clinical topic updates

Second-line Treatment for Advanced/Metastatic HR+ HER2- Breast Cancer

by Joseph A. Sparano, MD, FACP


Resistance to endocrine-based therapy remains a challenge in hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer; however, newer options continue to emerge. The approach to progression following endocrine therapy and CDK4/6 inhibitor therapy is often guided by molecular testing.

Expert Commentary

Joseph A. Sparano, MD, FACP

Ezra M. Greenspan, MD Professor in Clinical Cancer Therapeutics
Chief, Division of Hematology and Medical Oncology
Deputy Director
The Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
New York, NY

" . . . molecular testing of the blood for circulating tumor DNA or of the tumor is indicated. These tests primarily look for activating mutations in PIK3CA that result in the activation of the PI3K/AKT/mTOR pathway. . . . ”

Joseph A. Sparano, MD, FACP

To plan second-line therapy for patients with HR+/HER2- breast cancer after progression on first-line endocrine therapy plus CDK4/6 inhibitor therapy, molecular testing of the blood for circulating tumor DNA or of the tumor is indicated. These tests primarily look for activating mutations in PIK3CA that result in the activation of the PI3K/AKT/mTOR pathway; these mutations occur in approximately 40% of individuals with HR+/HER2- breast cancer. They tend to be truncal mutations in the alpha catalytic subunit of the PIK3CA gene. PIK3CA mutations are present at the time of diagnosis, and patients could be tested for them then, but they should certainly be tested for PIK3CA mutations at the time of progression after first-line endocrine therapy. This is because, if the patient has an activating PIK3CA mutation, treatment will generally include additional endocrine therapy (usually fulvestrant) in combination with a PIK3CA inhibitor such as alpelisib. 

PIK3CA inhibitors have been shown to improve response rates and progression-free survival (PFS)—but not overall survival (OS)—when added to endocrine therapy in the second-line setting. The downside is that these agents are associated with more adverse effects (eg, hyperglycemia, rash, and diarrhea) than CDK4/6 inhibitors. The SOLAR-1 study revealed that 25% of patients with PIK3CA-mutant disease had to stop taking alpelisib due to adverse events and that approximately 62% required dose reductions due to adverse events. These individuals also generally require pretreatment with antihistamines to prevent some of the adverse effects. 

For the patients who lack activating mutations of PIK3CA, blocking the PI3K/AKT/mTOR pathway downstream with a drug such as the mTOR inhibitor everolimus can also improve objective response and prolong PFS, but it does not have a positive impact on OS. Everolimus has side effects that are somewhat similar to those of alpelisib and include stomatitis, rash, and glucose intolerance. Stomatitis is a common side effect that can be abrogated with a corticosteroid mouthwash. 

Another option is an oral agent that just became available and was recently approved by the US Food and Drug Administration for patients who progress after 1 previous line of endocrine therapy and who develop ESR1 mutations (ie, the selective estrogen receptor degrader elacestrant). ESR1 mutations of the estrogen receptor gene confer resistance to endocrine therapy and are generally not apparent at the time of diagnosis but rather develop under selective pressure from endocrine therapy. They can occur in up to 40% of patients who have been on prolonged endocrine therapy. The presence of these mutations, which are detectable on circulating tumor DNA or on a tumor DNA assay, will identify patients who are more likely to benefit from treatment with elacestrant. 

A different approach has become available in the last year: trastuzumab deruxtecan, an antibody-drug conjugate that benefited patients with HR+/HER2-non-overexpressing (ie, HER2-low) disease. This agent resulted in significantly longer PFS and OS than the physician's choice of chemotherapy in this population and represents an important new treatment option. Sacituzumab govitecan is another antibody-drug conjugate that was initially approved in triple-negative metastatic breast cancer and is now showing promise in endocrine-resistant HR+/HER2- metastatic breast cancer.


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