Experts Focus on New Ways of Attacking Resistance in ER+ Breast Cancer

Christin Melton, ELS
Published: Wednesday, Oct 26, 2016
Adam M. Brufsky, MD, PhD<

Adam M. Brufsky, MD, PhD

Approximately 75% of invasive breast cancers are estrogen receptor (ER)–positive1. Although ER-positive breast cancer typically responds well to initial endocrine therapy, most patients eventually become resistant to treatment and experience disease progression.1 The discovery that ER gene mutations contribute to endocrine therapy resistance has led to the development of novel targeted therapies for progressive ER-positive breast cancer.

At an OncLive Peer Exchange panel titled “Expert Perspectives on the Latest Advancements in Breast Cancer,” a group of breast cancer specialists led by Adam M. Brufsky, MD, PhD, discussed recent progress in the understanding and management of ER-positive tumors. They reviewed emerging data presented at the 2016 ASCO Annual Meeting in June and expressed optimism about what those data suggest for the future of patients with heavily pretreated, metastatic, ER-positive disease.

ESR1 Mutations and Endocrine Therapy Resistance

Efforts to determine how ER-positive breast cancer escapes endocrine deprivation led to the identification of ESR1 mutations in hotspot regions of the ligand-binding domain (LBD) of ER, which Carlos L. Arteaga, MD, hailed as a “major discovery.”

The ESR1 gene encodes ER, and ESR1 mutations facilitate ligand-independent, constitutive ER activity in women receiving an aromatase inhibitor (AI).2 Because ESR1 mutations affect <1% of newly diagnosed breast cancers, their clinical significance was not fully appreciated until recently, when a series of studies detected a greater prevalence of ESR1 mutations in metastatic ER-positive breast cancer that became resistant to AI therapy.2,3

“Up to 30% of patients who progress on AI therapy in the metastatic setting have these alterations,” Arteaga said.4 The panel discussed abstracts presented at the 2016 ASCO Annual Meeting that addressed ESR1 mutations and their significance.

The PALOMA3 study was a randomized phase III trial that compared palbociclib (Ibrance) plus fulvestrant (Faslodex) versus fulvestrant plus placebo in 360 patients with metastatic breast cancer who had progressed during endocrine therapy.1,5 In PALOMA3, researchers analyzed circulating tumor DNA (ctDNA) in 395 plasma samples for ESR1. All 106 patients whose tumors tested positive for an ESR1 mutation had previously received an AI.5 “They didn’t see any [ESR1 mutations] in patients who had prior tamoxifen, so it’s a very treatment-dependent effect,” explained Sunil Verma, MD.

An ESR1 mutation independently predicted shorter progression-free survival (PFS). Median PFS was 5.7 months for patients with an ESR1 mutation versus 9.2 months for patients without one.5

In updated data from PALOMA3 published in the Journal of Clinical Oncology in September, the authors reported median PFS for patients with an ESR1 mutation of 9.4 months for those treated with palbociclib/fulvestrant compared with 3.6 months for those taking fulvestrant/placebo (P = .002).1 For ESR1 wild-type patients in the palbociclib/fulvestrant arm, median PFS was 9.5 months compared with 5.4 months for those in the fulvestrant/placebo arm (P <.001).1

“Despite these mutations, there was a benefit favoring palbociclib,” Verma said. Palbociclib is a CDK 4/6 inhibitor, and he said the findings are important because they suggest CDK 4/6 inhibitors are effective in patients with an ESR1 mutation.

Arteaga said he found it interesting that “the patients who had prior response to endocrine therapy—who showed some evidence of being luminal and hormone-dependent—were the ones who developed acquired ER mutations.”

He said the fact that patients who did not respond to endocrine therapy did not acquire mutations suggests their tumors had found other ways to circumvent ER inhibition.

He predicted that selective estrogen down-regulators (SERDs) could eventually become the standard of care for patients with an ESR1 mutation and suggested the ease of detecting the mutations (in plasma with no biopsy required) means “we may need to start thinking of incorporating measuring these mutations into our standard of care for patients who progress on an AI.”

Joyce A. O’Shaughnessy, MD, agreed that the findings from PALOMA3 are important and might have interesting implications for the adjuvant setting but said she was not ready to order ER assays for her patients based on the data. “I don’t think it’s really specifically actionable right now... we’re not going to change our practice patterns because we are going to use the CDK 4/6 inhibitors,” O’Shaughnessy explained.


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Clinical Vignette Series: 34th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 28, 20182.0
34th Annual Miami Breast Cancer Conference® Clinical Case Vignette Series™May 25, 20182.0
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