New criteria to select patients with breast cancer to perform germline BRCA1/2 testing

Abstract

In the future genetic testing to detect high/moderate susceptibility genes for breast cancer (BC) and other cancers will be generalized to the entire population. Until this happens, it is important to improve the current selection criteria for germline testing. We studied the genetic alterations of a total of 133 BC patients (32 women with bilateral BC: total of 165 BCs) in order to determine the molecular alteration responsible for their intense familial aggregation of cancer. We found 44 women with inherit mutations in the BRCA1 gene and 34 in the BRCA2 gene. We compared the series of BRCA1/2-positive BC patients with the rest of the BC patients. Based on the differences found in our series, we propose that the current guidelines for germline BRCA1/2 testing should also include the following criteria: 1) All BC patients with certain histological subtypes: medullary and metaplastic, as well as those that present a specific type of tumor frequently classified as "infiltrating ductal carcinoma of no special type" by pathologists but which we identify as "infiltrating ductal carcinomas with rows and necrosis" (since it has peculiar and easily recognizable histological features: distribution in cords and solid nests of cells with large areas of necrosis, abundant atypical mitoses, and highly pleomorphic nuclei); 2) All families with at least one relative with multiple cancer: especially when the cancer associated with BC is gynecological (BRCA1) or digestive cancer (BRCA2), consider in the presence of any other type of low prevalent cancer (gliomas, leukemias, melanomas); 3) All BC patients whose molecular subtype is triple negative (BRCA1), consider with the luminal B (HER2-negative) if there is familial aggregation of cancer (BRCA2).

Germline pathogenic variants in metaplastic breast cancer patients and the emerging role of the BRCA1 gene

“…However, only one of these patients underwent detailed germline analysis and proved to be carrier of a deleterious variant in NF1 gene [38]. Finally, Rodríguez-Fernández and colleagues [39,40] found a statistically signi cant difference in frequencies of histological types between BRCA1 carriers vs. non carriers. In particular, they reported 3.2% MpBCs in 93 BRCA1-positive BCs vs. 0.8% MpBCs in 3157 non BRCA-positive BCs.…”

Metaplastic breast cancer: an all-round multidisciplinary consensus

“…However, positive results of NeuroFibromin 1 (NF1) germline testing were available only for one of these patients (Suarez-Kelly et al, 2018). In their study, Rodríguez-Fernández et al (2021) found a statistically significant difference in frequencies of histological types and BRCA germline mutations. In particular, they described a frequency of 3.2% MpBCs in 93 BRCA-positive BCs vs. 0.8% MpBCs in 3157 non-BRCA-positive BCs.…”

“…Notably, all these MpBCs were BRCA1-positive. Based on these findings, they proposed to add positive personal history of MpBC to the clinical selection criteria for genetic testing (Rodríguez-Fernández et al, 2021). Thus, available data suggest a possible involvement of germline BRCA1 PVs in MpBC development.…”

A comprehensive overview of metaplastic breast cancer: Features and treatments

“…MpBCs have been shown to be relevant to BCRA-positive breast cancers. 45 Likewise, Corso et al 46 demonstrated breast cancer patients who carried a germline pathogenic variant in the BRCA genes proved to have an increased risk of developing MpBC relative to other BRCA noncarriers (1.2% vs. 0.2%; Table 1). In addition to being more susceptible to platinum agents, patients carrying a germline pathogenic variant may also be more sensitive to poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, which were approved by the FDA for a metastatic/locally advanced breast cancer indication.…”