For Q3b, 10 RCTs evaluated genetic counselling.
For Q4, four studies evaluated risk assessment, two studies evaluated risk assessment and testing, and three studies evaluated testing only.
For Q5, five studies evaluated chemoprevention, four studies evaluated prophylactic bilateral mastectomy and four studies evaluated prophylactic oophorectomy. For Q6, five studies reported adverse events of chemoprevention, and observational and descriptive data were used for adverse events of prophylactic surgery.
In terms of methodological quality, overall, most of the studies were rated 'fair' quality and others were rated 'good'.
Q3b. Does risk assessment and BRCA mutation testing lead to a reduction in the incidence of breast and ovarian cancer and cause-specific or all-cause mortality?
No studies were identified.
Q4. What are the adverse effects of risk assessment, genetic counselling and testing?
No studies evaluated cancer or mortality outcomes in relation to genetic counselling. Overall, more studies reported decreased rather than increased breast cancer worry or anxiety after risk assessment and testing, while studies with depression as an outcome had mixed results. The studies were conducted in highly selected populations who were mainly white and had a high socioeconomic status.
Q5 and Q6. How well do interventions reduce the incidence and mortality of breast and ovarian cancer in women identified as high-risk by history and/or positive genetic test results, and what are the adverse effects of interventions?
No trials evaluating the effectiveness of intensive cancer screening for BRCA mutation carriers in reducing mortality were identified. No studies reporting the adverse events of intensive screening for breast or ovarian cancer were identified.
For chemoprevention, four RCTs evaluating tamoxifen and one evaluating raloxifene were identified. None of the included studies specifically evaluated chemoprevention for women with BRCA mutations. Chemoprevention was associated with a significant reduction in breast cancer (RR 0.62, 95% CI 0.46 to 0.83). The results were similar for studies of tamoxifen that included women with a family history of breast cancer (three studies). The risk of oestrogen-receptor-positive breast cancer was also significantly reduced (RR 0.39, 95% CI 0.20 to 0.79).
Five RCTs found that chemoprevention was associated with an increased risk of thromboembolic events (RR 2.21, 95% CI 1.63 to 2.98), three found an increased risk of stroke (RR 1.50, 95% CI 1.01 to 2.24), and three found an increased risk of endometrial cancer (RR 2.42, 95% CI 1.46 to 4.03). Other commonly reported adverse events were cataracts, hot flashes and gynaecological problems.
No RCTs on the use of oral contraceptives to prevent breast or ovarian cancer were identified. Observation studies suggested that oral contraception was associated with reduced ovarian cancer in the general population (three studies) and in BRCA carriers (two studies), but an increased risk of breast cancer among those with a family history (one study) and mutation carriers (one study).
No RCTs on the use of prophylactic surgery were identified. Four observational studies of prophylactic bilateral mastectomy in high-risk women found a risk reduction of breast cancer ranging from 85 to 100%. One additional study found a 21% risk of complications in high-risk women who had a prophylactic mastectomy with immediate reconstruction. Four observational studies of prophylactic oophorectomy in high-risk women found a risk reduction ranging from 85 to 100% for ovarian cancer and from 53 to 68% for breast cancer. One study of prophylactic oophorectomy in carriers of BRCA mutations found a complication risk of 5%. Four observational studies found a decreased risk for invasive epithelial ovarian cancer.
Descriptive studies of the psychological harms of prophylactic mastectomy or oophorectomy in high-risk women found mixed results; some suggested that cancer distress improved, but self-esteem, body image and some other outcomes could be adversely affected.