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4bases’Paper of the Month – July 2022 -Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer

Our team’s reading recommendation for this month is “Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of Italian Scientific Societies”, an excellent scientific review written by A Russo et al., recently published in “European Society for Medical Oncology”1

The presence of deleterious variants in the BRCA1/BRCA2 gene is generally linked or associated with an increased risk of developing breast or ovarian cancer. These variants are called pathogenic variants (PV). These BRCA1/2 PVs have not only been linked to ovarian and breast cancers but also have been found to be associated with other types of cancer such as pancreatic cancer (BRCA1/2 PVs) and prostate cancer (only BRCA2 PVs).

The increase in the number of approved therapies, accompanied by a better understanding of BRCA1/2-related cancers and the emergence of rapid technological advances in germline and tumor analysis, has made the optimization of the BRCA testing an imperative. To this end, this article provides an update on the BRCA testing and how it can be implemented in clinical practice. First, the article focuses on the BRCA test to diagnose an inherited predisposition to cancer, and how it can be used as a predictive tool for the efficacy of cancer therapies (mentioning different examples related to the types of cancer already mentioned). Next, BRCA sequence analysis and its limitations are discussed, as well as the interpretation of genetic variants, while highlighting the importance of using standardized and harmonized procedures for the latter two points.

Because the BRCA testing generally considers different elements for the identification of tumors related to an inherited predisposition, the identification of individuals with BRCA PVs allows them or their families to benefit from prevention avenues such as access to genetic counseling, screening programs or risk reduction strategies. 

This article also mentions the importance of incorporating BRCA testing as a key routine in the clinical diagnostic pathway, as it could be a critical tool to aid in medical or surgical decision making. Indeed, BRCA testing has been shown to optimize preventive decision making and help select the most effective cancer treatment. For example, BRCA PVs have been shown to be predictive biomarkers of of higher responsiveness to treatment with PARP enzyme inhibitors. This enzyme is involved in the repair of damaged single-stranded DNA. More concretely, the presence of a BRCA PV has therapeutic implications for women with breast cancer that may influence the choice of locoregional and systemic adjuvant/neoadjuvant therapy; this makes BRCA testing an essential step to be performed promptly after diagnosis. This is also true for metastatic cases.

For BRCA sequence analysis, somatic and germline testing are routinely performed via next-generation sequencing (NGS), but standardization of the entire NGS-based BRCA analysis procedure is not fully realized for a number of reasons, both in terms of pre-analytical and analytical conditions. This remains problematic, so BRCA sequence analysis requires additional confirmatory testing to better manage the patient. On the other hand, the presence of variants of uncertain significance (VUS) in 1 to 2 out of 10 individuals undergoing BRCA genetic screening were also noticed. These variants have unknown functions and may be responsible for certain diseases, making it more difficult to interpret the genetic results and subsequently manage the patients. It should also be noted that failure to identify BRCA PVs in some cases does not imply the absence of breast or ovarian cancer risk, but this risk could be explained by other pathogenic variants in relation to other genes. Therefore, genotyping of multigene panels should be considered for better understanding/identification.

We at 4bases have developed a series of CE-IVD multigene BRCA panels to respond to this increasing need from the medical community. We do also support the scientific community in finding new diagnostic pathways, through custom – on-demand – panels and through our bioinformatics platforms. Find out more here.


1 Russo A, Incorvaia L, Capoluongo E, Tagliaferri P, Gori S, Cortesi L, Genuardi M, Turchetti D, De Giorgi U, Di Maio M, Barberis M, Dessena M, Del Re M, Lapini A, Luchini C, Jereczek-Fossa BA, Sapino A, Cinieri S; Italian Scientific Societies. Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of Italian Scientific Societies. ESMO Open. 2022 May 18;7(3):100459. doi: 10.1016/j.esmoop.2022.100459. Epub ahead of print. PMID: 35597177; PMCID: PMC9126927.

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