Untangling BRCA mutations, sex hormones, and cancer risk
Authors: Martha Hickey
Journal: The Lancet Oncology (2013)

Understanding basic disease mechanisms might allow development of novel strategies for the primary prevention of breast and ovarian cancer. For carriers of BRCA1/2 mutations, options for primary prevention are limited to bilateral salpingo-oophorectomy and prophylactic mastectomy. In The Lancet Oncology, Martin Widschwendter and colleagues1Widschwendter M Rosenthal AN Philpott S et al.The sex hormone system in carriers of BRCA1/2 mutations: a case-control study.Lancet Oncol. 2013; (published online Oct 17.)http://dx.doi.org/10.1016/S1470-2045(13)70448-0PubMed Google Scholar compare ovarian and endometrial function in carriers of the BRCA1/2 mutation with high-risk, mutation negative women in the UK Familial Ovarian Cancer Screening Study. BRCA1/2 mutations are thought to cause cancer via a defect in DNA damage response or in the DNA repair pathway, but this does not explain organ-specific cancer penetrance. These novel data suggest that end-organ response might have a role. Using endometrial thickness measurements collected during transvaginal ultrasound to detect ovarian cancer, cross-sectional data showed that premenopausal women carrying the mutation (n=203 scans in 116 BRCA1-positive women and 190 in 112 BRCA2-positive women) had a thicker endometrium in the follicular phase and a thinner endometrium in the luteal phase than did controls (n=1573 scans in 754 women). Using existing blood samples from a small number of women carrying the BRCA1 (n=38) and BRCA2 (n=32) mutations, the investigators did not identify any differences in circulating concentrations of oestradiol and progesterone in the follicular phase, but concentrations of both hormones were higher in the late luteal phase (days 21–26) compared with 339 controls. The investigators propose that this relates to a defect in steroid-hormone regulation, which potentiates the mutagenic effect of the BRCA1/2 mutation and explains the organ specific penetrance of malignancies. An important limitation of this approach is using endometrial thickness as a marker of hormone regulation. How endometrial thickness was measured is not defined. Endometrial ultrasound is highly user-dependent. Scans were done at 44 different sites but no data on reproducibility were reported. Normal premenopausal endometrial thickness varies substantially. It is increased during the follicular phase, plateaus around ovulation, and remains stable throughout the luteal phase.2Raine-Fenning NJ Campbell BK Kendall NR Clewes JS Johnson IR Quantifying the changes in endometrial vascularity throughout the normal menstrual cycle with three-dimensional power Doppler angiography.Hum Reprod. 2004; 19: 330-338Crossref PubMed Scopus (139) Google Scholar This variation does not support the assertion that in women carrying the BRCA1/2 mutation a thinner endometrium and higher luteal concentrations of oestradiol and progesterone are in complete concordance. Unlike exogenous progestogens, luteal progesterone does not typically induce a thin endometrium.3Hickey M Salamonsen LA Endometrial structural and inflammatory changes with exogenous progestogens.Trends Endocrinol Metab. 2008; 19: 167-174Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar It is also unclear how menopausal status was defined. Participants were younger than 50 years, but menstrual irregularity starts at a median age of 47 years, and participants with anovulatory cycles would have notably different endometrial thickness and circulating sex steroids.4Harlow SD Gass M Hall JE et al.Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging.Menopause. 2012; 19: 387-395Crossref PubMed Scopus (406) Google Scholar Exogenous sex steroids would also affect all measures but present use was not recorded. Higher circulating oestradiol in carriers of the gene mutation is consistent with general population data associating higher oestradiol with premenopausal breast cancer risk.5Endogenous Hormones and Breast Cancer Collaborative GroupSex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.Lancet Oncol. 2013; 14: 1009-1019Summary Full Text Full Text PDF PubMed Scopus (234) Google Scholar The proposed relation with higher progesterone concentrations is less convincing. Unlike testosterone levels, progesterone concentrations are not associated with breast cancer risk in premenopausal women.5Endogenous Hormones and Breast Cancer Collaborative GroupSex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.Lancet Oncol. 2013; 14: 1009-1019Summary Full Text Full Text PDF PubMed Scopus (234) Google Scholar Recent pilot data suggest that BRCA2 carriers with breast cancer have marginally higher oestradiol concentrations in the early follicular phase than do BRCA1 or mutation negative women.6Kimm J Oktay K Baseline E2 levels are higher in BRCA2 mutation carriers: a potential target for prevention?.Cancer Causes Control. 2013; 24: 421-426Crossref PubMed Scopus (30) Google Scholar Preclinical data in Brca1 mice suggest increased circulating and endometrial proliferation in proestrus.7Yen HY Gabet Y Liu Y et al.Alterations in Brca1 expression in mouse ovarian granulosa cells have short-term and long-term consequences on estrogen-responsive organs.Lab Invest. 2012; 92: 802-811Crossref PubMed Scopus (18) Google Scholar Recent data8Collins IM Milne RL McLachlan SA et al.Do BRCA1 and BRCA2 mutation carriers have earlier natural menopause than their noncarrier relatives? results from the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer.J Clin Oncol. 2013; (published online Sept 30.)https://doi.org/10.1200/JCO.2013.49.3007Crossref Scopus (38) Google Scholar do not support the speculation that women carrying the BRCA1/2 mutation have an earlier age at menopause. Combining data from carriers of the BRCA1 and BRCA2 mutations in the present study was justified as a measure to increase statistical power, but might have obscured key endocrine differences pertinent to variations in cancer risks. It is unclear why a gene mutation affecting DNA repair should affect ovarian sex steroid production in the late luteal phase and this needs further investigation. Both endometrial and sex steroid measurements were cross-sectional, making it impossible to infer within-cycle sex steroid or endometrial differences in BRCA carriers. These data are novel in combining ovarian and endometrial functional data in women with the BRCA1/2 mutation. The clinical importance is the potential for modulating ovarian sex steroid production to reduce cancer risk. Ovarian suppression with the oral contraceptive pill reduces ovarian but not breast cancer risk in BRCA1/2 mutation carriers.9Cibula D Zikan M Dusek L Majek O Oral contraceptives and risk of ovarian and breast cancers in BRCA mutation carriers: a meta-analysis.Expert Rev Anticancer Ther. 2011; 11: 1197-1207Crossref PubMed Scopus (82) Google Scholar It is unclear why exogenous sex steroids in the contraceptive pill should be protective, if endogenous sex steroids increase risk. Targeted therapies inhibiting oestrogen and HER2 are established in breast cancer treatment. Clarifying the role of progesterone might suggest a role for selective progesterone receptor modulators such as ulipristal.10Communal L Vilasco M Hugon-Rodin J et al.Ulipristal acetate does not impact human normal breast tissue.Hum Reprod. 2012; 27: 2785-2798Crossref PubMed Scopus (26) Google Scholar It is certainly premature to suggest that sex steroids are one of the major drivers for development of breast cancer in this population. Although of interest, cross-sectional studies can only provide limited information on relations in inherently dynamic pathways. The complex relation between gene mutations, ovarian cancer risk, endocrine function, endocrine production, and receptivity in BRCA1/2 mutation carriers still need to be established. These provocative findings might open a new direction in mechanistic studies that increase understanding of cancer mechanisms in high-risk women. I declare that I have no conflicts of interest. The sex hormone system in carriers of BRCA1/2 mutations: a case-control studyCarriers of BRCA1/BRCA2 mutations are exposed to higher titres of oestradiol and progesterone—known risk-factors for breast cancer. Higher titres of oestradiol in carriers are compatible with this hormone having a role in ovarian carcinogenesis in such women. Our findings could not be explained by differential contraceptive pill use. Full-Text PDF Open Access