Recommendation 4

• • In the absence of contraindications, premenopausal women who harbour a pathogenic or likely pathogenic variant in BRCA1 and BRCA2 undergoing RRSO should be offered hormone therapy until the average age of menopause (age 51). • • Systemic HRT, at any age, is not recommended for women who harbour a pathogenic or likely pathogenic variant in BRCA1 and BRCA2 who have had a personal history of breast cancer. These women can be offered non-hormonal alternatives for vasomotor symptom management. • • Symptoms related to the genitourinary syndrome of menopause should be treated with moisturizers, lubricants, and local low-dose estrogen therapy as needed.

Qualifying Statements for Recommendation 4

• • The treatment of symptoms relating to the genitourinary syndrome of menopause in the third bullet point is based on accepted general practice and not BRCA-carrier-specific evidence.

• • Where combination HRT is used, it is prudent to choose progesterone over synthetic progestins, or the TSEC (Tissue-Selective Estrogen Complex) [24].

Key Evidence for Recommendation 4

Five meta-analyses concerning HRT use in women who harbour a pathogenic or likely pathogenic variant in BRCA1 and BRCA2 were found [25–29]. The systematic review by Gordhandas et al. evaluated five studies that demonstrated that women who used HRT reported fewer endocrine symptoms (p < 0.05) and had similar levels of sexual functioning when compared to women without HRT after RRSO. Women had less discomfort (p = 0.001) and HRT reduced dyspareunia (p = 0.027) [26]. In the Gordhandas et al. systematic review bone health was assessed by three studies. The studies demonstrated that in women who used HRT the OR for bone disease was 1.2 (95% CI, 0.4 to 3.7). Another study showed that women who had been deprived of estrogen for greater than two years had a higher prevalence of bone loss compared with women who took HRT. Women who had not taken HRT after RRSO through at least age 45 had significantly higher mortality due to cardiovascular disease (HR, 1.84; 95% CI, 1.27 to 2.68, p = 0.001). Women who took HRT after RRSO had similar outcomes to women not undergoing RRSO (HR, 0.65; 95% CI, 0.30 to 1.41, p = 0.28) [26]. The risk of developing breast cancer was assessed by three systematic reviews. All three reviews showed that taking HRT was not associated with an increase in breast cancer diagnosis. The systematic review and meta-analysis by Marchetti et al. included three studies. The risk of breast cancer associated with HRT use after RRSO was 1.01 (95% CI, 0.16 to 1.54). When limited to prospective trials, the risk of breast cancer in women who harbour a pathogenic or likely pathogenic variant in BRCA1 and BRCA2 who used HRT did not have a negative impact (HR, 0.98; 95% CI, 0.63 to 1.52). A subgroup analysis on the type of HRT showed no significant difference in breast cancer risk for women who used estrogen alone compared to estrogen and progesterone. However, the breast cancer risk was lower for women who used estrogen alone versus estrogen and progesterone in the overall population (OR, 0.62; 95% CI, 0.29 to 1.31) [27]. The systematic review by Vermeulen et al. also examined the risk of breast cancer in women taking HRT following RRSO. Seven studies were evaluated and none of the studies showed that short-term use (2.8 to 4.3 years) was associated with an increase in breast cancer risk [29].