Mutation analysis using cell-free DNA for endocrine therapy in patients with HR+ metastatic breast cancer

Sung Hoon Sim,In Hae Park,Keun Seok Lee,Han Na Yang,Su Yeon Jeon

doi:10.1038/s41598-021-84999-9

Sung Hoon Sim, In Hae Park + Show 3 more

Open Access

https://doi.org/10.1038/s41598-021-84999-9

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Abstract

We prospectively evaluated the utility of ESR1 and PIK3CA mutation analysis with cell-free DNA (cfDNA) using droplet digital PCR (ddPCR) for the efficacy of endocrine therapy (ET) in hormone receptive positive (HR+) metastatic breast cancer (MBC) patients. CfDNA was analyzed just before the start of ET for MBC. E380Q, Y537N, Y537S, and D538G were assessed for ESR1 mutations and H1047R, E545K, and E542K were assessed for PIK3CA mutations. A total of 75 patients were enrolled. Of those, 31 (41.3%) received letrozole with palbociclib, and 28 (37.3%) received exemestane and everolimus (EverX). ESR1 mutations were found in 36 (48.0%) patients, of which 16 (21.3%) had more than one variant. Seventeen (23.6%) patients had one PIK3CA mutation and 8 (11.1%) had two. In the total population, time to progression of the first ET after enrollment (TTP1) decreased significantly as the number of ESR1 mutations increased (p < 0.001). PIK3CA mutations were also significantly associated with shorter TTP1 (median TTP1: 16.2 months vs. 10.9 months, p = 0.03). In contrast, PIK3CA mutations were significantly associated with longer TTP in patients receiving EverX treatment (median TTP of EverX: 15.9 months vs. 5.2 months, p = 0.01) and remained a significant factor in multivariable analysis for TTP of EverX in this subgroup (hazard ratio = 0.2, 95% CI = 0.1– 0.8, p = 0.03). ESR1 and PIK3CA mutations in cfDNA were associated with clinical efficacies of ET in HR+ MBC patients.

Highlights

Gaining knowledge of genetic variants of patients by molecular testing can help the management of personalized therapies
Two targeted therapies for the PI3K pathway are actively used with endocrine therapy (ET) for hormone receptor (HR)+ metastatic breast cancers (MBCs); namely, the mammalian target of rapamycin inhibitor and a PI3Kα-specific inhibitor[18,19]
We prospectively evaluated the clinical availability and utility of ESR1 and PIK3CA mutation analysis in cell-free DNA (cfDNA) using droplet digital polymerase chain reaction in a cohort of HR+ metastatic breast cancer (MBC) patients

Summary

Introduction

Gaining knowledge of genetic variants of patients by molecular testing can help the management of personalized therapies. Serial characterization of genetic variants by liquid biopsy may be useful because of its potential to provide valuable information about tumor h eterogeneity[6] Liquid biopsies, those involving cell-free DNA (cfDNA) from plasma, are emerging as an important alternative approach for current means of molecular profiling of tumors[6,7,8]. Like ESR1, PIK3CA is a promising predictive biomarker for HR+ breast cancer in patients treated with targeted therapy for the PI3K pathway. We prospectively evaluated the clinical availability and utility of ESR1 and PIK3CA mutation analysis in cfDNA using droplet digital polymerase chain reaction (ddPCR) in a cohort of HR+ metastatic breast cancer (MBC) patients

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