In this video, Judith Balmaña addresses the role of the BRCA1 and BRCA2 proteins in cancer risk assessment, early detection and cancer prevention, and the implication of BRCA deficiency as a predictive biomarker for targeted therapies in different tumour types.
BRCA1 and BRCA2 encode two large proteins, which localize to the cell nucleus and are widely expressed in different tissues during the S and G2 phases. These proteins work to preserve chromosome stability, mainly through DNA repair, cell cycle control, and fork stabilization during replication. BRCA1 is a pleiotropic DNA damage repair protein that functions in both checkpoint activation and DNA repair. BRCA1 links DNA damaging sensing and DNA damage repair effectors. BRCA2 is a mediator of the core mechanism of homologous recombination repair, responsible for error-free repair of double DNA strand breaks. Inactivation of either of the two proteins leads to carcinogenesis.
Germline mutations in these genes are relatively rare. It is estimated that their prevalence in the population is 1 out of 200-400 individuals, so 0.25%. This prevalence is higher in certain groups, such as individuals of Ashkenazi ancestry, where the prevalence is 1 out 40 individuals, or 2.5%, due to three founder mutations.
In unselected women with breast cancer, germline mutations in these genes are observed in 2-5%. This frequency is higher in women with triple negative breast cancer, or those of young onset, or with a family history.
Between 8-18% of women with invasive epithelial non-mucinous ovarian cancer might have a germline BRCA1 or BRCA2 mutation.
In pancreatic ductal adenocarcinoma, their frequency is 2-4%, and in prostate cancer the prevalence ranges from 1-2% if young onset or localised, to 4-6% among metastatic prostate cancer patients.
The cumulative risk of breast cancer in BRCA1 carriers is 40% at age 50, and 72% at age 80.
The cumulative risk of breast cancer in BRCA2 carriers is around 35% at age 50, and 68% at age 80.
Cumulative ovarian cancer risk is almost 40% for BRCA1 carriers, and almost 20% for BRCA2 carriers. The cumulative risk of pancreatic cancer, mainly in BRCA2 carriers, is between 1.5% and 3%, and that of prostate cancer, also mainly in BRCA2 carriers, is between 5% and 15%. These prostate tumours typically present earlier, with a more aggressive phenotype and a reduced survival than sporadic cancer.
Early detection of ovarian cancer still remains a challenge. Risk reducing bilateral salpingoophorectomy is recommended, usually around age 40, and around age 45 in BRCA2 carriers. In mutation carriers, this intervention has been associated with an ovarian cancer risk reduction of 80-95% and a mortality reduction.
Salpingectomy alone is a surgical procedure that is potentially as efficient as salpingoophorectomy, but it is still considered to be an investigational approach.
Prophylactic mastectomy has also been associated with a 90% or more breast cancer risk reduction and it is an option to individualise in women with a BRCA mutation.
Regarding surveillance options, women are recommended to undergo breast MRI from the age of 25, and add a mammogram at age 30, on a yearly basis. CA125 levels with transvaginal ultrasound every 6 months might be considered in women until the decision on prophylactic salpingoophorectomy. In men, prostate cancer screening is recommended from the age of 40-45 years.
Cancer cells with BRCA mutations lead to homologous recombination repair deficiency and are more sensitive to DNA damaging agents, such as platinum agents or PARP inhibitors.
Indeed, platinum-based regimens have shown higher efficacy in patients with advanced breast, ovarian, and pancreatic tumours associated with BRCA-deficiency.
PARP inhibitors have been approved for patients with advanced ovarian and breast cancer. In prostate cancer, a breakthrough designation by FDA has been granted; and in pancreatic cancer, clinical trials are currently ongoing.
Final take home messages:
- Germline testing of BRCA1/2 genes has implications for cancer risk assessment, surveillance/cancer prevention, and targeted therapy.
- Individuals with a germline BRCA1/2 mutation have an increased risk of breast cancer, ovarian cancer, pancreatic cancer, male breast cancer, prostate cancer.
- Surveillance recommendations and risk reduction surgeries are invidualised in patients with a germline BRCA1/2 mutation.
- BRCA1/2 mutations may cause homologous recombination deficiency and serve as a predictive biomarker for targeted therapies, such as platinum and PARP, among others.
- Mainstream BRCA genetic testing for therapeutic indications will likely increase the number of mutation carriers identified and represent an opportunity for cascade testing in relatives who may benefit from individualised surveillance and prevention programmes.
Produced by the European Society for Medical Oncology