Detection of ESR1 mutations in circulating cell-free DNA from patients with metastatic breast cancer treated with palbociclib and letrozole.

Rekha Gyanchandani,Adrian V Lee,Karthik J Kota,Amruth R Jonnalagadda,Tanya Minteer,Shannon L Puhalla,Adam M Brufsky,Steffi Oesterreich,Beth A Knapick

doi:10.18632/oncotarget.11383

Abstract

ESR1 mutations are frequently acquired in hormone-resistant metastatic breast cancer (MBC). CDK4/6 inhibition along with endocrine therapy is a promising strategy in hormone receptor-positive MBC. However, the incidence and impact of ESR1 mutations on clinical outcome in patients treated with CDK4/6 inhibitors have not been defined. In this study, we evaluated the frequency of ESR1 mutations in cfDNA from 16 patients with MBC undergoing palbociclib and letrozole therapy. Four common ESR1 mutations (D538G, Y537C, Y537N, and Y537S) were analyzed in serial blood draws using ddPCR. Mutation rate was 31.3% (5/16) (n=3; de novo, n=2; acquired). D538G was the most frequent mutation (n=3), followed by Y537N and Y537S (n=2). One patient showed multiple ESR1 mutations. Mutations were enriched during therapy. Progression-free survival (PFS) and overall survival (OS) were similar in patients with and without mutation detected at any given time during treatment. However, PFS was significantly shorter in patients with ESR1 mutation at initial blood draw (3.3 versus 9.0 months, P-value=0.038). In conclusion, ESR1 mutation prevalence is consistent with recent studies in hormone-refractory breast cancer. Further, treatment with palbociclib and letrozole does not prevent selection of ESR1 mutations in later lines of therapy. Larger studies are warranted to validate these findings.

Highlights

Estrogen receptor alpha (ERα) is expressed in approximately 70% of all breast cancers and endocrine therapy represents a major treatment modality in ERαpositive disease
We evaluated the frequency of ESR1 mutations in cfDNA from 16 patients with metastatic breast cancer (MBC) undergoing palbociclib and letrozole therapy
ESR1 mutations were examined in cfDNA from 16 patients with MBC starting palbociclib and letrozole treatment on an expanded access program (EAP) (NCT02142868, initiated by Pfizer, Inc.)

Summary

Introduction

Estrogen receptor alpha (ERα) is expressed in approximately 70% of all breast cancers and endocrine therapy represents a major treatment modality in ERαpositive disease. There have been tremendous advances in endocrine therapy with the development of third-generation AIs (anastrozole, letrozole, and exemestane) [3] These agents www.impactjournals.com/oncotarget are approved as first-line hormonal therapy in postmenopausal women with metastatic breast cancer and have contributed to the improved survival in MBC [4, 5]. Genomic alterations in many oncogenic genes have been identified in ER-positive advanced breast cancers such as PIK3CA mutations, FGFR1 and CCND1 gene amplifications, and more recently ESR1 mutations [8,9,10,11,12,13,14,15] These signaling molecules provide novel targets to develop more effective therapies to overcome or delay endocrine resistance

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