Mismatch Repair Protein Loss as a Prognostic and Predictive Biomarker in Breast Cancers Regardless of Microsatellite Instability.

Nicola Fusco,Stefano Ferrero,Luca Despini,Chiara Corti,Valentina Vaira,Monica Miozzo,Alice Faversani,Chiara Pesenti,Donatella Gambini,Patrizia Colapietro,Anna Michelotti,Gianluca Lopez,Gabriella Gaudioso,Concetta Blundo,Silvano Bosari,Giulia Ercoli

doi:10.1093/jncics/pky056

Abstract

BackgroundBreast cancers that harbor mismatch-repair (MMR) deficiency and/or microsatellite instability (MSI) might be sensitive to immune checkpoint blockade, but there are currently no specific guidelines for assessing MMR status in breast cancer. Here, we sought to define the clinical value of MMR immunohistochemistry (IHC) and MSI analysis in breast cancers.MethodsWe subjected 444 breast cancers to MMR IHC and MSI analysis. Cases were classified as MMR-proficient (pMMR), MMR-deficient (dMMR), and MMR-heterogeneous (hMMR) based on the loss of immunoreactivity; MSI was defined by instability in the five indicators recommended by the National Cancer Institute for endometrial and colorectal cancers. Correlation of MMR status with patients’ survival was assessed using the Kaplan-Meier estimator. Statistical tests were two-sided.ResultsLoss of MMR proteins was homogeneous (dMMR) in 75 patients (17%) and heterogeneous (hMMR) in 55 (12%). Among luminal breast cancers, there were similar frequencies of dMMR and hMMR tumors. Overall, the rate of discrepancy between IHC and MSI analysis was high (91%). Women with Luminal B-like dMMR carcinomas (n = 44) showed shorter overall survival (median = 77 months, range = 0–115 months) than those with pMMR (n = 205) or hMMR (n = 35) tumors (median = 84 months, range = 0–127 months) (P = .008). On the contrary, patients with estrogen receptor-negative breast cancers treated with chemotherapy lived longer in cases of dMMR (n = 9) than pMMR (n = 33) or hMMR (n = 7) tumors, with 87 months of median survival (range = 73–123 months) for the former compared with 79 months (range = 8–113 months) for the latter two categories (P < .001).ConclusionsImmunohistochemistry and MSI are not interchangeable tests in breast carcinomas. MMR protein loss is a more common event than MSI and shows intra-tumor heterogeneity. MMR IHC allows the identification of clinically relevant subclasses of breast cancer patients, provided that multiple areas of the tumor are analyzed.

Highlights

Breast cancers that harbor mismatch-repair (MMR) deficiency and/or microsatellite instability (MSI) might be sensitive to immune checkpoint blockade, but there are currently no specific guidelines for assessing MMR status in breast cancer
Patients with estrogen receptor-negative breast cancers treated with chemotherapy lived longer in cases of dMMR (n 1⁄4 9) than pMMR (n 1⁄4 33) or hMMR (n 1⁄4 7) tumors, with 87 months of median survival for the former compared with 79 months for the latter two categories (P < .001)
We show that MMR protein loss is a rather common event in breast cancer and shows a remarkable degree of intra-tumor heterogeneity, making the analysis of a small area of the tumor, or a small biopsy, of little clinical value

Summary

Introduction

Breast cancers that harbor mismatch-repair (MMR) deficiency and/or microsatellite instability (MSI) might be sensitive to immune checkpoint blockade, but there are currently no specific guidelines for assessing MMR status in breast cancer. We sought to define the clinical value of MMR immunohistochemistry (IHC) and MSI analysis in breast cancers. Women with Luminal B-like dMMR carcinomas (n 1⁄4 44) showed shorter overall survival (median 1⁄4 77 months, range 1⁄4 0–115 months) than those with pMMR (n 1⁄4 205) or hMMR (n 1⁄4 35) tumors (median 1⁄4 84 months, range 1⁄4 0–127 months) (P 1⁄4 .008). Patients with estrogen receptor-negative breast cancers treated with chemotherapy lived longer in cases of dMMR (n 1⁄4 9) than pMMR (n 1⁄4 33) or hMMR (n 1⁄4 7) tumors, with 87 months of median survival (range 1⁄4 73–123 months) for the former compared with 79 months (range 1⁄4 8–113 months) for the latter two categories (P < .001). MMR IHC allows the identification of clinically relevant subclasses of breast cancer patients, provided that multiple areas of the tumor are analyzed

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