Improving treatment management: genetics in focus

The genetics of breast cancer has become a fundamental aspect of treatment management. It influences screening, follow-up, prophylactic and therapeutic recommendations for women who carry a germinal breast cancer susceptibility gene. In addition, it helps identify patient subgroups with different prognosis or different response to therapy.

Pathogenic variants in breast cancer (BC) susceptibility genes represent the strongest inherited risk factor for disease development, particularly in the context of early-onset breast cancer (EOBC). In fact, about 10-20% of EOBC cases are hereditary. Consequently, individuals with a personal or family history of breast, ovarian, prostate, or pancreatic cancer may benefit from a hereditary risk assessment to determine their own and their family members’ risk for these and related cancers. In this context, 75 tumor samples from a cohort of Polish BC patients who had negative results for targeted mutations of breast cancer susceptibility gene 1 (BRCA1) were studied. All coding regions of BRCA1/2 genes were sequenced by next generation sequencing (NGS), with detection of nine pathogenic variants and six variants of unknown significance (VUS). However, the authors also focused on methodological aspects of NGS and emphasized the differences in VCF files derived from the same FASTQ file. They therefore concluded that this observation could potentially influence the identification and interpretation of variants.

Individual therapy decision

In addition, recent studies have shown that BRCA1/2 germline status is clinically relevant in the selection of therapy for patients already diagnosed with BC. Indeed, BRCA status predicts response to platinum-based chemotherapy and to inhibitors of poly(ADP-ribose) polymerase (PARP). This highlights the ability of these interventions to inhibit DNA repair pathways. From a surgical perspective, surgical risk reduction remains an effective tool in the therapeutic armamentarium for many women with genetic predispositions. However, initial BC and contralateral BC risks should be clearly identified to match risk mitigation strategies and ideal timing, also in accordance with the patient’s personal preferences. While the survival benefit of prophylactic bilateral mastectomy has been established, there is increasing oncologic safety of nipple-preserving mastectomy as a risk-reducing procedure in BRCA-mutated patients with low rates of new BCs, low rates of postoperative complications, and high satisfaction and postoperative quality of life.

Other gene variants with moderate to high risk for breast cancer

In addition to BRCA1/2, pathogenic variants in other high- to intermediate-risk genes such as tumor protein p53 (TP53), the partner and localizer of BRCA2 (PALB2), phosphatase and tensin homolog (PTEN), checkpoint kinase 2 (CHEK2), and ataxia telangiectasia mutation (ATM) are responsible for a smaller percentage of BC cancers and, in some cases, ovarian, prostate, or pancreatic cancers.

ATM is particularly involved in cell cycle control, apoptosis, oxidative stress, and telomere maintenance, and its role as a risk factor for cancer development is well established. Recent studies have confirmed that some ATM variants are associated with intermediate and high-grade disease, a higher rate of lymph node metastasis, HER2 positivity, and the development of a contralateral breast tumor. The clinicopathologic features of BC arising from an ATM and checkpoint kinase 2 (CHEK2) mutation were also investigated. A total of 19 ATM and 17 CHEK2 mutation carriers associated with 46 different BCs were identified. A high rate of bilateral tumors was observed in ATM (26.3%) and CHEK2 mutation carriers (41.2%). While 64.3% of CHEK2-mutated tumors were luminal A-like, 56.2% of ATM-mutated tumors were luminal B-like/HER2-negative. In addition, 21.4% of CHEK2-associated invasive tumors had a lobular histotype. Approximately one-quarter of all ATM-related and one-third of CHEK2-related BCs were in situ carcinomas, and more than half of ATM- and CHEK2-related BCs were diagnosed at stage I-II. The biological and clinical characteristics of ATM- and CHEK2-associated tumors may help improve diagnosis, prognosis, and targeted therapeutic approaches.

Correct DNA sequence mutations

While different disease-causing mutations have since been identified, therapy is still often aimed at interfering with an aberrantly activated metabolic pathway rather than correcting the mutation in the DNA sequence. Here, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 could be used for the identification and validation of genomic targets with tumorigenic potential. CRISPR/Cas9 surpasses its predecessors in simplicity, efficiency and affordability. However, both precise knowledge of the pathogenic variants and optimization of the system itself are essential for conventional use.