Standard of Care Treatments for HR+ Metastatic Breast Cancer
Key Points
-
Treatments for hormone receptor (HR)–positive metastatic breast cancer include endocrine therapy (ET), targeted agent combinations, chemotherapy, and antibody-drug conjugates (ADCs).
-
Recurrent or relapsed metastatic breast cancer after adjuvant therapy is a high-risk marker compared with de novo metastatic diagnoses.
-
Liquid and tissue next-generation sequencing (NGS) is necessary to select patients for targeted therapies and monitor for resistance–driving mutations.
-
Therapy for this population is palliative, so managing side effects to maintain quality of life is a central tenet of treatment decisions.
De Novo Versus Recurrent HR+ Metastatic Breast Cancer
On the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with Kevin Kalinsky, MD, MS, of Winship Cancer Institute of Emory University, to break down the treatment algorithm for HR–positive metastatic breast cancer. The doctors highlighted the importance of NGS, differences between de novo and recurrent or relapsed metastatic breast cancer, targeted therapy options, and sequencing lines of therapy.
Actionable Mutations in HR+ Metastatic Breast Cancer NGS
There are several actionable mutations for patients with HR–positive metastatic breast cancer, including ESR1, PIK3CA, PTEN, AKT1, and BRCA. Liquid and tissue biopsy are both relevant, as ESR1 mutations generally only appear in circulating tumor DNA on liquid biopsy, whereas PIK3CA and PTEN alterations are more observable on tumor tissue biopsy. It’s important to perform NGS upfront to identify available targeted options, but screening should be repeated throughout the treatment journey as ESR1 mutations can emerge over time and drive resistance to endocrine therapy.
Upfront Regimens for HR+ Metastatic Breast Cancer
The standard first-line therapy for de novo HR–positive metastatic breast cancer is ET plus a CDK4/6 inhibitor, typically abemaciclib or ribociclib. When choosing between CDK4/6 inhibitors, ribociclib has slightly more robust overall survival data compared with abemaciclib in the metastatic treatment setting, but abemaciclib may be favored when the central nervous system is involved or when the neutropenia associated with ribociclib could be a challenging toxicity, said Dr. Kalinsky.
HR–positive breast cancer that recurs or progresses during or shortly after completing adjuvant ET is defined as endocrine–resistant metastatic breast cancer, and is a high-risk subpopulation separate from de novo metastatic disease. The INAVO120 trial showed inavolisib plus fulvestrant and palbociclib improved survival versus fulvestrant and palbociclib for patients with endocrine–resistant HR–positive metastatic breast cancer with PIK3CA mutations. This regimen is a clear standard of care for this population, although it shouldn’t be used in place of first-line endocrine–based therapies, said Dr. Kalinsky.
Later-Lines of Treatment for HR+ Metastatic Breast Cancer
Subsequent treatment options for de novo and recurrent or relapsed HR–positive metastatic breast cancer include a variety of targeted agents. For ESR1–mutated metastatic breast cancer without evidence of aggressive progression, monotherapy with elacestrant or imlunestrant is reasonable. Alpelisib plus fulvestrant is approved for patients with PIK3CA mutations. However, this combination has largely been replaced by capivasertib plus fulvestrant, which has a more favorable toxicity profile, and is approved for PIK3CA, AKT1, and PTEN mutations. PARP inhibitors are approved for patients with germline BRCA mutations. Dr. Kalinsky said he tends to use PARP inhibitors after exhausting ET options.
The doctors also discussed the possibility of switching the ET agent while continuing the prior CDK4/6 inhibitor instead of using targeted therapies. Data from the EMBER-3 trial suggested that imlunestrant plus abemaciclib was effective, and showed a benefit regardless of ESR1 mutation status in pretreated patients. This combination may also be effective for patients with overlapping ESR1 and PIK3CA, AKT1, or PTEN mutations, although capivasertib plus fulvestrant may be more available.
Everolimus plus exemestane is feasible for patients with no targetable mutations as long as they are still endocrine–sensitive. This doublet could be combined with fulvestrant for patients with ESR1 mutations as well, said Dr. Kalinsky.
Turning to ADCs
After exhausting ET–based regimens and targeted agents, oncologists can consider chemotherapy or one of the three approved ADCs: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan, and datopotamab deruxtecan (Dato-DXd). For fully endocrine–resistant patients, capecitabine is appropriate for those with low-volume disease, said Dr. Kalinsky.
T-DXd is an anti-HER2 ADC, while sacituzumab govitecan and Dato-DXd are anti-TROP2 ADCs. T-DXd is standard of care for patients with low or ultra-low HER2 expression on immunohistochemistry based on the DESTINY-Breast06 trial. Sacituzumab govitecan is approved after at least two prior lines of systemic therapy and Dato-DXd is approved for chemotherapy–resistant disease. In patients with zero HER2 expression, Dr. Kalinsky said he prefers to use chemotherapy first and then move to one of the TROP2 ADCs.
Rounding out the discussion, the doctors emphasized the need to manage toxicities associated with these therapies, as treatment for HR–positive metastatic breast cancer is palliative in nature. Various agents have unique side effect profiles, but side effects like stomatitis, liver function test abnormalities, and hyperglycemia are shared by many of these options.