Metastatic Breast Cancer

Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.

Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.

Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.

The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
 

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).

Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
 

DESTINY-Breast 01 trial

In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.

Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.

The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.

The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.

The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.

The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
 

Tucatinib

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.

The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m² given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
 

HER2CLIMB trial

The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.

The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.

The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).

The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.

The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.

The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
 

Tucatinib in patients with brain involvement

A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.

There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.

The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P  < .0001).

The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.

The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.

There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.

Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
 

Neratinib

Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.

Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.

In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
 

NALA trial

The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.

Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m² orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m² orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS by blinded, independent, central review.

The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.

The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.

Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043). 

The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
 

Margetuximab-cmkb

Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.

Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.

In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.

The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
 

SOPHIA trial

SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.

Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.

Co–primary outcome measures were PFS by blinded, independent, central review and OS.

At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).

At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).

Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.

The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.

The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.

Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.

In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
 

Take-home messages

There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.

The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).

When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.

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

Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.

Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.

Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.

The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
 

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).

Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
 

DESTINY-Breast 01 trial

In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.

Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.

The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.

The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.

The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.

The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
 

Tucatinib

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.

The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m² given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
 

HER2CLIMB trial

The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.

The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.

The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).

The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.

The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.

The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
 

Tucatinib in patients with brain involvement

A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.

There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.

The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P  < .0001).

The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.

The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.

There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.

Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
 

Neratinib

Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.

Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.

In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
 

NALA trial

The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.

Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m² orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m² orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS by blinded, independent, central review.

The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.

The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.

Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043). 

The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
 

Margetuximab-cmkb

Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.

Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.

In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.

The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
 

SOPHIA trial

SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.

Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.

Co–primary outcome measures were PFS by blinded, independent, central review and OS.

At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).

At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).

Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.

The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.

The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.

Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.

In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
 

Take-home messages

There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.

The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).

When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.

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

Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.

Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.

Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.

The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
 

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).

Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
 

DESTINY-Breast 01 trial

In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.

Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.

The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.

The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.

The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.

The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
 

Tucatinib

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.

The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m² given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
 

HER2CLIMB trial

The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.

The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.

The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).

The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.

The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.

The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
 

Tucatinib in patients with brain involvement

A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.

There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.

The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P  < .0001).

The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.

The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.

There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.

Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
 

Neratinib

Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.

Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.

In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
 

NALA trial

The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.

Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m² orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m² orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS by blinded, independent, central review.

The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.

The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.

Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043). 

The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
 

Margetuximab-cmkb

Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.

Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.

In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.

The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
 

SOPHIA trial

SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.

Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.

Co–primary outcome measures were PFS by blinded, independent, central review and OS.

At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).

At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).

Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.

The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.

The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.

Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.

In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
 

Take-home messages

There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.

The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).

When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.

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

The PD-L1 inhibitor atezolizumab (Tecentriq) combined with carboplatin has shown signs of clinical activity in women with metastatic invasive lobular breast cancer (ILC) according to the first results to come from the ongoing GELATO trial.

The 6-month objective response rate was 19%, based on 4 of 21 patients who could be evaluated exhibiting a partial response to the chemoimmunotherapy. A further two (10%) patients had stable disease, meaning that clinical benefit rate was 29%.

GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer) is a phase 2 trial being conducted at four Dutch centers. The primary premise of the study is that “there’s an immune-related subtype of ILC,” researcher Leonie Voorwerk, BSc, reported at the European Society for Medical Oncology: Breast Cancer virtual meeting (Abstract LBA3).

This ILC subtype is “characterized by high expression of immune-related genes and high levels of TILs [tumor-infiltrating lymphocytes] and PDL-1,” said Ms. Voorwerk, a PhD student working with medical oncologist Marleen Kok, MD, PhD, at the Netherlands Cancer Institute in Amsterdam.

Furthermore, she added, in vitro data suggest sensitivity of immune-related-ILCs to platinum and there is preclinical work showing that there is synergy between platinum-based chemotherapy and checkpoint blockade.
 

First chemoimmunotherapy trial in lobular cancer setting

GELATO is a significant trial as it is “the first chemoimmunotherapy trial in metastatic lobular breast cancer,” said Sylvia Adams, MD, professor of medicine and director of the Breast Cancer Center at NYU Langone Health in New York City.

“Of note, the further research should include the immune-related genes and TMB [tumor mutational burden],” proposed Dr. Adams, who was not involved in the trial.

“We should look to tumor mutational burden because while it is not typically high in early disease, metastatic lesions can have higher TMB,” she explained. “Also, metastatic ILC is known to have higher tumor mutational burden compared to IDC [invasive ductal carcinoma], so this is an important thing along with the clinical factors as described in looking at outcomes.”
 

Trial design and patient characteristics

GELATO is a single-arm, nonrandomized trial in which 37 patients with metastatic ILC were screened for inclusion between November 2017 and January 2021. A total of 26 of these patients were registered for the trial, and 23 have so far received at least one cycle of atezolizumab.

Prerequisites for entry into the trial were that patients had to have negative or aberrant E-cadherin, a characteristic feature of ILC. Patients with estrogen receptor (ER)-positive (ER+) disease could be included, but they had to be proven to be resistant to endocrine therapies. No more than two prior lines of palliative chemotherapy were allowed, and all participants had to have lactose dehydrogenase levels of less than 2 times the upper limit of normal.

Patients were then treated with up to 12 cycles of weekly carboplatin (AUC = 1.5 mg/mL/min), with atezolizumab (1,200 mg) added in from cycle 3 onward. Treatment was continued until disease progression or unacceptable toxicity occurred.

“Baseline characteristics were mainly as expected for this patient population,” Ms. Voorwerk stated. Patients were aged 45-89 years, with a median of 60 years. Around half each had a WHO performance status of 0 or 1, and around half each had one to two or three or more metastatic sites; 78% had liver metastases.

“But I want to highlight that we included five patients with the triple-negative ILC,” said Ms. Voorwerk, also highlighting that approximately 50% of patients had received prior palliative chemotherapy. Later in her presentation she noted that four out of the six patients that showed any clinical benefit had triple negative disease.
 

Key findings and next steps

The primary endpoint was progression-free survival (PFS) at 6 months, with secondary endpoints of the best overall response rate, PFS at 1 year, overall survival, and safety.

While details of the latter three endpoints are yet to be reported, Ms. Voorwerk noted that there was a median duration of response of 12 weeks and the median PFS was 15 weeks. The primary endpoint of PFS was met as four patients were free of progression at 6 months and the statistical method used called for patients to be progression free at this time point.

“We observed that stromal TILs and CD8+ cells were not associated with clinical benefits,” said Ms. Voorwerk. There was, however, “a slight trend” toward higher PD-L1 expression in responding patients.

“Further translational research is needed to provide the rationale for new strategies to improve checkpoint blockade in patients with lobular breast cancer,” she concluded.

Dr. Adams concurred, adding that a future research question was whether either atezolizumab or carboplatin was contributing to the response. This is “difficult to tell as the study was a single arm trial.”

Another question, said Dr. Adams, is are “anti-CDK 4/6 inhibitors helpful in improving response rates and durability?” In the trial, 70% of patients had prior exposure to CDK 4/6 inhibitors.

The GELATO trial was sponsored by the Netherlands Cancer Institute with funding from Roche Pharma AG. Ms. Voorwerk had nothing to disclose. Dr. Adams disclosed uncompensated consulting or advisory roles with Bristol-Myers Squibb, Genentech, and Merck from whom she has received research funding. Dr. Adams also disclosed research funding from Amgen, Celgene, and Novartis.

The PD-L1 inhibitor atezolizumab (Tecentriq) combined with carboplatin has shown signs of clinical activity in women with metastatic invasive lobular breast cancer (ILC) according to the first results to come from the ongoing GELATO trial.

The 6-month objective response rate was 19%, based on 4 of 21 patients who could be evaluated exhibiting a partial response to the chemoimmunotherapy. A further two (10%) patients had stable disease, meaning that clinical benefit rate was 29%.

GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer) is a phase 2 trial being conducted at four Dutch centers. The primary premise of the study is that “there’s an immune-related subtype of ILC,” researcher Leonie Voorwerk, BSc, reported at the European Society for Medical Oncology: Breast Cancer virtual meeting (Abstract LBA3).

This ILC subtype is “characterized by high expression of immune-related genes and high levels of TILs [tumor-infiltrating lymphocytes] and PDL-1,” said Ms. Voorwerk, a PhD student working with medical oncologist Marleen Kok, MD, PhD, at the Netherlands Cancer Institute in Amsterdam.

Furthermore, she added, in vitro data suggest sensitivity of immune-related-ILCs to platinum and there is preclinical work showing that there is synergy between platinum-based chemotherapy and checkpoint blockade.
 

First chemoimmunotherapy trial in lobular cancer setting

GELATO is a significant trial as it is “the first chemoimmunotherapy trial in metastatic lobular breast cancer,” said Sylvia Adams, MD, professor of medicine and director of the Breast Cancer Center at NYU Langone Health in New York City.

“Of note, the further research should include the immune-related genes and TMB [tumor mutational burden],” proposed Dr. Adams, who was not involved in the trial.

“We should look to tumor mutational burden because while it is not typically high in early disease, metastatic lesions can have higher TMB,” she explained. “Also, metastatic ILC is known to have higher tumor mutational burden compared to IDC [invasive ductal carcinoma], so this is an important thing along with the clinical factors as described in looking at outcomes.”
 

Trial design and patient characteristics

GELATO is a single-arm, nonrandomized trial in which 37 patients with metastatic ILC were screened for inclusion between November 2017 and January 2021. A total of 26 of these patients were registered for the trial, and 23 have so far received at least one cycle of atezolizumab.

Prerequisites for entry into the trial were that patients had to have negative or aberrant E-cadherin, a characteristic feature of ILC. Patients with estrogen receptor (ER)-positive (ER+) disease could be included, but they had to be proven to be resistant to endocrine therapies. No more than two prior lines of palliative chemotherapy were allowed, and all participants had to have lactose dehydrogenase levels of less than 2 times the upper limit of normal.

Patients were then treated with up to 12 cycles of weekly carboplatin (AUC = 1.5 mg/mL/min), with atezolizumab (1,200 mg) added in from cycle 3 onward. Treatment was continued until disease progression or unacceptable toxicity occurred.

“Baseline characteristics were mainly as expected for this patient population,” Ms. Voorwerk stated. Patients were aged 45-89 years, with a median of 60 years. Around half each had a WHO performance status of 0 or 1, and around half each had one to two or three or more metastatic sites; 78% had liver metastases.

“But I want to highlight that we included five patients with the triple-negative ILC,” said Ms. Voorwerk, also highlighting that approximately 50% of patients had received prior palliative chemotherapy. Later in her presentation she noted that four out of the six patients that showed any clinical benefit had triple negative disease.
 

Key findings and next steps

The primary endpoint was progression-free survival (PFS) at 6 months, with secondary endpoints of the best overall response rate, PFS at 1 year, overall survival, and safety.

While details of the latter three endpoints are yet to be reported, Ms. Voorwerk noted that there was a median duration of response of 12 weeks and the median PFS was 15 weeks. The primary endpoint of PFS was met as four patients were free of progression at 6 months and the statistical method used called for patients to be progression free at this time point.

“We observed that stromal TILs and CD8+ cells were not associated with clinical benefits,” said Ms. Voorwerk. There was, however, “a slight trend” toward higher PD-L1 expression in responding patients.

“Further translational research is needed to provide the rationale for new strategies to improve checkpoint blockade in patients with lobular breast cancer,” she concluded.

Dr. Adams concurred, adding that a future research question was whether either atezolizumab or carboplatin was contributing to the response. This is “difficult to tell as the study was a single arm trial.”

Another question, said Dr. Adams, is are “anti-CDK 4/6 inhibitors helpful in improving response rates and durability?” In the trial, 70% of patients had prior exposure to CDK 4/6 inhibitors.

The GELATO trial was sponsored by the Netherlands Cancer Institute with funding from Roche Pharma AG. Ms. Voorwerk had nothing to disclose. Dr. Adams disclosed uncompensated consulting or advisory roles with Bristol-Myers Squibb, Genentech, and Merck from whom she has received research funding. Dr. Adams also disclosed research funding from Amgen, Celgene, and Novartis.

The PD-L1 inhibitor atezolizumab (Tecentriq) combined with carboplatin has shown signs of clinical activity in women with metastatic invasive lobular breast cancer (ILC) according to the first results to come from the ongoing GELATO trial.

The 6-month objective response rate was 19%, based on 4 of 21 patients who could be evaluated exhibiting a partial response to the chemoimmunotherapy. A further two (10%) patients had stable disease, meaning that clinical benefit rate was 29%.

GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer) is a phase 2 trial being conducted at four Dutch centers. The primary premise of the study is that “there’s an immune-related subtype of ILC,” researcher Leonie Voorwerk, BSc, reported at the European Society for Medical Oncology: Breast Cancer virtual meeting (Abstract LBA3).

This ILC subtype is “characterized by high expression of immune-related genes and high levels of TILs [tumor-infiltrating lymphocytes] and PDL-1,” said Ms. Voorwerk, a PhD student working with medical oncologist Marleen Kok, MD, PhD, at the Netherlands Cancer Institute in Amsterdam.

Furthermore, she added, in vitro data suggest sensitivity of immune-related-ILCs to platinum and there is preclinical work showing that there is synergy between platinum-based chemotherapy and checkpoint blockade.
 

First chemoimmunotherapy trial in lobular cancer setting

GELATO is a significant trial as it is “the first chemoimmunotherapy trial in metastatic lobular breast cancer,” said Sylvia Adams, MD, professor of medicine and director of the Breast Cancer Center at NYU Langone Health in New York City.

“Of note, the further research should include the immune-related genes and TMB [tumor mutational burden],” proposed Dr. Adams, who was not involved in the trial.

“We should look to tumor mutational burden because while it is not typically high in early disease, metastatic lesions can have higher TMB,” she explained. “Also, metastatic ILC is known to have higher tumor mutational burden compared to IDC [invasive ductal carcinoma], so this is an important thing along with the clinical factors as described in looking at outcomes.”
 

Trial design and patient characteristics

GELATO is a single-arm, nonrandomized trial in which 37 patients with metastatic ILC were screened for inclusion between November 2017 and January 2021. A total of 26 of these patients were registered for the trial, and 23 have so far received at least one cycle of atezolizumab.

Prerequisites for entry into the trial were that patients had to have negative or aberrant E-cadherin, a characteristic feature of ILC. Patients with estrogen receptor (ER)-positive (ER+) disease could be included, but they had to be proven to be resistant to endocrine therapies. No more than two prior lines of palliative chemotherapy were allowed, and all participants had to have lactose dehydrogenase levels of less than 2 times the upper limit of normal.

Patients were then treated with up to 12 cycles of weekly carboplatin (AUC = 1.5 mg/mL/min), with atezolizumab (1,200 mg) added in from cycle 3 onward. Treatment was continued until disease progression or unacceptable toxicity occurred.

“Baseline characteristics were mainly as expected for this patient population,” Ms. Voorwerk stated. Patients were aged 45-89 years, with a median of 60 years. Around half each had a WHO performance status of 0 or 1, and around half each had one to two or three or more metastatic sites; 78% had liver metastases.

“But I want to highlight that we included five patients with the triple-negative ILC,” said Ms. Voorwerk, also highlighting that approximately 50% of patients had received prior palliative chemotherapy. Later in her presentation she noted that four out of the six patients that showed any clinical benefit had triple negative disease.
 

Key findings and next steps

The primary endpoint was progression-free survival (PFS) at 6 months, with secondary endpoints of the best overall response rate, PFS at 1 year, overall survival, and safety.

While details of the latter three endpoints are yet to be reported, Ms. Voorwerk noted that there was a median duration of response of 12 weeks and the median PFS was 15 weeks. The primary endpoint of PFS was met as four patients were free of progression at 6 months and the statistical method used called for patients to be progression free at this time point.

“We observed that stromal TILs and CD8+ cells were not associated with clinical benefits,” said Ms. Voorwerk. There was, however, “a slight trend” toward higher PD-L1 expression in responding patients.

“Further translational research is needed to provide the rationale for new strategies to improve checkpoint blockade in patients with lobular breast cancer,” she concluded.

Dr. Adams concurred, adding that a future research question was whether either atezolizumab or carboplatin was contributing to the response. This is “difficult to tell as the study was a single arm trial.”

Another question, said Dr. Adams, is are “anti-CDK 4/6 inhibitors helpful in improving response rates and durability?” In the trial, 70% of patients had prior exposure to CDK 4/6 inhibitors.

The GELATO trial was sponsored by the Netherlands Cancer Institute with funding from Roche Pharma AG. Ms. Voorwerk had nothing to disclose. Dr. Adams disclosed uncompensated consulting or advisory roles with Bristol-Myers Squibb, Genentech, and Merck from whom she has received research funding. Dr. Adams also disclosed research funding from Amgen, Celgene, and Novartis.

Federal advisers have supported the efforts of pharmaceutical companies in four of six cases in which these firms are fighting to maintain cancer indications for approved drugs. The advisers voted against the companies in two cases.

The staff of the Food and Drug Administration will now consider these votes as they decide what to do regarding the six cases of what they have termed “dangling” accelerated approvals.

“One of the reasons I think we’re convening today is to prevent these accelerated approvals from dangling ad infinitum,” commented one of the members of the advisory panel.

In these cases, companies have been unable to prove the expected benefits that led the FDA to grant accelerated approvals for these indications.

These accelerated approvals, which are often based on surrogate endpoints, such as overall response rates, are granted on the condition that further findings show a clinical benefit – such as in progression-free survival or overall survival – in larger trials.

The FDA tasked its Oncologic Drugs Advisory Committee (ODAC) with conducting the review of the six accelerated approvals for cancer indications at a 3-day meeting (April 27-29).

These reviews were only for specific cancer indications and will not lead to the removal of drugs from the market. These drugs have already been approved for several cancer indications. For example, one of the drugs that was reviewed, pembrolizumab (Keytruda), is approved in the United States for 28 indications.

The FDA is facing growing pains in its efforts to manage the rapidly changing landscape for these immune checkpoint inhibitors. This field of medicine has experienced an “unprecedented level of drug development” in recent years, FDA officials said in briefing materials, owing in part to the agency’s willingness to accept surrogate markers for accelerated approvals. Although some companies have struggled with these, others have built strong cases for the use of their checkpoint inhibitors for these indications.

The ODAC panelists, for example, noted the emergence of nivolumab (Opdivo) as an option for patients with gastric cancer as a reason for seeking to withdraw an indication for pembrolizumab (Keytruda) for this disease.

Just weeks before the meeting, on April 16, the FDA approved nivolumab plus chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. This was a full approval based on data showing an overall survival benefit from a phase 3 trial.
 

Votes by indication

On April 29, the last day of the meeting, the ODAC panel voted 6-2 against maintaining pembrolizumab’s indication as monotherapy for an advanced form of gastric cancer. This was an accelerated approval (granted in 2017) that was based on overall response rates from an open-label trial.

That last day of the meeting also saw another negative vote. On April 29, the ODAC panel voted 5-4 against maintaining an indication for nivolumab in patients with hepatocellular carcinoma (HCC) who were previously treated with sorafenib (Nexavar).

This accelerated approval for nivolumab was granted in 2017. The FDA said it had requested ODAC’s feedback on this indication because of the recent full approval of another checkpoint inhibitor for HCC, atezolizumab (Tecentriq), in combination with bevacizumab (Avastin) for patients with unresectable or metastatic diseases who have not received prior systemic therapy. This full approval (in May 2020) was based on an overall survival benefit.

There was one last vote on the third day of the meeting, and it was positive. The ODAC panel voted 8-0 in favor of maintaining the indication for the use of pembrolizumab as monotherapy for patients with HCC who have previously been treated with sorafenib.

The FDA altered the composition of the ODAC panel during the week, adding members in some cases who had expertise in particular cancers. That led to different totals for the week’s ODAC votes, as shown in the tallies summarized below.

On the first day of the meeting (April 27), the ODAC panel voted 7-2 in favor of maintaining a breast cancer indication for atezolizumab (Tecentriq). This covered use of the immunotherapy in combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.

The second day of the meeting (April 28) also saw two positive votes. The ODAC panel voted 10-1 for maintaining the indication for atezolizumab for the first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma, pending final overall survival results from the IMvigor130 trial. The panel also voted 5-3 for maintaining the indication for pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1.

The FDA is not bound to follow the voting and recommendations of its advisory panels, but it usually does so.
 

Managing shifts in treatment

In both of the cases in which ODAC voted against maintaining indications, Richard Pazdur, MD, the FDA’s top regulator for cancer medicines, jumped into the debate. Dr. Pazdur countered arguments put forward by representatives of the manufacturers as they sought to maintain indications for their drugs.

Merck officials and representatives argued for pembrolizumab, saying that maintaining the gastric cancer indication might help patients whose disease has progressed despite earlier treatment.

Dr. Pazdur emphasized that the agency would help Merck and physicians to have access to pembrolizumab for these patients even if this one indication were to be withdrawn. But Dr. Pazdur and ODAC members also noted the recent shift in the landscape for gastric cancer, with the recent approval of a new indication for nivolumab.

“I want to emphasize to the patient community out there [that] we firmly believe in the role of checkpoint inhibitors in this disease,” Dr. Pazdur said during the discussion of the indication for pembrolizumab for gastric cancer. “We have to be cognizant of what is the appropriate setting for that, and it currently is in the first line.”

Dr. Pazdur noted that two studies had failed to confirm the expected benefit from pembrolizumab for patients with more advanced disease. Still, if “small numbers” of patients with advanced disease wanted access to Merck’s drug, the FDA and the company could accommodate them. The FDA could delay the removal of the gastric indication to allow patients to continue receiving it. The FDA also could work with physicians on other routes to provide the medicine, such as through single-patient investigational new drug applications or an expanded access program.

“Or Merck can alternatively give the drug gratis to patients,” Dr. Pazdur said.
 

#ProjectFacilitate for expanded access

One of Merck’s speakers at the ODAC meeting, Peter Enzinger, MD, of the Dana-Farber Cancer Institute, Boston, objected to Dr. Pazdur’s plan.

A loss of the gastric indication for pembrolizumab would result in patients with advanced cancer missing out on a chance to try this therapy. Some patients will not have had a chance to try a checkpoint inhibitor earlier in their treatment, and a loss of the indication would cost them that opportunity, he said.

“An expanded-access program sounds very nice, but the reality is that our patients are incredibly sick and that weeks matter,” Dr. Enzinger said, citing administrative hurdles as a barrier to treatment.

“Our patients just don’t have the time for that, and therefore I don’t think an expanded access program is the way to go,” Dr. Enzinger said.

Dr. Pazdur responded to these objections by highlighting an initiative called Project Facilitate at the FDA’s Oncology Center for Excellence. During the meeting, Dr. Pazdur’s division used its @FDAOncology Twitter handle to draw attention to this project.

ODAC panelist Diane Reidy-Lagunes, MD, of Memorial Sloan Kettering Cancer Center, New York, said she had struggled with this vote. She was one of the two panelists to vote in favor of keeping the indication.

“This is also incredibly hard for me. I actually changed it at the last minute,” she said of her vote.

But Dr. Reidy-Lagunes said she was concerned that some patients with advanced disease might not be able to get a checkpoint inhibitor.

“With disparities in healthcare and differences in the way that patients are treated throughout our country, I was nervous that they may not be able to get treated,” she said, noting that she shared her fellow panelists’ doubts about use of pembrolizumab as third-line treatment, owing to negative results in trials.

ODAC member David Mitchell, who served as a consumer representative, also said he found the vote on the gastric indication for pembrolizumab to be a difficult decision.

“As a patient with incurable cancer who’s now being given all three major classes of drugs to treat my disease in combination, these issues really cut close to home,” Mr. Mitchell said.

He said the expectation that the FDA’s expanded access program could help patients with advanced disease try pembrolizumab helped him decide to vote with the 6-2 majority against maintaining this gastric cancer approval.

His vote was based on “the changing treatment landscape.” There is general agreement that the patients in question should receive checkpoint inhibitors as first-line treatment, not third-line treatment, Mr. Mitchell said. The FDA should delay a withdrawal of the approval for pembrolizumab in this case and should allow a transition for those who missed out on treatment with a checkpoint inhibitor earlier in the disease course, he suggested.

“To protect the safety and well-being of patients, we have to base decisions on data,” Mr. Mitchell said. “The data don’t support maintaining the indication” for pembrolizumab.

 

Close split on nivolumab

In contrast to the 6-2 vote against maintaining the pembrolizumab indication, the ODAC panel split more closely, 5-4, on the question of maintaining an indication for the use as monotherapy of nivolumab in HCC.

ODAC panelist Philip C. Hoffman, MD, of the University of Chicago was among those who supported keeping the indication.

“There’s still an unmet need for second-line immunotherapy because there will always be some patients who are poor candidates for bevacizumab or who are not tolerating or responding to sorafenib,” he said.

ODAC panelist Mark A. Lewis, MD, of Intermountain Healthcare, Salt Lake City, said he voted “no” in part because he doubted that Bristol-Myers Squibb would be able to soon produce data for nivolumab that was needed to support this indication.

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

Federal advisers have supported the efforts of pharmaceutical companies in four of six cases in which these firms are fighting to maintain cancer indications for approved drugs. The advisers voted against the companies in two cases.

The staff of the Food and Drug Administration will now consider these votes as they decide what to do regarding the six cases of what they have termed “dangling” accelerated approvals.

“One of the reasons I think we’re convening today is to prevent these accelerated approvals from dangling ad infinitum,” commented one of the members of the advisory panel.

In these cases, companies have been unable to prove the expected benefits that led the FDA to grant accelerated approvals for these indications.

These accelerated approvals, which are often based on surrogate endpoints, such as overall response rates, are granted on the condition that further findings show a clinical benefit – such as in progression-free survival or overall survival – in larger trials.

The FDA tasked its Oncologic Drugs Advisory Committee (ODAC) with conducting the review of the six accelerated approvals for cancer indications at a 3-day meeting (April 27-29).

These reviews were only for specific cancer indications and will not lead to the removal of drugs from the market. These drugs have already been approved for several cancer indications. For example, one of the drugs that was reviewed, pembrolizumab (Keytruda), is approved in the United States for 28 indications.

The FDA is facing growing pains in its efforts to manage the rapidly changing landscape for these immune checkpoint inhibitors. This field of medicine has experienced an “unprecedented level of drug development” in recent years, FDA officials said in briefing materials, owing in part to the agency’s willingness to accept surrogate markers for accelerated approvals. Although some companies have struggled with these, others have built strong cases for the use of their checkpoint inhibitors for these indications.

The ODAC panelists, for example, noted the emergence of nivolumab (Opdivo) as an option for patients with gastric cancer as a reason for seeking to withdraw an indication for pembrolizumab (Keytruda) for this disease.

Just weeks before the meeting, on April 16, the FDA approved nivolumab plus chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. This was a full approval based on data showing an overall survival benefit from a phase 3 trial.
 

Votes by indication

On April 29, the last day of the meeting, the ODAC panel voted 6-2 against maintaining pembrolizumab’s indication as monotherapy for an advanced form of gastric cancer. This was an accelerated approval (granted in 2017) that was based on overall response rates from an open-label trial.

That last day of the meeting also saw another negative vote. On April 29, the ODAC panel voted 5-4 against maintaining an indication for nivolumab in patients with hepatocellular carcinoma (HCC) who were previously treated with sorafenib (Nexavar).

This accelerated approval for nivolumab was granted in 2017. The FDA said it had requested ODAC’s feedback on this indication because of the recent full approval of another checkpoint inhibitor for HCC, atezolizumab (Tecentriq), in combination with bevacizumab (Avastin) for patients with unresectable or metastatic diseases who have not received prior systemic therapy. This full approval (in May 2020) was based on an overall survival benefit.

There was one last vote on the third day of the meeting, and it was positive. The ODAC panel voted 8-0 in favor of maintaining the indication for the use of pembrolizumab as monotherapy for patients with HCC who have previously been treated with sorafenib.

The FDA altered the composition of the ODAC panel during the week, adding members in some cases who had expertise in particular cancers. That led to different totals for the week’s ODAC votes, as shown in the tallies summarized below.

On the first day of the meeting (April 27), the ODAC panel voted 7-2 in favor of maintaining a breast cancer indication for atezolizumab (Tecentriq). This covered use of the immunotherapy in combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.

The second day of the meeting (April 28) also saw two positive votes. The ODAC panel voted 10-1 for maintaining the indication for atezolizumab for the first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma, pending final overall survival results from the IMvigor130 trial. The panel also voted 5-3 for maintaining the indication for pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1.

The FDA is not bound to follow the voting and recommendations of its advisory panels, but it usually does so.
 

Managing shifts in treatment

In both of the cases in which ODAC voted against maintaining indications, Richard Pazdur, MD, the FDA’s top regulator for cancer medicines, jumped into the debate. Dr. Pazdur countered arguments put forward by representatives of the manufacturers as they sought to maintain indications for their drugs.

Merck officials and representatives argued for pembrolizumab, saying that maintaining the gastric cancer indication might help patients whose disease has progressed despite earlier treatment.

Dr. Pazdur emphasized that the agency would help Merck and physicians to have access to pembrolizumab for these patients even if this one indication were to be withdrawn. But Dr. Pazdur and ODAC members also noted the recent shift in the landscape for gastric cancer, with the recent approval of a new indication for nivolumab.

“I want to emphasize to the patient community out there [that] we firmly believe in the role of checkpoint inhibitors in this disease,” Dr. Pazdur said during the discussion of the indication for pembrolizumab for gastric cancer. “We have to be cognizant of what is the appropriate setting for that, and it currently is in the first line.”

Dr. Pazdur noted that two studies had failed to confirm the expected benefit from pembrolizumab for patients with more advanced disease. Still, if “small numbers” of patients with advanced disease wanted access to Merck’s drug, the FDA and the company could accommodate them. The FDA could delay the removal of the gastric indication to allow patients to continue receiving it. The FDA also could work with physicians on other routes to provide the medicine, such as through single-patient investigational new drug applications or an expanded access program.

“Or Merck can alternatively give the drug gratis to patients,” Dr. Pazdur said.
 

#ProjectFacilitate for expanded access

One of Merck’s speakers at the ODAC meeting, Peter Enzinger, MD, of the Dana-Farber Cancer Institute, Boston, objected to Dr. Pazdur’s plan.

A loss of the gastric indication for pembrolizumab would result in patients with advanced cancer missing out on a chance to try this therapy. Some patients will not have had a chance to try a checkpoint inhibitor earlier in their treatment, and a loss of the indication would cost them that opportunity, he said.

“An expanded-access program sounds very nice, but the reality is that our patients are incredibly sick and that weeks matter,” Dr. Enzinger said, citing administrative hurdles as a barrier to treatment.

“Our patients just don’t have the time for that, and therefore I don’t think an expanded access program is the way to go,” Dr. Enzinger said.

Dr. Pazdur responded to these objections by highlighting an initiative called Project Facilitate at the FDA’s Oncology Center for Excellence. During the meeting, Dr. Pazdur’s division used its @FDAOncology Twitter handle to draw attention to this project.

ODAC panelist Diane Reidy-Lagunes, MD, of Memorial Sloan Kettering Cancer Center, New York, said she had struggled with this vote. She was one of the two panelists to vote in favor of keeping the indication.

“This is also incredibly hard for me. I actually changed it at the last minute,” she said of her vote.

But Dr. Reidy-Lagunes said she was concerned that some patients with advanced disease might not be able to get a checkpoint inhibitor.

“With disparities in healthcare and differences in the way that patients are treated throughout our country, I was nervous that they may not be able to get treated,” she said, noting that she shared her fellow panelists’ doubts about use of pembrolizumab as third-line treatment, owing to negative results in trials.

ODAC member David Mitchell, who served as a consumer representative, also said he found the vote on the gastric indication for pembrolizumab to be a difficult decision.

“As a patient with incurable cancer who’s now being given all three major classes of drugs to treat my disease in combination, these issues really cut close to home,” Mr. Mitchell said.

He said the expectation that the FDA’s expanded access program could help patients with advanced disease try pembrolizumab helped him decide to vote with the 6-2 majority against maintaining this gastric cancer approval.

His vote was based on “the changing treatment landscape.” There is general agreement that the patients in question should receive checkpoint inhibitors as first-line treatment, not third-line treatment, Mr. Mitchell said. The FDA should delay a withdrawal of the approval for pembrolizumab in this case and should allow a transition for those who missed out on treatment with a checkpoint inhibitor earlier in the disease course, he suggested.

“To protect the safety and well-being of patients, we have to base decisions on data,” Mr. Mitchell said. “The data don’t support maintaining the indication” for pembrolizumab.

 

Close split on nivolumab

In contrast to the 6-2 vote against maintaining the pembrolizumab indication, the ODAC panel split more closely, 5-4, on the question of maintaining an indication for the use as monotherapy of nivolumab in HCC.

ODAC panelist Philip C. Hoffman, MD, of the University of Chicago was among those who supported keeping the indication.

“There’s still an unmet need for second-line immunotherapy because there will always be some patients who are poor candidates for bevacizumab or who are not tolerating or responding to sorafenib,” he said.

ODAC panelist Mark A. Lewis, MD, of Intermountain Healthcare, Salt Lake City, said he voted “no” in part because he doubted that Bristol-Myers Squibb would be able to soon produce data for nivolumab that was needed to support this indication.

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

Federal advisers have supported the efforts of pharmaceutical companies in four of six cases in which these firms are fighting to maintain cancer indications for approved drugs. The advisers voted against the companies in two cases.

The staff of the Food and Drug Administration will now consider these votes as they decide what to do regarding the six cases of what they have termed “dangling” accelerated approvals.

“One of the reasons I think we’re convening today is to prevent these accelerated approvals from dangling ad infinitum,” commented one of the members of the advisory panel.

In these cases, companies have been unable to prove the expected benefits that led the FDA to grant accelerated approvals for these indications.

These accelerated approvals, which are often based on surrogate endpoints, such as overall response rates, are granted on the condition that further findings show a clinical benefit – such as in progression-free survival or overall survival – in larger trials.

The FDA tasked its Oncologic Drugs Advisory Committee (ODAC) with conducting the review of the six accelerated approvals for cancer indications at a 3-day meeting (April 27-29).

These reviews were only for specific cancer indications and will not lead to the removal of drugs from the market. These drugs have already been approved for several cancer indications. For example, one of the drugs that was reviewed, pembrolizumab (Keytruda), is approved in the United States for 28 indications.

The FDA is facing growing pains in its efforts to manage the rapidly changing landscape for these immune checkpoint inhibitors. This field of medicine has experienced an “unprecedented level of drug development” in recent years, FDA officials said in briefing materials, owing in part to the agency’s willingness to accept surrogate markers for accelerated approvals. Although some companies have struggled with these, others have built strong cases for the use of their checkpoint inhibitors for these indications.

The ODAC panelists, for example, noted the emergence of nivolumab (Opdivo) as an option for patients with gastric cancer as a reason for seeking to withdraw an indication for pembrolizumab (Keytruda) for this disease.

Just weeks before the meeting, on April 16, the FDA approved nivolumab plus chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. This was a full approval based on data showing an overall survival benefit from a phase 3 trial.
 

Votes by indication

On April 29, the last day of the meeting, the ODAC panel voted 6-2 against maintaining pembrolizumab’s indication as monotherapy for an advanced form of gastric cancer. This was an accelerated approval (granted in 2017) that was based on overall response rates from an open-label trial.

That last day of the meeting also saw another negative vote. On April 29, the ODAC panel voted 5-4 against maintaining an indication for nivolumab in patients with hepatocellular carcinoma (HCC) who were previously treated with sorafenib (Nexavar).

This accelerated approval for nivolumab was granted in 2017. The FDA said it had requested ODAC’s feedback on this indication because of the recent full approval of another checkpoint inhibitor for HCC, atezolizumab (Tecentriq), in combination with bevacizumab (Avastin) for patients with unresectable or metastatic diseases who have not received prior systemic therapy. This full approval (in May 2020) was based on an overall survival benefit.

There was one last vote on the third day of the meeting, and it was positive. The ODAC panel voted 8-0 in favor of maintaining the indication for the use of pembrolizumab as monotherapy for patients with HCC who have previously been treated with sorafenib.

The FDA altered the composition of the ODAC panel during the week, adding members in some cases who had expertise in particular cancers. That led to different totals for the week’s ODAC votes, as shown in the tallies summarized below.

On the first day of the meeting (April 27), the ODAC panel voted 7-2 in favor of maintaining a breast cancer indication for atezolizumab (Tecentriq). This covered use of the immunotherapy in combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.

The second day of the meeting (April 28) also saw two positive votes. The ODAC panel voted 10-1 for maintaining the indication for atezolizumab for the first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma, pending final overall survival results from the IMvigor130 trial. The panel also voted 5-3 for maintaining the indication for pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1.

The FDA is not bound to follow the voting and recommendations of its advisory panels, but it usually does so.
 

Managing shifts in treatment

In both of the cases in which ODAC voted against maintaining indications, Richard Pazdur, MD, the FDA’s top regulator for cancer medicines, jumped into the debate. Dr. Pazdur countered arguments put forward by representatives of the manufacturers as they sought to maintain indications for their drugs.

Merck officials and representatives argued for pembrolizumab, saying that maintaining the gastric cancer indication might help patients whose disease has progressed despite earlier treatment.

Dr. Pazdur emphasized that the agency would help Merck and physicians to have access to pembrolizumab for these patients even if this one indication were to be withdrawn. But Dr. Pazdur and ODAC members also noted the recent shift in the landscape for gastric cancer, with the recent approval of a new indication for nivolumab.

“I want to emphasize to the patient community out there [that] we firmly believe in the role of checkpoint inhibitors in this disease,” Dr. Pazdur said during the discussion of the indication for pembrolizumab for gastric cancer. “We have to be cognizant of what is the appropriate setting for that, and it currently is in the first line.”

Dr. Pazdur noted that two studies had failed to confirm the expected benefit from pembrolizumab for patients with more advanced disease. Still, if “small numbers” of patients with advanced disease wanted access to Merck’s drug, the FDA and the company could accommodate them. The FDA could delay the removal of the gastric indication to allow patients to continue receiving it. The FDA also could work with physicians on other routes to provide the medicine, such as through single-patient investigational new drug applications or an expanded access program.

“Or Merck can alternatively give the drug gratis to patients,” Dr. Pazdur said.
 

#ProjectFacilitate for expanded access

One of Merck’s speakers at the ODAC meeting, Peter Enzinger, MD, of the Dana-Farber Cancer Institute, Boston, objected to Dr. Pazdur’s plan.

A loss of the gastric indication for pembrolizumab would result in patients with advanced cancer missing out on a chance to try this therapy. Some patients will not have had a chance to try a checkpoint inhibitor earlier in their treatment, and a loss of the indication would cost them that opportunity, he said.

“An expanded-access program sounds very nice, but the reality is that our patients are incredibly sick and that weeks matter,” Dr. Enzinger said, citing administrative hurdles as a barrier to treatment.

“Our patients just don’t have the time for that, and therefore I don’t think an expanded access program is the way to go,” Dr. Enzinger said.

Dr. Pazdur responded to these objections by highlighting an initiative called Project Facilitate at the FDA’s Oncology Center for Excellence. During the meeting, Dr. Pazdur’s division used its @FDAOncology Twitter handle to draw attention to this project.

ODAC panelist Diane Reidy-Lagunes, MD, of Memorial Sloan Kettering Cancer Center, New York, said she had struggled with this vote. She was one of the two panelists to vote in favor of keeping the indication.

“This is also incredibly hard for me. I actually changed it at the last minute,” she said of her vote.

But Dr. Reidy-Lagunes said she was concerned that some patients with advanced disease might not be able to get a checkpoint inhibitor.

“With disparities in healthcare and differences in the way that patients are treated throughout our country, I was nervous that they may not be able to get treated,” she said, noting that she shared her fellow panelists’ doubts about use of pembrolizumab as third-line treatment, owing to negative results in trials.

ODAC member David Mitchell, who served as a consumer representative, also said he found the vote on the gastric indication for pembrolizumab to be a difficult decision.

“As a patient with incurable cancer who’s now being given all three major classes of drugs to treat my disease in combination, these issues really cut close to home,” Mr. Mitchell said.

He said the expectation that the FDA’s expanded access program could help patients with advanced disease try pembrolizumab helped him decide to vote with the 6-2 majority against maintaining this gastric cancer approval.

His vote was based on “the changing treatment landscape.” There is general agreement that the patients in question should receive checkpoint inhibitors as first-line treatment, not third-line treatment, Mr. Mitchell said. The FDA should delay a withdrawal of the approval for pembrolizumab in this case and should allow a transition for those who missed out on treatment with a checkpoint inhibitor earlier in the disease course, he suggested.

“To protect the safety and well-being of patients, we have to base decisions on data,” Mr. Mitchell said. “The data don’t support maintaining the indication” for pembrolizumab.

 

Close split on nivolumab

In contrast to the 6-2 vote against maintaining the pembrolizumab indication, the ODAC panel split more closely, 5-4, on the question of maintaining an indication for the use as monotherapy of nivolumab in HCC.

ODAC panelist Philip C. Hoffman, MD, of the University of Chicago was among those who supported keeping the indication.

“There’s still an unmet need for second-line immunotherapy because there will always be some patients who are poor candidates for bevacizumab or who are not tolerating or responding to sorafenib,” he said.

ODAC panelist Mark A. Lewis, MD, of Intermountain Healthcare, Salt Lake City, said he voted “no” in part because he doubted that Bristol-Myers Squibb would be able to soon produce data for nivolumab that was needed to support this indication.

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

On the first day of a historic 3-day meeting about drugs that were granted an accelerated approval by the Food and Drug Administration for cancer indications, the first approval to come under discussion is staying in place, at least for now.

Members of the FDA’s Oncologic Drugs Advisory Committee voted 7-2 in favor of keeping in place the indication for atezolizumab (Tecentriq) for use in a certain form of breast cancer. At the same time, the committee urged the manufacturer, Genentech, to do the research needed to prove the medicine works for these patients.

The specific indication is for atezolizumab as part of a combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) whose tumors are PD-L1 positive.

The FDA granted accelerated approval in 2019 for this use of atezolizumab, expecting Genentech to produce more extensive evidence of this benefit. But so far, Genentech has not produced the data proving to the FDA that atezolizumab provides the expected benefit.

The drug was already available for use in bladder cancer, having been granted a full approval for this indication in 2016.
 

Other accelerated approvals withdrawn

This week’s 3-day ODAC meeting is part of the FDA’s broader reconsideration of what it has described as “dangling accelerated approvals.”

Earlier discussions between the FDA and drugmakers have already triggered four voluntary withdrawals of cancer indications with these accelerated approvals, noted Julia A. Beaver, MD, and Richard Pazdur, MD, two of the FDA’s top regulators of oncology medicine, in an April 21 perspective article in the New England Journal of Medicine.

“The small percentage of drugs whose clinical benefit is ultimately not confirmed should be viewed not as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with severe or life-threatening diseases,” Dr. Beaver and Dr. Pazdur wrote.

But making these calls can be tough. On the first day of the meeting, even ODAC panelists who backed Genentech’s bid to maintain an mTNBC indication for atezolizumab expressed discomfort with this choice.

The FDA granted the accelerated approval for use of this drug in March 2019 based on improved progression-free survival from the IMpassion130 trial. But the drug fell short in subsequent efforts to confirm the results seen in that study. The confirmatory IMpassion131 trial failed to meet the primary endpoint, the FDA staff noted in briefing materials for the ODAC meeting.

ODAC panelist Stan Lipkowitz, MD, PhD, of the National Cancer Institute, said he expected this vote had been a tough one for all members serving on ODAC that day.

“In some ways, the purist in me said I should have voted no. But when I looked at the data, there are a couple of things that struck me,” said Dr. Lipkowitz, who is the chief of the Women’s Malignancies Branch at NCI’s Center for Cancer Research. “First of all, the landscape hasn’t changed. There’s really no therapy in the first line for triple-negative metastatic that is shown to improve survival.”

Dr. Lipkowitz emphasized that Genentech needs to continue to try to prove atezolizumab works in this setting.

“There needs to be confirmatory study,” Dr. Lipkowitz concluded.

ODAC panelist Matthew Ellis, MD, PhD, of Baylor College of Medicine, Houston, said he also understood the difficult outlook for women fighting this cancer, but he voted against maintaining the approval.

“It’s not that I don’t feel the tragedy of these women,” said Dr. Ellis, citing his own decades of clinical experience.

“I just think that the data are the data,” Dr. Ellis said, adding that, in his view, “the only correct interpretation” of the evidence supported a vote against allowing the indication to stay.

The FDA considers the recommendations of its advisory committees but is not bound by them.

In a statement issued after the vote, Genentech said it intends to work with the FDA to determine the next steps for this indication of atezolizumab because “the clinically meaningful benefit demonstrated in the IMpassion130 study remains.”

The ODAC meeting continues for 2 more days, and will consider five more cancer indications that have been granted an accelerated approval.

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

On the first day of a historic 3-day meeting about drugs that were granted an accelerated approval by the Food and Drug Administration for cancer indications, the first approval to come under discussion is staying in place, at least for now.

Members of the FDA’s Oncologic Drugs Advisory Committee voted 7-2 in favor of keeping in place the indication for atezolizumab (Tecentriq) for use in a certain form of breast cancer. At the same time, the committee urged the manufacturer, Genentech, to do the research needed to prove the medicine works for these patients.

The specific indication is for atezolizumab as part of a combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) whose tumors are PD-L1 positive.

The FDA granted accelerated approval in 2019 for this use of atezolizumab, expecting Genentech to produce more extensive evidence of this benefit. But so far, Genentech has not produced the data proving to the FDA that atezolizumab provides the expected benefit.

The drug was already available for use in bladder cancer, having been granted a full approval for this indication in 2016.
 

Other accelerated approvals withdrawn

This week’s 3-day ODAC meeting is part of the FDA’s broader reconsideration of what it has described as “dangling accelerated approvals.”

Earlier discussions between the FDA and drugmakers have already triggered four voluntary withdrawals of cancer indications with these accelerated approvals, noted Julia A. Beaver, MD, and Richard Pazdur, MD, two of the FDA’s top regulators of oncology medicine, in an April 21 perspective article in the New England Journal of Medicine.

“The small percentage of drugs whose clinical benefit is ultimately not confirmed should be viewed not as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with severe or life-threatening diseases,” Dr. Beaver and Dr. Pazdur wrote.

But making these calls can be tough. On the first day of the meeting, even ODAC panelists who backed Genentech’s bid to maintain an mTNBC indication for atezolizumab expressed discomfort with this choice.

The FDA granted the accelerated approval for use of this drug in March 2019 based on improved progression-free survival from the IMpassion130 trial. But the drug fell short in subsequent efforts to confirm the results seen in that study. The confirmatory IMpassion131 trial failed to meet the primary endpoint, the FDA staff noted in briefing materials for the ODAC meeting.

ODAC panelist Stan Lipkowitz, MD, PhD, of the National Cancer Institute, said he expected this vote had been a tough one for all members serving on ODAC that day.

“In some ways, the purist in me said I should have voted no. But when I looked at the data, there are a couple of things that struck me,” said Dr. Lipkowitz, who is the chief of the Women’s Malignancies Branch at NCI’s Center for Cancer Research. “First of all, the landscape hasn’t changed. There’s really no therapy in the first line for triple-negative metastatic that is shown to improve survival.”

Dr. Lipkowitz emphasized that Genentech needs to continue to try to prove atezolizumab works in this setting.

“There needs to be confirmatory study,” Dr. Lipkowitz concluded.

ODAC panelist Matthew Ellis, MD, PhD, of Baylor College of Medicine, Houston, said he also understood the difficult outlook for women fighting this cancer, but he voted against maintaining the approval.

“It’s not that I don’t feel the tragedy of these women,” said Dr. Ellis, citing his own decades of clinical experience.

“I just think that the data are the data,” Dr. Ellis said, adding that, in his view, “the only correct interpretation” of the evidence supported a vote against allowing the indication to stay.

The FDA considers the recommendations of its advisory committees but is not bound by them.

In a statement issued after the vote, Genentech said it intends to work with the FDA to determine the next steps for this indication of atezolizumab because “the clinically meaningful benefit demonstrated in the IMpassion130 study remains.”

The ODAC meeting continues for 2 more days, and will consider five more cancer indications that have been granted an accelerated approval.

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

On the first day of a historic 3-day meeting about drugs that were granted an accelerated approval by the Food and Drug Administration for cancer indications, the first approval to come under discussion is staying in place, at least for now.

Members of the FDA’s Oncologic Drugs Advisory Committee voted 7-2 in favor of keeping in place the indication for atezolizumab (Tecentriq) for use in a certain form of breast cancer. At the same time, the committee urged the manufacturer, Genentech, to do the research needed to prove the medicine works for these patients.

The specific indication is for atezolizumab as part of a combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) whose tumors are PD-L1 positive.

The FDA granted accelerated approval in 2019 for this use of atezolizumab, expecting Genentech to produce more extensive evidence of this benefit. But so far, Genentech has not produced the data proving to the FDA that atezolizumab provides the expected benefit.

The drug was already available for use in bladder cancer, having been granted a full approval for this indication in 2016.
 

Other accelerated approvals withdrawn

This week’s 3-day ODAC meeting is part of the FDA’s broader reconsideration of what it has described as “dangling accelerated approvals.”

Earlier discussions between the FDA and drugmakers have already triggered four voluntary withdrawals of cancer indications with these accelerated approvals, noted Julia A. Beaver, MD, and Richard Pazdur, MD, two of the FDA’s top regulators of oncology medicine, in an April 21 perspective article in the New England Journal of Medicine.

“The small percentage of drugs whose clinical benefit is ultimately not confirmed should be viewed not as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with severe or life-threatening diseases,” Dr. Beaver and Dr. Pazdur wrote.

But making these calls can be tough. On the first day of the meeting, even ODAC panelists who backed Genentech’s bid to maintain an mTNBC indication for atezolizumab expressed discomfort with this choice.

The FDA granted the accelerated approval for use of this drug in March 2019 based on improved progression-free survival from the IMpassion130 trial. But the drug fell short in subsequent efforts to confirm the results seen in that study. The confirmatory IMpassion131 trial failed to meet the primary endpoint, the FDA staff noted in briefing materials for the ODAC meeting.

ODAC panelist Stan Lipkowitz, MD, PhD, of the National Cancer Institute, said he expected this vote had been a tough one for all members serving on ODAC that day.

“In some ways, the purist in me said I should have voted no. But when I looked at the data, there are a couple of things that struck me,” said Dr. Lipkowitz, who is the chief of the Women’s Malignancies Branch at NCI’s Center for Cancer Research. “First of all, the landscape hasn’t changed. There’s really no therapy in the first line for triple-negative metastatic that is shown to improve survival.”

Dr. Lipkowitz emphasized that Genentech needs to continue to try to prove atezolizumab works in this setting.

“There needs to be confirmatory study,” Dr. Lipkowitz concluded.

ODAC panelist Matthew Ellis, MD, PhD, of Baylor College of Medicine, Houston, said he also understood the difficult outlook for women fighting this cancer, but he voted against maintaining the approval.

“It’s not that I don’t feel the tragedy of these women,” said Dr. Ellis, citing his own decades of clinical experience.

“I just think that the data are the data,” Dr. Ellis said, adding that, in his view, “the only correct interpretation” of the evidence supported a vote against allowing the indication to stay.

The FDA considers the recommendations of its advisory committees but is not bound by them.

In a statement issued after the vote, Genentech said it intends to work with the FDA to determine the next steps for this indication of atezolizumab because “the clinically meaningful benefit demonstrated in the IMpassion130 study remains.”

The ODAC meeting continues for 2 more days, and will consider five more cancer indications that have been granted an accelerated approval.

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

Editor's Note:
The Case Challenge series includes difficult-to-diagnose conditions, some of which are not frequently encountered by most clinicians but are nonetheless important to accurately recognize. Test your diagnostic and treatment skills using the following patient scenario and corresponding questions. If you have a case that you would like to suggest for a future Case Challenge, please contact us .

Background

A 58-year-old woman seeks medical attention after she discovered a new mass in her left axilla during a routine monthly breast self-examination while showering. She has not noted any changes in either of her breasts. The mass in her left axilla is not tender, and she has not felt any other abnormal masses, including in her right axilla. She reports no other symptoms and specifically has no pain anywhere in her body. She also does not have shortness of breath, fever, night sweats, fatigue, rash, or abdominal discomfort or bloating.

Fifteen years earlier, the patient was diagnosed with high-grade, stage 1 cervical cancer and underwent surgery and chemoradiation. She has been closely monitored since that time with physical examinations and abdominal CT, with no evidence of recurrent disease. The patient has not had any other surgical procedure, except for removal of two basal cell carcinomas on her neck 4 years ago. She has had yearly routine mammograms for at least the past 15 years.

The patient has hypertension, which has been well controlled with the same medications for the past 10 years. She also has a 25-year history of type 2 diabetes mellitus, which is currently managed with diet alone. She had a "silent myocardial infarction" sometime within the past 5 years but has had no cardiac symptoms and is not taking any cardiac medications. She smoked approximately one pack of cigarettes a day for less than 2 years when she was "in her teens" but has not had any tobacco products since that time.

Pancreatic cancer was diagnosed in the patient's father at age 49 years, and breast cancer was diagnosed in her aunt on her father's side at age 67 years. Her paternal grandmother is reported to have died in her 60s after diagnosis of a "cancer in her stomach." No further information is available regarding either the actual diagnosis or the medical care provided to this individual.

To the best of the patient's knowledge, her mother's side of the family and her two brothers have no history of cancer. She has no sisters. Her mother is in her 80s and has mild dementia. The patient is not aware of any member of her family having undergone genetic testing.

Physical Examination and Workup

The patient appears well and is in no acute distress. The patient is afebrile, with a blood pressure of 135/85 mm Hg, a respiratory rate of 16 breaths/min, and a pulse of 72 beats/min. Her weight is 148 lb (67 kg), and she has no reported recent weight loss.

Examination of the skin reveals no suspicious lesions. Scars from the previous removal of the basal cell carcinomas are noted, but no evidence suggests recurrence.

Results of the head and neck examination are unremarkable; specifically, no abnormal cervical lymphadenopathy is detected. The cardiac and chest examination results are normal. The lungs are clear to percussion and auscultation. The breast examination reveals no abnormal masses. The right axilla is unremarkable; however, a single 3 × 2 cm, nontender, firm, movable but partially fixed mass is noted in the left axilla.

The abdomen appears normal, with no ascites or enlargement of the liver. The pelvic examination reveals evidence of previous surgery and local radiation but no signs of recurrence of cervical cancer. The lymph nodes appear normal, except for the findings noted above. Results of the neurologic examination are unremarkable.

Complete blood cell count, serum electrolyte levels, renal function tests, and urinalysis are all normal. Liver function tests are normal except for a mildly elevated serum alkaline phosphatase level. The fecal occult blood test result is negative.

Chest radiography reveals a suspicious small left-sided pleural effusion. No other abnormalities are observed, and no prior chest radiographs are available to compare with the current findings.

Chest CT confirms the presence of a possible small pleural effusion, with no other abnormalities noted. The radiologist suggests it will not be possible to obtain fluid safely through an interventional procedure, owing to the limited (if any) amount of fluid present. Furthermore, the radiologist recommends PET/CT to look for other evidence of metastatic cancer in the lungs or elsewhere.

Bilateral mammograms reveal no suspicious abnormalities, and the results are unchanged from a previous examination 11 months earlier. Figure 1 shows a similar bilateral mammogram in another patient. Breast MRI shows no evidence of cancer. Figure 2 shows similar breast MRI findings in another patient.

CT of the abdomen and pelvis reveals no changes compared with a scan obtained 2 years earlier for follow-up of the previous diagnosis of cervical cancer. Specifically, no evidence suggests ascites or any pelvic masses.

An incisional biopsy sample is obtained from the left axillary mass. Light microscopy reveals a moderately well-differentiated adenocarcinoma. Immunostaining shows the cancer to be cytokeratin (CK) 7 positive and CK 20 negative (CK 7+/CK 20-, thyroid transcription factor 1 (TTF-1) negative, thyroglobulin negative, napsin A negative, and mammaglobin positive. The tumor is estrogen receptor positive (2% staining), progesterone receptor negative, and human epidermal growth factor receptor 2 (HER2) negative.

[polldaddy:10837180]

Discussion

The correct answer: Breast.

This case is a classic example of cancer of unknown primary site or origin (CUP). CUP represents approximately 5% of cancers diagnosed in the United States (50,000 to 60,000 cases each year), with various series reporting that the site of origin is not diagnosed in between 2% and 6% of all cancer cases.^[1] Worldwide, the incidence of CUP is even higher, resulting from the limited availability of sophisticated (and expensive) diagnostic technology in many regions. The median age at diagnosis of CUP is 60 years, and men and women are equally likely to be affected.

A cancer is considered a CUP if, after routine clinical assessment, physical and laboratory examination, standard imaging studies, and routine pathologic evaluation (biopsy or surgical removal of a metastatic mass lesion), a site of origin cannot be defined. With the availability of more sophisticated imaging technologies (eg, MRI), the overall percentage of cancers that are defined as a CUP has been reduced. However, even at autopsy, the site of origin of such cancer is often unable to be determined if the location was unknown before the patient's death.

Several theories have been proposed for why a metastatic lesion becomes clinically evident despite the site of origin of the cancer remaining obscure. These include (1) very slow growth of the primary cancer compared with that of the metastasis; (2) spontaneous regression of the primary cancer; (3) a prominent vascular component of the cancer, which enhances the rate of spread; and (4) unique molecular events associated with the cancer, which result in rapid progression and the growth of metastatic lesions.

Approximately 60% of CUPs are adenocarcinomas (well or moderately well differentiated); 25%-30% are poorly differentiated (including poorly differentiated adenocarcinomas); 5% are completely undifferentiated, with no defining histologic features; 5% are squamous cell cancers; and approximately 1% are carcinomas, with evidence of neuroendocrine differentiation.^[1]

Immunohistochemical staining of biopsy material can be helpful in narrowing the possible anatomical sites of origin. The results are particularly relevant in the selection of therapeutic strategies and in ensuring that a rare, potentially highly curable cancer is not missed (eg, lymphoma, germ cell tumor).^[2]

A critical initial test is examination of several CK subtypes that are more likely to be expressed in certain carcinomas than in others. For example, the CK 7+/CK 20- staining seen in this patient is characteristic of breast and lung cancers (among others), whereas CK 7+/CK 20+ staining would be expected in pancreatic, gastric, and urothelial cancers. A CK 7-/CK 20+ finding would be more suggestive of colon or mucinous ovarian cancer. Furthermore, approximately 70% of lung adenocarcinomas are TTF-1 positive and 60%-80% are napsin A positive. The negative findings in this patient's case make the diagnosis of metastatic lung cancer less likely.

Examination for the presence (or absence) of well-established biomarkers for breast cancer can potentially be helpful in suggesting the site of origin or in helping to define subsequent therapy. These markers include estrogen and progesterone receptors and HER2 overexpression. An additional biomarker, mammaglobin, has been reported to be expressed in 48% of breast cancers but is absent in cancers of the lung, gastrointestinal tract, ovary, and head and neck region.^[2]

Of note, mammaglobin was found to be expressed in this patient. Although only 2% of the cells were reported to stain for the estrogen receptor, this finding is still considered positive and supports breast cancer as the correct diagnosis.

Recognized relevant prognostic factors in CUP include baseline performance status, the number and location of metastatic lesions, and the response to cytotoxic chemotherapy.

Unfortunately, the overall prognosis associated with a diagnosis of CUP is poor, with median survival in various series reported to be less than 6 months. However, important exceptions to this outcome include women who present with an isolated metastatic axillary mass, as described in this case.

Previous reports of axillary adenopathy as the initial presentation of cancer in women revealed that the majority had evidence of cancer in the breast at the time of subsequent mastectomy.^[3,4] As a result, in the absence of other indications found during routine workup (eg, a single pulmonary lesion suggestive of a primary lung cancer, pathologic findings inconsistent with breast cancer), an isolated adenocarcinoma in the breast (with no evidence of metastatic cancer elsewhere) should be treated as either stage II or stage III breast cancer. Note that this recommendation specifically relates to female patients. If a male patient has CUP with an isolated axillary mass, it is generally assumed that the lung is the origin of the malignancy.

In a female patient with negative mammographic findings, breast MRI can be helpful. In one series, 28 of 40 women (70%) with evidence of cancer in the axilla and a normal mammogram were found to have a breast abnormality on MRI.^[5] Of note, and of considerable relevance to subsequent disease management, five of the 12 women with negative findings in this series underwent surgery, and in four of the cases no cancer was found. Although the number of participants in this series is limited, the absence of an MRI abnormality in the patient in this case can reasonably be considered in her future treatment plans.

Specifically, it might be suggested in this case that treatment include surgical removal of the axillary mass (if possible) followed by radiation to this area and the breast (rather than performing a mastectomy). Alternatively, treatment might begin with chemotherapy (a neoadjuvant approach) followed by surgery to remove any residual axillary mass and local/regional radiation or local/regional radiation alone. Adjuvant chemotherapy and/or hormonal therapy would then be administered.

The presence of a possible small pleural effusion is a concern because it potentially indicates more widespread metastatic disease, as does the mild elevation of the serum alkaline phosphatase level (eg, suggesting metastatic disease in bone or the liver). In the absence of other evidence of tumor spread, PET would not be unreasonable. A negative scan for evidence of metastatic disease would support a "curative" approach to the management of local disease in the axilla and presumably the breast, whereas a finding of other metastatic sites would lead to the conclusion that treatment should probably be delivered with more palliative intent.

The family history of cancer (father, paternal aunt with breast cancer, paternal grandmother with possible ovarian cancer) is intriguing and would suggest a role for genetic counseling and possibly genetic testing (eg, for BRCA mutation).

The patient in this case underwent PET. The only abnormality observed was in the left axilla. The axillary mass was subsequently resected. This was followed by curative radiation to both the axilla and left breast, adjuvant chemotherapy, and 5 years of hormonal therapy. The patient has showed no evidence of recurrence 2 years after completion of the hormonal treatment.

[polldaddy:10841207]

Discussion

The correct answer: Lung

The lungs are generally assumed to be the site of origin of the cancer in a male patient who has CUP with an isolated axillary mass. In contrast, the majority of women with axillary adenopathy as the initial presentation of cancer were found to have evidence of cancer in the breast at the time of subsequent mastectomy.^[3,4]

[polldaddy:10837187]

Discussion

The correct answer: MRI

Breast MRI can be helpful in a female patient with negative mammographic findings. In one series, MRI detected a breast abnormality in 28 of 40 women (70%) with evidence of cancer in the axilla and a normal mammogram.^[5]

Editor's Note:
The Case Challenge series includes difficult-to-diagnose conditions, some of which are not frequently encountered by most clinicians but are nonetheless important to accurately recognize. Test your diagnostic and treatment skills using the following patient scenario and corresponding questions. If you have a case that you would like to suggest for a future Case Challenge, please contact us .

Background

A 58-year-old woman seeks medical attention after she discovered a new mass in her left axilla during a routine monthly breast self-examination while showering. She has not noted any changes in either of her breasts. The mass in her left axilla is not tender, and she has not felt any other abnormal masses, including in her right axilla. She reports no other symptoms and specifically has no pain anywhere in her body. She also does not have shortness of breath, fever, night sweats, fatigue, rash, or abdominal discomfort or bloating.

Fifteen years earlier, the patient was diagnosed with high-grade, stage 1 cervical cancer and underwent surgery and chemoradiation. She has been closely monitored since that time with physical examinations and abdominal CT, with no evidence of recurrent disease. The patient has not had any other surgical procedure, except for removal of two basal cell carcinomas on her neck 4 years ago. She has had yearly routine mammograms for at least the past 15 years.

The patient has hypertension, which has been well controlled with the same medications for the past 10 years. She also has a 25-year history of type 2 diabetes mellitus, which is currently managed with diet alone. She had a "silent myocardial infarction" sometime within the past 5 years but has had no cardiac symptoms and is not taking any cardiac medications. She smoked approximately one pack of cigarettes a day for less than 2 years when she was "in her teens" but has not had any tobacco products since that time.

Pancreatic cancer was diagnosed in the patient's father at age 49 years, and breast cancer was diagnosed in her aunt on her father's side at age 67 years. Her paternal grandmother is reported to have died in her 60s after diagnosis of a "cancer in her stomach." No further information is available regarding either the actual diagnosis or the medical care provided to this individual.

To the best of the patient's knowledge, her mother's side of the family and her two brothers have no history of cancer. She has no sisters. Her mother is in her 80s and has mild dementia. The patient is not aware of any member of her family having undergone genetic testing.

Physical Examination and Workup

The patient appears well and is in no acute distress. The patient is afebrile, with a blood pressure of 135/85 mm Hg, a respiratory rate of 16 breaths/min, and a pulse of 72 beats/min. Her weight is 148 lb (67 kg), and she has no reported recent weight loss.

Examination of the skin reveals no suspicious lesions. Scars from the previous removal of the basal cell carcinomas are noted, but no evidence suggests recurrence.

Results of the head and neck examination are unremarkable; specifically, no abnormal cervical lymphadenopathy is detected. The cardiac and chest examination results are normal. The lungs are clear to percussion and auscultation. The breast examination reveals no abnormal masses. The right axilla is unremarkable; however, a single 3 × 2 cm, nontender, firm, movable but partially fixed mass is noted in the left axilla.

The abdomen appears normal, with no ascites or enlargement of the liver. The pelvic examination reveals evidence of previous surgery and local radiation but no signs of recurrence of cervical cancer. The lymph nodes appear normal, except for the findings noted above. Results of the neurologic examination are unremarkable.

Complete blood cell count, serum electrolyte levels, renal function tests, and urinalysis are all normal. Liver function tests are normal except for a mildly elevated serum alkaline phosphatase level. The fecal occult blood test result is negative.

Chest radiography reveals a suspicious small left-sided pleural effusion. No other abnormalities are observed, and no prior chest radiographs are available to compare with the current findings.

Chest CT confirms the presence of a possible small pleural effusion, with no other abnormalities noted. The radiologist suggests it will not be possible to obtain fluid safely through an interventional procedure, owing to the limited (if any) amount of fluid present. Furthermore, the radiologist recommends PET/CT to look for other evidence of metastatic cancer in the lungs or elsewhere.

Bilateral mammograms reveal no suspicious abnormalities, and the results are unchanged from a previous examination 11 months earlier. Figure 1 shows a similar bilateral mammogram in another patient. Breast MRI shows no evidence of cancer. Figure 2 shows similar breast MRI findings in another patient.

CT of the abdomen and pelvis reveals no changes compared with a scan obtained 2 years earlier for follow-up of the previous diagnosis of cervical cancer. Specifically, no evidence suggests ascites or any pelvic masses.

An incisional biopsy sample is obtained from the left axillary mass. Light microscopy reveals a moderately well-differentiated adenocarcinoma. Immunostaining shows the cancer to be cytokeratin (CK) 7 positive and CK 20 negative (CK 7+/CK 20-, thyroid transcription factor 1 (TTF-1) negative, thyroglobulin negative, napsin A negative, and mammaglobin positive. The tumor is estrogen receptor positive (2% staining), progesterone receptor negative, and human epidermal growth factor receptor 2 (HER2) negative.

[polldaddy:10837180]

Discussion

The correct answer: Breast.

This case is a classic example of cancer of unknown primary site or origin (CUP). CUP represents approximately 5% of cancers diagnosed in the United States (50,000 to 60,000 cases each year), with various series reporting that the site of origin is not diagnosed in between 2% and 6% of all cancer cases.^[1] Worldwide, the incidence of CUP is even higher, resulting from the limited availability of sophisticated (and expensive) diagnostic technology in many regions. The median age at diagnosis of CUP is 60 years, and men and women are equally likely to be affected.

A cancer is considered a CUP if, after routine clinical assessment, physical and laboratory examination, standard imaging studies, and routine pathologic evaluation (biopsy or surgical removal of a metastatic mass lesion), a site of origin cannot be defined. With the availability of more sophisticated imaging technologies (eg, MRI), the overall percentage of cancers that are defined as a CUP has been reduced. However, even at autopsy, the site of origin of such cancer is often unable to be determined if the location was unknown before the patient's death.

Several theories have been proposed for why a metastatic lesion becomes clinically evident despite the site of origin of the cancer remaining obscure. These include (1) very slow growth of the primary cancer compared with that of the metastasis; (2) spontaneous regression of the primary cancer; (3) a prominent vascular component of the cancer, which enhances the rate of spread; and (4) unique molecular events associated with the cancer, which result in rapid progression and the growth of metastatic lesions.

Approximately 60% of CUPs are adenocarcinomas (well or moderately well differentiated); 25%-30% are poorly differentiated (including poorly differentiated adenocarcinomas); 5% are completely undifferentiated, with no defining histologic features; 5% are squamous cell cancers; and approximately 1% are carcinomas, with evidence of neuroendocrine differentiation.^[1]

Immunohistochemical staining of biopsy material can be helpful in narrowing the possible anatomical sites of origin. The results are particularly relevant in the selection of therapeutic strategies and in ensuring that a rare, potentially highly curable cancer is not missed (eg, lymphoma, germ cell tumor).^[2]

A critical initial test is examination of several CK subtypes that are more likely to be expressed in certain carcinomas than in others. For example, the CK 7+/CK 20- staining seen in this patient is characteristic of breast and lung cancers (among others), whereas CK 7+/CK 20+ staining would be expected in pancreatic, gastric, and urothelial cancers. A CK 7-/CK 20+ finding would be more suggestive of colon or mucinous ovarian cancer. Furthermore, approximately 70% of lung adenocarcinomas are TTF-1 positive and 60%-80% are napsin A positive. The negative findings in this patient's case make the diagnosis of metastatic lung cancer less likely.

Examination for the presence (or absence) of well-established biomarkers for breast cancer can potentially be helpful in suggesting the site of origin or in helping to define subsequent therapy. These markers include estrogen and progesterone receptors and HER2 overexpression. An additional biomarker, mammaglobin, has been reported to be expressed in 48% of breast cancers but is absent in cancers of the lung, gastrointestinal tract, ovary, and head and neck region.^[2]

Of note, mammaglobin was found to be expressed in this patient. Although only 2% of the cells were reported to stain for the estrogen receptor, this finding is still considered positive and supports breast cancer as the correct diagnosis.

Recognized relevant prognostic factors in CUP include baseline performance status, the number and location of metastatic lesions, and the response to cytotoxic chemotherapy.

Unfortunately, the overall prognosis associated with a diagnosis of CUP is poor, with median survival in various series reported to be less than 6 months. However, important exceptions to this outcome include women who present with an isolated metastatic axillary mass, as described in this case.

Previous reports of axillary adenopathy as the initial presentation of cancer in women revealed that the majority had evidence of cancer in the breast at the time of subsequent mastectomy.^[3,4] As a result, in the absence of other indications found during routine workup (eg, a single pulmonary lesion suggestive of a primary lung cancer, pathologic findings inconsistent with breast cancer), an isolated adenocarcinoma in the breast (with no evidence of metastatic cancer elsewhere) should be treated as either stage II or stage III breast cancer. Note that this recommendation specifically relates to female patients. If a male patient has CUP with an isolated axillary mass, it is generally assumed that the lung is the origin of the malignancy.

In a female patient with negative mammographic findings, breast MRI can be helpful. In one series, 28 of 40 women (70%) with evidence of cancer in the axilla and a normal mammogram were found to have a breast abnormality on MRI.^[5] Of note, and of considerable relevance to subsequent disease management, five of the 12 women with negative findings in this series underwent surgery, and in four of the cases no cancer was found. Although the number of participants in this series is limited, the absence of an MRI abnormality in the patient in this case can reasonably be considered in her future treatment plans.

Specifically, it might be suggested in this case that treatment include surgical removal of the axillary mass (if possible) followed by radiation to this area and the breast (rather than performing a mastectomy). Alternatively, treatment might begin with chemotherapy (a neoadjuvant approach) followed by surgery to remove any residual axillary mass and local/regional radiation or local/regional radiation alone. Adjuvant chemotherapy and/or hormonal therapy would then be administered.

The presence of a possible small pleural effusion is a concern because it potentially indicates more widespread metastatic disease, as does the mild elevation of the serum alkaline phosphatase level (eg, suggesting metastatic disease in bone or the liver). In the absence of other evidence of tumor spread, PET would not be unreasonable. A negative scan for evidence of metastatic disease would support a "curative" approach to the management of local disease in the axilla and presumably the breast, whereas a finding of other metastatic sites would lead to the conclusion that treatment should probably be delivered with more palliative intent.

The family history of cancer (father, paternal aunt with breast cancer, paternal grandmother with possible ovarian cancer) is intriguing and would suggest a role for genetic counseling and possibly genetic testing (eg, for BRCA mutation).

The patient in this case underwent PET. The only abnormality observed was in the left axilla. The axillary mass was subsequently resected. This was followed by curative radiation to both the axilla and left breast, adjuvant chemotherapy, and 5 years of hormonal therapy. The patient has showed no evidence of recurrence 2 years after completion of the hormonal treatment.

[polldaddy:10841207]

Discussion

The correct answer: Lung

The lungs are generally assumed to be the site of origin of the cancer in a male patient who has CUP with an isolated axillary mass. In contrast, the majority of women with axillary adenopathy as the initial presentation of cancer were found to have evidence of cancer in the breast at the time of subsequent mastectomy.^[3,4]

[polldaddy:10837187]

Discussion

The correct answer: MRI

Breast MRI can be helpful in a female patient with negative mammographic findings. In one series, MRI detected a breast abnormality in 28 of 40 women (70%) with evidence of cancer in the axilla and a normal mammogram.^[5]

Editor's Note:
The Case Challenge series includes difficult-to-diagnose conditions, some of which are not frequently encountered by most clinicians but are nonetheless important to accurately recognize. Test your diagnostic and treatment skills using the following patient scenario and corresponding questions. If you have a case that you would like to suggest for a future Case Challenge, please contact us .

Background

A 58-year-old woman seeks medical attention after she discovered a new mass in her left axilla during a routine monthly breast self-examination while showering. She has not noted any changes in either of her breasts. The mass in her left axilla is not tender, and she has not felt any other abnormal masses, including in her right axilla. She reports no other symptoms and specifically has no pain anywhere in her body. She also does not have shortness of breath, fever, night sweats, fatigue, rash, or abdominal discomfort or bloating.

Fifteen years earlier, the patient was diagnosed with high-grade, stage 1 cervical cancer and underwent surgery and chemoradiation. She has been closely monitored since that time with physical examinations and abdominal CT, with no evidence of recurrent disease. The patient has not had any other surgical procedure, except for removal of two basal cell carcinomas on her neck 4 years ago. She has had yearly routine mammograms for at least the past 15 years.

The patient has hypertension, which has been well controlled with the same medications for the past 10 years. She also has a 25-year history of type 2 diabetes mellitus, which is currently managed with diet alone. She had a "silent myocardial infarction" sometime within the past 5 years but has had no cardiac symptoms and is not taking any cardiac medications. She smoked approximately one pack of cigarettes a day for less than 2 years when she was "in her teens" but has not had any tobacco products since that time.

Pancreatic cancer was diagnosed in the patient's father at age 49 years, and breast cancer was diagnosed in her aunt on her father's side at age 67 years. Her paternal grandmother is reported to have died in her 60s after diagnosis of a "cancer in her stomach." No further information is available regarding either the actual diagnosis or the medical care provided to this individual.

To the best of the patient's knowledge, her mother's side of the family and her two brothers have no history of cancer. She has no sisters. Her mother is in her 80s and has mild dementia. The patient is not aware of any member of her family having undergone genetic testing.

Physical Examination and Workup

The patient appears well and is in no acute distress. The patient is afebrile, with a blood pressure of 135/85 mm Hg, a respiratory rate of 16 breaths/min, and a pulse of 72 beats/min. Her weight is 148 lb (67 kg), and she has no reported recent weight loss.

Examination of the skin reveals no suspicious lesions. Scars from the previous removal of the basal cell carcinomas are noted, but no evidence suggests recurrence.

Results of the head and neck examination are unremarkable; specifically, no abnormal cervical lymphadenopathy is detected. The cardiac and chest examination results are normal. The lungs are clear to percussion and auscultation. The breast examination reveals no abnormal masses. The right axilla is unremarkable; however, a single 3 × 2 cm, nontender, firm, movable but partially fixed mass is noted in the left axilla.

The abdomen appears normal, with no ascites or enlargement of the liver. The pelvic examination reveals evidence of previous surgery and local radiation but no signs of recurrence of cervical cancer. The lymph nodes appear normal, except for the findings noted above. Results of the neurologic examination are unremarkable.

Complete blood cell count, serum electrolyte levels, renal function tests, and urinalysis are all normal. Liver function tests are normal except for a mildly elevated serum alkaline phosphatase level. The fecal occult blood test result is negative.

Chest radiography reveals a suspicious small left-sided pleural effusion. No other abnormalities are observed, and no prior chest radiographs are available to compare with the current findings.

Chest CT confirms the presence of a possible small pleural effusion, with no other abnormalities noted. The radiologist suggests it will not be possible to obtain fluid safely through an interventional procedure, owing to the limited (if any) amount of fluid present. Furthermore, the radiologist recommends PET/CT to look for other evidence of metastatic cancer in the lungs or elsewhere.

Bilateral mammograms reveal no suspicious abnormalities, and the results are unchanged from a previous examination 11 months earlier. Figure 1 shows a similar bilateral mammogram in another patient. Breast MRI shows no evidence of cancer. Figure 2 shows similar breast MRI findings in another patient.

CT of the abdomen and pelvis reveals no changes compared with a scan obtained 2 years earlier for follow-up of the previous diagnosis of cervical cancer. Specifically, no evidence suggests ascites or any pelvic masses.

An incisional biopsy sample is obtained from the left axillary mass. Light microscopy reveals a moderately well-differentiated adenocarcinoma. Immunostaining shows the cancer to be cytokeratin (CK) 7 positive and CK 20 negative (CK 7+/CK 20-, thyroid transcription factor 1 (TTF-1) negative, thyroglobulin negative, napsin A negative, and mammaglobin positive. The tumor is estrogen receptor positive (2% staining), progesterone receptor negative, and human epidermal growth factor receptor 2 (HER2) negative.

[polldaddy:10837180]

Discussion

The correct answer: Breast.

This case is a classic example of cancer of unknown primary site or origin (CUP). CUP represents approximately 5% of cancers diagnosed in the United States (50,000 to 60,000 cases each year), with various series reporting that the site of origin is not diagnosed in between 2% and 6% of all cancer cases.^[1] Worldwide, the incidence of CUP is even higher, resulting from the limited availability of sophisticated (and expensive) diagnostic technology in many regions. The median age at diagnosis of CUP is 60 years, and men and women are equally likely to be affected.

A cancer is considered a CUP if, after routine clinical assessment, physical and laboratory examination, standard imaging studies, and routine pathologic evaluation (biopsy or surgical removal of a metastatic mass lesion), a site of origin cannot be defined. With the availability of more sophisticated imaging technologies (eg, MRI), the overall percentage of cancers that are defined as a CUP has been reduced. However, even at autopsy, the site of origin of such cancer is often unable to be determined if the location was unknown before the patient's death.

Several theories have been proposed for why a metastatic lesion becomes clinically evident despite the site of origin of the cancer remaining obscure. These include (1) very slow growth of the primary cancer compared with that of the metastasis; (2) spontaneous regression of the primary cancer; (3) a prominent vascular component of the cancer, which enhances the rate of spread; and (4) unique molecular events associated with the cancer, which result in rapid progression and the growth of metastatic lesions.

Approximately 60% of CUPs are adenocarcinomas (well or moderately well differentiated); 25%-30% are poorly differentiated (including poorly differentiated adenocarcinomas); 5% are completely undifferentiated, with no defining histologic features; 5% are squamous cell cancers; and approximately 1% are carcinomas, with evidence of neuroendocrine differentiation.^[1]

Immunohistochemical staining of biopsy material can be helpful in narrowing the possible anatomical sites of origin. The results are particularly relevant in the selection of therapeutic strategies and in ensuring that a rare, potentially highly curable cancer is not missed (eg, lymphoma, germ cell tumor).^[2]

A critical initial test is examination of several CK subtypes that are more likely to be expressed in certain carcinomas than in others. For example, the CK 7+/CK 20- staining seen in this patient is characteristic of breast and lung cancers (among others), whereas CK 7+/CK 20+ staining would be expected in pancreatic, gastric, and urothelial cancers. A CK 7-/CK 20+ finding would be more suggestive of colon or mucinous ovarian cancer. Furthermore, approximately 70% of lung adenocarcinomas are TTF-1 positive and 60%-80% are napsin A positive. The negative findings in this patient's case make the diagnosis of metastatic lung cancer less likely.

Examination for the presence (or absence) of well-established biomarkers for breast cancer can potentially be helpful in suggesting the site of origin or in helping to define subsequent therapy. These markers include estrogen and progesterone receptors and HER2 overexpression. An additional biomarker, mammaglobin, has been reported to be expressed in 48% of breast cancers but is absent in cancers of the lung, gastrointestinal tract, ovary, and head and neck region.^[2]

Of note, mammaglobin was found to be expressed in this patient. Although only 2% of the cells were reported to stain for the estrogen receptor, this finding is still considered positive and supports breast cancer as the correct diagnosis.

Recognized relevant prognostic factors in CUP include baseline performance status, the number and location of metastatic lesions, and the response to cytotoxic chemotherapy.

Unfortunately, the overall prognosis associated with a diagnosis of CUP is poor, with median survival in various series reported to be less than 6 months. However, important exceptions to this outcome include women who present with an isolated metastatic axillary mass, as described in this case.

Previous reports of axillary adenopathy as the initial presentation of cancer in women revealed that the majority had evidence of cancer in the breast at the time of subsequent mastectomy.^[3,4] As a result, in the absence of other indications found during routine workup (eg, a single pulmonary lesion suggestive of a primary lung cancer, pathologic findings inconsistent with breast cancer), an isolated adenocarcinoma in the breast (with no evidence of metastatic cancer elsewhere) should be treated as either stage II or stage III breast cancer. Note that this recommendation specifically relates to female patients. If a male patient has CUP with an isolated axillary mass, it is generally assumed that the lung is the origin of the malignancy.

In a female patient with negative mammographic findings, breast MRI can be helpful. In one series, 28 of 40 women (70%) with evidence of cancer in the axilla and a normal mammogram were found to have a breast abnormality on MRI.^[5] Of note, and of considerable relevance to subsequent disease management, five of the 12 women with negative findings in this series underwent surgery, and in four of the cases no cancer was found. Although the number of participants in this series is limited, the absence of an MRI abnormality in the patient in this case can reasonably be considered in her future treatment plans.

Specifically, it might be suggested in this case that treatment include surgical removal of the axillary mass (if possible) followed by radiation to this area and the breast (rather than performing a mastectomy). Alternatively, treatment might begin with chemotherapy (a neoadjuvant approach) followed by surgery to remove any residual axillary mass and local/regional radiation or local/regional radiation alone. Adjuvant chemotherapy and/or hormonal therapy would then be administered.

The presence of a possible small pleural effusion is a concern because it potentially indicates more widespread metastatic disease, as does the mild elevation of the serum alkaline phosphatase level (eg, suggesting metastatic disease in bone or the liver). In the absence of other evidence of tumor spread, PET would not be unreasonable. A negative scan for evidence of metastatic disease would support a "curative" approach to the management of local disease in the axilla and presumably the breast, whereas a finding of other metastatic sites would lead to the conclusion that treatment should probably be delivered with more palliative intent.

The family history of cancer (father, paternal aunt with breast cancer, paternal grandmother with possible ovarian cancer) is intriguing and would suggest a role for genetic counseling and possibly genetic testing (eg, for BRCA mutation).

The patient in this case underwent PET. The only abnormality observed was in the left axilla. The axillary mass was subsequently resected. This was followed by curative radiation to both the axilla and left breast, adjuvant chemotherapy, and 5 years of hormonal therapy. The patient has showed no evidence of recurrence 2 years after completion of the hormonal treatment.

[polldaddy:10841207]

Discussion

The correct answer: Lung

The lungs are generally assumed to be the site of origin of the cancer in a male patient who has CUP with an isolated axillary mass. In contrast, the majority of women with axillary adenopathy as the initial presentation of cancer were found to have evidence of cancer in the breast at the time of subsequent mastectomy.^[3,4]

[polldaddy:10837187]

Discussion

The correct answer: MRI

Breast MRI can be helpful in a female patient with negative mammographic findings. In one series, MRI detected a breast abnormality in 28 of 40 women (70%) with evidence of cancer in the axilla and a normal mammogram.^[5]

Combining plasma cell-free DNA (cfDNA) assessment with MRI improves prediction of pathological complete response to neoadjuvant chemotherapy in locally advanced breast cancer, according to researchers.

When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.

“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.

Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).

Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.

Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.

He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.

When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.

The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.

A total of 11 patients had pathological complete responses to neoadjuvant therapy.

The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.

The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.

The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.

Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.

The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.

[email protected]

Combining plasma cell-free DNA (cfDNA) assessment with MRI improves prediction of pathological complete response to neoadjuvant chemotherapy in locally advanced breast cancer, according to researchers.

When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.

“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.

Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).

Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.

Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.

He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.

When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.

The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.

A total of 11 patients had pathological complete responses to neoadjuvant therapy.

The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.

The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.

The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.

Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.

The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.

[email protected]

Combining plasma cell-free DNA (cfDNA) assessment with MRI improves prediction of pathological complete response to neoadjuvant chemotherapy in locally advanced breast cancer, according to researchers.

When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.

“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.

Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).

Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.

Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.

He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.

When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.

The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.

A total of 11 patients had pathological complete responses to neoadjuvant therapy.

The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.

The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.

The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.

Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.

The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.

[email protected]

Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.

“TNBC is incredibly heterogeneous, which makes it challenging to treat,” said Rita Nanda, MD, director of the breast oncology program and associate professor of medicine at the University of Chicago. “We have subsets of TNBC that don’t respond to currently available therapies and, as of yet, have no identifiable therapeutic targets.”

Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy – typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.

When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).

Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.

“For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential,” said Kelly McCann, MD, PhD, a hematologist/oncologist in the department of medicine at the University of California, Los Angeles. “Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets.”
 

A targeted strategy

The Food and Drug Administration’s approval of sacituzumab govitecan, the first antibody-drug conjugate to treat metastatic TNBC, marked an important addition to the TNBC drug armamentarium. “Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease,” Dr. Nanda said.

Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells.

In the phase 1/2 ASCENT trial, the median progression-free survival was 5.5 months and overall survival was 13.0 months in 108 patients with metastatic TNBC who had received at least two therapies prior to sacituzumab govitecan.

A subsequent phase 3 trial showed progression-free survival of 5.6 months with sacituzumab govitecan and 1.7 months with physician’s choice of chemotherapy. The median overall survival was 12.1 months and 6.7 months, respectively.

But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given sacituzumab govitecan, compared with chemotherapy alone.

In other words, “patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit,” Dr. Nanda said.

Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.

Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, “trastuzumab deruxtecan represents potential in treating HER2-low TNBC,” said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

Early results from a phase 1b study showed that trastuzumab deruxtecan produced a response rate of 37% in patients with HER2-low breast cancer.

Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
 

Immunotherapy advances

Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing PD-L1. Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.

Yet, data on which patients will benefit are not so clear-cut. “These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker,” Dr. Yuan said.

Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). As with the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs. 17.6 months with nab-paclitaxel alone.

However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs. 6 months, respectively, and overall survival was 28.3 months vs. 22.1 months.

“It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel,” Dr. Nanda said. “Perhaps the negative finding has to do with how the trial was conducted, or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit.”
 

Continued efforts to understand TNBC

Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.

On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received olaparib exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.

When considering signaling pathways, the PI3K/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3K and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival – 19.1 months vs. 12.6 with placebo plus paclitaxel – with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.

But there’s more to learn about treating metastatic TNBC. “Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go,” said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York. “Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail.”

Dr. Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. “For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available,” she said.

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

Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.

“TNBC is incredibly heterogeneous, which makes it challenging to treat,” said Rita Nanda, MD, director of the breast oncology program and associate professor of medicine at the University of Chicago. “We have subsets of TNBC that don’t respond to currently available therapies and, as of yet, have no identifiable therapeutic targets.”

Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy – typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.

When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).

Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.

“For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential,” said Kelly McCann, MD, PhD, a hematologist/oncologist in the department of medicine at the University of California, Los Angeles. “Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets.”
 

A targeted strategy

The Food and Drug Administration’s approval of sacituzumab govitecan, the first antibody-drug conjugate to treat metastatic TNBC, marked an important addition to the TNBC drug armamentarium. “Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease,” Dr. Nanda said.

Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells.

In the phase 1/2 ASCENT trial, the median progression-free survival was 5.5 months and overall survival was 13.0 months in 108 patients with metastatic TNBC who had received at least two therapies prior to sacituzumab govitecan.

A subsequent phase 3 trial showed progression-free survival of 5.6 months with sacituzumab govitecan and 1.7 months with physician’s choice of chemotherapy. The median overall survival was 12.1 months and 6.7 months, respectively.

But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given sacituzumab govitecan, compared with chemotherapy alone.

In other words, “patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit,” Dr. Nanda said.

Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.

Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, “trastuzumab deruxtecan represents potential in treating HER2-low TNBC,” said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

Early results from a phase 1b study showed that trastuzumab deruxtecan produced a response rate of 37% in patients with HER2-low breast cancer.

Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
 

Immunotherapy advances

Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing PD-L1. Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.

Yet, data on which patients will benefit are not so clear-cut. “These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker,” Dr. Yuan said.

Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). As with the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs. 17.6 months with nab-paclitaxel alone.

However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs. 6 months, respectively, and overall survival was 28.3 months vs. 22.1 months.

“It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel,” Dr. Nanda said. “Perhaps the negative finding has to do with how the trial was conducted, or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit.”
 

Continued efforts to understand TNBC

Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.

On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received olaparib exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.

When considering signaling pathways, the PI3K/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3K and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival – 19.1 months vs. 12.6 with placebo plus paclitaxel – with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.

But there’s more to learn about treating metastatic TNBC. “Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go,” said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York. “Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail.”

Dr. Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. “For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available,” she said.

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

Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.

“TNBC is incredibly heterogeneous, which makes it challenging to treat,” said Rita Nanda, MD, director of the breast oncology program and associate professor of medicine at the University of Chicago. “We have subsets of TNBC that don’t respond to currently available therapies and, as of yet, have no identifiable therapeutic targets.”

Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy – typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.

When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).

Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.

“For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential,” said Kelly McCann, MD, PhD, a hematologist/oncologist in the department of medicine at the University of California, Los Angeles. “Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets.”
 

A targeted strategy

The Food and Drug Administration’s approval of sacituzumab govitecan, the first antibody-drug conjugate to treat metastatic TNBC, marked an important addition to the TNBC drug armamentarium. “Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease,” Dr. Nanda said.

Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells.

In the phase 1/2 ASCENT trial, the median progression-free survival was 5.5 months and overall survival was 13.0 months in 108 patients with metastatic TNBC who had received at least two therapies prior to sacituzumab govitecan.

A subsequent phase 3 trial showed progression-free survival of 5.6 months with sacituzumab govitecan and 1.7 months with physician’s choice of chemotherapy. The median overall survival was 12.1 months and 6.7 months, respectively.

But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given sacituzumab govitecan, compared with chemotherapy alone.

In other words, “patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit,” Dr. Nanda said.

Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.

Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, “trastuzumab deruxtecan represents potential in treating HER2-low TNBC,” said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

Early results from a phase 1b study showed that trastuzumab deruxtecan produced a response rate of 37% in patients with HER2-low breast cancer.

Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
 

Immunotherapy advances

Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing PD-L1. Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.

Yet, data on which patients will benefit are not so clear-cut. “These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker,” Dr. Yuan said.

Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). As with the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs. 17.6 months with nab-paclitaxel alone.

However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs. 6 months, respectively, and overall survival was 28.3 months vs. 22.1 months.

“It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel,” Dr. Nanda said. “Perhaps the negative finding has to do with how the trial was conducted, or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit.”
 

Continued efforts to understand TNBC

Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.

On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received olaparib exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.

When considering signaling pathways, the PI3K/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3K and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival – 19.1 months vs. 12.6 with placebo plus paclitaxel – with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.

But there’s more to learn about treating metastatic TNBC. “Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go,” said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York. “Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail.”

Dr. Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. “For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available,” she said.

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

Hormone-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is not curable, but it can have an indolent course that can be controlled for many years with effective treatment.

For postmenopausal women with HR+ breast cancers, the standard of care is endocrine therapy such as exemestane, anastrozole, tamoxifen, or fulvestrant.

In the first-line setting, endocrine therapy may be given alone. In advanced or metastatic disease, endocrine therapy may be combined with one of several newer treatment options, most notably CDK4/6 inhibitors.

Dr Peter Kaufman, of the University of Vermont Cancer Center, takes us through the latest evidence underlining the benefit of CDK4/6 inhibitors in terms of both progression-free and overall survival.

He also outlines the key research questions relating to the use of these drugs, including whether biomarkers can be identified to allow better patient selection.

Finally, Dr Kaufman discusses other therapeutic options for HR+/HER2- advanced breast cancer, such as CDK4/6 inhibitors combined with alpelisib or everolimus, and the emerging use of selective estrogen receptor degraders.

--

Professor, Department of Medicine, Division of Hematology and Oncology, The Robert Larner, M.D. College of Medicine, University of Vermont

Attending Physician, Department of Medicine, Division of Hematology and Oncology, University of Vermont Cancer Center, Burlington, Vermont.

Peter A. Kaufman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly and Company

Received research grant from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi

Received income in an amount equal to or greater than $250 from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi; Amgen; Puma

Hormone-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is not curable, but it can have an indolent course that can be controlled for many years with effective treatment.

For postmenopausal women with HR+ breast cancers, the standard of care is endocrine therapy such as exemestane, anastrozole, tamoxifen, or fulvestrant.

In the first-line setting, endocrine therapy may be given alone. In advanced or metastatic disease, endocrine therapy may be combined with one of several newer treatment options, most notably CDK4/6 inhibitors.

Dr Peter Kaufman, of the University of Vermont Cancer Center, takes us through the latest evidence underlining the benefit of CDK4/6 inhibitors in terms of both progression-free and overall survival.

He also outlines the key research questions relating to the use of these drugs, including whether biomarkers can be identified to allow better patient selection.

Finally, Dr Kaufman discusses other therapeutic options for HR+/HER2- advanced breast cancer, such as CDK4/6 inhibitors combined with alpelisib or everolimus, and the emerging use of selective estrogen receptor degraders.

--

Professor, Department of Medicine, Division of Hematology and Oncology, The Robert Larner, M.D. College of Medicine, University of Vermont

Attending Physician, Department of Medicine, Division of Hematology and Oncology, University of Vermont Cancer Center, Burlington, Vermont.

Peter A. Kaufman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly and Company

Received research grant from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi

Received income in an amount equal to or greater than $250 from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi; Amgen; Puma

Hormone-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is not curable, but it can have an indolent course that can be controlled for many years with effective treatment.

For postmenopausal women with HR+ breast cancers, the standard of care is endocrine therapy such as exemestane, anastrozole, tamoxifen, or fulvestrant.

In the first-line setting, endocrine therapy may be given alone. In advanced or metastatic disease, endocrine therapy may be combined with one of several newer treatment options, most notably CDK4/6 inhibitors.

Dr Peter Kaufman, of the University of Vermont Cancer Center, takes us through the latest evidence underlining the benefit of CDK4/6 inhibitors in terms of both progression-free and overall survival.

He also outlines the key research questions relating to the use of these drugs, including whether biomarkers can be identified to allow better patient selection.

Finally, Dr Kaufman discusses other therapeutic options for HR+/HER2- advanced breast cancer, such as CDK4/6 inhibitors combined with alpelisib or everolimus, and the emerging use of selective estrogen receptor degraders.

--

Professor, Department of Medicine, Division of Hematology and Oncology, The Robert Larner, M.D. College of Medicine, University of Vermont

Attending Physician, Department of Medicine, Division of Hematology and Oncology, University of Vermont Cancer Center, Burlington, Vermont.

Peter A. Kaufman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly and Company

Received research grant from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi

Received income in an amount equal to or greater than $250 from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi; Amgen; Puma

Patients with metastatic breast cancer (MBC) face an elevated risk of severe illness or dying from COVID-19. Given the slow rollout of the Moderna and Pfizer COVID vaccines and new, more infectious viral variants circulating in the United States, oncologists will face a challenging balancing act for the foreseeable future: sustaining patients› MBC care while safeguarding them from COVID. The scale leans heavily toward continuing treatment, experts say.

“If we stop treatment for metastatic breast cancer, death will occur quickly,” Fatima F. Cardoso, MD, director of the breast unit at Champalimaud Clinical Centre in Lisbon, Portugal, stated this past August in a Medscape perspective.

Joanne Mortimer, MD, director of Women’s Cancer Programs at City of Hope, a comprehensive cancer center near Los Angeles, expressed a similar sentiment. “Having MBC is worse than getting COVID,” she told Medscape. “We can’t stop treating patients with MBC because of concerns of exposure.”

But maintaining treatment does not mean business as usual. Oncologists have had to modify their pre-pandemic practices to some degree, and that degree largely depends on local COVID conditions.

“Weighing the risk of treatment with the risk of contracting the virus means that many places have carried on treating metastatic breast cancer in a more thoughtful, careful way,” said Jill Dietz, MD, president of the American Society of Breast Surgeons. “That means focusing on high-value treatments for patients with the goal of maximizing their outcomes and quality of life while limiting in-person visits and potentially unnecessary elements of care.”

To guide this more careful approach, Dr. Dietz and colleagues from the recently formed COVID-19 Pandemic Breast Cancer Consortium published recommendations in April 2020 to account for different disease types and severities. These recommendations align closely with those from Cardoso and colleagues in Europe, also published last April.

Although issued early in the pandemic when there was greater uncertainty about viral transmission, adverse outcomes, and treatment for COVID-19, these recommendations still hold almost a year later.

“The framework has proven to be timeless in that it can help institutions where they are in the pandemic,” Dr. Dietz said.

The recommendations at play

For MBC, in particular, Dr. Dietz and colleagues focused on patients who need systemic care but whose treatment can be modified to keep them home more. The modifications include prescribing oral agents such as capecitabine, vinorelbine, and cyclophosphamide to minimize visits to the hospital or infusion suite.

To limit adverse events associated with these oral drugs, Dr. Dietz and colleagues also recommended reducing the dose when possible. For instance, research shows that lowering the dose of the CDK4/6 inhibitor palbociclib in patients with HR+/HER2-negative MBC does not diminish efficacy.

When oral agents are not an option, Dr. Dietz and colleagues suggested stretching out the intervals for chemotherapy infusions or injections. Data show that trastuzumab and pertuzumab injections for metastatic HER2-positive tumors «may reasonably be administered at longer intervals,» such as 4 weeks instead of 3 weeks.

The extent to which oncologists have applied these recommendations hinges on two factors: the local severity of COVID-19 cases and institution-specific policies.

For some oncologists, the pandemic has largely left treatment decisions untouched. “COVID-19 has only minimally impacted my practice,” said Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

Dr. Nanda recalled her concerns in the early days of the pandemic. As the nation watched COVID cases surge across New York City, Chicagoans prepared for the worst, fashioning the McCormick Place Convention Center into a field hospital for COVID patients.

“But fortunately, we were never overwhelmed at the University of Chicago and never needed to use the convention center,” Dr. Nanda said. “We did not have to alter or limit the type of therapy patients with MBC could receive.”

The main changes described by Dr. Nanda at the University of Chicago have centered around limiting the flow of traffic within the infusion suite or hospital by implementing prescreening checks to catch patients with COVID symptoms, keeping waiting rooms empty and infusion centers socially distanced, and having patients come in for appointments solo. The university’s home phlebotomy service also came in handy. Implemented before the pandemic, this service allowed patients with MBC to get their labs done at home before coming in for treatment.

“Overall, with social distancing, mask wearing, and limiting who comes in to the clinic, we have been able to keep patients and staff safe without altering treatment-specific decisions,” Dr. Nanda said.

Streamlining the foot traffic in the cancer center also worked well for Lisa A. Carey, MD, chief of the Division of Hematology/Oncology and deputy director of clinical sciences at University of North Carolina-Chapel Hill. “The truth is, oncological principles of care are still in place,” said Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research. “COVID hasn’t altered those; it has only thrown a little wrench in how we deliver that care.”

Kelly McCann, MD, PhD, a hematologist/oncologist in the Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, has had to walk a tighter rope to protect her patients with MBC, as COVID cases began to soar in LA county last fall.

To keep patients with MBC home more, Dr. McCann said many chose oral cytotoxic chemotherapies over infusional therapies. Some patients with HER2-positive MBC, for instance, opted for the oral combination neratinib + capecitabine over a trastuzumab-deruxtecan infusion, and others with triple-negative tumors chose capecitabine over a taxane.

At City of Hope, Mortimer has had a different experience of LA county’s COVID surge. Because the center only treats patients with cancer, “we have not had huge numbers of patients with COVID or had to significantly modify our practice outside of screening patients who come in and doing fewer scans compared to pre-COVID,” she said. With these precautions, “we have had no internal transmission of COVID within our institution.”

Still, patients with MBC have gotten COVID, and treating both illnesses does complicate decision-making. In some cases, Mortimer has postponed cancer treatment for patients who can delay for a few weeks while they recover from COVID. But patients who need to continue MBC treatment receive care in a separate unit, and Mortimer considers prescribing Eli Lilly’s recently approved antibody therapy bamlanivimab to treat COVID symptoms. “For each situation, we can always page our infectious disease experts to address any concerns or questions,” Dr. Mortimer said.

The MBC and COVID toll

The biggest hurdle for patients with MBC has been less about treatment decisions and more about handling the psychological toll of the pandemic, according to Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai in New York City.

“These are my personal observations, but I’ve seen how much more stressful it is to have metastatic breast cancer during the pandemic,” said Dr. Shapiro, who worries that fear of COVID may fuel or exacerbate patients’ depression and anxiety. “Patients can’t have family and friends by their side during infusions or appointments, and many feel isolated because of the risk of exposure.”

Because most patients with MBC still need in-person care such as exams, blood draws, or chemotherapy infusions, Dr. McCann has found that many of her patients “are afraid to come to a medical center and have been delaying appointments, imaging, and procedures.”

The psychological toll of treating breast cancer during the pandemic has touched oncologists as well. A recent survey found that burnout scores were significantly higher among physicians whose patients experienced delays in care, including chemotherapy or specialty consultations.

Getting patients vaccinated will improve protection and hopefully lessen fears surrounding COVID infection and transmission. Preliminary recommendations from the National Comprehensive Cancer Network›s COVID-19 Vaccination Advisory Committee state that patients with cancer «should be prioritized for vaccination.»

Dr. McCann agreed. “I’ve recommended COVID-19 vaccination to all of my patients with MBC,” she said. But because a lot of these therapies suppress the immune system to some degree, “I’ll recommend a period of time for vaccination in which the immune system is expected to have recovered, such as in the days prior to a dose of chemotherapy.”

Overall, according to Dr. Carey, institutional responses to treating MBC during the pandemic have been very similar: The key has been that “no one is keeping secrets,” she said. “Our global oncology community is sharing and adopting best practices. Our focus has been doing right by our patients.”

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

Patients with metastatic breast cancer (MBC) face an elevated risk of severe illness or dying from COVID-19. Given the slow rollout of the Moderna and Pfizer COVID vaccines and new, more infectious viral variants circulating in the United States, oncologists will face a challenging balancing act for the foreseeable future: sustaining patients› MBC care while safeguarding them from COVID. The scale leans heavily toward continuing treatment, experts say.

“If we stop treatment for metastatic breast cancer, death will occur quickly,” Fatima F. Cardoso, MD, director of the breast unit at Champalimaud Clinical Centre in Lisbon, Portugal, stated this past August in a Medscape perspective.

Joanne Mortimer, MD, director of Women’s Cancer Programs at City of Hope, a comprehensive cancer center near Los Angeles, expressed a similar sentiment. “Having MBC is worse than getting COVID,” she told Medscape. “We can’t stop treating patients with MBC because of concerns of exposure.”

But maintaining treatment does not mean business as usual. Oncologists have had to modify their pre-pandemic practices to some degree, and that degree largely depends on local COVID conditions.

“Weighing the risk of treatment with the risk of contracting the virus means that many places have carried on treating metastatic breast cancer in a more thoughtful, careful way,” said Jill Dietz, MD, president of the American Society of Breast Surgeons. “That means focusing on high-value treatments for patients with the goal of maximizing their outcomes and quality of life while limiting in-person visits and potentially unnecessary elements of care.”

To guide this more careful approach, Dr. Dietz and colleagues from the recently formed COVID-19 Pandemic Breast Cancer Consortium published recommendations in April 2020 to account for different disease types and severities. These recommendations align closely with those from Cardoso and colleagues in Europe, also published last April.

Although issued early in the pandemic when there was greater uncertainty about viral transmission, adverse outcomes, and treatment for COVID-19, these recommendations still hold almost a year later.

“The framework has proven to be timeless in that it can help institutions where they are in the pandemic,” Dr. Dietz said.

The recommendations at play

For MBC, in particular, Dr. Dietz and colleagues focused on patients who need systemic care but whose treatment can be modified to keep them home more. The modifications include prescribing oral agents such as capecitabine, vinorelbine, and cyclophosphamide to minimize visits to the hospital or infusion suite.

To limit adverse events associated with these oral drugs, Dr. Dietz and colleagues also recommended reducing the dose when possible. For instance, research shows that lowering the dose of the CDK4/6 inhibitor palbociclib in patients with HR+/HER2-negative MBC does not diminish efficacy.

When oral agents are not an option, Dr. Dietz and colleagues suggested stretching out the intervals for chemotherapy infusions or injections. Data show that trastuzumab and pertuzumab injections for metastatic HER2-positive tumors «may reasonably be administered at longer intervals,» such as 4 weeks instead of 3 weeks.

The extent to which oncologists have applied these recommendations hinges on two factors: the local severity of COVID-19 cases and institution-specific policies.

For some oncologists, the pandemic has largely left treatment decisions untouched. “COVID-19 has only minimally impacted my practice,” said Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

Dr. Nanda recalled her concerns in the early days of the pandemic. As the nation watched COVID cases surge across New York City, Chicagoans prepared for the worst, fashioning the McCormick Place Convention Center into a field hospital for COVID patients.

“But fortunately, we were never overwhelmed at the University of Chicago and never needed to use the convention center,” Dr. Nanda said. “We did not have to alter or limit the type of therapy patients with MBC could receive.”

The main changes described by Dr. Nanda at the University of Chicago have centered around limiting the flow of traffic within the infusion suite or hospital by implementing prescreening checks to catch patients with COVID symptoms, keeping waiting rooms empty and infusion centers socially distanced, and having patients come in for appointments solo. The university’s home phlebotomy service also came in handy. Implemented before the pandemic, this service allowed patients with MBC to get their labs done at home before coming in for treatment.

“Overall, with social distancing, mask wearing, and limiting who comes in to the clinic, we have been able to keep patients and staff safe without altering treatment-specific decisions,” Dr. Nanda said.

Streamlining the foot traffic in the cancer center also worked well for Lisa A. Carey, MD, chief of the Division of Hematology/Oncology and deputy director of clinical sciences at University of North Carolina-Chapel Hill. “The truth is, oncological principles of care are still in place,” said Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research. “COVID hasn’t altered those; it has only thrown a little wrench in how we deliver that care.”

Kelly McCann, MD, PhD, a hematologist/oncologist in the Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, has had to walk a tighter rope to protect her patients with MBC, as COVID cases began to soar in LA county last fall.

To keep patients with MBC home more, Dr. McCann said many chose oral cytotoxic chemotherapies over infusional therapies. Some patients with HER2-positive MBC, for instance, opted for the oral combination neratinib + capecitabine over a trastuzumab-deruxtecan infusion, and others with triple-negative tumors chose capecitabine over a taxane.

At City of Hope, Mortimer has had a different experience of LA county’s COVID surge. Because the center only treats patients with cancer, “we have not had huge numbers of patients with COVID or had to significantly modify our practice outside of screening patients who come in and doing fewer scans compared to pre-COVID,” she said. With these precautions, “we have had no internal transmission of COVID within our institution.”

Still, patients with MBC have gotten COVID, and treating both illnesses does complicate decision-making. In some cases, Mortimer has postponed cancer treatment for patients who can delay for a few weeks while they recover from COVID. But patients who need to continue MBC treatment receive care in a separate unit, and Mortimer considers prescribing Eli Lilly’s recently approved antibody therapy bamlanivimab to treat COVID symptoms. “For each situation, we can always page our infectious disease experts to address any concerns or questions,” Dr. Mortimer said.

The MBC and COVID toll

The biggest hurdle for patients with MBC has been less about treatment decisions and more about handling the psychological toll of the pandemic, according to Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai in New York City.

“These are my personal observations, but I’ve seen how much more stressful it is to have metastatic breast cancer during the pandemic,” said Dr. Shapiro, who worries that fear of COVID may fuel or exacerbate patients’ depression and anxiety. “Patients can’t have family and friends by their side during infusions or appointments, and many feel isolated because of the risk of exposure.”

Because most patients with MBC still need in-person care such as exams, blood draws, or chemotherapy infusions, Dr. McCann has found that many of her patients “are afraid to come to a medical center and have been delaying appointments, imaging, and procedures.”

The psychological toll of treating breast cancer during the pandemic has touched oncologists as well. A recent survey found that burnout scores were significantly higher among physicians whose patients experienced delays in care, including chemotherapy or specialty consultations.

Getting patients vaccinated will improve protection and hopefully lessen fears surrounding COVID infection and transmission. Preliminary recommendations from the National Comprehensive Cancer Network›s COVID-19 Vaccination Advisory Committee state that patients with cancer «should be prioritized for vaccination.»

Dr. McCann agreed. “I’ve recommended COVID-19 vaccination to all of my patients with MBC,” she said. But because a lot of these therapies suppress the immune system to some degree, “I’ll recommend a period of time for vaccination in which the immune system is expected to have recovered, such as in the days prior to a dose of chemotherapy.”

Overall, according to Dr. Carey, institutional responses to treating MBC during the pandemic have been very similar: The key has been that “no one is keeping secrets,” she said. “Our global oncology community is sharing and adopting best practices. Our focus has been doing right by our patients.”

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

Patients with metastatic breast cancer (MBC) face an elevated risk of severe illness or dying from COVID-19. Given the slow rollout of the Moderna and Pfizer COVID vaccines and new, more infectious viral variants circulating in the United States, oncologists will face a challenging balancing act for the foreseeable future: sustaining patients› MBC care while safeguarding them from COVID. The scale leans heavily toward continuing treatment, experts say.

“If we stop treatment for metastatic breast cancer, death will occur quickly,” Fatima F. Cardoso, MD, director of the breast unit at Champalimaud Clinical Centre in Lisbon, Portugal, stated this past August in a Medscape perspective.

Joanne Mortimer, MD, director of Women’s Cancer Programs at City of Hope, a comprehensive cancer center near Los Angeles, expressed a similar sentiment. “Having MBC is worse than getting COVID,” she told Medscape. “We can’t stop treating patients with MBC because of concerns of exposure.”

But maintaining treatment does not mean business as usual. Oncologists have had to modify their pre-pandemic practices to some degree, and that degree largely depends on local COVID conditions.

“Weighing the risk of treatment with the risk of contracting the virus means that many places have carried on treating metastatic breast cancer in a more thoughtful, careful way,” said Jill Dietz, MD, president of the American Society of Breast Surgeons. “That means focusing on high-value treatments for patients with the goal of maximizing their outcomes and quality of life while limiting in-person visits and potentially unnecessary elements of care.”

To guide this more careful approach, Dr. Dietz and colleagues from the recently formed COVID-19 Pandemic Breast Cancer Consortium published recommendations in April 2020 to account for different disease types and severities. These recommendations align closely with those from Cardoso and colleagues in Europe, also published last April.

Although issued early in the pandemic when there was greater uncertainty about viral transmission, adverse outcomes, and treatment for COVID-19, these recommendations still hold almost a year later.

“The framework has proven to be timeless in that it can help institutions where they are in the pandemic,” Dr. Dietz said.

The recommendations at play

For MBC, in particular, Dr. Dietz and colleagues focused on patients who need systemic care but whose treatment can be modified to keep them home more. The modifications include prescribing oral agents such as capecitabine, vinorelbine, and cyclophosphamide to minimize visits to the hospital or infusion suite.

To limit adverse events associated with these oral drugs, Dr. Dietz and colleagues also recommended reducing the dose when possible. For instance, research shows that lowering the dose of the CDK4/6 inhibitor palbociclib in patients with HR+/HER2-negative MBC does not diminish efficacy.

When oral agents are not an option, Dr. Dietz and colleagues suggested stretching out the intervals for chemotherapy infusions or injections. Data show that trastuzumab and pertuzumab injections for metastatic HER2-positive tumors «may reasonably be administered at longer intervals,» such as 4 weeks instead of 3 weeks.

The extent to which oncologists have applied these recommendations hinges on two factors: the local severity of COVID-19 cases and institution-specific policies.

For some oncologists, the pandemic has largely left treatment decisions untouched. “COVID-19 has only minimally impacted my practice,” said Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

Dr. Nanda recalled her concerns in the early days of the pandemic. As the nation watched COVID cases surge across New York City, Chicagoans prepared for the worst, fashioning the McCormick Place Convention Center into a field hospital for COVID patients.

“But fortunately, we were never overwhelmed at the University of Chicago and never needed to use the convention center,” Dr. Nanda said. “We did not have to alter or limit the type of therapy patients with MBC could receive.”

The main changes described by Dr. Nanda at the University of Chicago have centered around limiting the flow of traffic within the infusion suite or hospital by implementing prescreening checks to catch patients with COVID symptoms, keeping waiting rooms empty and infusion centers socially distanced, and having patients come in for appointments solo. The university’s home phlebotomy service also came in handy. Implemented before the pandemic, this service allowed patients with MBC to get their labs done at home before coming in for treatment.

“Overall, with social distancing, mask wearing, and limiting who comes in to the clinic, we have been able to keep patients and staff safe without altering treatment-specific decisions,” Dr. Nanda said.

Streamlining the foot traffic in the cancer center also worked well for Lisa A. Carey, MD, chief of the Division of Hematology/Oncology and deputy director of clinical sciences at University of North Carolina-Chapel Hill. “The truth is, oncological principles of care are still in place,” said Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research. “COVID hasn’t altered those; it has only thrown a little wrench in how we deliver that care.”

Kelly McCann, MD, PhD, a hematologist/oncologist in the Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, has had to walk a tighter rope to protect her patients with MBC, as COVID cases began to soar in LA county last fall.

To keep patients with MBC home more, Dr. McCann said many chose oral cytotoxic chemotherapies over infusional therapies. Some patients with HER2-positive MBC, for instance, opted for the oral combination neratinib + capecitabine over a trastuzumab-deruxtecan infusion, and others with triple-negative tumors chose capecitabine over a taxane.

At City of Hope, Mortimer has had a different experience of LA county’s COVID surge. Because the center only treats patients with cancer, “we have not had huge numbers of patients with COVID or had to significantly modify our practice outside of screening patients who come in and doing fewer scans compared to pre-COVID,” she said. With these precautions, “we have had no internal transmission of COVID within our institution.”

Still, patients with MBC have gotten COVID, and treating both illnesses does complicate decision-making. In some cases, Mortimer has postponed cancer treatment for patients who can delay for a few weeks while they recover from COVID. But patients who need to continue MBC treatment receive care in a separate unit, and Mortimer considers prescribing Eli Lilly’s recently approved antibody therapy bamlanivimab to treat COVID symptoms. “For each situation, we can always page our infectious disease experts to address any concerns or questions,” Dr. Mortimer said.

The MBC and COVID toll

The biggest hurdle for patients with MBC has been less about treatment decisions and more about handling the psychological toll of the pandemic, according to Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai in New York City.

“These are my personal observations, but I’ve seen how much more stressful it is to have metastatic breast cancer during the pandemic,” said Dr. Shapiro, who worries that fear of COVID may fuel or exacerbate patients’ depression and anxiety. “Patients can’t have family and friends by their side during infusions or appointments, and many feel isolated because of the risk of exposure.”

Because most patients with MBC still need in-person care such as exams, blood draws, or chemotherapy infusions, Dr. McCann has found that many of her patients “are afraid to come to a medical center and have been delaying appointments, imaging, and procedures.”

The psychological toll of treating breast cancer during the pandemic has touched oncologists as well. A recent survey found that burnout scores were significantly higher among physicians whose patients experienced delays in care, including chemotherapy or specialty consultations.

Getting patients vaccinated will improve protection and hopefully lessen fears surrounding COVID infection and transmission. Preliminary recommendations from the National Comprehensive Cancer Network›s COVID-19 Vaccination Advisory Committee state that patients with cancer «should be prioritized for vaccination.»

Dr. McCann agreed. “I’ve recommended COVID-19 vaccination to all of my patients with MBC,” she said. But because a lot of these therapies suppress the immune system to some degree, “I’ll recommend a period of time for vaccination in which the immune system is expected to have recovered, such as in the days prior to a dose of chemotherapy.”

Overall, according to Dr. Carey, institutional responses to treating MBC during the pandemic have been very similar: The key has been that “no one is keeping secrets,” she said. “Our global oncology community is sharing and adopting best practices. Our focus has been doing right by our patients.”

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

Endocrine therapy is the standard of care for estrogen receptor–positive (ER+) breast cancer, but only about half of women respond. At present, there is no method for identifying the women who are likely – and also unlikely – to respond.

But a new approach looks to be useful. It involves a trial of estrogen followed by imaging that measures the function of estrogen receptors in the cancer cells.

This functional testing of estrogen receptors on breast cancer cells was perfectly accurate in predicting endocrine therapy response in 43 postmenopausal women with advanced ER+ disease, say researchers from Washington University, St. Louis, led by Farrokh Dehdashti, MD.

“There is an unmet clinical need to develop more precise predictive biomarkers. The results of this study are extremely promising,” they conclude.  

The study was published online in Nature Communications.

For the study, the women were first infused with a radioactive progestin analog – 21-[18F]fluorofuranylnorprogesterone (FFNP) – that binds progesterone receptors. About 40 minutes later, they had a PET scan to assess its uptake, an indication of progesterone-receptor abundance.

The women were then given three 200-mg doses of estradiol over 24 hours.

The FFNP infusion and PET scan were repeated the next day.

Estradiol will cause cancer cells with functional estrogen receptors to produce more progesterone receptors, so increased uptake of the radioactive analog indicates functional estrogen receptors that will respond to endocrine therapy. If estrogen receptors are not functional, and therefore not amenable to endocrine therapy (ET), estradiol will not upregulate progesterone receptors.

The results proved the theory. FFNP uptake increased more than 6.7% in 28 subjects and a median of 25.4%. All 28 women responded to subsequent ET, including 15 partial responses and 13 women with stable disease at 6 months.

Median survival was not reached after a median follow up of 27.1 months.

Uptake increased no more than 6.7% in 15 subjects and, in fact, fell a median of 0.7% from baseline. None of these women responded to ET. The median survival was 22.6 months.

“We observed 100% agreement between the response to estrogen challenge and the response to hormone therapy. … This method should work for any therapy that depends on a functional estrogen receptor, and it could provide valuable information to oncologists deciding how best to treat their patients,” Dr. Dehdashti said in a press release.

A larger multicenter confirmation trial is in the works.

Oncology needs “to get away from empiric therapies and make therapy more individualized” to save patients from the morbidity and expense of ineffective treatment and wasting time when other options are available, Dr. Dehdashti told this news organization.

“It would be a good thing if we could identify endocrine-resistant patients,” said Charles Shapiro, MD, a professor and director of translational breast cancer research at Mount Sinai Hospital, New York.

However, he wondered “about the exportability to less resource-intensive community settings where most oncology care occurs. This technology, assuming the results are confirmed in a larger study, [needs] a cost-effectiveness analysis” vs. the empiric approach, Dr. Shapiro said in an interview.

The women taking part in this study were a median of 60 years old, and most had metastatic disease. PET imaging extended from the base of the skull to the upper thighs, with data derived from bone, lung, breast, and other tumor sites. ET options included aromatase inhibitors, fulvestrant, and tamoxifen in combination with other agents.

Almost three-quarters of the women had prior systemic treatment, most often a hormone therapy–based regimen. Prior treatment had no effect on FFNP uptake.

There were no adverse events with the radiotracer, but the estradiol made a few women nauseous, among other transient discomforts, the team reported.

The work was funded by the National Cancer Institute and Washington University, St. Louis. Dr. Shapiro and Dr. Dehdashti have disclosed no relevant financial relationships. Several investigators reported consulting fees and/or other ties to a number of companies, including Pfizer, Merck, Avid Radiopharmaceutical, and Radius Health.

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

Endocrine therapy is the standard of care for estrogen receptor–positive (ER+) breast cancer, but only about half of women respond. At present, there is no method for identifying the women who are likely – and also unlikely – to respond.

But a new approach looks to be useful. It involves a trial of estrogen followed by imaging that measures the function of estrogen receptors in the cancer cells.

This functional testing of estrogen receptors on breast cancer cells was perfectly accurate in predicting endocrine therapy response in 43 postmenopausal women with advanced ER+ disease, say researchers from Washington University, St. Louis, led by Farrokh Dehdashti, MD.

“There is an unmet clinical need to develop more precise predictive biomarkers. The results of this study are extremely promising,” they conclude.  

The study was published online in Nature Communications.

For the study, the women were first infused with a radioactive progestin analog – 21-[18F]fluorofuranylnorprogesterone (FFNP) – that binds progesterone receptors. About 40 minutes later, they had a PET scan to assess its uptake, an indication of progesterone-receptor abundance.

The women were then given three 200-mg doses of estradiol over 24 hours.

The FFNP infusion and PET scan were repeated the next day.

Estradiol will cause cancer cells with functional estrogen receptors to produce more progesterone receptors, so increased uptake of the radioactive analog indicates functional estrogen receptors that will respond to endocrine therapy. If estrogen receptors are not functional, and therefore not amenable to endocrine therapy (ET), estradiol will not upregulate progesterone receptors.

The results proved the theory. FFNP uptake increased more than 6.7% in 28 subjects and a median of 25.4%. All 28 women responded to subsequent ET, including 15 partial responses and 13 women with stable disease at 6 months.

Median survival was not reached after a median follow up of 27.1 months.

Uptake increased no more than 6.7% in 15 subjects and, in fact, fell a median of 0.7% from baseline. None of these women responded to ET. The median survival was 22.6 months.

“We observed 100% agreement between the response to estrogen challenge and the response to hormone therapy. … This method should work for any therapy that depends on a functional estrogen receptor, and it could provide valuable information to oncologists deciding how best to treat their patients,” Dr. Dehdashti said in a press release.

A larger multicenter confirmation trial is in the works.

Oncology needs “to get away from empiric therapies and make therapy more individualized” to save patients from the morbidity and expense of ineffective treatment and wasting time when other options are available, Dr. Dehdashti told this news organization.

“It would be a good thing if we could identify endocrine-resistant patients,” said Charles Shapiro, MD, a professor and director of translational breast cancer research at Mount Sinai Hospital, New York.

However, he wondered “about the exportability to less resource-intensive community settings where most oncology care occurs. This technology, assuming the results are confirmed in a larger study, [needs] a cost-effectiveness analysis” vs. the empiric approach, Dr. Shapiro said in an interview.

The women taking part in this study were a median of 60 years old, and most had metastatic disease. PET imaging extended from the base of the skull to the upper thighs, with data derived from bone, lung, breast, and other tumor sites. ET options included aromatase inhibitors, fulvestrant, and tamoxifen in combination with other agents.

Almost three-quarters of the women had prior systemic treatment, most often a hormone therapy–based regimen. Prior treatment had no effect on FFNP uptake.

There were no adverse events with the radiotracer, but the estradiol made a few women nauseous, among other transient discomforts, the team reported.

The work was funded by the National Cancer Institute and Washington University, St. Louis. Dr. Shapiro and Dr. Dehdashti have disclosed no relevant financial relationships. Several investigators reported consulting fees and/or other ties to a number of companies, including Pfizer, Merck, Avid Radiopharmaceutical, and Radius Health.

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

Endocrine therapy is the standard of care for estrogen receptor–positive (ER+) breast cancer, but only about half of women respond. At present, there is no method for identifying the women who are likely – and also unlikely – to respond.

But a new approach looks to be useful. It involves a trial of estrogen followed by imaging that measures the function of estrogen receptors in the cancer cells.

This functional testing of estrogen receptors on breast cancer cells was perfectly accurate in predicting endocrine therapy response in 43 postmenopausal women with advanced ER+ disease, say researchers from Washington University, St. Louis, led by Farrokh Dehdashti, MD.

“There is an unmet clinical need to develop more precise predictive biomarkers. The results of this study are extremely promising,” they conclude.  

The study was published online in Nature Communications.

For the study, the women were first infused with a radioactive progestin analog – 21-[18F]fluorofuranylnorprogesterone (FFNP) – that binds progesterone receptors. About 40 minutes later, they had a PET scan to assess its uptake, an indication of progesterone-receptor abundance.

The women were then given three 200-mg doses of estradiol over 24 hours.

The FFNP infusion and PET scan were repeated the next day.

Estradiol will cause cancer cells with functional estrogen receptors to produce more progesterone receptors, so increased uptake of the radioactive analog indicates functional estrogen receptors that will respond to endocrine therapy. If estrogen receptors are not functional, and therefore not amenable to endocrine therapy (ET), estradiol will not upregulate progesterone receptors.

The results proved the theory. FFNP uptake increased more than 6.7% in 28 subjects and a median of 25.4%. All 28 women responded to subsequent ET, including 15 partial responses and 13 women with stable disease at 6 months.

Median survival was not reached after a median follow up of 27.1 months.

Uptake increased no more than 6.7% in 15 subjects and, in fact, fell a median of 0.7% from baseline. None of these women responded to ET. The median survival was 22.6 months.

“We observed 100% agreement between the response to estrogen challenge and the response to hormone therapy. … This method should work for any therapy that depends on a functional estrogen receptor, and it could provide valuable information to oncologists deciding how best to treat their patients,” Dr. Dehdashti said in a press release.

A larger multicenter confirmation trial is in the works.

Oncology needs “to get away from empiric therapies and make therapy more individualized” to save patients from the morbidity and expense of ineffective treatment and wasting time when other options are available, Dr. Dehdashti told this news organization.

“It would be a good thing if we could identify endocrine-resistant patients,” said Charles Shapiro, MD, a professor and director of translational breast cancer research at Mount Sinai Hospital, New York.

However, he wondered “about the exportability to less resource-intensive community settings where most oncology care occurs. This technology, assuming the results are confirmed in a larger study, [needs] a cost-effectiveness analysis” vs. the empiric approach, Dr. Shapiro said in an interview.

The women taking part in this study were a median of 60 years old, and most had metastatic disease. PET imaging extended from the base of the skull to the upper thighs, with data derived from bone, lung, breast, and other tumor sites. ET options included aromatase inhibitors, fulvestrant, and tamoxifen in combination with other agents.

Almost three-quarters of the women had prior systemic treatment, most often a hormone therapy–based regimen. Prior treatment had no effect on FFNP uptake.

There were no adverse events with the radiotracer, but the estradiol made a few women nauseous, among other transient discomforts, the team reported.

The work was funded by the National Cancer Institute and Washington University, St. Louis. Dr. Shapiro and Dr. Dehdashti have disclosed no relevant financial relationships. Several investigators reported consulting fees and/or other ties to a number of companies, including Pfizer, Merck, Avid Radiopharmaceutical, and Radius Health.

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