Abstract
PurposeAlterations to mismatch repair (MMR) pathways are a known cause of cancer, particularly colorectal and endometrial carcinomas. Recently, checkpoint inhibitors have been approved for use in MMR-deficient cancers of any type (Prasad et al. in JAMA Oncol 4:157–158, 2018). Functional studies in breast cancer have shown associations between MMR loss, resistance to aromatase inhibitors and sensitivity to palbociclib (Haricharan et al. in Cancer Discov 7:1168–1183, 2017). Herein, we investigate the clinical meaning of MMR deficiency in breast cancer by immunohistochemical assessment of MSH2, MSH6, MLH1 and PMS2 on a large series of breast cancers linked to detailed biomarker and long-term outcome data.MethodsCases were classified as MMR intact when all four markers expressed nuclear reactivity, but MMR-deficient when at least one of the four biomarkers displayed loss of nuclear staining in the presence of positive internal stromal controls on the tissue microarray core.ResultsAmong the 1635 cases with interpretable staining, we identified 31 (1.9%) as MMR-deficient. In our cohort, MMR deficiency was present across all major breast cancer subtypes, and was associated with high-grade, low-progesterone receptor expression and high tumor-infiltrating lymphocyte counts. MMR deficiency is significantly associated with inferior overall (HR 2.29, 95% CI 1.02–5.17, p = 0.040) and disease-specific survival (HR 2.71, 95% CI 1.00–7.35, p = 0.042) in the 431 estrogen receptor-positive patients who were uniformly treated with tamoxifen as their sole adjuvant systemic therapy.ConclusionOverall, this study supports the concept that breast cancer patients with MMR deficiency as assessed by immunohistochemistry may be good candidates for alternative treatment approaches such as immune checkpoint or CDK4 inhibitors.
Highlights
Mismatch repair is a highly conserved mechanism that maintains replication fidelity and mediates DNA damage signaling [1,2,3,4]
MMR deficiency is rare in breast cancer
We present the largest series to date assessing mismatch repair protein deficiency in breast cancer, as determined by immunohistochemistry and linked to survival outcomes
Summary
Mismatch repair is a highly conserved mechanism that maintains replication fidelity and mediates DNA damage signaling [1,2,3,4]. MutS recognizes and attaches to abnormal DNA whereas MutL enhances recognition and facilitates the formation of a repair complex [5, 6]. The MMR pathway corrects base pair mismatches and insertion or deletion loops commonly found in microsatellite regions, it is involved in cell cycle checkpoints and apoptosis [2,3,4].
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