Selective estrogen receptor degraders and their effect on the breast cancer immune microenvironment
Kristen S. Young, Sean W. Fanning
Kristen S. Young, Sean W. Fanning
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Review Series

Selective estrogen receptor degraders and their effect on the breast cancer immune microenvironment

Abstract

One in eight women will be diagnosed with breast cancer in their lifetime. Most breast cancers express estrogen receptor α (ERα) and depend on its signaling, which promotes tumor growth, survival, and metastatic spread through hormone-dependent transcriptional reprogramming. Selective estrogen receptor degraders/downregulators (SERDs), such as fulvestrant (faslodex), which was FDA approved in 2002, are second-line endocrine therapies for the treatment of advanced metastatic disease. Tumors containing activating hotspot mutations in ESR1 (the gene encoding ERα) retain some sensitivity to fulvestrant but require higher doses to achieve inhibition of the mutant receptor. Substantial efforts to develop next-generation SERDs with improved pharmacology over fulvestrant have led to the FDA approval of the first-in-class orally available SERD elacestrant (Orserdu), followed by imlunestrant (Inluriyo), and the anticipated approval of several more therapies. Excitingly, recent studies show that in addition to their previously described antitumoral mechanisms, SERDs also act by increasing antitumor immunity. In this Review, we detail the current SERD clinical landscape and our emerging understanding of the interplay among SERDs, breast cancer cells, and the tumor immune microenvironment.

Authors

Kristen S. Young, Sean W. Fanning

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Figure 1

ERα signaling contributes to the immunosuppressive phenotype in ER+ breast cancer.

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ERα signaling contributes to the immunosuppressive phenotype in ER+ brea...
ERα signaling contributes to the immunosuppressive phenotype in ER+ breast cancer. (A) In addition to the direct effects of E2 on tumor cell proliferation, the hormone also acts on the TIME. In innate immune cells (left), ERα signaling downregulates IFN-γ signaling and inflammatory chemokines. In the adaptive immune compartment (right), E2 signaling promotes Treg proliferation and decreases B cell receptor signaling. These effects contribute to the reduced efficacy of immunotherapy in ER+ BC. (B) SERDs can act on both tumor cells and the TIME. In addition to blocking the proliferative effect of E2 signaling in tumor cells, SERDs may make the TIME more immunogenic, increasing the efficacy of immunotherapy. ERE, estrogen response element; MSC, mesenchymal stem cell; TMB, tumor mutational burden; TIL, tumor-infiltrating lymphocyte.