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Mutation D538G – a novel mechanism conferring acquired Endocrine Resistance causes a change in the Estrogen Receptor and Treatment of Breast Cancer with Tamoxifen

Reporter: Aviva Lev-Ari, PhD, RN

 

Mutation Linked to Resistance in Breast Cancer

Published: Nov 12, 2013

By Charles Bankhead, Staff Writer, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

A mutation on the estrogen receptor altered tamoxifen bindings and conferred tumor cell resistance to the breast cancer agent, suggesting a pathway to treatment resistance, investigators reported.

The D538G mutation appeared in liver metastases but not primary breast tumors of women treated with hormonal therapy, according to Ido Wolf, MD, of the University of Tel Aviv in Israel, and colleagues.

Laboratory studies suggested that D538Gcauses a change in the estrogen receptor that “disrupts the interaction between the receptor and either estrogen or tamoxifen, bur mimics the conformation of the activated receptor,” they wrote online inCancer Research. “Studies in cell lines confirmed ligand-independent, constitutive activity of the mutated receptor.”

“Taken together, these data indicate the mutation D538G as a novel mechanism conferring acquired endocrine resistance.”

About three-fourths of all breast cancers express estrogen receptor-alpha. Targeting the receptor with tamoxifen, or another hormonal therapy, disrupts signaling that reduces levels of the functional protein produced that binds to the receptor or inhibits the receptor.

Some patients with metastatic breast cancer do not respond to any form of endocrine treatment (primary resistance). Almost all patients who initially respond to endocrine therapy eventually develop resistance to the therapy (acquired resistance).

Several mechanisms of acquired resistance have been identified, including reduced expression of estrogen receptor alpha, altered activity of regulatory proteins, and increased activity of growth factor signaling pathways that help drive tumor growth and progression, the authors noted.

Protein mutation occurs with some regularity in tumorigenesis, but fewer than 1% of primary breast tumors develop mutations in estrogen receptor-alpha. No previous studies had shown that acquired mutations in estrogen receptor-alpha might play a role in the development of resistance to hormonal therapy.

As part of their search for cancer-related genes, Wolf and colleagues examined tumor specimens from 13 patients with metastatic breast cancer that had proven unresponsive to multiple lines of therapy. Genetic analysis showed that metastases from five patients had developed mutations in estrogen receptor-alpha, resulting in the substitution of aspartic acid to glycine at position 538 of the receptor gene.

“Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment,” the authors noted in their discussion of the findings.

Two previous activating mutations of estrogen receptor-alpha have been identified, but neither has been linked to resistance to hormonal therapy for breast cancer. Moreover, no acquired mutations (not present in the primary tumor) had been identified previously.

A limitation of this study was that the women were “highly selected, heavily pretreated patients and may not represent the general population of patients with breast cancer,” the authors pointed out.

“The actual prevalence of the D538G mutation needs to be determined in large cohorts of patients,” Wolf and colleagues concluded. “If indeed the mutation is identified in a significant proportion of patients, direct testing of it may be an easy and cheap method to predict response to hormonal therapy.”