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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2020

Open Access 01-01-2020 | Breast Cancer | Preclinical study

Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort

Authors: Angela S. Cheng, Samuel C. Y. Leung, Dongxia Gao, Samantha Burugu, Meenakshi Anurag, Matthew J. Ellis, Torsten O. Nielsen

Published in: Breast Cancer Research and Treatment | Issue 1/2020

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Abstract

Purpose

Alterations 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.

Methods

Cases 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.

Results

Among 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.

Conclusion

Overall, 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.
Appendix
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Metadata
Title
Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort
Authors
Angela S. Cheng
Samuel C. Y. Leung
Dongxia Gao
Samantha Burugu
Meenakshi Anurag
Matthew J. Ellis
Torsten O. Nielsen
Publication date
01-01-2020
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-019-05438-y

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