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

Abstract

Background 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. Here, we sought to define the clinical value of MMR immunohistochemistry (IHC) and MSI analysis in breast cancers. Methods We 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. Results Loss 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). Conclusions Immunohistochemistry 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.

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

“…Furthermore, a recent study in 94 HER2-positive luminal B breast cancer patients showed that, although 13.5% of cases had a germline mutation (V384D) in the MLH1 gene, only 3 cases (3.2%) were MLH1-deficient by IHC [37]. In contrast, a recently published cohort from Italy reported a ten-times higher frequency (17%, 75 out of 444 cases) of homogenous MMR loss by immunohistochemistry [30]; although when further investigated by microsatellite instability assay, all but seven of these were negative (meaning only 1.6% of cases overall were MSI positive). The discrepancy in their reported frequency of MMR-deficient cases in breast cancer by IHC could be due to the inclusion of cases which lack an internal positive control.…”

“…Another limitation of our study is that the determination of MMR loss by IHC is based on its strong correlation with the functionality of MMR rather than direct assessment of DNA mutational patterns. We are aware of the potential misrepresentation, but have found many sources supporting the robustness of IHC compared to genomic methods [19,30]. Some reports suggest there is a tradeoff Fig.…”

“…MMR protein expression was scored by a pathologist blinded to the associated outcome data. According to published guidelines, only cores with absent nuclear staining in all carcinoma cells in the concurrent presence of positive stromal cell internal controls on the same tissue microarray core were categorized as deficient [30,31]. Cores with nuclear staining in carcinoma cells and stromal controls were categorized as intact.…”

PTEN Expression as a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer

“…In breast cancers, alterations in the expression patterns of the MMR proteins are not exceptional, being observed at a frequency of 2-29%, and have both a prognostic and predictive value [7][8][9][10]. The pathological evaluation of MMR status, however, is controversial in these neoplasms [10,11].…”

VUS-type alteration in POLD1 and microsatellite instability in a metastatic luminal B breast cancer patient

“…During replication, they may suffer errors which are quickly repaired, and normal replication follows. Hence, microsatellite instability (MSI) is the name given to the germline allele portion of the microsatellite that has suffered addition or deletion of its units, product of loss of cell capacity to correct errors associated with replication, resulting in a somatic length alteration [3,11].…”