Clinical Pearls & Morning Reports

By Carla Rothaus

Published November 14, 2018


Do ESR1 mutations confer potential resistance to aromatase inhibitors?

More than 50% of recurrences of estrogen receptor (ER)-positive breast cancer occur more than 5 years after the initial diagnosis, and the risk of recurrence persists for at least 15 to 20 years, particularly for lobular cancers. Although the risk of recurrence in women with breast cancer is correlated with clinicopathological features such as tumor size and lymph-node status, the risk of late recurrence (after 5 years) is especially associated with hormone receptor–positive breast cancer. Read the latest NEJM Case Records of the Massachusetts General Hospital here

Clinical Pearls

Q: What are major therapeutic considerations in the adjuvant management of ER-positive localized invasive breast cancer?

A: In the adjuvant management of ER-positive localized invasive breast cancer, there are two major therapeutic considerations. The first is whether to administer adjuvant chemotherapy after surgical resection. The second is whether to administer adjuvant endocrine therapy beyond the standard 5-year duration. Some randomized clinical trials show that extending the duration of endocrine therapy can be beneficial; for example, among patients who received tamoxifen therapy, outcomes were better with 10 years of treatment than with 5 years of treatment. However, other trials do not show an advantage of this approach with regard to survival outcomes. Even in studies showing that extended endocrine therapy was associated with improved outcomes, the decrease in the risk of recurrence was relatively modest and needs to be weighed against the difficulty of ensuring adherence to the treatment and the potential toxic effects of the treatment, including the development of osteoporosis.

Q: How do CDK4/6 inhibitors work?

A: Although options for the treatment of ER-positive metastatic breast cancer have evolved considerably, perhaps the most striking development in recent years has been the advent of potent tyrosine kinase inhibitors that selectively bind to cyclin-dependent kinases 4 and 6 (CDK4/6) and block the cell-cycle transition from the G1 phase to the S phase. Several clinical trials show prolonged progression-free survival with the addition of a CDK4/6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib) to endocrine therapy in patients with ER-positive metastatic breast cancer.

Morning Report Questions

Q: Do ESR1 mutations confer potential resistance to aromatase inhibitors?

A: ESR1 mutations in the ligand-binding domain of the ER result in constitutively active ER conformation and confer estrogen-independent but ER-dependent signaling. Since ESR1 mutations are acquired, analysis of the metastatic specimen (as opposed to the primary specimen) or of circulating tumor cells or ctDNA, is critical. Although ESR1 mutations confer estrogen independence (and therefore potential resistance to aromatase inhibitors), tumors with ESR1 mutations are still ER-dependent and could be inhibited by drugs that target the ER directly, such as fulvestrant. However, preclinical models showed that mutated ESR1 cell lines were not adequately suppressed by standard doses of fulvestrant but could be substantially inhibited by more potent selective ER degraders (SERDs), agents that bind and degrade the ER, including mutated ESR1. Indeed, multiple ongoing clinical trials are investigating new oral SERDs.

Q: Can an ESR1 mutation be detected in peripheral blood but not in tumor tissue from a patient with metastatic breast disease?

A: Although such a discrepancy could be due to differences in tumor processing and genotyping assays, an additional factor to consider is the presence of subclonal (as opposed to clonal) molecular alterations and tumor heterogeneity — that is, the presence of different subclones at different metastatic sites that were driven by unique oncogenes and signaling mechanisms. Indeed, tumor heterogeneity is a challenge to the field of targeted therapy and precision medicine.

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