HDAC) inhibitor entinostat failed to overcome resistance to endocrine therapy in hormone receptor–positive, HER2-negative, advanced breast cancer in a phase 3 trial.

The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.

These results were reported at the 2020 San Antonio Breast Cancer Symposium.

“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.

“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.

“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
 

Why HDAC inhibitors in advanced breast cancer?

“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.

One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.

Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
 

Phase 3 trial details and results

The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.

The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.

A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.

“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.

Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).

The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).

The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.

Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).

There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
 

Implications and next steps

“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.

“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.

Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”

When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”

Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.

“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”

The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.

The histone deacetylase (HDAC) inhibitor entinostat failed to overcome resistance to endocrine therapy in hormone receptor–positive, HER2-negative, advanced breast cancer in a phase 3 trial.

The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.

These results were reported at the 2020 San Antonio Breast Cancer Symposium.

“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.

“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.

“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
 

Why HDAC inhibitors in advanced breast cancer?

“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.

One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.

Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
 

Phase 3 trial details and results

The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.

The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.

A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.

“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.

Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).

The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).

The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.

Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).

There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
 

Implications and next steps

“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.

“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.

Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”

When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”

Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.

“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”

The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.

The histone deacetylase (HDAC) inhibitor entinostat failed to overcome resistance to endocrine therapy in hormone receptor–positive, HER2-negative, advanced breast cancer in a phase 3 trial.

The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.

These results were reported at the 2020 San Antonio Breast Cancer Symposium.

“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.

“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.

“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
 

Why HDAC inhibitors in advanced breast cancer?

“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.

One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.

Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
 

Phase 3 trial details and results

The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.

The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.

A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.

“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.

Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).

The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).

The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.

Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).

There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
 

Implications and next steps

“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.

“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.

Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”

When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”

Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.

“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”

The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.