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Updated: Oct 4, 2025
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Evaluating Mismatch Repair Status to Screen Clinical Advanced Breast Carcinomas for Immunotherapy: Experience From a
Vidya Arole1, Saba Shafi1, Bindu Challa1
1The Ohio State University Wexner Medical Center, Columbus, OH; Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH.
Background:
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.
Patients And Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Mismatch repair (MMR) deficiency is rare in advanced breast cancer (BC), found in only 0.6% of cases. Routine MMR testing for immunotherapy screening in BC patients may not be cost-effective due to its low prevalence.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Mismatch repair (MMR) deficiency is a biomarker for immunotherapy response.
- Few studies have evaluated MMR deficiency in clinical breast carcinoma (BC) settings.
- Pembrolizumab is approved for solid tumors with MMR deficiency.
Purpose of the Study:
- To screen advanced breast carcinoma patients for immunotherapy by examining their MMR status.
- To investigate the prevalence of MMR deficiency in clinical advanced breast carcinoma.
- To evaluate the relationship between MMR status and clinicopathologic characteristics.
Main Methods:
- 163 advanced breast carcinoma cases were analyzed.
- MMR status was assessed using immunohistochemistry (IHC) and next-generation sequencing (NGS).
- Clinicopathologic characteristics and PD-L1 expression were evaluated.
Main Results:
- Only 1 out of 163 (0.6%) advanced BC cases showed MMR deficiency.
- The MMR-deficient case had an MLH1 genetic alteration.
- No correlation was found between MMR status and PD-L1 expression.
Conclusions:
- MMR deficiency is extremely rare in advanced breast carcinomas, including triple-negative breast cancer (TNBC).
- Routine MMR testing for immunotherapy screening in breast cancer patients may not be cost-effective.
- Further research may be needed to identify optimal biomarkers for immunotherapy in breast cancer.
