Defects in specific components of the MMR system can causally induce ET resistance in HR+ breast cancer and thereby, poor patient outcomes [
7]. However, MMR deficiency also appears to uncouple hormone signaling and cell cycle regulation at the G1/S cell cycle transition, thereby potentially making these tumors more susceptible to cyclin-dependent kinase (CDK)4/6 inhibition, even as a front-line therapy [
7,
48]. Interestingly, it has been previously reported that a possible mechanism of chemoresistance in HR+/HER2-transformed breast cancer is related to MSH2 downregulation by TGFβ-induced miR-21 [
49]. In addition, preclinical data suggest that the DNA homologous recombination gene BRCA1 may be a positive regulator of MSH2 in HR+/HER2+ breast cancer, suggesting that its tumor-suppressor function can be mediated by the MMR system [
50]. In tamoxifen-treated HR+ breast cancer patients, MMR deficiency is related to worse overall and disease-specific survival (HR 2.29, 95 % CI 1.02–5.17,
p = 0.040 and HR 2.71, 95 % CI 1.00–7.35,
p = 0.042, respectively). This finding suggests a potential role of MMR status to detect HR+ patients who may benefit from treatments other than ET [
29]. In another study, the overall survival (OS) rate of dMMR and non-dMMR tumors were profoundly different in both Luminal B and HR- breast cancers. Accordingly, patients with HR+ dMMR carcinomas had worse OS (median = 77 months, range = 0–115 months) than those with MMR-proficient (pMMR) or MMR-heterogeneous (hMMR) tumors (median = 84 months, range = 0–127 months) (
p = 0.008). In contrast, HR− dMMR patients treated with chemotherapy showed a better OS compared to the pMMR or hMMR group (median = 87 and 79 months, range = 73–123 and 8–113 months, respectively;
p < 0.001) [
21]. Likewise, the potential effect of each MMR protein has also been studied in different subtypes of breast cancer. In this regard, the most recurrent type of MMR deficiency both in HR+ and HR− breast cancers is related to the loss of expression of MSH2 alone, with a significant correlation with shorter survival times (
p = 0.04) [
30]. As discussed above, although dMMR colorectal and endometrial tumors demonstrate a response to ICB, whether dMMR breast tumors would do so as well remains untested. This is an interesting question for further study because of the apparent innate differences in the impact of MMR deficiency on TMB in HR+ breast cancers relative to that observed in colorectal or endometrial cancers [
37,
51]. A final point of interest to improve actionability against this driver of poor outcomes in HR+ breast cancer is to better understand the biological and functional impact of mutations in MMR genes that are observable in the neoplastic cells. The vast majority of these are individual missense mutations that, at this time, remain variants of unknown significance.