Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization

Abstract

The clinical outcome of patients with a diagnosis of hormone receptor (HR)+ breast cancer has improved remarkably since the arrival of endocrine therapy. Yet, resistance to standard treatments is a major clinical challenge for breast cancer specialists and a life-threatening condition for the patients. In breast cancer, mismatch repair (MMR) status assessment has been demonstrated to be clinically relevant not only in terms of screening for inherited conditions such as Lynch syndrome, but also for prognostication, selection for immunotherapy, and early identification of therapy resistance. Peculiar traits characterize the MMR biology in HR+ breast cancers compared to other cancer types. In these tumors, MMR genetic alterations are relatively rare, occurring in ~3 % of cases. On the other hand, modifications at the protein level can be observed also in the absence of gene alterations and vice versa. In HR+ breast cancers, the prognostic role of MMR deficiency has been confirmed by several studies, but its predictive value remains a matter of controversy. The characterization of MMR status in these patients is troubled by the lack of tumor-specific guidelines and/or companion diagnostic tests. For this reason, precise identification of MMR-deficient breast cancers can be problematic. A deeper understanding of the MMR biology and clinical actionability in HR+ breast cancer may light the path to effective tumor-specific diagnostic tools. For a precise MMR status profiling, the specific strengths and limitations of the available technologies should be taken into consideration. This article aims at providing a comprehensive overview of the current state of knowledge of MMR alterations in HR+ breast cancer. The available armamentarium for MMR testing in these tumors is also examined along with possible strategies for a tailored pathological characterization.

Commentary: Mismatch Repair Deficiency and Microsatellite Instability in Triple-Negative Breast Cancer: A Retrospective Study of 440 Patients

“…The actual frequency of dMMR in TNBC, however, is controversial, since MMR mutations are reported in ∼2% of cases, while an impaired protein expression seems to be more frequent (15,17,18), probably due to post-transcriptional modifications (Figure 1). Interestingly, dMMR TNBC often present a single protein loss (19), as also noted by Ren et al…”

HER2 Low, Ultra-low, and Novel Complementary Biomarkers: Expanding the Spectrum of HER2 Positivity in Breast Cancer

“…MMR is known as one of the fundamental DNA repair pathways ( Piciotti et al, 2021 ) Defects in the MMR system are commonly due to molecular alterations involving the MutS and MutL dimeric homologs ( Corti et al, 2019 ; Lopez et al, 2020 ). These complexes interact with each other to regulate the recognition and cleavage of incorrect base insertions ( Sajjadi et al, 2021a ). Almost 15–17% of ER+/HER2− breast cancer patients are correlated with endocrine treatment resistance due to MutL deficiency ( Haricharan et al, 2017 ; Sajjadi et al, 2021 ).…”

“…Recent preclinical studies on HER2 targeting in MutL-deficient estrogen receptor (ER)+/HER2-negative breast cancers have shown positive results ( Punturi et al, 2021 ). These data might provide a further rationale for expanding our pathological armamentarium towards mismatch repair (MMR)-related biomarkers ( Venetis et al, 2020b ; Sajjadi et al, 2021b ).…”

Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

“…Unbalances in this mechanism lead to an increased risk of fractures, particularly at the distal femur and proximal tibia levels [28]. This complex process is regulated by resident bone cells and other cell types of the bone microenvironment, including lymphocytes, macrophages, hematopoietic cells, and endocrine signaling molecules [29][30][31][32][33][34]. In particular, the discovery of endocrine mediators produced by the skeleton has radically changed our understanding not only of the bone biology but also of the endocrinology in general [34].…”