High-Penetrance Susceptibility Genes in Hereditary Breast Cancer Syndromes: An Updated Review on Clinical Approach

Abstract

: Breast cancer remains the most prevalent malignancy worldwide, ranking second in terms of cancer-related mortality. While exposure to modifiable risk factors, variations in screening efficacy, and inaccessibility to early-stage diagnosis contrast, an increased focus has been directed toward the study of its genetic profiles; particularly those attributed to germline pathogenic variants. This narrative review aims to present the major hereditary cancer syndromes associated with an increased breast cancer risk, and to highlight the evidence-based genotype-specific screening and treatment protocols. We examined current published literature and synthesized evidence from randomized controlled trials, observational studies and current clinical guidelines. The significance of genetic testing in breast cancer extends beyond prognostic, diagnostic and risk-assessment utility, with major contributions in therapeutic decision-making. Well-defined criteria for genetic testing are established, encompassing age, familial clustering of cancer, or tumor subtype. The most prevalent hereditary cancer syndrome is the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, driven by mutations in the BRCA1 , BRCA2, and PALB2 genes, while other syndromes, less prevalent but with an increased risk of breast cancer development, like Li-Fraumeni syndrome and Peutz-Jeghers syndrome, arise from mutations in tumor suppressor genes. Despite the contrast in penetrance and risk profiles between the two categories, surveillance should be initiated at early ages, across all syndromes. The therapeutic approach is based on PARP (poly-(adenosine diphosphate–ribose) polymerase (PARP)) inhibitors for BRCA1/2 and PALB2 carriers, while in cases with TP53 mutations, radiotherapy is contraindicated, due to the risk of radiation-induced secondary malignancies. Germline pathogenic variant testing in high-penetrance susceptibility genes serves as the cornerstone of personalized, risk-stratified breast cancer management, enabling prevention, surveillance, and case-specific therapeutic decision-making. The broader integration of multigene panel testing and genetic counselling into routine cancer care remains a fundamental step toward optimizing outcomes across hereditary breast cancer syndromes.