Targeting Estrogen Receptors

By Komal Jhaveri, MD, FACP ,

Thursday, June 23, 2016

While breast cancer is the most common cancer occurring in women worldwide, it is no longer considered to be a single disease. The presence or absence of an estrogen receptor, a progesterone receptor, and a protein called HER2 distinguish the subtypes of invasive breast cancer: endocrine-receptor positive, HER2 positive, triple positive, and triple negative. Each of these four broad subtypes exhibit different patterns of growth and response to specific classes of drugs.

The largest group, representing approximately 60 to 70 percent of cases, is hormone receptor positive/HER2 negative. Therapies that interfere with estrogen and the estrogen receptor signaling pathway include selective estrogen receptor blockers such as tamoxifen; aromatase inhibitors that reduce the normal conversion of male hormones (androgens) to estrogen throughout the body; and, more recently, a selective estrogen receptor down-regulator (SERD) called fulvestrant. However, approximately one third of patients with metastatic breast cancer exhibit early resistance to these agents and do not gain much benefit. To better treat these patients, we need new and more effective ways of targeting the estrogen receptor and its signaling within cancer cells.

Shedding Light on Ligand-Independent Cancer Cell Signaling

Interestingly, while these resistant tumors do not respond well to the three standard anti-estrogen therapies now in wide use, they are still dependent on a specific estrogen receptor called estrogen receptor alpha for their growth. (1)There is growing evidence that this receptor can signal cells to grow even without estrogen present in a process called ligand-independent signaling. (2)

We are learning more about how ligand-independent signaling occurs. For example, we have found activating mutations commonly seen in tumors resistant to estrogen deprivation by aromatase inhibitors (3)in the ligand-binding domain of estrogen receptor 1 (ESR1). These mutations are very rare in newly identified primary breast tumors but have been observed in approximately 20 percent of tumors after they spread elsewhere in the body, especially when resistance to aromatase inhibitors develops. (4)Overcoming the effect of these acquired tumor gene mutations can require much higher doses of tamoxifen or fulvestrant than those used in laboratory studies, and it is not easy for patients to tolerate those levels. (3), (4), (5)

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Dual-Action Drugs to Block and Degrade Estrogen Receptor Function  

Investigators at Memorial Sloan Kettering Cancer Center (MSK) are working in both laboratory and clinical settings to understand and overcome these challenges. In the Human Oncology & Pathogenesis Program, Sarat Chandarlapaty, MD, PhD studies SERDs and the impact of ESR1 mutations so that we can develop better treatments in the clinic. His work, along with the findings described above, suggest that a new agent with a dual mechanism of action could be more effective, by blocking estrogen when it is functioning as a ligand and by degrading the receptor directly when it is signaling without the ligand. This one-two punch on the same target is the goal of some new endocrine treatments for breast cancer, including novel SERDs that can be taken orally and that specifically degrade the mutated form of the estrogen receptor.

At MSK, we are uniquely able to identify patients with the ESR1 mutation rapidly using MSK-IMPACT™ (Integrated Mutation Profiling of Actionable Cancer Targets). This targeted tumor sequencing test allows us to detect gene mutations quickly and evaluate promising new agents. Currently, we are studying three novel SERDs in phase I and phase II clinical trials (see Table 1). To enroll a patient in one of these studies, please call the Breast Medicine Service at 646-497-9064.

Table 1: Ongoing Studies of Selective Estrogen Receptor Down-Regulators in Phase I and Phase II Clinical Trials

Trial Title Clinical Identifier MSK IRB#; Principal Investigator

A Phase I, Open-Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity of Ascending Doses of AZD9496 in Women with Estrogen Receptor Positive HER2 Negative Advanced Breast Cancer


15-330; Komal Jhaveri, MD, FACP

An Open-Label, Phase I/IIA Study Of GDC-0810 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer


13-049; Maura Dickler, MD

An Open-Label, Phase I Study of GD-0927 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer


15-075; Maura Dickler, MD




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  1. Baselga J, Campone M, Piccart M, Burris HA, 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012; 366(6):520-9.

  2. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010; 120(7):2406-13.

  3. Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 2013; 45(12):1439-45.

  4. Segal CV, Dowsett M. Estrogen receptor mutations in breast cancer—new focus on an old target. Clin Cancer Res 2014; 20(7):1724-6.

  5. Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 2014; 20(7):1757-67.