Risk-Reducing surgery in BRCA1 or 2 mutation carriers

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; ALCARAZ, A.; GLUJOVSKY, D.; LOPEZ, A.; REY-ARES, L.; BARDACH, A.; CIAPPONI, A; GONZALEZ, L

Documento de Evaluación de tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Breast cancer type 1/2 (BRCA1/2) susceptibility genes may undergo deleterious mutations leading to a significant increase in the risk of cancer if compared with that of the general population (50-85% breast cancer versus 11%; ovarian cancer above 20% versus 1.5%). In the general population, the frequency of harmful mutations is less than 1%, but above 8% in those women at high risk due to family history. There is international consensus on the fact that BRCA gene identification should be recommended only in women at high risk as stated by predefined criteria. Different therapeutic strategies are proposed to reduce the risk associated with these mutations: Preventive chemotherapy, intensive screening and surgery. Bilateral mastectomy (RRBM) and salpingo oophorectomy (RRSO), both known as risk-reducing surgeries are proposed as therapeutic options in these patients.TechnologyFor risk-reducing surgery, mastectomy may be simple (complete) or subcutaneous, while salpingo oophorectomy require resection of fallopian tubes as well as both ovaries.PurposeTo assess the available evidence on the efficacy, safety and coverage related aspect regarding the use of risk-reducing surgery in BRCA1/2 mutation female carriers.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsTwo systematic reviews, four prospective cohort studies, five clinical practice guidelines, one health technology assessment, two economic evaluations and eight coverage policies were selected.MortalityThe PROSE cohort (n=2,482 mutation female carriers) associated RRSO with a decrease in the risk of death due to all causes (3.1% versus 9.8%; HR= 0.40; 95% CI: 0.26-0.61) after a median follow up of 3.7 years. There was also lower mortality due to breast cancer (2.1% versus 5.7%; HR= 0.44; 95% CI, 0.26 - 0.76) and ovarian cancer (0.04% versus 2.5%, HR= 0.21; 95% CI: 0.06-0.80).Incidence of Breast CancerThe PROSE study evidenced the association of RRBM with a lower risk of breast cancer (n=1,619), since no event was detected during the three-year follow up in women undergoing RRBM (0/247), versus 7.14% (98/1,372) in the group choosing intensive screening. In this very same study, the RRSO was also associated to a decrease in the risk of primary breast cancer (HR=0.54; 95% CI: 0.37 - 0.69). One meta-analysis (n=5,703) published earlier showed that the RRSO was also associated to a significant reduction in the risk of breast cancer (HR=0.49; 95% CI: 0.37 - 0.65). The EMBRACE study (a cohort of 1,639 mutation female carriers) confirmed these results but only when the RRSO was performed before the age of 45 (HR: 0.39; 95% CI: 0.17 ? 0.87; p=0.02). Other two cohort prospective studies showed similar results about RRBM.Incidence of Ovarian CancerOne three-study meta-analysis (n=2,840) reported a significant reduction in the risk of ovarian or fallopian tube cancer in those patients undergoing RRSO (HR= 0.21; 95%:CI 0.12 ? 0.39). The PROSE study showed similar results (HR: 0.28; 95% CI: 0.12 - 0.69).Clinical Practice GuidelinesThe United States National Cancer Network and the European Oncology Society recommend RRSO in female carriers of a deleterious mutation of BRCA1/2 genes, ideally 35 to 40 years old or after the child-bearing period. They recommend RRBM as a therapeutic option that should be considered case by case. The United States Preventive Service Taskforce concludes that there is reasonable evidence that prophylactic surgery decreases the incidence of breast and ovarian cancer in these women and that the related complications are non significant when compared with the expected benefits. In Canada, the National Hereditary Cancer Taskforce considers that both RRBM and RRSO should be considered in all women with known BRCA1/2 gene mutations.Coverage PoliciesThere is agreement among the United States health insurance companies consulted in providing coverage of RRBM and RRSO in female BRCA 1/2 gene mutation carriers.ConclusionsThe quality of the evidence found is poor. RRBM and RRSO as risk-reducing strategies showed a decrease in the incidence of cancer in deleterious mutation female carriers, although only in the case of RRSO, this benefit was associated with a lower mortality. Even though the evidence is still poor and low quality, there is an international consensus to recommend RRSO, specially in women under 40, and in considering and discussing in detail the risks and benefits of RRBM. Since the individual risk may differ among carriers, as well as the benefit expected from the different therapeutic strategies, a genetic consultation is considered key to the decision making process