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4bases’paper of The Month – October 2023 -Impact of non-BRCA genes in the indication of risk-reducing surgery in hereditary breast and ovarian cancer syndrome (HBOC)

BRCA1 and BRCA2 stand out as the most well-known genes associated with hereditary breast and ovarian cancer (HBOC). Individuals carrying a pathogenic or likely pathogenic (P/LP) variant in these genes face a 45% to 75% risk of developing breast cancer and an 18% to 40% risk of developing ovarian cancer.
However, it is crucial to recognize that other non-BRCA genes also carry varying degrees of risk, categorized as high, moderate, or low risk based on their penetrance. For instance, TP53 is considered a high-risk gene, elevating the predisposition to HBOC by more than 60%, while genes like PTEN, CDH1, or PALB2 also fall into the high-risk category, with a 40% to 60% increased predisposition to HBOC.

Fortunately, these conditions are not insurmountable. Surgical interventions such as prophylactic bilateral mastectomy (PBM) and risk-reducing salpingo-oophorectomy (RRSO) are recommended for patients with P/LP variants in these high-risk genes. However, it’s essential to acknowledge and address the emotional impact of these surgeries when proposing them to patients.

Prophylactic bilateral mastectomy (PBM) emerges as a potent risk-reduction strategy, slashing the risk of contralateral breast cancer by 83% to 100%. This applies to both sporadic and hereditary breast cancer populations, including patients with BRCA mutations and high-risk non-BRCA gene variants. Recommendations for patients carrying non-BRCA P/LP variants in moderate-risk genes should be individualized, considering the patient’s familial history and preferences.

Risk-reducing salpingo-oophorectomy (RRSO) effectively lowers the risk of ovarian cancer and fallopian tube cancer by approximately 80% to 90%. Therefore, it should be suggested to women carrying mutated BRCA1/2 genes and non-BRCA P/LP variants, particularly after they have completed their gestational desires. The timing of this procedure should be tailored based on the specific gene affected, the patient’s preferences, and their familial history. In cases where RRSO is declined, bi-annual control should commence at age 30 to 35 or ten years prior to the earliest age of ovarian cancer diagnosis in affected families.

The objective of this descriptive, retrospective, and observational audit is to investigate the influence of non-BRCA genes in determining the need for risk-reducing surgeries. From May 2015 to May 2023, 288 families in Huelva, Spain underwent multigene panel testing using NGS, focusing on genes known to be high and moderate risk for HBOC, including PTEN, RAD51C, RAD51D, STK11, ATM, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, PALB2, and TP53.
Non-BRCA P/LP variants were identified in 38 families, prompting recommendations for risk-reducing surgery for 18 patients. The study’s findings lend support to the guidelines recommending the use of multigene panels for HBOC assessment. Identifying non-BRCA P/LP variants significantly impacts the management and prevention of affected families and reduces unnecessary monitoring in non-carrier relatives.

This study underscores the pivotal role of genetic diagnostics in the prevention of hereditary breast and ovarian cancer. To address this need, we at 4Bases propose three of our products:

  • the BRaCA panel, a kit for the identification of both of germline mutations in BRCA1 and BRCA2 genes.
  • HEVA pro, a kit for the identification of mutations in genes related to Breast and Ovary cancer, Familial adenomatous polyposis (FAP) and hereditary non polyposis colorectal cancer (HNPCC).
  • the HRD pro kit for the variants profiling and HRD score in Breast, Ovary and Prostate Cancer.

We at 4Bases take pride in our contribution to alleviating the burden of HBOC for patients!

Source: Madrigal, L. F., Garcé, M. Y. R., & Ruiz, F. J. J. (2023). Impact of non-BRCA genes in the indication of risk-reducing surgery in Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Current Problems in Cancer, 101008. https://doi.org/10.1016/j.currproblcancer.2023.101008


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