Hormone Replacement Therapy in Carriers of the BRCA1 Mutation

By Pelin Batur, MD

A 41-year-old healthy mother of three was recently found to be a carrier of the BRCA1 mutation. She is planning to undergo prophylactic bilateral salpingo-oophorectomy for ovarian cancer prevention. However, she is apprehensive about undergoing surgical menopause. Should she be started on hormone replacement therapy after oophorectomy? How would hormone replacement therapy affect her risk of breast cancer?

In females who carry the BRCA1 mutation, the cumulative risk of both ovarian and breast cancer approaches 44% (95% confidence interval [CI] 36%–53%) and 72% (95% CI 65%–79%) by age 80.1 Prophylactic salpingo-oophorectomy reduces the risk of breast cancer by 50% and the risk of ovarian cancer by 90%. Unfortunately, premature withdrawal of ovarian hormones has been associated with long-term adverse effects including significant vasomotor symptoms, decreased quality of life, sexual dysfunction, early mortality, bone loss, decline in mood and cognition, and poor cardiovascular outcomes.2 Many of these effects can be avoided or lessened with hormone replacement therapy.

No significant difference in breast cancer diagnosis rates in hormone replacement therapy users

Kotsopoulos et al3 conducted a longitudinal, prospective analysis of BRCA1 mutation carriers in a multicenter study between 1995 and 2017. The mean follow-up period was 7.6 years (range 0.4–22.1). The study assessed associations between the use of hormone replacement therapy and breast cancer risk in carriers of the BRCA1 mutation who underwent prophylactic salpingo-oophorectomy. Study participants did not have a personal history of cancer. Those with a history of prophylactic mastectomy were excluded.

Participants completed a series of questionnaires every two years, disclosing updates in personal medical, cancer, and reproductive history. The questionnaires also inquired about the use of hormone replacement therapy, including the type used (estrogen only, progestin only, estrogen plus progestin, other), brand name, duration of use, and dose and route of administration (pill, patch, suppository).

Of the 13,087 BRCA1 mutation carriers identified, 872 met the study criteria. Of those, 377 (43%) reported using some form of hormone replacement therapy after salpingo-oophorectomy, and 495 (57%) did not. The average duration of use was 3.9 years (range 0.5–19), with most (69%) using estrogen alone; 18% used other regimens, including estrogen plus progestin and progestin only. A small percentage of participants did not indicate which formulation they used. On average, women using hormone replacement therapy underwent prophylactic oophorectomy earlier than nonusers (age 43.0 vs 48.4; absolute difference 5.5 years, p < .001).

During follow-up, there was no significant difference noted in the proportion of women diagnosed with breast cancer between hormone replacement therapy users and nonusers (10.3 vs 10.7%; absolute difference 0.4%; p = .86). In fact, for each year of estrogen-containing hormone replacement therapy, there was an 18% reduction in breast cancer risk when oophorectomy was performed before age 45 (95% CI 0.69–0.97). The authors also noted a nonsignificant 14% trend toward an increase in breast cancer risk for each year of progestin use after oophorectomy when surgery was performed before age 45 (95% CI 0.9–1.46).

Although prophylactic hysterectomy was not recommended, the authors noted that hysterectomy would eliminate the need for progestin-containing hormone replacement therapy. For those who underwent oophorectomy after age 45, hormone replacement therapy did not increase or decrease the risk of breast cancer.2

A meta-analysis by Marchetti et al4 also supports the safety of hormone replacement therapy after risk-reducing salpingo-oophorectomy. Three studies that included 1,100 patients were analyzed (including the Kotsopoulos study noted above). There was a nonsignificant decrease in breast cancer risk in women on estrogen-only hormone replacement therapy compared with women on estrogen-plus-progestin therapy (odds ratio 0.53, 95% CI 0.25–1.15). Overall, the authors regarded hormone replacement therapy as a safe therapeutic option after prophylactic salpingo-oophorectomy in carriers of the BRCA1 and BRCA2 mutations.4

In a case-control study published in 2016,5 hormone replacement therapy was assessed in 432 postmenopausal BRCA1 mutation carriers with invasive breast cancer (cases) and in 432 BRCA1 mutation carriers without a history of breast cancer (controls). Results showed no difference in breast cancer risk between hormone replacement therapy users and nonusers.5

Rebbeck et al6 evaluated short-term hormone replacement therapy in BRCA1 and BRCA2 gene-mutation carriers after they underwent prophylactic salpingo-oophorectomy. The results showed that hormone replacement did not affect the breast cancer risk-reduction conferred with prophylactic bilateral salpingo-oophorectomy.

Johansen et al7 evaluated hormone replacement therapy in premenopausal women after prophylactic salpingo-oophorectomy. They studied 324 carriers of BRCA gene mutations after they underwent prophylactic salpingo-oophorectomy and a subset of 950 controls who had bilateral salpingo-oophorectomy for reasons unrelated to cancer. In both groups, hormone replacement therapy was underutilized. The authors recommended using it when clinically indicated.

Should your patient start hormone replacement therapy?

This patient is healthy, and in the absence of contraindications, systemic hormone replacement therapy after prophylactic oophorectomy could mitigate the potential adverse effects of surgically induced menopause. The patient can be reassured that estrogen-containing short-term hormone replacement therapy is unlikely to increase her breast cancer risk.

References

1. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402–2416.
2. Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric. 2015;18(4):483–491.
3. Kotsopoulos J, Gronwald J, Karlan BY, et al; Hereditary Breast Cancer Clinical Study Group. Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1 mutation carriers. JAMA Oncol. 2018;4(8):1059–1065.
4. Marchetti C, De Felice F, Boccia S, et al. Hormone replacement therapy after prophylactic risk reducing salpingo-oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a metaanalysis. Crit Rev Oncol Hematol. 2018;132:111–115.
5. Kotsopoulos J, Huzarski T, Gronwald J, et al. Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case-control study. Breast Cancer Res Treat. 2016;155(2):365–373.
6. Rebbeck TR, Friebel T, Wagner T, et al; PROSE Study Group. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2005;23(31):7804–7810.
7. Johansen N, Liavaag AH, Iversen OE, Dørum A, Braaten T, Michelsen TM. Use of hormone replacement therapy after risk-reducing salpingo-oophorectomy. Acta Obstet Gynecol Scand. 2017;96(5):547–555.

***This is an abridged version of an article originally published in the Cleveland Clinic Journal of Medicine.***