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Date of release: 19 September, 2016

Is hormone replacement therapy safe in women with a BRCA mutation?

Birrer and colleagues recently reviewed the available literature on the safety of hormone replacement therapy (HRT) in BRCA carriers [1]. Four publications were considered relevant for the purpose of this review. Studies were done to evaluate the impact of HRT on menopausal symptoms (n = 2) or breast cancer risk (n = 2) after bilateral salpingo-oophorectomy (BSO) in BRCA mutation carriers. The concern of an elevated breast cancer risk among mBRCA carriers on HRT does not appear to be a significant issue based on the limited data available, which indicate that HRT appears to be safe in young mBRCA carriers who have undergone BSO. This was demonstrated best in the Prevention and Observation of Surgical Endpoints study that included 462 female mBRCA carriers, all of whom were followed from time to BSO (note, patients were censored at the time of prophylactic mastectomy) [2]. Within this population, 114 women took HRT, 93 of 155 who had a BSO, and 21 of 307 who did not have a BSO. Compared with the entire cohort, there was no impact on breast cancer risk with HRT among those who underwent a BSO (hazard ratio (HR) 0.37; 95% confidence interval (CI) 0.14-0.96). It is also interesting to note that, although in a limited sample size, among the 93 patients who had a BSO, 54 patients took estrogen alone and 34 took progesterone with or without estrogen (five did not specify). There was no significant difference in breast cancer risk reduction between the two groups. An additional analysis concentrated on those women who underwent a BSO before 50 years; the authors reported that HRT had no significant impact on the subsequent risk of breast cancer. In a matched case–control study by Eisen and colleagues [3], a subset of 472 postmenopausal women with BRCA1 mutations were examined to compare an increased risk of breast cancer in patients treated with estrogen alone (n = 28) or combination estrogen and progesterone (n = 19). An inverse association between estrogen use alone (odds ratio (OR) 0.51; 95% CI 0.27-0.98) and breast cancer risk was observed, whereas no significant association was seen in combination therapy and risk of breast cancer (OR 0.66; 95% CI 0.34-1.27).



In a study by Armstrong and colleagues [4], the use of HRT (both progesterone and estrogen) after risk-reducing surgery (BSO and prophylactic mastectomy) until age 50 translated into a gain in life expectancy for these patients, which varied by age: there was a gain of 0.78, 0.79, and 0.79 years for a 30-, 35-, and 40-year-old women, respectively. Interestingly, the gains in life expectancy were less pronounced if women used HRT for life, with added 0.39, 0.39, and 0.37 years calculated.

Comment

Estimates of the prevalence of BRCA1 and BRCA2 gene mutations in the general female population have been based on extrapolations from prevalence in breast cancer cases and the resulting figures are low: 0.07-0.09% for mBRCA1 and 0.14-0.22 for mBCRA2 in the Anglian Breast Cancer Study [5] and 0.11 % for mBRCA1 and 0.12% for mBRCA2 in the study by Peto and colleagues [6]. However, Malone and colleagues reported on a population-based case-control study in breast cancer patients and non-breast cancer controls aged 35-64 [7]. Cases showed an overall prevalence of 2.4% for mBRCA1 and 2.3% for mBRCA2, while controls yielded rates close to 0 (one subject for mBRCA1 and five for mBRCA2). The number of positive test results was largest in women aged 35-44 (6.3%) and declined strongly in the older age groups containing very few subjects, rendering conclusions on these age groups difficult. Ethnic differences were observed. The contribution of mBRCA to the risk of breast and ovarian cancer appears small but is of great clinical importance for those concerned.

BSO is recommended for mBRCA carriers, preferably between 35 and 40 years of age. This surgical intervention greatly reduces the risk of breast cancer by 48%, ovarian and peritoneal cancer by 80% and overall reduction of all-cause mortality at age 70 if BSO was performed at 35 years [4]. The fact that ovarian cancer risk is not zero after BSO is somewhat puzzling. This is considered the result of pre- or operative cancer cell implantation in the peritoneum or in the area where the Fallopian tubes are attached to the uterus in cases where no simultaneous hysterectomy is performed. The immediate outcome of BSO is, of course, induction of an acute menopause years before the average time of natural menopause. Short- and mid-term effects such as vasomotor symptoms, urogenital complaints and sexual dysfunction are unavoidable, while the longer-term effects such as cardiovascular disease and osteoporosis are not yet known but biologically very likely.

The use of HRT to alleviate the symptoms of this acute and premature menopause is an obvious clinical measure. Several studies have been conducted to establish the risk-benefit balance – including that of breast cancer – of HRT in post-BSO patients; based on the results of these studies, Birrer and colleagues [1] make a positive case for the use of HRT. In a nutshell, breast cancer risk and overall mortality do not seem to be affected by the use of HRT in these patients. The problem with a final verdict appears to be, to some extent, the limit of clinical testing, as in all likelihood a randomized, controlled study will and should (for ethical reasons) perhaps never be conducted. Thus we depend on case-control and cohort studies that face methodological difficulties, report differing follow-up periods and require complicated statistics that are not improving the accessibility of the reports. Additionally, the low prevalence of mBRCA and the confounding factors (for instance indication bias) account for low study numbers and this makes the collection of clinical data even harder.

There are, however, still additional questions for further study. These relate to the type of HRT used, the duration of use and the non-desirability of total hysterectomy at the time of BSO. The WHI study found no increase in breast cancer risk in subjects using estrogen only [8]. In view of the increased risk of endometrial cancer with the use of estrogen/progestin, estrogen only might be preferable in BSO subjects, but this requires endometrial surveillance in non-hysterectomized patients, whereas hysterectomy at the time of BSO carries increased postoperative risks. Another puzzle is the relative lack of efficacy of HRT in BSO patients as compared to natural menopausal subjects [9]. The underlying reason for this has not been clarified; perhaps there is residual ovarian activity after natural menopause which is lacking in BSO patients? Should higher doses of HRT be given to these patients to obtain more effect? Would the route of administration make a difference? Are there other potential treatments?

HRT appears to be given to BSO subjects for a period up to age 50 years, the mean time of natural menopause. Safety concerns might be the reason for this but it leaves the patients with some 20 years of estrogen deprivation with the known long-term consequences, bringing up the question of longer or even lifetime use. As Birrer and colleagues rightly point out [1], more specific investigation is needed to refine the use of HRT in BSO subjects, a task for menopause researchers.

Comentario

Frits Riphagen


Brussels, Belgium



    References

  1. Birrer N, Chinchilla C, Del Carmen M, Dizon DS. Is hormone therapy safe in women with a BRCA mutation? A systematic review of the contemporary literature. Am J Clin Oncol 2016 Feb 2. Epub ahead of print


    http://www.ncbi.nlm.nih.gov/pubmed/26840041

  2. Rebbeck TR, Friebel T, Wagner T, et al. Effect of short-term hormone replacement therapy on breast cancer reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2005;23:7804-10


    http://www.ncbi.nlm.nih.gov/pubmed/16219936

  3. Eisen A, Lubinski J, Gronwald J, et al. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 2008;100:1361-7


    http://www.ncbi.nlm.nih.gov/pubmed/18812548

  4. Armstrong K, Schwartz JS, Randall T, et al. Hormone replacement therapy and life expectancy after prophylactic oophorectomy in women with BRCA1/2 mutation: a decision analysis. J Clin Oncol 2004;22:1045-54


    http://www.ncbi.nlm.nih.gov/pubmed/14981106

  5. Anglian Breast Cancer Study Group. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer 2000;83:1301-8


    http://www.ncbi.nlm.nih.gov/pubmed/11044354

  6. Peto J, Collins N, Barfoot R, et al. Prevalence of BRCA1 and BRCA2 mutations in patients with early-onset breast cancer. J Natl Cancer Inst 1999;91:943-9


    http://www.ncbi.nlm.nih.gov/pubmed/10359546

  7. Malone KE, Daling JR, Doody D, et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women aged 35 to 64.Cancer Res 2006;66:8297-308


    http://www.ncbi.nlm.nih.gov/pubmed/16912212

  8. Chlebowski RT, Hendrix S, Langer R, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA 2003;289:3243-53


    http://www.ncbi.nlm.nih.gov/pubmed/12824205

  9. Madalinska JB, van Beurden M, Bleiker EM, et al. The impact of hormone replacement therapy on menopausal symptoms in younger high-risk women after prophylactic salpingo-oophorectomy. J Clin Oncol 2006;24:3576-82


    http://www.ncbi.nlm.nih.gov/pubmed/16877724