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The Relationship Between Mismatch Repair Deficiency and PD-L1 Expression in Breast Carcinoma

Mills, Anne, M., MD*; Dill, Erik, A., MD*; Moskaluk, Christopher, A., MD, PhD*; Dziegielewski, Jaroslaw, PhD; Bullock, Tim, N., PhD*; Dillon, Patrick, M., MD

The American Journal of Surgical Pathology: February 2018 - Volume 42 - Issue 2 - p 183–191
doi: 10.1097/PAS.0000000000000949
Original Articles

Mismatch repair (MMR) deficiency in solid tumors has recently been linked to susceptibility to immunotherapies targeting the programmed cell death-1 (PD-1)/programmed cell death-1 ligand (PD-L1) axis. Loss of MMR proteins has been shown to correlate with tumoral PD-L1 expression in colorectal and endometrial carcinomas, but the association between expression of MMR proteins and PD-L1 has not previously been studied in breast carcinoma, where MMR deficiency is less common. We assessed the relationship between PD-L1 and MMR protein expression by immunohistochemistry in 245 primary and 40 metastatic breast carcinomas. Tumoral staining for PD-L1 was positive in 12% of all cases, including 32% of triple-negative cancers. MMR deficiency was observed in 0.04% of breast cancers; the single MMR-deficient case was a high-grade, triple-negative ductal carcinoma which showed dual loss of MLH1 and PMS2 proteins and expressed PD-L1. Two ER+ carcinomas initially were scored with MMR protein loss in tissue microarray format but were subsequently shown to be MMR-intact on whole sections. Analysis of MMR gene mutation in The Cancer Genome Atlas corroborates low frequency of MMR deficiency for invasive breast cancer. MMR protein expression is therefore unlikely to show utility as a screen for immunotherapeutic vulnerability in this tumor type, and may provoke unwarranted genetic testing in patients unlikely to have a heritable cancer syndrome. PD-L1 may be a more clinically relevant biomarker for anti-PD-1/PD-L1 therapies in this setting.

Departments of *Pathology

Radiation Oncology

Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Anne M. Mills, MD, Department of Surgical Pathology, University of Virginia Health System, 3rd Floor Hospital Expansion, Room 3001, 1215 Lee Street, Charlottesville, VA 22908. (e-mail:

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