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Evaluating Mismatch Repair Status to Screen Clinical Advanced Breast Carcinomas for Immunotherapy: Experience From a Large Academic Institution.

Authors
  • Arole, Vidya1
  • Shafi, Saba1
  • Challa, Bindu1
  • Parwani, Anil V1
  • Tozbikian, Gary1
  • Li, Zaibo2
  • 1 The Ohio State University Wexner Medical Center, Columbus, OH; Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH.
  • 2 The Ohio State University Wexner Medical Center, Columbus, OH; Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH. Electronic address: [email protected]
Type
Published Article
Journal
Clinical breast cancer
Publication Date
Jul 01, 2022
Volume
22
Issue
5
Identifiers
DOI: 10.1016/j.clbc.2022.01.010
PMID: 35131187
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Very few studies have investigated mismatch repair (MMR) deficiency in breast carcinoma (BC) in clinical setting. Given the recent approval of Pembrolizumab for solid tumors with MMR deficiency, we screened clinically advanced breast carcinoma patients for immunotherapy by examining their MMR status. The cohort consisted of 163 clinical advanced BCs, including 5 primary, 14 locally recurrent, and 144 metastatic BCs. Immunohistochemistry (IHC) with anti-MMR proteins or next generation sequencing (NGS) to detect microsatellite instability was performed to evaluate MMR status. The relationship between MMR status and clinicopathologic characteristics was evaluated. Among 163 advanced BCs, 19 were hormone receptor (HR)-positive (≥ 10%)/HER2-negative, 17 were HER2+, and 127 were TNBCs/low HR-positive (< 10%). MMR status was evaluated by IHC in 131 cases and by NGS in 32 cases. Among all cases, only 1 case (0.6%) showed MMR deficiency. The case with MMR deficiency showed loss of MLH1 and PMS2 proteins, but no hypermethylation of MLH1 promoter. Sequencing analysis revealed MLH1 genetic alteration with a splice site mutation (208-1G > A), which results in disruption of the N-terminal ATPase-containing domain (amino acids 25-336). All 127 TNBCs/low HR-positive BCs showed preserved MMR. PD-L1 (SP142) testing was performed in 66 cases with 18 (27%) as positive and 48 (73%) as negative, and its expression showed no correlation with MMR status. MMR deficiency exists in an extremely low percentage of breast carcinomas, including TNBCs, suggesting a routine MMR testing to screen BC patients for immunotherapy may not be cost effective. Copyright © 2022. Published by Elsevier Inc.

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