High tumor mutation burden is associated with DNA damage repair gene mutation in breast carcinomas

Ping Mei,C Eric Freitag,Zaibo Li,Yunxiang Zhang,Anil V Parwani,Lai Wei

doi:10.1186/s13000-020-00971-7

Abstract

BackgroundImmunotherapy has demonstrated encouraging clinical benefits in patients with advanced breast carcinomas and Programmed death ligand 1 (PD-L1) expression has been proposed as an immunotherapy biomarker. Challenges with current PD-L1 testing exist and tumor mutation burden (TMB) is emerging as a biomarker to predict clinical response to immunotherapy in melanoma and non-small cell lung cancer patients. However, TMB has not been well characterized in breast carcinomas.MethodsThe study cohort included 62 advanced breast cancer patients (13 primary and 49 metastatic). Genetic alterations and TMB were determined by FoundationOne CDx next generation sequencing (NGS) and the association with clinicopathologic features was analyzed.ResultsHigh TMB was observed in a relatively low frequency (3/62, 4.8%). TMB levels were positively associated tumor infiltrating lymphocytes and significantly higher TMB was observed in breast carcinomas with DNA damage repair gene mutation(s). There was no significant association between TMB levels and other analyzed clinicopathologic characteristics.ConclusionsOur data indicate the importance of DNA damage repair proteins in maintaining DNA integrity and immune reaction and breast carcinoma patients with DDR mutation may benefit from immunotherapy.

Highlights

Breast cancer (BC) is the most common malignancy in women [1] and biomarkers including estrogen receptor (ER)s, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), are routinely performed for therapeutic decision-making [2]
tumor mutation burden (TMB) is emerging as potential biomarker for immunotherapy decisions in melanoma or non-small lung cancer patients [15,16,17,18,19,20,21,22,23]; TMB has not been well characterized in BCs
We aimed to investigate TMB in BCs using FoundationOne CDx next generation sequencing (NGS) and its association with different clinicopathologic features including histologic types, hormone receptor and HER2 status, and different genetic mutations

Summary

Introduction

Breast cancer (BC) is the most common malignancy in women [1] and biomarkers including estrogen receptor (ER)s, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), are routinely performed for therapeutic decision-making [2]. Programmed death ligand 1 (PD-L1) expression has been proposed as a biomarker for immunotherapy, challenges with PD-L1 testing exist, including interassay variability among different PD-L1 immunohistochemistry (IHC) assays with different reagents and platforms, lack of standardization. TMB is emerging as potential biomarker for immunotherapy decisions in melanoma or non-small lung cancer patients [15,16,17,18,19,20,21,22,23]; TMB has not been well characterized in BCs. Whole exome sequencing is the standard method to determine TMB, but it is time consuming and too expensive for routine clinical practice. Immunotherapy has demonstrated encouraging clinical benefits in patients with advanced breast carcinomas and Programmed death ligand 1 (PD-L1) expression has been proposed as an immunotherapy biomarker. Challenges with current PD-L1 testing exist and tumor mutation burden (TMB) is emerging as a biomarker to predict clinical response to immunotherapy in melanoma and non-small cell lung cancer patients. TMB has not been well characterized in breast carcinomas

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Conclusion