Secondary Prevention in Hereditary Breast and/or Ovarian Cancer Syndromes Other Than BRCA

Abstract

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndromes are among the best-known and most extensively studied hereditary cancer syndromes. Nevertheless, many patients who proved negative at BRCA genetic testing bring pathogenic mutations in other suppressor genes and oncogenes associated with hereditary breast and/or ovarian cancers. These genes include TP53 in Li–Fraumeni syndrome, PTEN in Cowden syndrome, mismatch repair (MMR) genes in Lynch syndrome, CDH1 in diffuse gastric cancer syndrome, STK11 in Peutz–Jeghers syndrome, and NF1 in neurofibromatosis type 1 syndrome. To these, several other genes can be added that act jointly with BRCA1 and BRCA2 in the double-strand break repair system, such as PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D. Management of primary and secondary cancer prevention in these hereditary cancer syndromes is crucial. In particular, secondary prevention by screening aims to discover precancerous lesions or cancers at their initial stages because early detection could allow for effective treatment and a full recovery. The present review aims to summarize the available literature and suggest proper screening strategies for hereditary breast and/or ovarian cancer syndromes other than BRCA.

Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers

“…Second to the BRCA1 and BRCA2 genes, the most common germline pathogenic or likely pathogenic variants predisposing to BC were found in the ATM and CHEK2 genes [ 2 , 3 ]. Individuals carrying heterozygous pathogenic variants in ATM or CHEK2 present a 33% and 28–37% cumulative lifetime risk for BC by 80 years of age, respectively [ 7 , 8 , 9 ]. Nevertheless, while the phenotypes of BRCA-related tumors have been widely characterized, little is known about the clinicopathologic features of ATM and CHEK2 -associated tumors, BC in the first place.…”

“…Individuals carrying heterozygous pathogenic variants in ATM present a 33% cumulative lifetime risk for BC by 80 years of age [ 7 ], whereas certain variants in the CHEK2 gene are associated with increased BC risk, with a cumulative lifetime risk ranging from 28% to 37% depending on family history [ 8 , 9 ]. Due to this increased risk, for both ATM and CHEK2 carriers, mammogram with consideration of breast MRI is recommended yearly from 40 years of age according to the current National Comprehensive Cancer Network (NCCN) guidelines [ 10 ].…”

Heritability of Low ER Staining/HER2-Breast Tumors: Are We Missing an Opportunity for Germline Testing?

“…In patients with TNBC and BRCA mutations, platinum salts and PARP inhibitors, which exploit the genomic instability of cells with defective DNA repair, may be beneficial [ 16 ]. Surveillance and surgical strategies have also been developed for women with germline mutations in non-BRCA genes in order to prevent or facilitate in the early detection of additional cancers [ 17 ]. The opportunity to utilize these precision medicine approaches may not be available for women who harbor germline mutations but that are ineligible for germline testing using the current criteria.…”

Disease Spectrum of Breast Cancer Susceptibility Genes

“…Women with genes such as TP53, CDH1, PTEN, STK11, and NF1 may be managed according to established guidelines for the associated cancer predisposition syndrome. For instance, in Li-Fraumeni syndrome, annual whole-body MRI is advised in TP53 pathogenic variant carriers (45,46). More aggressive interventions may be recommended, such as consideration of prophylactic gastrectomy if a CDH1 mutation is found, even in the absence of gastric cancer in the family (47).…”