Breast Cancer

SAN ANTONIO – When choosing between chemotherapy and endocrine therapy for patients with hormone receptor (HR)+/HER2- metastatic breast cancer, allowing the results from a blood test that measures circulating tumor cell (CTC) count to overrule physician’s choice of therapy can significantly improve overall survival.

But are these results enough to change clinical practice? One expert reacting to the findings says probably not, and another pointed out that the CTC count test used in the trial (CellSearch), although approved by the Food and Drug Administration, is not widely used in clinical practice.

The findings comes from updated results from the STIC CTC study.

“When the trial was designed, the question related to the choice between single-agent endocrine therapy and chemotherapy [in] first-line therapy,” explained study presenter François-Clément Bidard, MD, PhD, professor of medical oncology at Institut Curie and Versailles Saint-Quentin University, Paris.

Since then, the first-line treatment has changed and can now can also include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but Dr. Bidard said the results are still clinically relevant.

Nowadays, endocrine therapy plus CDK4/6 inhibitors is the “preferred option for treatment-naive patients, but the dilemma between endocrine therapy and chemotherapy remains after disease progression on adjuvant or first-line therapy with CDK4/6 inhibitors, where current guidelines advocate in favor of endocrine therapy, despite its short-lived efficacy.”

“In that scenario, based on the STIC CTC trial results, the CTC count in combination with predictive biomarkers, whenever available, may help customize the early use of chemotherapy or antibody-drug conjugates, which are becoming more and more attractive,” Dr. Bidard said.

The research was presented here at the San Antonio Breast Cancer Symposium (SABCS).

The study involved more than 750 patients with HR+/HER2- metastatic breast cancer randomly assigned to physician choice or CTC-guided therapy, although the physician decision and the recommendation based on the CTC count was recorded in both groups.

Using the CellSearch (Menarini Silicon Biosystems) to perform the CTC count at baseline only, the team defined patients as low or high risk, with low-risk patients deemed to need only endocrine therapy and high-risk patients recommended chemotherapy.

Physicians based their decisions on current guidelines and their clinical experience.

In the 25% of cases where CTC count would recommend chemotherapy while the physician would recommend endocrine therapy, following the CTC count–based choice resulted in a 35% improvement in progression-free survival (PFS) and a 47% increase in overall survival.

In all other situations, including those when the CTC count recommended endocrine therapy in contrast to the physicians, or the approximately 60% of cases in which the two were in agreement, there was no difference in survival outcomes between the approaches.

Reacting to the findings, Nancy Chan, MD, medical oncologist and the director of breast cancer clinical research at NYU Langone’s Perlmutter Cancer Center, said that the “goal is really to understand how we can personalize treatment options for patients.”

Another aim is to avoid performing a tumor biopsy, if possible, “as that has increased morbidity for patients.”

She noted also that choosing between endocrine therapy and chemotherapy is a “big decision.” These researchers “really wanted to help some patients get less chemotherapy,” as they felt that “some patients are getting too much” as they are not really that high risk and should get endocrine therapy instead.

However, Dr. Chan said that the CTC count is a “complicated concept” and is “not something we’re all using in our clinical practice yet.”

With regard to the approximately 40% discordance between the CTC- and physician-guided choices, Dr. Chan said that clinicians are perhaps not as accurate as they believed in predicting risk when relying on the clinical or pathological features of the tumor.

On Twitter, Guilherme Nader-Marta, MD, Jules Bordet Institute, Université Libre de Bruxelles, Belgium, commented that the question behind the study was whether CTC measurement is a “clinically useful strategy for first-line treatment decision-making.”

“Amazingly,” he continued, the trial went “straight to the point” to answer the question and showed that CTC-based decisions can offer a survival benefit.

Daniel F. Hayes, MD, co-director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center, Ann Arbor, echoed these thoughts, saying that the goals of therapy are to make patients live longer and “better.”

He said that the point of any clinical biomarker is not only to show that testing for it offers “analytical validity” but that it also provides “clinical utility” in that it can guide treatment decisions to improve outcomes.

Dr. Hayes, who was not involved in the study but has worked for many years on the development of CellSearch, said that the results do not make it clear whether measuring CTC counts meets the definition of clinical utility, but it’s “very close.”

On the other hand, the analytical validity of the test is “excellent,” and, in that context, was well-chosen, he said, adding that the endpoint of the trial “is the one most important to us: improvement in overall survival.”

Dr. Hayes noted that the magnitude of benefit from CTC-guided therapy was “moderate,” although that is a “matter of perception,” and the “level of evidence is probably 2 or 3.” Although the trial was prospective, he said, the key results were in a “relatively small” subgroup.

The question is, Dr. Hayes continued: “Is this enough to change practice? My conclusions are: probably not.”

Although patients rated as low risk based on their low CTC count avoided chemotherapy, “it’s not clear to me that this whole thing is sufficient for clinical utility in context of what we know today.” The key issue, however, is who decides whether CTC counts are measured and whether they will be used to guide therapy decisions – will it be the patient, the caregiver, an expert guidelines panel, or third party payers/society?
 

Study details

In his presentation, Dr. Bidard explained that CTC count is an FDA-approved standardized liquid biopsy biomarker, with a count of greater than or equal to 5 cells per 7.5 mL of blood deemed an adverse prognostic marker, regardless of the line of therapy, with a grade 1 level of evidence.

Previous studies have indicated that a high CTC count is strongly associated with overall survival, at a hazard ratio of 2.78.

Crucially, the CTC count “complements” and does not duplicate standard clinicopathological prognostic factors, Dr. Bidard said.

To determine the potential of the CTC count as an aid to treatment decisions, Dr. Bidard and colleagues conducted a trial in pre- and postmenopausal women with untreated HR+/HER2- metastatic breast cancer who were able to receive either endocrine therapy or chemotherapy.

They were randomly assigned to either a standard group, in which the treatment decision followed the physician’s choice, regardless of their CTC count, or to a CTC group, in which the physicians made a treatment recommendation but the choice was driven by the CTC count.

Dr. Bidard reminded the audience that the primary endpoint of PFS to demonstrate the non-inferiority of CTC versus physician treatment decisions has already been met, with the results published in 2020. Those results came from an analysis of 788 patients enrolled between February 2012 and July 2016 at 17 sites in France and showed after 42 months of follow-up that the median PFS in the CTC arm was 15.6 months versus 14 months in the physician choice arm, at a hazard ratio of 0.92.

The current pre-planned analysis involved 755 patients who were followed up for a median of 57 months by the time the trial was stopped in 2021.

In the standard treatment arm, endocrine therapy was favored by physicians in 72.7% of cases (Clin-low), while 27.3% were given chemotherapy (Clin-high).

In the CTC group, 73.5% of patients were recommended to have endocrine therapy by their physician based on their clinical characteristics (Clin-low), whereas 26.5% were suggested to have chemotherapy (Clin-high).

In contrast, 60.1% of patients in the standard arm would have received endocrine therapy based on their CTC count (CTC-low), and 39.9% chemotherapy (CTC-high), while 63.4% of those in the CTC arm were given endocrine therapy based on their CTC count (CTC-low), and 36.6% were assigned to chemotherapy (CTC-high).

Once the allocated treatment was known in both treatment groups, the physicians were free to choose between endocrine therapy (mostly a single-agent aromatase inhibitor or fulvestrant) and chemotherapy (mostly paclitaxel or capecitabine).

Although CDK4/6 inhibitors were not approved at the time of enrollment, 42.2% of patients across both treatment groups received one of these drugs as a second-line or later therapy.
 

Guiding treatment decisions

Dr. Bidard said that, overall, more patients in the CTC arm were assigned to chemotherapy, at a difference of 9.7%. There was approximately 60% concordance between physician- and CTC-guided treatment choices; in other words, patients were recommended the same treatment by the two approaches in both treatment groups.

In these patients, there was no significant difference in overall survival between the physician choice and CTC groups, at a median of 45.5 months versus 51.3 months (hazard ratio, 0.85; P = .11).

The updated PFS data revealed a median PFS of 15.7 months in the CTC group versus 13.8 months, again at a nonsignificant HR of 0.94.

These results, Dr. Bidard said, indicate that CTC-based treatment choices are “safe.”

However, there was discordance between physician and CTC-based treatment choices in around 40% of cases, meaning that the two approaches recommended different therapies.

The physician recommended endocrine therapy, in contrast to the CTC count indicating chemotherapy, in 25% of patients (Clin-low/CTC-high), whereas 13.6% of cases were recommended chemotherapy while their CTC count indicated otherwise (Clin-high/CTC-low).

In Clin-low/CTC-high patients, this resulted in 26.1% of patients in the standard group receiving endocrine therapy when their CTC count indicated chemotherapy, while 23.9% of patients in the CTC group received chemotherapy even though their physician did not recommended it.

Comparing these two groups, the researchers found that patients in the CTC group had a significantly longer PFS, at 15.7 months versus 10 months (HR, 0.65; P = .005). They also had a significantly longer median overall survival, at a median of 51.8 months versus 35.4 months with physician choice (HR, 0.53; P = .001).

Among Clin-high/CTC-low, there was no benefit from physician’s choice of chemotherapy over the CTC-guided recommendation of endocrine therapy, at an HR for PFS of 1.14 for CTC- versus physician-guided therapy (P = .54), and an HR for overall survival of 0.88 (P = .64).

Dr. Bidard highlighted that the treatment effects were seen across prespecified subgroups.

The study was funded by the Institut National du Cancer, the Institut Curie SIRIC2 program, and Menarini Silicon Biosystems. Dr. Chan reports no relevant financial relationships. Dr. Hayes and Dr. Bidard reported relationships with numerous pharmaceutical companies.

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

SAN ANTONIO – When choosing between chemotherapy and endocrine therapy for patients with hormone receptor (HR)+/HER2- metastatic breast cancer, allowing the results from a blood test that measures circulating tumor cell (CTC) count to overrule physician’s choice of therapy can significantly improve overall survival.

But are these results enough to change clinical practice? One expert reacting to the findings says probably not, and another pointed out that the CTC count test used in the trial (CellSearch), although approved by the Food and Drug Administration, is not widely used in clinical practice.

The findings comes from updated results from the STIC CTC study.

“When the trial was designed, the question related to the choice between single-agent endocrine therapy and chemotherapy [in] first-line therapy,” explained study presenter François-Clément Bidard, MD, PhD, professor of medical oncology at Institut Curie and Versailles Saint-Quentin University, Paris.

Since then, the first-line treatment has changed and can now can also include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but Dr. Bidard said the results are still clinically relevant.

Nowadays, endocrine therapy plus CDK4/6 inhibitors is the “preferred option for treatment-naive patients, but the dilemma between endocrine therapy and chemotherapy remains after disease progression on adjuvant or first-line therapy with CDK4/6 inhibitors, where current guidelines advocate in favor of endocrine therapy, despite its short-lived efficacy.”

“In that scenario, based on the STIC CTC trial results, the CTC count in combination with predictive biomarkers, whenever available, may help customize the early use of chemotherapy or antibody-drug conjugates, which are becoming more and more attractive,” Dr. Bidard said.

The research was presented here at the San Antonio Breast Cancer Symposium (SABCS).

The study involved more than 750 patients with HR+/HER2- metastatic breast cancer randomly assigned to physician choice or CTC-guided therapy, although the physician decision and the recommendation based on the CTC count was recorded in both groups.

Using the CellSearch (Menarini Silicon Biosystems) to perform the CTC count at baseline only, the team defined patients as low or high risk, with low-risk patients deemed to need only endocrine therapy and high-risk patients recommended chemotherapy.

Physicians based their decisions on current guidelines and their clinical experience.

In the 25% of cases where CTC count would recommend chemotherapy while the physician would recommend endocrine therapy, following the CTC count–based choice resulted in a 35% improvement in progression-free survival (PFS) and a 47% increase in overall survival.

In all other situations, including those when the CTC count recommended endocrine therapy in contrast to the physicians, or the approximately 60% of cases in which the two were in agreement, there was no difference in survival outcomes between the approaches.

Reacting to the findings, Nancy Chan, MD, medical oncologist and the director of breast cancer clinical research at NYU Langone’s Perlmutter Cancer Center, said that the “goal is really to understand how we can personalize treatment options for patients.”

Another aim is to avoid performing a tumor biopsy, if possible, “as that has increased morbidity for patients.”

She noted also that choosing between endocrine therapy and chemotherapy is a “big decision.” These researchers “really wanted to help some patients get less chemotherapy,” as they felt that “some patients are getting too much” as they are not really that high risk and should get endocrine therapy instead.

However, Dr. Chan said that the CTC count is a “complicated concept” and is “not something we’re all using in our clinical practice yet.”

With regard to the approximately 40% discordance between the CTC- and physician-guided choices, Dr. Chan said that clinicians are perhaps not as accurate as they believed in predicting risk when relying on the clinical or pathological features of the tumor.

On Twitter, Guilherme Nader-Marta, MD, Jules Bordet Institute, Université Libre de Bruxelles, Belgium, commented that the question behind the study was whether CTC measurement is a “clinically useful strategy for first-line treatment decision-making.”

“Amazingly,” he continued, the trial went “straight to the point” to answer the question and showed that CTC-based decisions can offer a survival benefit.

Daniel F. Hayes, MD, co-director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center, Ann Arbor, echoed these thoughts, saying that the goals of therapy are to make patients live longer and “better.”

He said that the point of any clinical biomarker is not only to show that testing for it offers “analytical validity” but that it also provides “clinical utility” in that it can guide treatment decisions to improve outcomes.

Dr. Hayes, who was not involved in the study but has worked for many years on the development of CellSearch, said that the results do not make it clear whether measuring CTC counts meets the definition of clinical utility, but it’s “very close.”

On the other hand, the analytical validity of the test is “excellent,” and, in that context, was well-chosen, he said, adding that the endpoint of the trial “is the one most important to us: improvement in overall survival.”

Dr. Hayes noted that the magnitude of benefit from CTC-guided therapy was “moderate,” although that is a “matter of perception,” and the “level of evidence is probably 2 or 3.” Although the trial was prospective, he said, the key results were in a “relatively small” subgroup.

The question is, Dr. Hayes continued: “Is this enough to change practice? My conclusions are: probably not.”

Although patients rated as low risk based on their low CTC count avoided chemotherapy, “it’s not clear to me that this whole thing is sufficient for clinical utility in context of what we know today.” The key issue, however, is who decides whether CTC counts are measured and whether they will be used to guide therapy decisions – will it be the patient, the caregiver, an expert guidelines panel, or third party payers/society?
 

Study details

In his presentation, Dr. Bidard explained that CTC count is an FDA-approved standardized liquid biopsy biomarker, with a count of greater than or equal to 5 cells per 7.5 mL of blood deemed an adverse prognostic marker, regardless of the line of therapy, with a grade 1 level of evidence.

Previous studies have indicated that a high CTC count is strongly associated with overall survival, at a hazard ratio of 2.78.

Crucially, the CTC count “complements” and does not duplicate standard clinicopathological prognostic factors, Dr. Bidard said.

To determine the potential of the CTC count as an aid to treatment decisions, Dr. Bidard and colleagues conducted a trial in pre- and postmenopausal women with untreated HR+/HER2- metastatic breast cancer who were able to receive either endocrine therapy or chemotherapy.

They were randomly assigned to either a standard group, in which the treatment decision followed the physician’s choice, regardless of their CTC count, or to a CTC group, in which the physicians made a treatment recommendation but the choice was driven by the CTC count.

Dr. Bidard reminded the audience that the primary endpoint of PFS to demonstrate the non-inferiority of CTC versus physician treatment decisions has already been met, with the results published in 2020. Those results came from an analysis of 788 patients enrolled between February 2012 and July 2016 at 17 sites in France and showed after 42 months of follow-up that the median PFS in the CTC arm was 15.6 months versus 14 months in the physician choice arm, at a hazard ratio of 0.92.

The current pre-planned analysis involved 755 patients who were followed up for a median of 57 months by the time the trial was stopped in 2021.

In the standard treatment arm, endocrine therapy was favored by physicians in 72.7% of cases (Clin-low), while 27.3% were given chemotherapy (Clin-high).

In the CTC group, 73.5% of patients were recommended to have endocrine therapy by their physician based on their clinical characteristics (Clin-low), whereas 26.5% were suggested to have chemotherapy (Clin-high).

In contrast, 60.1% of patients in the standard arm would have received endocrine therapy based on their CTC count (CTC-low), and 39.9% chemotherapy (CTC-high), while 63.4% of those in the CTC arm were given endocrine therapy based on their CTC count (CTC-low), and 36.6% were assigned to chemotherapy (CTC-high).

Once the allocated treatment was known in both treatment groups, the physicians were free to choose between endocrine therapy (mostly a single-agent aromatase inhibitor or fulvestrant) and chemotherapy (mostly paclitaxel or capecitabine).

Although CDK4/6 inhibitors were not approved at the time of enrollment, 42.2% of patients across both treatment groups received one of these drugs as a second-line or later therapy.
 

Guiding treatment decisions

Dr. Bidard said that, overall, more patients in the CTC arm were assigned to chemotherapy, at a difference of 9.7%. There was approximately 60% concordance between physician- and CTC-guided treatment choices; in other words, patients were recommended the same treatment by the two approaches in both treatment groups.

In these patients, there was no significant difference in overall survival between the physician choice and CTC groups, at a median of 45.5 months versus 51.3 months (hazard ratio, 0.85; P = .11).

The updated PFS data revealed a median PFS of 15.7 months in the CTC group versus 13.8 months, again at a nonsignificant HR of 0.94.

These results, Dr. Bidard said, indicate that CTC-based treatment choices are “safe.”

However, there was discordance between physician and CTC-based treatment choices in around 40% of cases, meaning that the two approaches recommended different therapies.

The physician recommended endocrine therapy, in contrast to the CTC count indicating chemotherapy, in 25% of patients (Clin-low/CTC-high), whereas 13.6% of cases were recommended chemotherapy while their CTC count indicated otherwise (Clin-high/CTC-low).

In Clin-low/CTC-high patients, this resulted in 26.1% of patients in the standard group receiving endocrine therapy when their CTC count indicated chemotherapy, while 23.9% of patients in the CTC group received chemotherapy even though their physician did not recommended it.

Comparing these two groups, the researchers found that patients in the CTC group had a significantly longer PFS, at 15.7 months versus 10 months (HR, 0.65; P = .005). They also had a significantly longer median overall survival, at a median of 51.8 months versus 35.4 months with physician choice (HR, 0.53; P = .001).

Among Clin-high/CTC-low, there was no benefit from physician’s choice of chemotherapy over the CTC-guided recommendation of endocrine therapy, at an HR for PFS of 1.14 for CTC- versus physician-guided therapy (P = .54), and an HR for overall survival of 0.88 (P = .64).

Dr. Bidard highlighted that the treatment effects were seen across prespecified subgroups.

The study was funded by the Institut National du Cancer, the Institut Curie SIRIC2 program, and Menarini Silicon Biosystems. Dr. Chan reports no relevant financial relationships. Dr. Hayes and Dr. Bidard reported relationships with numerous pharmaceutical companies.

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

SAN ANTONIO – When choosing between chemotherapy and endocrine therapy for patients with hormone receptor (HR)+/HER2- metastatic breast cancer, allowing the results from a blood test that measures circulating tumor cell (CTC) count to overrule physician’s choice of therapy can significantly improve overall survival.

But are these results enough to change clinical practice? One expert reacting to the findings says probably not, and another pointed out that the CTC count test used in the trial (CellSearch), although approved by the Food and Drug Administration, is not widely used in clinical practice.

The findings comes from updated results from the STIC CTC study.

“When the trial was designed, the question related to the choice between single-agent endocrine therapy and chemotherapy [in] first-line therapy,” explained study presenter François-Clément Bidard, MD, PhD, professor of medical oncology at Institut Curie and Versailles Saint-Quentin University, Paris.

Since then, the first-line treatment has changed and can now can also include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but Dr. Bidard said the results are still clinically relevant.

Nowadays, endocrine therapy plus CDK4/6 inhibitors is the “preferred option for treatment-naive patients, but the dilemma between endocrine therapy and chemotherapy remains after disease progression on adjuvant or first-line therapy with CDK4/6 inhibitors, where current guidelines advocate in favor of endocrine therapy, despite its short-lived efficacy.”

“In that scenario, based on the STIC CTC trial results, the CTC count in combination with predictive biomarkers, whenever available, may help customize the early use of chemotherapy or antibody-drug conjugates, which are becoming more and more attractive,” Dr. Bidard said.

The research was presented here at the San Antonio Breast Cancer Symposium (SABCS).

The study involved more than 750 patients with HR+/HER2- metastatic breast cancer randomly assigned to physician choice or CTC-guided therapy, although the physician decision and the recommendation based on the CTC count was recorded in both groups.

Using the CellSearch (Menarini Silicon Biosystems) to perform the CTC count at baseline only, the team defined patients as low or high risk, with low-risk patients deemed to need only endocrine therapy and high-risk patients recommended chemotherapy.

Physicians based their decisions on current guidelines and their clinical experience.

In the 25% of cases where CTC count would recommend chemotherapy while the physician would recommend endocrine therapy, following the CTC count–based choice resulted in a 35% improvement in progression-free survival (PFS) and a 47% increase in overall survival.

In all other situations, including those when the CTC count recommended endocrine therapy in contrast to the physicians, or the approximately 60% of cases in which the two were in agreement, there was no difference in survival outcomes between the approaches.

Reacting to the findings, Nancy Chan, MD, medical oncologist and the director of breast cancer clinical research at NYU Langone’s Perlmutter Cancer Center, said that the “goal is really to understand how we can personalize treatment options for patients.”

Another aim is to avoid performing a tumor biopsy, if possible, “as that has increased morbidity for patients.”

She noted also that choosing between endocrine therapy and chemotherapy is a “big decision.” These researchers “really wanted to help some patients get less chemotherapy,” as they felt that “some patients are getting too much” as they are not really that high risk and should get endocrine therapy instead.

However, Dr. Chan said that the CTC count is a “complicated concept” and is “not something we’re all using in our clinical practice yet.”

With regard to the approximately 40% discordance between the CTC- and physician-guided choices, Dr. Chan said that clinicians are perhaps not as accurate as they believed in predicting risk when relying on the clinical or pathological features of the tumor.

On Twitter, Guilherme Nader-Marta, MD, Jules Bordet Institute, Université Libre de Bruxelles, Belgium, commented that the question behind the study was whether CTC measurement is a “clinically useful strategy for first-line treatment decision-making.”

“Amazingly,” he continued, the trial went “straight to the point” to answer the question and showed that CTC-based decisions can offer a survival benefit.

Daniel F. Hayes, MD, co-director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center, Ann Arbor, echoed these thoughts, saying that the goals of therapy are to make patients live longer and “better.”

He said that the point of any clinical biomarker is not only to show that testing for it offers “analytical validity” but that it also provides “clinical utility” in that it can guide treatment decisions to improve outcomes.

Dr. Hayes, who was not involved in the study but has worked for many years on the development of CellSearch, said that the results do not make it clear whether measuring CTC counts meets the definition of clinical utility, but it’s “very close.”

On the other hand, the analytical validity of the test is “excellent,” and, in that context, was well-chosen, he said, adding that the endpoint of the trial “is the one most important to us: improvement in overall survival.”

Dr. Hayes noted that the magnitude of benefit from CTC-guided therapy was “moderate,” although that is a “matter of perception,” and the “level of evidence is probably 2 or 3.” Although the trial was prospective, he said, the key results were in a “relatively small” subgroup.

The question is, Dr. Hayes continued: “Is this enough to change practice? My conclusions are: probably not.”

Although patients rated as low risk based on their low CTC count avoided chemotherapy, “it’s not clear to me that this whole thing is sufficient for clinical utility in context of what we know today.” The key issue, however, is who decides whether CTC counts are measured and whether they will be used to guide therapy decisions – will it be the patient, the caregiver, an expert guidelines panel, or third party payers/society?
 

Study details

In his presentation, Dr. Bidard explained that CTC count is an FDA-approved standardized liquid biopsy biomarker, with a count of greater than or equal to 5 cells per 7.5 mL of blood deemed an adverse prognostic marker, regardless of the line of therapy, with a grade 1 level of evidence.

Previous studies have indicated that a high CTC count is strongly associated with overall survival, at a hazard ratio of 2.78.

Crucially, the CTC count “complements” and does not duplicate standard clinicopathological prognostic factors, Dr. Bidard said.

To determine the potential of the CTC count as an aid to treatment decisions, Dr. Bidard and colleagues conducted a trial in pre- and postmenopausal women with untreated HR+/HER2- metastatic breast cancer who were able to receive either endocrine therapy or chemotherapy.

They were randomly assigned to either a standard group, in which the treatment decision followed the physician’s choice, regardless of their CTC count, or to a CTC group, in which the physicians made a treatment recommendation but the choice was driven by the CTC count.

Dr. Bidard reminded the audience that the primary endpoint of PFS to demonstrate the non-inferiority of CTC versus physician treatment decisions has already been met, with the results published in 2020. Those results came from an analysis of 788 patients enrolled between February 2012 and July 2016 at 17 sites in France and showed after 42 months of follow-up that the median PFS in the CTC arm was 15.6 months versus 14 months in the physician choice arm, at a hazard ratio of 0.92.

The current pre-planned analysis involved 755 patients who were followed up for a median of 57 months by the time the trial was stopped in 2021.

In the standard treatment arm, endocrine therapy was favored by physicians in 72.7% of cases (Clin-low), while 27.3% were given chemotherapy (Clin-high).

In the CTC group, 73.5% of patients were recommended to have endocrine therapy by their physician based on their clinical characteristics (Clin-low), whereas 26.5% were suggested to have chemotherapy (Clin-high).

In contrast, 60.1% of patients in the standard arm would have received endocrine therapy based on their CTC count (CTC-low), and 39.9% chemotherapy (CTC-high), while 63.4% of those in the CTC arm were given endocrine therapy based on their CTC count (CTC-low), and 36.6% were assigned to chemotherapy (CTC-high).

Once the allocated treatment was known in both treatment groups, the physicians were free to choose between endocrine therapy (mostly a single-agent aromatase inhibitor or fulvestrant) and chemotherapy (mostly paclitaxel or capecitabine).

Although CDK4/6 inhibitors were not approved at the time of enrollment, 42.2% of patients across both treatment groups received one of these drugs as a second-line or later therapy.
 

Guiding treatment decisions

Dr. Bidard said that, overall, more patients in the CTC arm were assigned to chemotherapy, at a difference of 9.7%. There was approximately 60% concordance between physician- and CTC-guided treatment choices; in other words, patients were recommended the same treatment by the two approaches in both treatment groups.

In these patients, there was no significant difference in overall survival between the physician choice and CTC groups, at a median of 45.5 months versus 51.3 months (hazard ratio, 0.85; P = .11).

The updated PFS data revealed a median PFS of 15.7 months in the CTC group versus 13.8 months, again at a nonsignificant HR of 0.94.

These results, Dr. Bidard said, indicate that CTC-based treatment choices are “safe.”

However, there was discordance between physician and CTC-based treatment choices in around 40% of cases, meaning that the two approaches recommended different therapies.

The physician recommended endocrine therapy, in contrast to the CTC count indicating chemotherapy, in 25% of patients (Clin-low/CTC-high), whereas 13.6% of cases were recommended chemotherapy while their CTC count indicated otherwise (Clin-high/CTC-low).

In Clin-low/CTC-high patients, this resulted in 26.1% of patients in the standard group receiving endocrine therapy when their CTC count indicated chemotherapy, while 23.9% of patients in the CTC group received chemotherapy even though their physician did not recommended it.

Comparing these two groups, the researchers found that patients in the CTC group had a significantly longer PFS, at 15.7 months versus 10 months (HR, 0.65; P = .005). They also had a significantly longer median overall survival, at a median of 51.8 months versus 35.4 months with physician choice (HR, 0.53; P = .001).

Among Clin-high/CTC-low, there was no benefit from physician’s choice of chemotherapy over the CTC-guided recommendation of endocrine therapy, at an HR for PFS of 1.14 for CTC- versus physician-guided therapy (P = .54), and an HR for overall survival of 0.88 (P = .64).

Dr. Bidard highlighted that the treatment effects were seen across prespecified subgroups.

The study was funded by the Institut National du Cancer, the Institut Curie SIRIC2 program, and Menarini Silicon Biosystems. Dr. Chan reports no relevant financial relationships. Dr. Hayes and Dr. Bidard reported relationships with numerous pharmaceutical companies.

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

A former associate professor at Purdue University faked data in two published papers and hundreds of images in 16 grant applications, according to a U.S. government research watchdog. 

Alice C. Chang, PhD, whose publications and grants listed her name as Chun-Ju Chang, received nearly $700,000 in funding from the National Institutes of Health through grant applications that the U.S. Office of Research Integrity said contained fake data. She will be banned from receiving federal grants for a decade – a more severe sanction than ORI has typically imposed in recent years.

In its findings, ORI said Dr. Chang, who was an associate professor of basic medical sciences at Purdue’s College of Veterinary Medicine, West Lafayette, Ind., “knowingly, intentionally, or recklessly falsified and/or fabricated data from the same mouse models or cell lines by reusing the data, with or without manipulation, to represent unrelated experiments from different mouse models or cell lines with different treatments in three hundred eighty-four (384) figure panels in sixteen (16) grant applications.”

Two of the grant applications were funded. Dr. Chang received $688,196 from the National Cancer Institute, a division of NIH, from 2018 to 2019 for “Targeting metformin-directed stem cell fate in triple negative breast cancer.” The other grant ORI says was submitted in 2014 and funded, “Targeting cell polarity machinery to exhaust breast cancer stem cell pool,” does not show up in NIH RePorter. The rest of the grants were not approved. 

We found a Chun-Ju Chang who is dean of the College of Life Sciences at China Medical University in Taiwan and has published papers with a group that Chun-Ju Chang at Purdue also published with. She did not immediately respond to our request for comment. 

ORI’s finding also stated Dr. Chang faked data in two papers supported by government funding by reusing figures reporting gene expression in mice and cells after drug treatments, relabeling them to say they showed the results of different experiments. According to the agency, she has agreed to request corrections for the papers: 

“Leptin–STAT3–G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression,” published in May 2015 in Cancer Research and cited 83 times, according to Clarivate’s Web of Science. 

“Retinoic acid directs breast cancer cell state changes through regulation of TET2-PKC-zeta pathway,” published in February 2017 in Oncogene and cited 26 times. 

Between the two papers and 15 of the grant applications, ORI said that Dr. Chang reused gene expression data, sometimes with manipulation, in 119 figure panels. She reused other types of data and images in hundreds of figures across multiple grant applications, ORI found. 

As well as correcting the two papers, Dr. Chang agreed to a 10-year ban from all federal contracting, including grant funding. She also agreed not to serve in any advisory or consulting role with the U.S. Public Health Service, which includes the NIH, for that time period.

A version of this article first appeared on Retraction Watch.

A former associate professor at Purdue University faked data in two published papers and hundreds of images in 16 grant applications, according to a U.S. government research watchdog. 

Alice C. Chang, PhD, whose publications and grants listed her name as Chun-Ju Chang, received nearly $700,000 in funding from the National Institutes of Health through grant applications that the U.S. Office of Research Integrity said contained fake data. She will be banned from receiving federal grants for a decade – a more severe sanction than ORI has typically imposed in recent years.

In its findings, ORI said Dr. Chang, who was an associate professor of basic medical sciences at Purdue’s College of Veterinary Medicine, West Lafayette, Ind., “knowingly, intentionally, or recklessly falsified and/or fabricated data from the same mouse models or cell lines by reusing the data, with or without manipulation, to represent unrelated experiments from different mouse models or cell lines with different treatments in three hundred eighty-four (384) figure panels in sixteen (16) grant applications.”

Two of the grant applications were funded. Dr. Chang received $688,196 from the National Cancer Institute, a division of NIH, from 2018 to 2019 for “Targeting metformin-directed stem cell fate in triple negative breast cancer.” The other grant ORI says was submitted in 2014 and funded, “Targeting cell polarity machinery to exhaust breast cancer stem cell pool,” does not show up in NIH RePorter. The rest of the grants were not approved. 

We found a Chun-Ju Chang who is dean of the College of Life Sciences at China Medical University in Taiwan and has published papers with a group that Chun-Ju Chang at Purdue also published with. She did not immediately respond to our request for comment. 

ORI’s finding also stated Dr. Chang faked data in two papers supported by government funding by reusing figures reporting gene expression in mice and cells after drug treatments, relabeling them to say they showed the results of different experiments. According to the agency, she has agreed to request corrections for the papers: 

“Leptin–STAT3–G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression,” published in May 2015 in Cancer Research and cited 83 times, according to Clarivate’s Web of Science. 

“Retinoic acid directs breast cancer cell state changes through regulation of TET2-PKC-zeta pathway,” published in February 2017 in Oncogene and cited 26 times. 

Between the two papers and 15 of the grant applications, ORI said that Dr. Chang reused gene expression data, sometimes with manipulation, in 119 figure panels. She reused other types of data and images in hundreds of figures across multiple grant applications, ORI found. 

As well as correcting the two papers, Dr. Chang agreed to a 10-year ban from all federal contracting, including grant funding. She also agreed not to serve in any advisory or consulting role with the U.S. Public Health Service, which includes the NIH, for that time period.

A version of this article first appeared on Retraction Watch.

A former associate professor at Purdue University faked data in two published papers and hundreds of images in 16 grant applications, according to a U.S. government research watchdog. 

Alice C. Chang, PhD, whose publications and grants listed her name as Chun-Ju Chang, received nearly $700,000 in funding from the National Institutes of Health through grant applications that the U.S. Office of Research Integrity said contained fake data. She will be banned from receiving federal grants for a decade – a more severe sanction than ORI has typically imposed in recent years.

In its findings, ORI said Dr. Chang, who was an associate professor of basic medical sciences at Purdue’s College of Veterinary Medicine, West Lafayette, Ind., “knowingly, intentionally, or recklessly falsified and/or fabricated data from the same mouse models or cell lines by reusing the data, with or without manipulation, to represent unrelated experiments from different mouse models or cell lines with different treatments in three hundred eighty-four (384) figure panels in sixteen (16) grant applications.”

Two of the grant applications were funded. Dr. Chang received $688,196 from the National Cancer Institute, a division of NIH, from 2018 to 2019 for “Targeting metformin-directed stem cell fate in triple negative breast cancer.” The other grant ORI says was submitted in 2014 and funded, “Targeting cell polarity machinery to exhaust breast cancer stem cell pool,” does not show up in NIH RePorter. The rest of the grants were not approved. 

We found a Chun-Ju Chang who is dean of the College of Life Sciences at China Medical University in Taiwan and has published papers with a group that Chun-Ju Chang at Purdue also published with. She did not immediately respond to our request for comment. 

ORI’s finding also stated Dr. Chang faked data in two papers supported by government funding by reusing figures reporting gene expression in mice and cells after drug treatments, relabeling them to say they showed the results of different experiments. According to the agency, she has agreed to request corrections for the papers: 

“Leptin–STAT3–G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression,” published in May 2015 in Cancer Research and cited 83 times, according to Clarivate’s Web of Science. 

“Retinoic acid directs breast cancer cell state changes through regulation of TET2-PKC-zeta pathway,” published in February 2017 in Oncogene and cited 26 times. 

Between the two papers and 15 of the grant applications, ORI said that Dr. Chang reused gene expression data, sometimes with manipulation, in 119 figure panels. She reused other types of data and images in hundreds of figures across multiple grant applications, ORI found. 

As well as correcting the two papers, Dr. Chang agreed to a 10-year ban from all federal contracting, including grant funding. She also agreed not to serve in any advisory or consulting role with the U.S. Public Health Service, which includes the NIH, for that time period.

A version of this article first appeared on Retraction Watch.

Women who have survived hormone receptor–positive (HR+) breast cancer can interrupt their endocrine therapy for up to 2 years to pursue pregnancy without affecting their short-term disease outcomes, suggest results from the prospective POSITIVE trial.

The study involved more than 500 premenopausal women from 20 countries who had received at least 18 months of endocrine therapy for HR+ breast cancer. After a 3-month washout, they were given 2 years to conceive, deliver, and breastfeed a baby before resuming treatment.

Crucially, taking a treatment break had no impact on recurrence rates, with the 3-year breast cancer–free interval (BCFI) failure rate of nearly 9% comparing favorably with historical controls.

Moreover, almost three-quarters of women achieved at least one pregnancy, the majority within 2 years, and the vast majority had resumed endocrine therapy by the end of the study period.

The research was presented at the San Antonio Breast Cancer Symposium.

“These data stress the need to incorporate patient-centered reproductive health care, treatments, and choices in the treatment and follow-up of our young women with breast cancer so that they can not only survive, but thrive in their survivorship,” said study presenter Ann Partridge, MD, MPH, vice chair of medical oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.

She noted, however, that the results so far are from a 3-year follow-up. The team now plans on following the women for “at least a decade ... to monitor for independent therapy resumption, and disease outcomes, because of course there is great concern about the late return” of HR+ breast cancer.

This point was also raised by Marleen I. Meyers, MD, a medical oncologist New York University Langone Perlmutter Cancer Center, who was not involved in the study. While she praised the study as offering the “first real evidence” that treatment can be interrupted safely, she said she would be “cautious, as the follow-up is short and we know that hormone positive breast cancer can recur within 10 years of diagnosis and beyond.”

Meyer also emphasized that “the potential loss of fertility and ability to have biologic children ... [is] one of the most devastating results for young women with breast cancer.”

“We have come a long way with fertility preservation,” Dr. Meyers continued, but waiting to complete the recommended 5-10 years of endocrine therapy “makes the possibility of carrying a child less realistic.”

“This study offers hope for some women with hormone receptor–positive breast cancer to be able to interrupt cancer treatment and still have good outcomes,” she said.

Dr. Partridge said that “women are often discouraged” from becoming pregnant, in addition to which giving adjuvant endocrine therapy for the standard 5-10 years “compromises conception” in women with HR+ disease.

POSITIVE was a single-arm trial involving premenopausal women aged up to 42 years at study entry. They were required to have undergone at least 18 months and no more than 30 months of adjuvant endocrine therapy for stage I-III HR+ breast cancer, with no clinical evidence of recurrence. The women could also have undergone prior neoadjuvant chemotherapy with or without fertility preservation.

Women halted endocrine therapy within 1 month of trial enrollment and then underwent a 3-month washout period before having up to 2 years to attempt pregnancy, and to conceive, give birth to, and breastfeed a baby. They were then “strongly recommended” to resume endocrine therapy to complete the planned 5-10 years of treatment, with follow-up planned for up to 10 years.

In all, 518 women were enrolled at 116 centers in 20 countries on four continents, of whom 516 were available for the primary efficacy analysis. The median time from breast cancer diagnosis to enrollment was 29 months.

The median age of the participants at enrollment was 37 years, and 75% had no prior births. Stage I or II disease was diagnosed in 93%. The median duration of endocrine therapy prior to enrollment was 23.4 months.

Selective estrogen receptor modulators were given alone in 42% of patients, while 36% had a SERM plus ovarian function suppression. A further 16% of women received an aromatase inhibitor alongside ovarian function suppression. The majority (62%) of women had received prior neoadjuvant chemotherapy.

The primary endpoint of 3-year BCFI was measured after a median follow-up of 41 months. There were 44 events, with a 3-year BCFI failure rate of 8.9%. The 3-year distant recurrence–free interval (DRFI) failure rate was calculated at 4.5%, with 22 events.

To provide an external control, the researchers examined data from the SOFT and TEXT trials to assemble a cohort of 1,499 women balanced for patient, disease, and treatment characteristics.

This revealed no significant differences in BCFI between the two groups (hazard ratio, 0.81; 95% confidence interval, 0.57-1.15) and a difference in BCFI rates at 3 years of 0.2% between the SOFT, TEXT, and POSITIVE trials.

There was also no significant difference in DRFI rates (HR, 0.70; 95% CI, 0.44-1.12), with a 3-year rate difference of 1.4%.

For the secondary endpoint analysis, the team included 497 women from the POSITIVE cohort, of whom 368 (74%) had at least one pregnancy, giving a total of 507 pregnancies. At least one live birth was recorded in 64% of the women, or 86% of those who became pregnant.

Dr. Partridge noted that around 43% of women used some form of assisted reproductive technology at some point during the study period.

Pregnancy complications were observed in 11% of pregnancies, the most common of which were hypertension/preeclampsia in 3%, and diabetes in 2%.

There were a total of 350 live births in 317 women, including 335 singleton births and 15 sets of twins. Only 8% of the offspring had a low birth weight, and 2% had a birth defect. Breastfeeding was reported by 62% of women.

Conducting an 18-month landmark analysis, the team found that pregnancy did not increase BCFI rates, at an HR versus nonpregnant women of 0.53 after controlling for age, body mass index, lymph node status, prior chemotherapy, and prior aromatase inhibitor therapy.

At 48 months of follow-up, 76% of women had resumed endocrine therapy. A further 8% of women had cancer recurrence or death before they could restart therapy, while 15% had not yet resumed treatment for other reasons.

Among disease-free women who had not resumed endocrine therapy, 79% reported at their most recent follow-up continuing to pursue pregnancy, having an active or recent pregnancy, or continuing to breastfeed as the reason.

Commenting on the study, Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said that this was a “challenging study to design and execute.”

“It gives us really a first look into the safety of a practice that was already happening,” she commented, and emphasized that the interruption of treatment to pursue pregnancy remains “an exceptionally individual decision.”

Dr. Litton also underlined that these results apply only to endocrine therapy and not to women on other therapies such as abemaciclib, for example, for which the course should be “fully completed” before considering any treatment interruptions.

She added more generally that “we need to continue to improve discussing fertility concerns with our breast cancer patients who want future pregnancies.”

The study was sponsored and conducted by the International Breast Cancer Study Group, a division of ETOP IBCSG Partners Foundation, and by the Alliance for Clinical Trials in Oncology in North America, in collaboration with the Breast International Group. Dr. Partridge and Dr. Litton reported no relevant relationships.

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

Women who have survived hormone receptor–positive (HR+) breast cancer can interrupt their endocrine therapy for up to 2 years to pursue pregnancy without affecting their short-term disease outcomes, suggest results from the prospective POSITIVE trial.

The study involved more than 500 premenopausal women from 20 countries who had received at least 18 months of endocrine therapy for HR+ breast cancer. After a 3-month washout, they were given 2 years to conceive, deliver, and breastfeed a baby before resuming treatment.

Crucially, taking a treatment break had no impact on recurrence rates, with the 3-year breast cancer–free interval (BCFI) failure rate of nearly 9% comparing favorably with historical controls.

Moreover, almost three-quarters of women achieved at least one pregnancy, the majority within 2 years, and the vast majority had resumed endocrine therapy by the end of the study period.

The research was presented at the San Antonio Breast Cancer Symposium.

“These data stress the need to incorporate patient-centered reproductive health care, treatments, and choices in the treatment and follow-up of our young women with breast cancer so that they can not only survive, but thrive in their survivorship,” said study presenter Ann Partridge, MD, MPH, vice chair of medical oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.

She noted, however, that the results so far are from a 3-year follow-up. The team now plans on following the women for “at least a decade ... to monitor for independent therapy resumption, and disease outcomes, because of course there is great concern about the late return” of HR+ breast cancer.

This point was also raised by Marleen I. Meyers, MD, a medical oncologist New York University Langone Perlmutter Cancer Center, who was not involved in the study. While she praised the study as offering the “first real evidence” that treatment can be interrupted safely, she said she would be “cautious, as the follow-up is short and we know that hormone positive breast cancer can recur within 10 years of diagnosis and beyond.”

Meyer also emphasized that “the potential loss of fertility and ability to have biologic children ... [is] one of the most devastating results for young women with breast cancer.”

“We have come a long way with fertility preservation,” Dr. Meyers continued, but waiting to complete the recommended 5-10 years of endocrine therapy “makes the possibility of carrying a child less realistic.”

“This study offers hope for some women with hormone receptor–positive breast cancer to be able to interrupt cancer treatment and still have good outcomes,” she said.

Dr. Partridge said that “women are often discouraged” from becoming pregnant, in addition to which giving adjuvant endocrine therapy for the standard 5-10 years “compromises conception” in women with HR+ disease.

POSITIVE was a single-arm trial involving premenopausal women aged up to 42 years at study entry. They were required to have undergone at least 18 months and no more than 30 months of adjuvant endocrine therapy for stage I-III HR+ breast cancer, with no clinical evidence of recurrence. The women could also have undergone prior neoadjuvant chemotherapy with or without fertility preservation.

Women halted endocrine therapy within 1 month of trial enrollment and then underwent a 3-month washout period before having up to 2 years to attempt pregnancy, and to conceive, give birth to, and breastfeed a baby. They were then “strongly recommended” to resume endocrine therapy to complete the planned 5-10 years of treatment, with follow-up planned for up to 10 years.

In all, 518 women were enrolled at 116 centers in 20 countries on four continents, of whom 516 were available for the primary efficacy analysis. The median time from breast cancer diagnosis to enrollment was 29 months.

The median age of the participants at enrollment was 37 years, and 75% had no prior births. Stage I or II disease was diagnosed in 93%. The median duration of endocrine therapy prior to enrollment was 23.4 months.

Selective estrogen receptor modulators were given alone in 42% of patients, while 36% had a SERM plus ovarian function suppression. A further 16% of women received an aromatase inhibitor alongside ovarian function suppression. The majority (62%) of women had received prior neoadjuvant chemotherapy.

The primary endpoint of 3-year BCFI was measured after a median follow-up of 41 months. There were 44 events, with a 3-year BCFI failure rate of 8.9%. The 3-year distant recurrence–free interval (DRFI) failure rate was calculated at 4.5%, with 22 events.

To provide an external control, the researchers examined data from the SOFT and TEXT trials to assemble a cohort of 1,499 women balanced for patient, disease, and treatment characteristics.

This revealed no significant differences in BCFI between the two groups (hazard ratio, 0.81; 95% confidence interval, 0.57-1.15) and a difference in BCFI rates at 3 years of 0.2% between the SOFT, TEXT, and POSITIVE trials.

There was also no significant difference in DRFI rates (HR, 0.70; 95% CI, 0.44-1.12), with a 3-year rate difference of 1.4%.

For the secondary endpoint analysis, the team included 497 women from the POSITIVE cohort, of whom 368 (74%) had at least one pregnancy, giving a total of 507 pregnancies. At least one live birth was recorded in 64% of the women, or 86% of those who became pregnant.

Dr. Partridge noted that around 43% of women used some form of assisted reproductive technology at some point during the study period.

Pregnancy complications were observed in 11% of pregnancies, the most common of which were hypertension/preeclampsia in 3%, and diabetes in 2%.

There were a total of 350 live births in 317 women, including 335 singleton births and 15 sets of twins. Only 8% of the offspring had a low birth weight, and 2% had a birth defect. Breastfeeding was reported by 62% of women.

Conducting an 18-month landmark analysis, the team found that pregnancy did not increase BCFI rates, at an HR versus nonpregnant women of 0.53 after controlling for age, body mass index, lymph node status, prior chemotherapy, and prior aromatase inhibitor therapy.

At 48 months of follow-up, 76% of women had resumed endocrine therapy. A further 8% of women had cancer recurrence or death before they could restart therapy, while 15% had not yet resumed treatment for other reasons.

Among disease-free women who had not resumed endocrine therapy, 79% reported at their most recent follow-up continuing to pursue pregnancy, having an active or recent pregnancy, or continuing to breastfeed as the reason.

Commenting on the study, Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said that this was a “challenging study to design and execute.”

“It gives us really a first look into the safety of a practice that was already happening,” she commented, and emphasized that the interruption of treatment to pursue pregnancy remains “an exceptionally individual decision.”

Dr. Litton also underlined that these results apply only to endocrine therapy and not to women on other therapies such as abemaciclib, for example, for which the course should be “fully completed” before considering any treatment interruptions.

She added more generally that “we need to continue to improve discussing fertility concerns with our breast cancer patients who want future pregnancies.”

The study was sponsored and conducted by the International Breast Cancer Study Group, a division of ETOP IBCSG Partners Foundation, and by the Alliance for Clinical Trials in Oncology in North America, in collaboration with the Breast International Group. Dr. Partridge and Dr. Litton reported no relevant relationships.

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

Women who have survived hormone receptor–positive (HR+) breast cancer can interrupt their endocrine therapy for up to 2 years to pursue pregnancy without affecting their short-term disease outcomes, suggest results from the prospective POSITIVE trial.

The study involved more than 500 premenopausal women from 20 countries who had received at least 18 months of endocrine therapy for HR+ breast cancer. After a 3-month washout, they were given 2 years to conceive, deliver, and breastfeed a baby before resuming treatment.

Crucially, taking a treatment break had no impact on recurrence rates, with the 3-year breast cancer–free interval (BCFI) failure rate of nearly 9% comparing favorably with historical controls.

Moreover, almost three-quarters of women achieved at least one pregnancy, the majority within 2 years, and the vast majority had resumed endocrine therapy by the end of the study period.

The research was presented at the San Antonio Breast Cancer Symposium.

“These data stress the need to incorporate patient-centered reproductive health care, treatments, and choices in the treatment and follow-up of our young women with breast cancer so that they can not only survive, but thrive in their survivorship,” said study presenter Ann Partridge, MD, MPH, vice chair of medical oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.

She noted, however, that the results so far are from a 3-year follow-up. The team now plans on following the women for “at least a decade ... to monitor for independent therapy resumption, and disease outcomes, because of course there is great concern about the late return” of HR+ breast cancer.

This point was also raised by Marleen I. Meyers, MD, a medical oncologist New York University Langone Perlmutter Cancer Center, who was not involved in the study. While she praised the study as offering the “first real evidence” that treatment can be interrupted safely, she said she would be “cautious, as the follow-up is short and we know that hormone positive breast cancer can recur within 10 years of diagnosis and beyond.”

Meyer also emphasized that “the potential loss of fertility and ability to have biologic children ... [is] one of the most devastating results for young women with breast cancer.”

“We have come a long way with fertility preservation,” Dr. Meyers continued, but waiting to complete the recommended 5-10 years of endocrine therapy “makes the possibility of carrying a child less realistic.”

“This study offers hope for some women with hormone receptor–positive breast cancer to be able to interrupt cancer treatment and still have good outcomes,” she said.

Dr. Partridge said that “women are often discouraged” from becoming pregnant, in addition to which giving adjuvant endocrine therapy for the standard 5-10 years “compromises conception” in women with HR+ disease.

POSITIVE was a single-arm trial involving premenopausal women aged up to 42 years at study entry. They were required to have undergone at least 18 months and no more than 30 months of adjuvant endocrine therapy for stage I-III HR+ breast cancer, with no clinical evidence of recurrence. The women could also have undergone prior neoadjuvant chemotherapy with or without fertility preservation.

Women halted endocrine therapy within 1 month of trial enrollment and then underwent a 3-month washout period before having up to 2 years to attempt pregnancy, and to conceive, give birth to, and breastfeed a baby. They were then “strongly recommended” to resume endocrine therapy to complete the planned 5-10 years of treatment, with follow-up planned for up to 10 years.

In all, 518 women were enrolled at 116 centers in 20 countries on four continents, of whom 516 were available for the primary efficacy analysis. The median time from breast cancer diagnosis to enrollment was 29 months.

The median age of the participants at enrollment was 37 years, and 75% had no prior births. Stage I or II disease was diagnosed in 93%. The median duration of endocrine therapy prior to enrollment was 23.4 months.

Selective estrogen receptor modulators were given alone in 42% of patients, while 36% had a SERM plus ovarian function suppression. A further 16% of women received an aromatase inhibitor alongside ovarian function suppression. The majority (62%) of women had received prior neoadjuvant chemotherapy.

The primary endpoint of 3-year BCFI was measured after a median follow-up of 41 months. There were 44 events, with a 3-year BCFI failure rate of 8.9%. The 3-year distant recurrence–free interval (DRFI) failure rate was calculated at 4.5%, with 22 events.

To provide an external control, the researchers examined data from the SOFT and TEXT trials to assemble a cohort of 1,499 women balanced for patient, disease, and treatment characteristics.

This revealed no significant differences in BCFI between the two groups (hazard ratio, 0.81; 95% confidence interval, 0.57-1.15) and a difference in BCFI rates at 3 years of 0.2% between the SOFT, TEXT, and POSITIVE trials.

There was also no significant difference in DRFI rates (HR, 0.70; 95% CI, 0.44-1.12), with a 3-year rate difference of 1.4%.

For the secondary endpoint analysis, the team included 497 women from the POSITIVE cohort, of whom 368 (74%) had at least one pregnancy, giving a total of 507 pregnancies. At least one live birth was recorded in 64% of the women, or 86% of those who became pregnant.

Dr. Partridge noted that around 43% of women used some form of assisted reproductive technology at some point during the study period.

Pregnancy complications were observed in 11% of pregnancies, the most common of which were hypertension/preeclampsia in 3%, and diabetes in 2%.

There were a total of 350 live births in 317 women, including 335 singleton births and 15 sets of twins. Only 8% of the offspring had a low birth weight, and 2% had a birth defect. Breastfeeding was reported by 62% of women.

Conducting an 18-month landmark analysis, the team found that pregnancy did not increase BCFI rates, at an HR versus nonpregnant women of 0.53 after controlling for age, body mass index, lymph node status, prior chemotherapy, and prior aromatase inhibitor therapy.

At 48 months of follow-up, 76% of women had resumed endocrine therapy. A further 8% of women had cancer recurrence or death before they could restart therapy, while 15% had not yet resumed treatment for other reasons.

Among disease-free women who had not resumed endocrine therapy, 79% reported at their most recent follow-up continuing to pursue pregnancy, having an active or recent pregnancy, or continuing to breastfeed as the reason.

Commenting on the study, Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said that this was a “challenging study to design and execute.”

“It gives us really a first look into the safety of a practice that was already happening,” she commented, and emphasized that the interruption of treatment to pursue pregnancy remains “an exceptionally individual decision.”

Dr. Litton also underlined that these results apply only to endocrine therapy and not to women on other therapies such as abemaciclib, for example, for which the course should be “fully completed” before considering any treatment interruptions.

She added more generally that “we need to continue to improve discussing fertility concerns with our breast cancer patients who want future pregnancies.”

The study was sponsored and conducted by the International Breast Cancer Study Group, a division of ETOP IBCSG Partners Foundation, and by the Alliance for Clinical Trials in Oncology in North America, in collaboration with the Breast International Group. Dr. Partridge and Dr. Litton reported no relevant relationships.

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

SAN ANTONIO – While major reports on hormone receptor (HR)–positive breast cancer took center stage at the San Antonio Breast Cancer Symposium, research highlighting new findings in triple-negative breast cancer (TNBC) stood out as well.

This news organization spoke with SABCS program director Virginia Kaklamani, MD, leader of the Breast Cancer Program at UT Health, San Antonio, and Kevin Kalinsky, MD, a medical oncologist and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University in Atlanta, about the TNBC data that caught their eye and what the findings could mean for clinical practice.
 

1. Carboplatin for TNBC

Dr. Kalinsky’s first pick was a study on the impact of platinum therapy on long-term TNBC outcomes.

The phase 3 randomized controlled trial, presented in general session (GS) 5-01, explored whether adding carboplatin to sequential taxane-anthracycline neoadjuvant chemotherapy for patients with TNBC improved disease-free survival, pathologic complete response, or overall survival.

Overall, 365 patients received carboplatin, and 355 did not. At a median follow-up of 67.6 months, the 5-year disease-free survival rate was 70.6% in the carboplatin group vs. 64.5% in the control arm (hazard ratio, 0.79); the 5-year overall survival was also higher in the carboplatin group (74.0% vs. 66.7%; HR, 0.75). Pathologic complete response occurred in 55.2% of carboplatin patients, vs. 41.5% of control patients.

“These results are important,” Dr. Kalinsky said. “The results of this study suggest that there is a benefit to the TNBC population from being treated with carboplatin.”

Dr. Kalinsky cautioned, however, that despite the encouraging results, it remains unclear whether there is a specific biomarker for selecting patients who may derive the most benefit from treatment with carboplatin. “This remains an outstanding question,” he said.
 

2. Risk of contralateral breast cancer

Women with breast cancer who have germline pathogenic variants in BRCA1, BRCA2, CHEK2, or PALB2 had nearly double the risk of contralateral breast cancer in comparison with patients without those variants, according to recent data presented at the meeting (GS4-04).

Researchers estimated the risk of contralateral breast cancer in women with pathogenic variants in comparison with control patients. They found that having ATM does not increase this risk.

“The reason this study is important is that many women with these mutations want to have a bilateral mastectomy, but thus far, the data have been unclear, and the question is, are they going to benefit from having a bilateral mastectomy?” said Dr. Kaklamani. “The results of this study help shine a light on what mutations might warrant a bilateral mastectomy. Most of these patients are going to be triple negative.”

Hal Burstein, MD, also weighed in, saying the “data should allow many to avoid prophylactic mastectomy.”
 

3. Cemiplimab plus LAG-3 inhibitor in TNBC

Another session that caught Dr. Kalinsky’s attention explored results from the I-SPY2 trial (GS5-03), which evaluated the use of the checkpoint inhibitior cemiplimab in combination with LAG-3 inhibitor REGN3767 for patients with early-stage, high-risk, HER2-negative breast cancer.

Among the 73 patients with HER2-negative disease who received cemiplimab plus REGN3767, 33 had TNBC. The control group included 357 patients with HER2-negative tumors, of whom 156 had TNBC. Overall, the combination of a LAG-3 and anti-PD1 inhibitor resulted in a pathologic complete response rate of 60% for patients with TNBC and 37% for patients with HR-positive disease.

“We know that checkpoint inhibitors benefit patients with TNBC, and there has been a lot of interest in looking beyond checkpoint inhibition,” said Dr. Kalinsky, who is a coinvestigator on the I-SPY trial. “LAG-3 has been a target of interest, and this is the first study looking in the neoadjuvant setting of giving a LAG-3 inhibitor along with a checkpoint inhibitor.”
 

4. Efficacy vs. side effect profile of cemiplimab

Taking adverse events of immune checkpoint inhibitors into account is also important. Dr. Kalinsky and colleagues presented research on the efficacy as well as the side-effect profile associated with cemiplimab (PD11-01) among patients in the I-SPY trial.

Overall, cemiplimab was associated with a higher pathologic complete response rate for patients with TNBC (55%), compared with control patients who received paclitaxel followed by doxorubicin/cyclophosphamide (29%). The rate of immune-related adverse events was higher in the cemiplimab group: hypothyroidism, 3% vs. 0%; adrenal insufficiency, 6% vs. 0%; hyperthyroid, 8% vs. 0%; and thyroiditis, 3% vs. 0%. However, only one case of grade 3 adrenal insufficiency occurred in the cemiplimab arm.

“I really think the key takeaway is not just the efficacy that is seen in the HER2-negative population but also what the side-effect profile is going to be,” Dr. Kalinsky said.
 

5. Olaparib or carboplatinum?

Dr. Kaklamani highlighted data from the GeparOLA study (GS5-02), which evaluated the efficacy and safety of using olaparib instead of carboplatinum along with paclitaxel as neoadjuvant chemotherapy in early-stage HER2-negative breast cancer.

The results of the study indicate that among patients in the cohort with HER2-negative homologous recombination deficiency tumors – those with a g/tBRCA mutation – the two groups had similar pathologic complete responses. Overall, patients in the olaparib group had more invasive disease-free survival events (15 vs. 3), more distant disease-free survival events (11 vs. 2), and more deaths (6 vs. 1). However, when comparing patients with a g/tBRCA mutation, outcomes were comparable in both arms.

“The majority of these patients were triple negative, and I think the importance here is that this [study] shows us whether we should be adding olaparib in some patients who have a homologous recombination deficiency,” Dr. Kaklamani said.

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

SAN ANTONIO – While major reports on hormone receptor (HR)–positive breast cancer took center stage at the San Antonio Breast Cancer Symposium, research highlighting new findings in triple-negative breast cancer (TNBC) stood out as well.

This news organization spoke with SABCS program director Virginia Kaklamani, MD, leader of the Breast Cancer Program at UT Health, San Antonio, and Kevin Kalinsky, MD, a medical oncologist and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University in Atlanta, about the TNBC data that caught their eye and what the findings could mean for clinical practice.
 

1. Carboplatin for TNBC

Dr. Kalinsky’s first pick was a study on the impact of platinum therapy on long-term TNBC outcomes.

The phase 3 randomized controlled trial, presented in general session (GS) 5-01, explored whether adding carboplatin to sequential taxane-anthracycline neoadjuvant chemotherapy for patients with TNBC improved disease-free survival, pathologic complete response, or overall survival.

Overall, 365 patients received carboplatin, and 355 did not. At a median follow-up of 67.6 months, the 5-year disease-free survival rate was 70.6% in the carboplatin group vs. 64.5% in the control arm (hazard ratio, 0.79); the 5-year overall survival was also higher in the carboplatin group (74.0% vs. 66.7%; HR, 0.75). Pathologic complete response occurred in 55.2% of carboplatin patients, vs. 41.5% of control patients.

“These results are important,” Dr. Kalinsky said. “The results of this study suggest that there is a benefit to the TNBC population from being treated with carboplatin.”

Dr. Kalinsky cautioned, however, that despite the encouraging results, it remains unclear whether there is a specific biomarker for selecting patients who may derive the most benefit from treatment with carboplatin. “This remains an outstanding question,” he said.
 

2. Risk of contralateral breast cancer

Women with breast cancer who have germline pathogenic variants in BRCA1, BRCA2, CHEK2, or PALB2 had nearly double the risk of contralateral breast cancer in comparison with patients without those variants, according to recent data presented at the meeting (GS4-04).

Researchers estimated the risk of contralateral breast cancer in women with pathogenic variants in comparison with control patients. They found that having ATM does not increase this risk.

“The reason this study is important is that many women with these mutations want to have a bilateral mastectomy, but thus far, the data have been unclear, and the question is, are they going to benefit from having a bilateral mastectomy?” said Dr. Kaklamani. “The results of this study help shine a light on what mutations might warrant a bilateral mastectomy. Most of these patients are going to be triple negative.”

Hal Burstein, MD, also weighed in, saying the “data should allow many to avoid prophylactic mastectomy.”
 

3. Cemiplimab plus LAG-3 inhibitor in TNBC

Another session that caught Dr. Kalinsky’s attention explored results from the I-SPY2 trial (GS5-03), which evaluated the use of the checkpoint inhibitior cemiplimab in combination with LAG-3 inhibitor REGN3767 for patients with early-stage, high-risk, HER2-negative breast cancer.

Among the 73 patients with HER2-negative disease who received cemiplimab plus REGN3767, 33 had TNBC. The control group included 357 patients with HER2-negative tumors, of whom 156 had TNBC. Overall, the combination of a LAG-3 and anti-PD1 inhibitor resulted in a pathologic complete response rate of 60% for patients with TNBC and 37% for patients with HR-positive disease.

“We know that checkpoint inhibitors benefit patients with TNBC, and there has been a lot of interest in looking beyond checkpoint inhibition,” said Dr. Kalinsky, who is a coinvestigator on the I-SPY trial. “LAG-3 has been a target of interest, and this is the first study looking in the neoadjuvant setting of giving a LAG-3 inhibitor along with a checkpoint inhibitor.”
 

4. Efficacy vs. side effect profile of cemiplimab

Taking adverse events of immune checkpoint inhibitors into account is also important. Dr. Kalinsky and colleagues presented research on the efficacy as well as the side-effect profile associated with cemiplimab (PD11-01) among patients in the I-SPY trial.

Overall, cemiplimab was associated with a higher pathologic complete response rate for patients with TNBC (55%), compared with control patients who received paclitaxel followed by doxorubicin/cyclophosphamide (29%). The rate of immune-related adverse events was higher in the cemiplimab group: hypothyroidism, 3% vs. 0%; adrenal insufficiency, 6% vs. 0%; hyperthyroid, 8% vs. 0%; and thyroiditis, 3% vs. 0%. However, only one case of grade 3 adrenal insufficiency occurred in the cemiplimab arm.

“I really think the key takeaway is not just the efficacy that is seen in the HER2-negative population but also what the side-effect profile is going to be,” Dr. Kalinsky said.
 

5. Olaparib or carboplatinum?

Dr. Kaklamani highlighted data from the GeparOLA study (GS5-02), which evaluated the efficacy and safety of using olaparib instead of carboplatinum along with paclitaxel as neoadjuvant chemotherapy in early-stage HER2-negative breast cancer.

The results of the study indicate that among patients in the cohort with HER2-negative homologous recombination deficiency tumors – those with a g/tBRCA mutation – the two groups had similar pathologic complete responses. Overall, patients in the olaparib group had more invasive disease-free survival events (15 vs. 3), more distant disease-free survival events (11 vs. 2), and more deaths (6 vs. 1). However, when comparing patients with a g/tBRCA mutation, outcomes were comparable in both arms.

“The majority of these patients were triple negative, and I think the importance here is that this [study] shows us whether we should be adding olaparib in some patients who have a homologous recombination deficiency,” Dr. Kaklamani said.

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

SAN ANTONIO – While major reports on hormone receptor (HR)–positive breast cancer took center stage at the San Antonio Breast Cancer Symposium, research highlighting new findings in triple-negative breast cancer (TNBC) stood out as well.

This news organization spoke with SABCS program director Virginia Kaklamani, MD, leader of the Breast Cancer Program at UT Health, San Antonio, and Kevin Kalinsky, MD, a medical oncologist and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University in Atlanta, about the TNBC data that caught their eye and what the findings could mean for clinical practice.
 

1. Carboplatin for TNBC

Dr. Kalinsky’s first pick was a study on the impact of platinum therapy on long-term TNBC outcomes.

The phase 3 randomized controlled trial, presented in general session (GS) 5-01, explored whether adding carboplatin to sequential taxane-anthracycline neoadjuvant chemotherapy for patients with TNBC improved disease-free survival, pathologic complete response, or overall survival.

Overall, 365 patients received carboplatin, and 355 did not. At a median follow-up of 67.6 months, the 5-year disease-free survival rate was 70.6% in the carboplatin group vs. 64.5% in the control arm (hazard ratio, 0.79); the 5-year overall survival was also higher in the carboplatin group (74.0% vs. 66.7%; HR, 0.75). Pathologic complete response occurred in 55.2% of carboplatin patients, vs. 41.5% of control patients.

“These results are important,” Dr. Kalinsky said. “The results of this study suggest that there is a benefit to the TNBC population from being treated with carboplatin.”

Dr. Kalinsky cautioned, however, that despite the encouraging results, it remains unclear whether there is a specific biomarker for selecting patients who may derive the most benefit from treatment with carboplatin. “This remains an outstanding question,” he said.
 

2. Risk of contralateral breast cancer

Women with breast cancer who have germline pathogenic variants in BRCA1, BRCA2, CHEK2, or PALB2 had nearly double the risk of contralateral breast cancer in comparison with patients without those variants, according to recent data presented at the meeting (GS4-04).

Researchers estimated the risk of contralateral breast cancer in women with pathogenic variants in comparison with control patients. They found that having ATM does not increase this risk.

“The reason this study is important is that many women with these mutations want to have a bilateral mastectomy, but thus far, the data have been unclear, and the question is, are they going to benefit from having a bilateral mastectomy?” said Dr. Kaklamani. “The results of this study help shine a light on what mutations might warrant a bilateral mastectomy. Most of these patients are going to be triple negative.”

Hal Burstein, MD, also weighed in, saying the “data should allow many to avoid prophylactic mastectomy.”
 

3. Cemiplimab plus LAG-3 inhibitor in TNBC

Another session that caught Dr. Kalinsky’s attention explored results from the I-SPY2 trial (GS5-03), which evaluated the use of the checkpoint inhibitior cemiplimab in combination with LAG-3 inhibitor REGN3767 for patients with early-stage, high-risk, HER2-negative breast cancer.

Among the 73 patients with HER2-negative disease who received cemiplimab plus REGN3767, 33 had TNBC. The control group included 357 patients with HER2-negative tumors, of whom 156 had TNBC. Overall, the combination of a LAG-3 and anti-PD1 inhibitor resulted in a pathologic complete response rate of 60% for patients with TNBC and 37% for patients with HR-positive disease.

“We know that checkpoint inhibitors benefit patients with TNBC, and there has been a lot of interest in looking beyond checkpoint inhibition,” said Dr. Kalinsky, who is a coinvestigator on the I-SPY trial. “LAG-3 has been a target of interest, and this is the first study looking in the neoadjuvant setting of giving a LAG-3 inhibitor along with a checkpoint inhibitor.”
 

4. Efficacy vs. side effect profile of cemiplimab

Taking adverse events of immune checkpoint inhibitors into account is also important. Dr. Kalinsky and colleagues presented research on the efficacy as well as the side-effect profile associated with cemiplimab (PD11-01) among patients in the I-SPY trial.

Overall, cemiplimab was associated with a higher pathologic complete response rate for patients with TNBC (55%), compared with control patients who received paclitaxel followed by doxorubicin/cyclophosphamide (29%). The rate of immune-related adverse events was higher in the cemiplimab group: hypothyroidism, 3% vs. 0%; adrenal insufficiency, 6% vs. 0%; hyperthyroid, 8% vs. 0%; and thyroiditis, 3% vs. 0%. However, only one case of grade 3 adrenal insufficiency occurred in the cemiplimab arm.

“I really think the key takeaway is not just the efficacy that is seen in the HER2-negative population but also what the side-effect profile is going to be,” Dr. Kalinsky said.
 

5. Olaparib or carboplatinum?

Dr. Kaklamani highlighted data from the GeparOLA study (GS5-02), which evaluated the efficacy and safety of using olaparib instead of carboplatinum along with paclitaxel as neoadjuvant chemotherapy in early-stage HER2-negative breast cancer.

The results of the study indicate that among patients in the cohort with HER2-negative homologous recombination deficiency tumors – those with a g/tBRCA mutation – the two groups had similar pathologic complete responses. Overall, patients in the olaparib group had more invasive disease-free survival events (15 vs. 3), more distant disease-free survival events (11 vs. 2), and more deaths (6 vs. 1). However, when comparing patients with a g/tBRCA mutation, outcomes were comparable in both arms.

“The majority of these patients were triple negative, and I think the importance here is that this [study] shows us whether we should be adding olaparib in some patients who have a homologous recombination deficiency,” Dr. Kaklamani said.

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

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN ANTONIO – The investigational selective estrogen receptor degrader camizestrant was associated with significantly longer progression-free survival for women with advanced estrogen receptor–positive, HER2-negative (ER+/HER2–) breast cancers, compared with the first-generation SERD fulvestrant Faslodex, in the SERENA-2 trial, shows a study recently presented at the San Antonio Breast Cancer Symposium.

Among 180 postmenopausal women with ER+/HER2– breast cancers that had recurred or progressed following at least one line of endocrine therapy, the median progression-free survival (PFS) after a median follow-up of 16.6-17.4 months was 7.2 months for patients treated at a 75-mg dose of camizestrant and 7.7 months for those treated at a 150-mg dose, compared with 3.7 months for patients who received fulvestrant, reported Mafalda Oliveira, MD, PhD, from Vall d’Hebron University Hospital in Barcelona.

Oral agent

Camizestrant is a next-generation oral SERD and pure estrogen receptor antagonist that was shown in the SERENA-1 trial to be safe and to have clinical activity against ER+ breast cancers.

SERENA-2 pitted camizestrant at doses of 75 mg, 150 mg, or 300 mg against standard-dose fulvestrant, although the 300-mg dose was dropped in a protocol amendment after 20 patients had been assigned to that arm. (Currently planned studies with camizestrant will be conducted with the 75-mg dose.)

The investigators enrolled women with ER+/HER2– advanced breast cancer who had not previously received fulvestrant or an oral SERD. Eligible patients were limited to no more than one prior line of endocrine and one prior line of chemotherapy for advanced breast cancers. The study included patients with both measurable and unmeasurable disease.

The median patient age was about 60 years. Approximately 59% of patients in each arm had either lung or liver metastases. Patients with recurrence in bone only comprised 14.9%-19.4%.

Mutations in ESR1, a gene associated with hormonal resistance, were detectable in 29.7%-47.9% of patients.
 

Better PFS

As noted before, the primary endpoint of investigator-assessed median PFS favored camizestrant in both the 75-mg arm (7.2 months) and the 150-mg arm (7.7 months), with respective adjusted hazard ratios for progression versus fulvestrant of 0.58 (P = .0124) and 0.67 (P = .0161).

Camizestrant at the 75-mg dose was also superior to fulvestrant among patients who had previously received a cyclin-dependent kinase 4/6 inhibitor, with median PFS of 5.5 months and 3.8 months for the 75-mg and 150-mg doses, respectively, compared with 2.1 months.

The adjusted HR for progression with camizestrant with the 75-mg dose was 0.49, with a 90% confidence interval indicating significance. The 150-mg dose was not significantly superior to fulvestrant, however.

Both camizestrant doses were also superior for prolonging PFS versus fulvestrant among patients with lung and/or liver metastases, with median PFS of 7.2 months, 5.6 months, and 2.0 months, respectively.

The experimental SERD also outperformed fulvestrant in an analysis looking at PFS by ESR1 mutational status and ER-driven disease. Among patients with ESR1 wild type, however, median PFS rates with camizestrant 75 mg and fulvestrant were the same (7.2 months).

The 24-week objective response rates were 15.7% in the 75-mg camizestrant arm, 20% in the 150-mg arm, and 11.8% in the fulvestrant arm. The respective clinical benefit rates, including all patients with responses or stable disease, were 47.3%, 49.3%, and 38.4%. The camizestrant clinical benefit rates did not differ significantly from those with fulvestrant, however.

Treatment-related adverse events of grade 3 or greater occurred in only five patients, and only two patients, both in the 75-mg camizestrant arm, discontinued therapy because of adverse events. There were no treatment-related deaths.

Adverse events that occurred only with camizestrant included photopsia (flashing lights or floaters in the field of vision) and sinus bradycardia.
 

Promising, but early

Carlos Artega, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, who was not involved in the study, said the data look promising in comparison with fulvestrant.

“There is a clear suggestion that this might be better,” he said. “[Camizestrant] seems to be better at reducing the titer in plasma of the ESR1 mutation, and there is very strong basic science that supports that.”

He noted that the study numbers were relatively small, however.

Dr. Arteaga was speaking at a media briefing held immediately prior to the presentation of the data in an oral abstract session.

Fabrice Andre, MD, from Gustave Roussy in Villejuif, France, the invited discussant for the oral session, noted that, in patients with ESR1 wild type, where fulvestrant shows some efficacy, camizestrant appears to be equally effective, and that the latter agent may be more synergistic with targeted therapies than fulvestrant.

Given high patient dropout rates with currently available SERDs, there is a need for SERDs used in the adjuvant setting that are effective at minimally bioactive doses for patients who are predicted to poorly adherent, Dr. Andre said.

The study was funded by AstraZeneca. Dr. Oliveira has received personal funding from AstraZeneca, Guardant Health, Roche, Merck Sharp & Dohme, Pfizer, Seagen, iTeos Therapeutics, Eisai, Novartis, Relay Therapeutics, and Gilead. Dr. Arteaga is a scientific adviser to AstraZeneca and others, and has received grant support from Pfizer Lilly and Takeda. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – The investigational selective estrogen receptor degrader camizestrant was associated with significantly longer progression-free survival for women with advanced estrogen receptor–positive, HER2-negative (ER+/HER2–) breast cancers, compared with the first-generation SERD fulvestrant Faslodex, in the SERENA-2 trial, shows a study recently presented at the San Antonio Breast Cancer Symposium.

Among 180 postmenopausal women with ER+/HER2– breast cancers that had recurred or progressed following at least one line of endocrine therapy, the median progression-free survival (PFS) after a median follow-up of 16.6-17.4 months was 7.2 months for patients treated at a 75-mg dose of camizestrant and 7.7 months for those treated at a 150-mg dose, compared with 3.7 months for patients who received fulvestrant, reported Mafalda Oliveira, MD, PhD, from Vall d’Hebron University Hospital in Barcelona.

Oral agent

Camizestrant is a next-generation oral SERD and pure estrogen receptor antagonist that was shown in the SERENA-1 trial to be safe and to have clinical activity against ER+ breast cancers.

SERENA-2 pitted camizestrant at doses of 75 mg, 150 mg, or 300 mg against standard-dose fulvestrant, although the 300-mg dose was dropped in a protocol amendment after 20 patients had been assigned to that arm. (Currently planned studies with camizestrant will be conducted with the 75-mg dose.)

The investigators enrolled women with ER+/HER2– advanced breast cancer who had not previously received fulvestrant or an oral SERD. Eligible patients were limited to no more than one prior line of endocrine and one prior line of chemotherapy for advanced breast cancers. The study included patients with both measurable and unmeasurable disease.

The median patient age was about 60 years. Approximately 59% of patients in each arm had either lung or liver metastases. Patients with recurrence in bone only comprised 14.9%-19.4%.

Mutations in ESR1, a gene associated with hormonal resistance, were detectable in 29.7%-47.9% of patients.
 

Better PFS

As noted before, the primary endpoint of investigator-assessed median PFS favored camizestrant in both the 75-mg arm (7.2 months) and the 150-mg arm (7.7 months), with respective adjusted hazard ratios for progression versus fulvestrant of 0.58 (P = .0124) and 0.67 (P = .0161).

Camizestrant at the 75-mg dose was also superior to fulvestrant among patients who had previously received a cyclin-dependent kinase 4/6 inhibitor, with median PFS of 5.5 months and 3.8 months for the 75-mg and 150-mg doses, respectively, compared with 2.1 months.

The adjusted HR for progression with camizestrant with the 75-mg dose was 0.49, with a 90% confidence interval indicating significance. The 150-mg dose was not significantly superior to fulvestrant, however.

Both camizestrant doses were also superior for prolonging PFS versus fulvestrant among patients with lung and/or liver metastases, with median PFS of 7.2 months, 5.6 months, and 2.0 months, respectively.

The experimental SERD also outperformed fulvestrant in an analysis looking at PFS by ESR1 mutational status and ER-driven disease. Among patients with ESR1 wild type, however, median PFS rates with camizestrant 75 mg and fulvestrant were the same (7.2 months).

The 24-week objective response rates were 15.7% in the 75-mg camizestrant arm, 20% in the 150-mg arm, and 11.8% in the fulvestrant arm. The respective clinical benefit rates, including all patients with responses or stable disease, were 47.3%, 49.3%, and 38.4%. The camizestrant clinical benefit rates did not differ significantly from those with fulvestrant, however.

Treatment-related adverse events of grade 3 or greater occurred in only five patients, and only two patients, both in the 75-mg camizestrant arm, discontinued therapy because of adverse events. There were no treatment-related deaths.

Adverse events that occurred only with camizestrant included photopsia (flashing lights or floaters in the field of vision) and sinus bradycardia.
 

Promising, but early

Carlos Artega, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, who was not involved in the study, said the data look promising in comparison with fulvestrant.

“There is a clear suggestion that this might be better,” he said. “[Camizestrant] seems to be better at reducing the titer in plasma of the ESR1 mutation, and there is very strong basic science that supports that.”

He noted that the study numbers were relatively small, however.

Dr. Arteaga was speaking at a media briefing held immediately prior to the presentation of the data in an oral abstract session.

Fabrice Andre, MD, from Gustave Roussy in Villejuif, France, the invited discussant for the oral session, noted that, in patients with ESR1 wild type, where fulvestrant shows some efficacy, camizestrant appears to be equally effective, and that the latter agent may be more synergistic with targeted therapies than fulvestrant.

Given high patient dropout rates with currently available SERDs, there is a need for SERDs used in the adjuvant setting that are effective at minimally bioactive doses for patients who are predicted to poorly adherent, Dr. Andre said.

The study was funded by AstraZeneca. Dr. Oliveira has received personal funding from AstraZeneca, Guardant Health, Roche, Merck Sharp & Dohme, Pfizer, Seagen, iTeos Therapeutics, Eisai, Novartis, Relay Therapeutics, and Gilead. Dr. Arteaga is a scientific adviser to AstraZeneca and others, and has received grant support from Pfizer Lilly and Takeda. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – The investigational selective estrogen receptor degrader camizestrant was associated with significantly longer progression-free survival for women with advanced estrogen receptor–positive, HER2-negative (ER+/HER2–) breast cancers, compared with the first-generation SERD fulvestrant Faslodex, in the SERENA-2 trial, shows a study recently presented at the San Antonio Breast Cancer Symposium.

Among 180 postmenopausal women with ER+/HER2– breast cancers that had recurred or progressed following at least one line of endocrine therapy, the median progression-free survival (PFS) after a median follow-up of 16.6-17.4 months was 7.2 months for patients treated at a 75-mg dose of camizestrant and 7.7 months for those treated at a 150-mg dose, compared with 3.7 months for patients who received fulvestrant, reported Mafalda Oliveira, MD, PhD, from Vall d’Hebron University Hospital in Barcelona.

Oral agent

Camizestrant is a next-generation oral SERD and pure estrogen receptor antagonist that was shown in the SERENA-1 trial to be safe and to have clinical activity against ER+ breast cancers.

SERENA-2 pitted camizestrant at doses of 75 mg, 150 mg, or 300 mg against standard-dose fulvestrant, although the 300-mg dose was dropped in a protocol amendment after 20 patients had been assigned to that arm. (Currently planned studies with camizestrant will be conducted with the 75-mg dose.)

The investigators enrolled women with ER+/HER2– advanced breast cancer who had not previously received fulvestrant or an oral SERD. Eligible patients were limited to no more than one prior line of endocrine and one prior line of chemotherapy for advanced breast cancers. The study included patients with both measurable and unmeasurable disease.

The median patient age was about 60 years. Approximately 59% of patients in each arm had either lung or liver metastases. Patients with recurrence in bone only comprised 14.9%-19.4%.

Mutations in ESR1, a gene associated with hormonal resistance, were detectable in 29.7%-47.9% of patients.
 

Better PFS

As noted before, the primary endpoint of investigator-assessed median PFS favored camizestrant in both the 75-mg arm (7.2 months) and the 150-mg arm (7.7 months), with respective adjusted hazard ratios for progression versus fulvestrant of 0.58 (P = .0124) and 0.67 (P = .0161).

Camizestrant at the 75-mg dose was also superior to fulvestrant among patients who had previously received a cyclin-dependent kinase 4/6 inhibitor, with median PFS of 5.5 months and 3.8 months for the 75-mg and 150-mg doses, respectively, compared with 2.1 months.

The adjusted HR for progression with camizestrant with the 75-mg dose was 0.49, with a 90% confidence interval indicating significance. The 150-mg dose was not significantly superior to fulvestrant, however.

Both camizestrant doses were also superior for prolonging PFS versus fulvestrant among patients with lung and/or liver metastases, with median PFS of 7.2 months, 5.6 months, and 2.0 months, respectively.

The experimental SERD also outperformed fulvestrant in an analysis looking at PFS by ESR1 mutational status and ER-driven disease. Among patients with ESR1 wild type, however, median PFS rates with camizestrant 75 mg and fulvestrant were the same (7.2 months).

The 24-week objective response rates were 15.7% in the 75-mg camizestrant arm, 20% in the 150-mg arm, and 11.8% in the fulvestrant arm. The respective clinical benefit rates, including all patients with responses or stable disease, were 47.3%, 49.3%, and 38.4%. The camizestrant clinical benefit rates did not differ significantly from those with fulvestrant, however.

Treatment-related adverse events of grade 3 or greater occurred in only five patients, and only two patients, both in the 75-mg camizestrant arm, discontinued therapy because of adverse events. There were no treatment-related deaths.

Adverse events that occurred only with camizestrant included photopsia (flashing lights or floaters in the field of vision) and sinus bradycardia.
 

Promising, but early

Carlos Artega, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, who was not involved in the study, said the data look promising in comparison with fulvestrant.

“There is a clear suggestion that this might be better,” he said. “[Camizestrant] seems to be better at reducing the titer in plasma of the ESR1 mutation, and there is very strong basic science that supports that.”

He noted that the study numbers were relatively small, however.

Dr. Arteaga was speaking at a media briefing held immediately prior to the presentation of the data in an oral abstract session.

Fabrice Andre, MD, from Gustave Roussy in Villejuif, France, the invited discussant for the oral session, noted that, in patients with ESR1 wild type, where fulvestrant shows some efficacy, camizestrant appears to be equally effective, and that the latter agent may be more synergistic with targeted therapies than fulvestrant.

Given high patient dropout rates with currently available SERDs, there is a need for SERDs used in the adjuvant setting that are effective at minimally bioactive doses for patients who are predicted to poorly adherent, Dr. Andre said.

The study was funded by AstraZeneca. Dr. Oliveira has received personal funding from AstraZeneca, Guardant Health, Roche, Merck Sharp & Dohme, Pfizer, Seagen, iTeos Therapeutics, Eisai, Novartis, Relay Therapeutics, and Gilead. Dr. Arteaga is a scientific adviser to AstraZeneca and others, and has received grant support from Pfizer Lilly and Takeda. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – Results of a study being hailed as practice changing showed that, for pre- or perimenopausal women with aggressive hormone receptor-positive, HER2-negative (HR+/HER2–) untreated breast cancers, the combination of the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib (Kisqali) and endocrine therapy offers a safer and equally efficacious alternative to combination chemotherapy.

That’s according to investigators of the phase 2 RIGHT Choice study who found that first-line ribociclib, combined with either letrozole or anastrozole plus goserelin, was associated with a doubling of progression-free survival (PFS), compared with the investigator’s choice of combination chemotherapy, reported Yen-Shen Lu, MD, from National Taiwan University Hospital in Taipei, at the San Antonio Breast Cancer Symposium.

“These results from RIGHT Choice have now shown that first-line ribociclib plus endocrine therapy should be considered the preferred treatment option for this patient population,” he said.
 

Chemo loses its luster

“This is not time first time that we’ve looked at a CDK4/6 inhibitor compared to chemotherapy, but this is the first time that we’ve seen it compared to a combination chemotherapy,” commented Virginia Kaklamani, MD, from University of Texas Health, San Antonio, who moderated a media briefing held prior to Dr. Lu’s presentation of the data in an oral abstract session.

“I think with this study we’re finding that chemotherapy, at least in the early stages of [estrogen receptor]–positive breast cancer, is probably not appropriate for our patients,” she said.

Chemotherapy is the current standard of care for patients with advanced breast cancers with aggressive disease features that can include rapidly progressive disease, high symptom burden, and/or life-threatening visceral crises requiring rapid control of disease, Dr. Lu said.

Compared with single-agent chemotherapy, combination chemotherapy, for those who can tolerate it, is associated with higher overall response rates and longer PFS.

Although ribociclib plus endocrine therapy has been shown to offer significant PFS and overall survival (OS) benefits, compared with endocrine therapy alone, there have not been any head-to-head studies pitting these agents against combination chemotherapy.
 

Study details

To rectify this, Dr. Lu and colleagues enrolled 222 pre- or perimenopausal women with HR+/HER2– advanced breast cancers with aggressive features who had not yet received systemic therapy for advanced breast cancer.

After stratification for the presence or absence of liver metastases and by length of disease-free interval (time from complete resection of a primary tumor to documented recurrence), the patients were randomly assigned to receive either ribociclib 600 mg 3 weeks on, 1 week off) plus letrozole or anastrozole and goserelin, or the investigators choice of either docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine.

After a median follow-up of 24.1 months at the time of data cutoff in April 2022, median PFS, the primary endpoint, was 24 months in the ribociclib plus endocrine therapy arm versus 12.3 months in the chemotherapy arm.

This translated into a hazard ratio for progression on ribociclib plus endocrine therapy of 0.54 (P = .0007).

The benefit for the ribociclib combination, compared with combination chemotherapy, was consistent across most patient subgroups, Dr. Lu said.

The median time to treatment failure was also longer with ribociclib, at 18.6 months versus 8.5 months, respectively, translating into a HR of 0.45 favoring ribociclib, with a statistically significant confidence interval.

Overall response rates were similar between the groups, at 65.2% with ribociclib versus 60% with chemotherapy. The respective clinical benefit rates (including complete and partial responses plus stable disease) were 80.4% versus 72.7%.

The time to response was similar between the treatment arms, an important consideration for patients with rapidly progressive disease, Dr. Lu noted.

Adverse events that occurred more frequently with ribociclib were neutropenia and leukopenia. Events more common with chemotherapy included anemia, liver enzyme elevations, nausea, vomiting, diarrhea, alopecia, fatigue, and palmar-plantar erythrodysesthesia.
 

Confirmation

“These data are just confirming what we’ve already known, and that is that with ER-positive, HER2-negative breast cancer where you have metastatic disease and more aggressive characteristics, treating with a CDK4/6 inhibitor and endocrine therapy leads to high response rates,” breast cancer specialist Matthew P. Goetz, MD, from the Mayo Clinic in Rochester, Minn., said in an interview. Dr. Goetz was not involved in the study.

“What was surprising to me was the fact that the response rates with chemotherapy were not higher,” he said. “We sometime think that the more chemotherapy, the higher the response rates. It was nice to see a direct comparison with chemotherapy, and really to see that giving a target therapy actually led to very, very good results. That tells us that there should be very few situations where we would be prescribing chemotherapy over CDK4/6 inhibitor–based therapies.”

The study was funded by Novartis Pharma. Dr. Lu disclosed personal funding from Novartis and others. Dr. Goetz disclosed grants and other supports for work with the development of abemaciclib and palbociclib, and consulting for Pfizer and others. Dr. Kaklamani disclosed speakers bureau activity for Novartis and others, research support from Eisai, and consulting for other companies.

SAN ANTONIO – Results of a study being hailed as practice changing showed that, for pre- or perimenopausal women with aggressive hormone receptor-positive, HER2-negative (HR+/HER2–) untreated breast cancers, the combination of the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib (Kisqali) and endocrine therapy offers a safer and equally efficacious alternative to combination chemotherapy.

That’s according to investigators of the phase 2 RIGHT Choice study who found that first-line ribociclib, combined with either letrozole or anastrozole plus goserelin, was associated with a doubling of progression-free survival (PFS), compared with the investigator’s choice of combination chemotherapy, reported Yen-Shen Lu, MD, from National Taiwan University Hospital in Taipei, at the San Antonio Breast Cancer Symposium.

“These results from RIGHT Choice have now shown that first-line ribociclib plus endocrine therapy should be considered the preferred treatment option for this patient population,” he said.
 

Chemo loses its luster

“This is not time first time that we’ve looked at a CDK4/6 inhibitor compared to chemotherapy, but this is the first time that we’ve seen it compared to a combination chemotherapy,” commented Virginia Kaklamani, MD, from University of Texas Health, San Antonio, who moderated a media briefing held prior to Dr. Lu’s presentation of the data in an oral abstract session.

“I think with this study we’re finding that chemotherapy, at least in the early stages of [estrogen receptor]–positive breast cancer, is probably not appropriate for our patients,” she said.

Chemotherapy is the current standard of care for patients with advanced breast cancers with aggressive disease features that can include rapidly progressive disease, high symptom burden, and/or life-threatening visceral crises requiring rapid control of disease, Dr. Lu said.

Compared with single-agent chemotherapy, combination chemotherapy, for those who can tolerate it, is associated with higher overall response rates and longer PFS.

Although ribociclib plus endocrine therapy has been shown to offer significant PFS and overall survival (OS) benefits, compared with endocrine therapy alone, there have not been any head-to-head studies pitting these agents against combination chemotherapy.
 

Study details

To rectify this, Dr. Lu and colleagues enrolled 222 pre- or perimenopausal women with HR+/HER2– advanced breast cancers with aggressive features who had not yet received systemic therapy for advanced breast cancer.

After stratification for the presence or absence of liver metastases and by length of disease-free interval (time from complete resection of a primary tumor to documented recurrence), the patients were randomly assigned to receive either ribociclib 600 mg 3 weeks on, 1 week off) plus letrozole or anastrozole and goserelin, or the investigators choice of either docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine.

After a median follow-up of 24.1 months at the time of data cutoff in April 2022, median PFS, the primary endpoint, was 24 months in the ribociclib plus endocrine therapy arm versus 12.3 months in the chemotherapy arm.

This translated into a hazard ratio for progression on ribociclib plus endocrine therapy of 0.54 (P = .0007).

The benefit for the ribociclib combination, compared with combination chemotherapy, was consistent across most patient subgroups, Dr. Lu said.

The median time to treatment failure was also longer with ribociclib, at 18.6 months versus 8.5 months, respectively, translating into a HR of 0.45 favoring ribociclib, with a statistically significant confidence interval.

Overall response rates were similar between the groups, at 65.2% with ribociclib versus 60% with chemotherapy. The respective clinical benefit rates (including complete and partial responses plus stable disease) were 80.4% versus 72.7%.

The time to response was similar between the treatment arms, an important consideration for patients with rapidly progressive disease, Dr. Lu noted.

Adverse events that occurred more frequently with ribociclib were neutropenia and leukopenia. Events more common with chemotherapy included anemia, liver enzyme elevations, nausea, vomiting, diarrhea, alopecia, fatigue, and palmar-plantar erythrodysesthesia.
 

Confirmation

“These data are just confirming what we’ve already known, and that is that with ER-positive, HER2-negative breast cancer where you have metastatic disease and more aggressive characteristics, treating with a CDK4/6 inhibitor and endocrine therapy leads to high response rates,” breast cancer specialist Matthew P. Goetz, MD, from the Mayo Clinic in Rochester, Minn., said in an interview. Dr. Goetz was not involved in the study.

“What was surprising to me was the fact that the response rates with chemotherapy were not higher,” he said. “We sometime think that the more chemotherapy, the higher the response rates. It was nice to see a direct comparison with chemotherapy, and really to see that giving a target therapy actually led to very, very good results. That tells us that there should be very few situations where we would be prescribing chemotherapy over CDK4/6 inhibitor–based therapies.”

The study was funded by Novartis Pharma. Dr. Lu disclosed personal funding from Novartis and others. Dr. Goetz disclosed grants and other supports for work with the development of abemaciclib and palbociclib, and consulting for Pfizer and others. Dr. Kaklamani disclosed speakers bureau activity for Novartis and others, research support from Eisai, and consulting for other companies.

SAN ANTONIO – Results of a study being hailed as practice changing showed that, for pre- or perimenopausal women with aggressive hormone receptor-positive, HER2-negative (HR+/HER2–) untreated breast cancers, the combination of the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib (Kisqali) and endocrine therapy offers a safer and equally efficacious alternative to combination chemotherapy.

That’s according to investigators of the phase 2 RIGHT Choice study who found that first-line ribociclib, combined with either letrozole or anastrozole plus goserelin, was associated with a doubling of progression-free survival (PFS), compared with the investigator’s choice of combination chemotherapy, reported Yen-Shen Lu, MD, from National Taiwan University Hospital in Taipei, at the San Antonio Breast Cancer Symposium.

“These results from RIGHT Choice have now shown that first-line ribociclib plus endocrine therapy should be considered the preferred treatment option for this patient population,” he said.
 

Chemo loses its luster

“This is not time first time that we’ve looked at a CDK4/6 inhibitor compared to chemotherapy, but this is the first time that we’ve seen it compared to a combination chemotherapy,” commented Virginia Kaklamani, MD, from University of Texas Health, San Antonio, who moderated a media briefing held prior to Dr. Lu’s presentation of the data in an oral abstract session.

“I think with this study we’re finding that chemotherapy, at least in the early stages of [estrogen receptor]–positive breast cancer, is probably not appropriate for our patients,” she said.

Chemotherapy is the current standard of care for patients with advanced breast cancers with aggressive disease features that can include rapidly progressive disease, high symptom burden, and/or life-threatening visceral crises requiring rapid control of disease, Dr. Lu said.

Compared with single-agent chemotherapy, combination chemotherapy, for those who can tolerate it, is associated with higher overall response rates and longer PFS.

Although ribociclib plus endocrine therapy has been shown to offer significant PFS and overall survival (OS) benefits, compared with endocrine therapy alone, there have not been any head-to-head studies pitting these agents against combination chemotherapy.
 

Study details

To rectify this, Dr. Lu and colleagues enrolled 222 pre- or perimenopausal women with HR+/HER2– advanced breast cancers with aggressive features who had not yet received systemic therapy for advanced breast cancer.

After stratification for the presence or absence of liver metastases and by length of disease-free interval (time from complete resection of a primary tumor to documented recurrence), the patients were randomly assigned to receive either ribociclib 600 mg 3 weeks on, 1 week off) plus letrozole or anastrozole and goserelin, or the investigators choice of either docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine.

After a median follow-up of 24.1 months at the time of data cutoff in April 2022, median PFS, the primary endpoint, was 24 months in the ribociclib plus endocrine therapy arm versus 12.3 months in the chemotherapy arm.

This translated into a hazard ratio for progression on ribociclib plus endocrine therapy of 0.54 (P = .0007).

The benefit for the ribociclib combination, compared with combination chemotherapy, was consistent across most patient subgroups, Dr. Lu said.

The median time to treatment failure was also longer with ribociclib, at 18.6 months versus 8.5 months, respectively, translating into a HR of 0.45 favoring ribociclib, with a statistically significant confidence interval.

Overall response rates were similar between the groups, at 65.2% with ribociclib versus 60% with chemotherapy. The respective clinical benefit rates (including complete and partial responses plus stable disease) were 80.4% versus 72.7%.

The time to response was similar between the treatment arms, an important consideration for patients with rapidly progressive disease, Dr. Lu noted.

Adverse events that occurred more frequently with ribociclib were neutropenia and leukopenia. Events more common with chemotherapy included anemia, liver enzyme elevations, nausea, vomiting, diarrhea, alopecia, fatigue, and palmar-plantar erythrodysesthesia.
 

Confirmation

“These data are just confirming what we’ve already known, and that is that with ER-positive, HER2-negative breast cancer where you have metastatic disease and more aggressive characteristics, treating with a CDK4/6 inhibitor and endocrine therapy leads to high response rates,” breast cancer specialist Matthew P. Goetz, MD, from the Mayo Clinic in Rochester, Minn., said in an interview. Dr. Goetz was not involved in the study.

“What was surprising to me was the fact that the response rates with chemotherapy were not higher,” he said. “We sometime think that the more chemotherapy, the higher the response rates. It was nice to see a direct comparison with chemotherapy, and really to see that giving a target therapy actually led to very, very good results. That tells us that there should be very few situations where we would be prescribing chemotherapy over CDK4/6 inhibitor–based therapies.”

The study was funded by Novartis Pharma. Dr. Lu disclosed personal funding from Novartis and others. Dr. Goetz disclosed grants and other supports for work with the development of abemaciclib and palbociclib, and consulting for Pfizer and others. Dr. Kaklamani disclosed speakers bureau activity for Novartis and others, research support from Eisai, and consulting for other companies.

SAN ANTONIO – Black women with estrogen receptor–positive, HER2-negative (ER+/HER2–) breast cancers have higher levels of a marker of distant metastasis in residual tumors following neoadjuvant chemotherapy, compared with White women, a discovery that may at least partially explain racial differences in breast cancer outcomes, investigators say.

The finding, which comes from a retrospective study comparing differences in tumor microenvironment of metastasis (TMEM) “doorways” between Black and White women suggest that tumors in Black women may have a stronger prometastatic response to neoadjuvant chemotherapy than tumors in White women, reported Maja H. Oktay, MD, PhD, of Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, New York, at the San Antonio Breast Cancer Symposium.

Neil Osterweil/MDedge News

“Looking forward ... we propose to use TMEM doorway density as a prognostic marker for distant recurrence-free survival as a marker of dissemination, and also as a predictive marker of response to drugs that can block TMEM doorways,” she said at a briefing held prior to the presentation of data in an oral abstract session.
 

Entry points

As their name implies, TMEM doorways are transient entry points or portals that allow cancer cells to disseminate to distant sites. TMEM doorways are composed of tumor cells, macrophages, and endothelial cells that come into direct contact and together create temporary vascular openings that allow tumor cells to cross cell walls into circulation, where they can then hitch a ride and travel to distant organ sites.

Previous studies have shown that TMEM doorway density is a prognostic marker of metastasis in breast cancer patients treated with adjuvant chemotherapy. And as Dr. Oktay and colleagues showed in the current study, TMEM doorway density, as measured by a TMEM doorway score, is a prognostic marker for distant metastatic recurrence of ER+/HER2– breast cancer following neoadjuvant chemotherapy.

They also showed that neoadjuvant chemotherapy may increase the TMEM doorway score and lead to a pro–metastatic tumor microenvironment in some women.
 

Doorway scores

The investigators measured TMEM doorway scores from residual breast cancers in women who had undergone standard neoadjuvant chemotherapy. The cohort consisted of 96 Black women, 43 of whom had ER+/HER2– breast cancer and 37 of whom had triple-negative breast cancer (TNBC), and 87 White women, 50 with ER+/HER2– cancer and 22 with TNBC. The remaining patients had other breast cancer subtypes.

They found that TNBCs had higher TMEM doorway density score and higher macrophage density scores, which may explain why patients with TNBC often have early recurrence of disease.

They also found that, compared with White patients, Black patients with ER+/HER2– tumors, but not TNBC tumors, had higher TMEM doorway density scores. Similarly, Black patients with ER+/HER– cancers, but not TNBC, had higher macrophage levels than White women, a finding that may explain racial disparity in ER+/HER2– disease, Dr. Oktay said.

For the entire cohort, patients with high TMEM doorway density scores had significantly worse distant recurrence–free survival than patients with intermediate or low scores (P = .008), and there was a trend toward worse DRFS among all patients with ER+/HER2– who were in the highest third of scores, but this did not quite reach statistical significance.

High versus low TMEM doorway density score was also an independent prognostic factor for worse outcomes among the entire cohort (P = .01).

There was no significant difference in TMEM density scores among patients with TNBC.

Neither high macrophage counts nor microvascular density alone were significantly associated with inferior DRFS. TMEM doorway score was the only factor significantly prognostic for worse outcomes among patients in the entire cohort.
 

Hypothesis needs further testing

Invited discussant Lori Pierce, MD, a radiation oncologist with Michigan Medicine, University of Michigan, Ann Arbor, said it’s unclear whether TMEM doorway density changed following neoadjuvant chemotherapy as there were no prechemotherapy scores available in this study.

“But I think the key part is that, if we think neoadjuvant chemotherapy promotes metastasis, then there should be an inferior outcome compared to adjuvant chemotherapy, but that’s not what we see. Well-powered randomized trials show equivalent outcomes with neoadjuvant chemotherapy as well as adjuvant,” she said.

She noted that a 2018 meta-analysis of individual patient data from 10 randomized trials comparing neoadjuvant with adjuvant chemotherapy in early breast cancer showed no differences in long-term distant recurrences, breast cancer–specific mortality, or all-cause mortality between the two modalities.

“While I think these data are very provocative, I certainly wouldn’t want Black women or any women who need neoadjuvant therapy to be discouraged because of these data. We need these data to be tested rigorously, so I look forward to the clinical trials that will test this question and can really give us more information about this very interesting hypothesis,” Dr. Pierce said.

The study was funded by the National Institutes of Health, New York State Department of Health Peter T. Rowley Breast Cancer Scientific Research Projects, Helen & Irving Spatz Family Foundation, Evelyn Gruss Lipper Charitable Foundation, and the Gruss-Lipper Biophotonics Center and the integrated imaging program at the Albert Einstein College of Medicine. Dr. Oktay reported no conflicts of interests.

SAN ANTONIO – Black women with estrogen receptor–positive, HER2-negative (ER+/HER2–) breast cancers have higher levels of a marker of distant metastasis in residual tumors following neoadjuvant chemotherapy, compared with White women, a discovery that may at least partially explain racial differences in breast cancer outcomes, investigators say.

The finding, which comes from a retrospective study comparing differences in tumor microenvironment of metastasis (TMEM) “doorways” between Black and White women suggest that tumors in Black women may have a stronger prometastatic response to neoadjuvant chemotherapy than tumors in White women, reported Maja H. Oktay, MD, PhD, of Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, New York, at the San Antonio Breast Cancer Symposium.

Neil Osterweil/MDedge News

“Looking forward ... we propose to use TMEM doorway density as a prognostic marker for distant recurrence-free survival as a marker of dissemination, and also as a predictive marker of response to drugs that can block TMEM doorways,” she said at a briefing held prior to the presentation of data in an oral abstract session.
 

Entry points

As their name implies, TMEM doorways are transient entry points or portals that allow cancer cells to disseminate to distant sites. TMEM doorways are composed of tumor cells, macrophages, and endothelial cells that come into direct contact and together create temporary vascular openings that allow tumor cells to cross cell walls into circulation, where they can then hitch a ride and travel to distant organ sites.

Previous studies have shown that TMEM doorway density is a prognostic marker of metastasis in breast cancer patients treated with adjuvant chemotherapy. And as Dr. Oktay and colleagues showed in the current study, TMEM doorway density, as measured by a TMEM doorway score, is a prognostic marker for distant metastatic recurrence of ER+/HER2– breast cancer following neoadjuvant chemotherapy.

They also showed that neoadjuvant chemotherapy may increase the TMEM doorway score and lead to a pro–metastatic tumor microenvironment in some women.
 

Doorway scores

The investigators measured TMEM doorway scores from residual breast cancers in women who had undergone standard neoadjuvant chemotherapy. The cohort consisted of 96 Black women, 43 of whom had ER+/HER2– breast cancer and 37 of whom had triple-negative breast cancer (TNBC), and 87 White women, 50 with ER+/HER2– cancer and 22 with TNBC. The remaining patients had other breast cancer subtypes.

They found that TNBCs had higher TMEM doorway density score and higher macrophage density scores, which may explain why patients with TNBC often have early recurrence of disease.

They also found that, compared with White patients, Black patients with ER+/HER2– tumors, but not TNBC tumors, had higher TMEM doorway density scores. Similarly, Black patients with ER+/HER– cancers, but not TNBC, had higher macrophage levels than White women, a finding that may explain racial disparity in ER+/HER2– disease, Dr. Oktay said.

For the entire cohort, patients with high TMEM doorway density scores had significantly worse distant recurrence–free survival than patients with intermediate or low scores (P = .008), and there was a trend toward worse DRFS among all patients with ER+/HER2– who were in the highest third of scores, but this did not quite reach statistical significance.

High versus low TMEM doorway density score was also an independent prognostic factor for worse outcomes among the entire cohort (P = .01).

There was no significant difference in TMEM density scores among patients with TNBC.

Neither high macrophage counts nor microvascular density alone were significantly associated with inferior DRFS. TMEM doorway score was the only factor significantly prognostic for worse outcomes among patients in the entire cohort.
 

Hypothesis needs further testing

Invited discussant Lori Pierce, MD, a radiation oncologist with Michigan Medicine, University of Michigan, Ann Arbor, said it’s unclear whether TMEM doorway density changed following neoadjuvant chemotherapy as there were no prechemotherapy scores available in this study.

“But I think the key part is that, if we think neoadjuvant chemotherapy promotes metastasis, then there should be an inferior outcome compared to adjuvant chemotherapy, but that’s not what we see. Well-powered randomized trials show equivalent outcomes with neoadjuvant chemotherapy as well as adjuvant,” she said.

She noted that a 2018 meta-analysis of individual patient data from 10 randomized trials comparing neoadjuvant with adjuvant chemotherapy in early breast cancer showed no differences in long-term distant recurrences, breast cancer–specific mortality, or all-cause mortality between the two modalities.

“While I think these data are very provocative, I certainly wouldn’t want Black women or any women who need neoadjuvant therapy to be discouraged because of these data. We need these data to be tested rigorously, so I look forward to the clinical trials that will test this question and can really give us more information about this very interesting hypothesis,” Dr. Pierce said.

The study was funded by the National Institutes of Health, New York State Department of Health Peter T. Rowley Breast Cancer Scientific Research Projects, Helen & Irving Spatz Family Foundation, Evelyn Gruss Lipper Charitable Foundation, and the Gruss-Lipper Biophotonics Center and the integrated imaging program at the Albert Einstein College of Medicine. Dr. Oktay reported no conflicts of interests.

SAN ANTONIO – Black women with estrogen receptor–positive, HER2-negative (ER+/HER2–) breast cancers have higher levels of a marker of distant metastasis in residual tumors following neoadjuvant chemotherapy, compared with White women, a discovery that may at least partially explain racial differences in breast cancer outcomes, investigators say.

The finding, which comes from a retrospective study comparing differences in tumor microenvironment of metastasis (TMEM) “doorways” between Black and White women suggest that tumors in Black women may have a stronger prometastatic response to neoadjuvant chemotherapy than tumors in White women, reported Maja H. Oktay, MD, PhD, of Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, New York, at the San Antonio Breast Cancer Symposium.

Neil Osterweil/MDedge News

“Looking forward ... we propose to use TMEM doorway density as a prognostic marker for distant recurrence-free survival as a marker of dissemination, and also as a predictive marker of response to drugs that can block TMEM doorways,” she said at a briefing held prior to the presentation of data in an oral abstract session.
 

Entry points

As their name implies, TMEM doorways are transient entry points or portals that allow cancer cells to disseminate to distant sites. TMEM doorways are composed of tumor cells, macrophages, and endothelial cells that come into direct contact and together create temporary vascular openings that allow tumor cells to cross cell walls into circulation, where they can then hitch a ride and travel to distant organ sites.

Previous studies have shown that TMEM doorway density is a prognostic marker of metastasis in breast cancer patients treated with adjuvant chemotherapy. And as Dr. Oktay and colleagues showed in the current study, TMEM doorway density, as measured by a TMEM doorway score, is a prognostic marker for distant metastatic recurrence of ER+/HER2– breast cancer following neoadjuvant chemotherapy.

They also showed that neoadjuvant chemotherapy may increase the TMEM doorway score and lead to a pro–metastatic tumor microenvironment in some women.
 

Doorway scores

The investigators measured TMEM doorway scores from residual breast cancers in women who had undergone standard neoadjuvant chemotherapy. The cohort consisted of 96 Black women, 43 of whom had ER+/HER2– breast cancer and 37 of whom had triple-negative breast cancer (TNBC), and 87 White women, 50 with ER+/HER2– cancer and 22 with TNBC. The remaining patients had other breast cancer subtypes.

They found that TNBCs had higher TMEM doorway density score and higher macrophage density scores, which may explain why patients with TNBC often have early recurrence of disease.

They also found that, compared with White patients, Black patients with ER+/HER2– tumors, but not TNBC tumors, had higher TMEM doorway density scores. Similarly, Black patients with ER+/HER– cancers, but not TNBC, had higher macrophage levels than White women, a finding that may explain racial disparity in ER+/HER2– disease, Dr. Oktay said.

For the entire cohort, patients with high TMEM doorway density scores had significantly worse distant recurrence–free survival than patients with intermediate or low scores (P = .008), and there was a trend toward worse DRFS among all patients with ER+/HER2– who were in the highest third of scores, but this did not quite reach statistical significance.

High versus low TMEM doorway density score was also an independent prognostic factor for worse outcomes among the entire cohort (P = .01).

There was no significant difference in TMEM density scores among patients with TNBC.

Neither high macrophage counts nor microvascular density alone were significantly associated with inferior DRFS. TMEM doorway score was the only factor significantly prognostic for worse outcomes among patients in the entire cohort.
 

Hypothesis needs further testing

Invited discussant Lori Pierce, MD, a radiation oncologist with Michigan Medicine, University of Michigan, Ann Arbor, said it’s unclear whether TMEM doorway density changed following neoadjuvant chemotherapy as there were no prechemotherapy scores available in this study.

“But I think the key part is that, if we think neoadjuvant chemotherapy promotes metastasis, then there should be an inferior outcome compared to adjuvant chemotherapy, but that’s not what we see. Well-powered randomized trials show equivalent outcomes with neoadjuvant chemotherapy as well as adjuvant,” she said.

She noted that a 2018 meta-analysis of individual patient data from 10 randomized trials comparing neoadjuvant with adjuvant chemotherapy in early breast cancer showed no differences in long-term distant recurrences, breast cancer–specific mortality, or all-cause mortality between the two modalities.

“While I think these data are very provocative, I certainly wouldn’t want Black women or any women who need neoadjuvant therapy to be discouraged because of these data. We need these data to be tested rigorously, so I look forward to the clinical trials that will test this question and can really give us more information about this very interesting hypothesis,” Dr. Pierce said.

The study was funded by the National Institutes of Health, New York State Department of Health Peter T. Rowley Breast Cancer Scientific Research Projects, Helen & Irving Spatz Family Foundation, Evelyn Gruss Lipper Charitable Foundation, and the Gruss-Lipper Biophotonics Center and the integrated imaging program at the Albert Einstein College of Medicine. Dr. Oktay reported no conflicts of interests.