Is hormone replacement therapy (HRT) following risk-reducing salpingo-oophorectomy (RRSO) in BRCA1 (B1)- and BRCA2 (B2)-mutation carriers associated with an increased risk of breast cancer?

Reporter: Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 7, 2011

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Presenter: S. Domchek
Presenter’s Institution: U. of Pennsylvania School of Medicine

Background

  • Research has shown that women who carry the BRCA mutations benefit from risk-reduction procedures to reduce their risk of developing breast and ovarian cancers.
    • The best risk-reduction strategy appears to be surgical removal of the ovaries [Risk-reducing salpingo-oopophorectomy (RRSO)] in the mid-30s or early 40s (following childbearing);
    • RRSO in this population results in an 80% reduction in ovarian/fallopian tube cancer risk and a 50% reduction in breast cancer risk.
    • The reduction in breast cancer risk may be greatest when oophorectomy is performed prior to age 40, to allow the procedure to be carried out at an earlier age than when breast cancers are first observed in this group of women.
    • RRSO for women in their 30s to 40s carrying a BRCA 1 or 2 mutation is currently recommended by the NCCN.
  • The decrease in cancer risk from ovary removal results in early menopause and menopausal symptoms including hot flashes, mood swings, sleep disturbances and vaginal dryness which are quality-of-life issues that may cause some women to delay or avoid the procedure.
    • Hormone replacement therapy (HRT) may minimize these symptoms.
  • BRCA carriers, and their physicians, may worry, based on other studies conducted in the general population showing a link between HRT and elevated cancer risk, that taking HRT will increase their risk of breast cancer despite having RRSO.
  • Small prior studies have suggested that HRT following RRSO does not increase the risk of breast cancer, but further data are needed to establish the role of HRT, if any, in this specific population.

Methods

  • The study described here was a non-randomized prospective study of 1,299 women - 795 women with BRCA1 mutations and 504 women with BRCA2 mutations- who have not had cancer.
  • The patients were recruited from the Prevention and Observation of Surgical Endpoints (PROSE) consortium database, and consisted of those who underwent prophylactic oophorectomy, divided into groups of those who took HRT and those who did not.
  • The mean age of ascertainment of BRCA status was 37 years.
  • Those for whom HRT status was known were followed prospectively. Data were collected on HRT use and subsequent breast cancer diagnosis.
  • Patients were censored for mastectomy, ovarian cancer diagnosis, death or date of last contact.
  • The effect of HRT was estimated using a Cox proportional hazard model.

Results

  • 45% of women used HRT following RRSO. The average duration of HRT was 3-5 years. Both oral and transdermal HRT was used, though the majority of women were treated with oral HRT.
    • Both combination estrogen/progesterone and estrogen only HRT was used.
  • 14% of the women who took HRT after surgery developed breast cancer compared to 12% of the women who did not take HRT after surgery. The difference was not statistically significant.
  • In both BRCA1 and BRCA2 mutation carriers with ever use of HRT following RRSO, no increased risk of breast cancer was observed compared to those with no RRSO.
  • In BRCA1 carriers, HRT use both with (HR 0.52) and without (HR 0.29) RRSO was associated with a decreased risk of breast cancer. No increased risk of breast cancer was seen with either combination HRT or estrogen-only HRT.
  • In the table below, data presented refers to, from left to right columns, the reference group (those with no RRSO and no HRT use), those with no RRSO who had used HRT, those with RRSO and no HRT use, and lastly, those with RRSO and HRT use.

Patient Cohort

No RRSO
No HRT (Controls)

  No RRSO
+ HRT

+ RRSO
No HRT

+ RRSO
+ HRT


Mean age at RRSO

-

-

45.0 (20.5-79.0)

40.8 (29.4-63.4)

Mean age in controls

34.4 (18.1-90.4)

45.6 (18.7-90.0)

-

-

Mean follow-up to BC

4.8 (0.5-17.6)

7.4 (0.9-20.6)

2.7 (0.5-6.0)

4.9 (0.8-20.2)

Mean follow-up to censoring

5.1 (0.5-27.8)

5.9 (0.5-27.7)

3.6 (0.5-18.8)

5.4 (0.6-27.4)

Total sample (N)

867

111

177

144

BC in follow-up

194 (22%)

19 (17%)

22 (12%)

20 (14%)

HR (95% CI)

[1]

0.51 (0.32-0.80)

0.62 (0.38-1.01)

0.46 (0.28-0.76)

BRCA1 (N)

520

55

115

105

BC in follow-up

118 (23%)

5 (9%)

16 (14%)

17 (16%)

HR (95% CI)

[1]

0.29 (0.13-0.69)

0.63 (0.35-1.14)

0.52 (0.30-0.92)

BRCA2 (N)

347

56

62

39

BC in follow-up

76 (22%)

14 (25%)

6 (10%)

3 (8%)

HR (95% CI)

[1]

0.73 (0.42-1.27)

0.52 (0.21-1.27)

0.24 (0.05-1.03)


Authors’ Conclusions

  • In this prospective study of 1,299 BRCA 1 and 2 mutation carriers with limited follow-up, HRT following RRSO was not associated with an increased risk of breast cancer.
  • While this is the largest study of its kind, it is important to recall that the data are not randomized.
  • The type of HRT (combination hormones vs. estrogen only) did not appear to matter, but the numbers are too small to evaluate this specific question.

Clinical Implications

  • At this time, these data are the most robust available regarding use of HRT after RRSO for women with BRCA, mutations and should be discussed with women who are planning cancer risk-reduction strategies.
    • This study, which has provided useful information for patients and practitioners, is not definitive, and a randomized controlled trial would provide further information regarding the risk/benefit ratio of HRT in this specific clinical situation.
    • While the findings are reassuring regarding use of HRT, the duration of HRT may be an issue. It is unclear if there would be increased risk of breast cancer with prolonged usage of HRT.
    • Because HRT is associated with an increased risk of endometrial carcinoma, some experts advocate the removal of the uterus at the time of RRSO. Those who do use HRT long-term may benefit from counseling regarding this suggestion.
  • Women undergoing RRSO need to be aware that while surgically-induced early menopause decreases breast and ovarian cancer risk, it may also increase their risk of osteopenia/osteoporosis and cardiovascular problems. Women who receive HRT may derive important cardiovascular, bone-health, and quality-of-life benefits as a result.
    • Women who undergo RRSO, particularly those who do not receive HRT, will require close monitoring of bone and cardiovascular health.
  • The role of aromatase inhibitors (AI) after RRSO is unknown. Further study may elucidate a prophylactic role of AIs for BRCA gene carriers who opt to undergo RRSO.

References

  1. Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. JAMA. 2006;296:185-192.
  2. Rebbeck T, Kauff N, Domchek S, Meta-analysis of Risk Reduction Estimates Associated With Risk-Reducing Salpingo-Oophorectomy in BRCA1 or BRCA2 Mutation Carriers. J Nat Cancer Inst. 2009;101(2):80-87.


News
Risk-reducing salpingo-oophorectomy lowers risk of ovarian cancer, first breast cancer diagnoses

Sep 1, 2010 - Among women with BRCA1 or BRCA2 mutations, risk-reducing mastectomy is linked to a lower risk of breast cancer, and risk-reducing salpingo-oophorectomy is associated with numerous benefits, including lower risk of ovarian cancer and first breast cancer diagnosis, according to research published in the Sept. 1 issue of the Journal of the American Medical Association.



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