Mismatch repair protein loss is a prognostic and predictive biomarker in breast cancers regardless of microsatellite instability

Despite the approval of pembrolizumab in all tumors showing mismatch-repair (MMR) deficiency and/or microsatellite instability (MSI), there are currently no companion diagnostics for MMR status assessment in breast cancer. Here, we sought to define the diagnostic and prognostic role of MMR and MSI testing in breast cancer patients. We subjected 444 breast cancers to MMR immunohistochemistry (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 the 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. In 75 patients (17%) the loss of MMR proteins was homogeneous, classified as dMMR, while 55 cases (12%) were hMMR. The prevalence of cancers with loss of the MMR proteins was homogeneous across ER+ breast cancers (15-19% for dMMR and 10-18% for hMMR tumors). The level of overlap between IHC and MSI analysis was 9% (p<0.0001). Among ER+/HER2- carcinomas, pMMR and hMMR patients displayed better survival rates (p=0.008). In chemo-treated ER-/HER2- breast cancers, the dMMR status was a marker of good prognosis (p<0.001). Our study documents the clinical impact of MMR testing in a large series of breast cancers, using the most commonly adopted diagnostic tools and criteria. We show that MMR protein loss is a rather common event in breast cancer and has a remarkable degree of intra-tumor heterogeneity, therefore making the analysis of a small area of the tumor, or a small biopsy, of little clinical value. Our investigation supports the concept that MSI occurs rarely in breast cancer and demonstrate that this condition is restricted to a minority of tumors with MMR protein loss. These data suggest that MMR IHC and MSI analysis should not be considered as interchangeable tests in the diagnostic workup of breast carcinomas. Finally, our observations indicate that the complete loss of at least one of the MMR proteins assessed by IHC is able to identify high-risk ER+/HER2- breast cancers that can potentially benefit from pembrolizumab therapy, whereas first-line chemotherapy shows comparatively good results in dMMR ER-/HER2- breast cancers.