Journal of the National Cancer Institute Advance Access originally published online on September 23, 2008
JNCI Journal of the National Cancer Institute 2008 100(19):1341-1343; doi:10.1093/jnci/djn327
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© The Author 2008. Published by Oxford University Press.
EDITORIALS |
Menopausal Hormone Therapy in BRCA1 Mutation Carriers: Uncertainty and Caution
Affiliations of authors: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (RTC); Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (RLP)
Correspondence to: Rowan T. Chlebowski, MD, PhD, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 Carson St, Torrance, CA 90502 (e-mail: rchlebowski{at}gmail.com).
Previous observational studies suggest that oophorectomy substantially reduces breast cancer risk in women with BRCA mutations (1) and that this association is not abrogated by hormone therapy (2). In a case–control study of women with deleterious BRCA1 mutations, Eisen et al. (3) attempt to extend these findings regarding hormone therapy use in postmenopausal BRCA1 mutation carriers. The authors conclude that use of hormone therapy, including combined estrogen plus progestin and estrogen alone, does not appear to be associated with increased risk of breast cancer and may be associated with decreased risk.
This provocative result—especially regarding combined hormone therapy use, which potentially could inform current clinical practice—raises several issues. Are there study design concerns that bring the overall results into question? Historically, how reliable have observational studies been in identifying the influence of hormone therapy on breast cancer risk as compared with randomized prospective clinical trials? Are there characteristics of tumors commonly associated with BRCA1 mutations that could afford biologic plausibility to the findings? Finally, what are the current indications for hormone therapy use in general populations and what should they be for women at increased risk of breast cancer?
The study methodology raises two concerns. The case patients and control subjects appear to be drawn from separate populations, and no information on breast cancer detection history is provided. Generally, in case–control analyses, case patients are identified in a given population and then matched to control subjects in the same population. In the current analysis, the authors state that in most cases germline mutation testing was initially offered to women who were diagnosed with breast or ovarian cancer. However, limited information is provided regarding how the control population with BRCA1 mutations was identified. We are told that family members were offered BRCA mutation testing after a proband who was diagnosed with breast cancer and had a BRCA mutation. However, it is unclear what proportion of the control subjects were family members of the case patients. How many of the control subjects were unrelated health care conscious individuals who were perhaps more likely to adhere to breast cancer detection programs than the general population and the comparison group? The similar number of relatives with breast cancer in case patients and control subjects suggests that most control subjects were recruited for reasons other than family history. Regardless, the described methodology suggests that separate and perhaps disparate populations were used to identify case patients and control subjects. Thus, differences in screening patterns and study populations provide a potential alternative explanation for study findings.
In several respects, results from observational studies that evaluate use of estrogen plus progestin and estrogen alone in postmenopausal women that are performed in the general population have been at odds with those from randomized clinical trials. The preponderance of observational studies suggest that estrogen plus progestin increases breast cancer risk but that the cancers would be of relatively low grade and favorable stage (4). In the Women's Health Initiative (WHI) trial that evaluated conjugated equine estrogen plus medroxyprogesterone acetate vs placebo for women with an intact uterus, breast cancer incidence was higher with hormone therapy but the cancers were larger and in a more advanced stage; the frequency of mammograms with abnormalities and breast biopsies was also higher, with both detecting breast cancers less reliably (5,6). With respect to use of estrogen alone, most older observational studies reported a modest increase in breast cancer risk with estrogen use (7). In contrast, the WHI randomized trial that evaluated conjugated equine estrogens for women with prior hysterectomy reported no increase in breast cancer incidence with estrogen use vs placebo, with a trend to a decreased risk (8).
The issue of therapy related to premature menopause and climacteric symptoms represents a substantial problem in women who have early-stage resected breast cancer. In this setting, a meta-analysis of observational studies (9) suggested that hormone therapy could be administered safely and would not increase risk of breast cancer recurrence. However, when three randomized trials were conducted, two demonstrated a substantial and statistically significant increase in breast cancer recurrence with hormone therapy (10–12), prompting editorials challenging the ability of observational studies to address such questions (13,14). Given this history, the suggestion of safety of hormone therapy, especially of combined estrogen plus progestin, in women with BRCA1 mutations that is based on a single observational study requires extremely cautious interpretation.
The authors correctly recognize that a substantial body of evidence relates use of combined estrogen plus progestin to increased risk of breast cancer, including the recent dramatic reduction in hormone receptor–positive breast cancer seen among 50- to 69-year-old US women following the publication of the WHI combined hormone therapy results (15) and the subsequent decrease in hormone therapy use (16). However, there is a basis for at least a null finding for estrogen plus progestin influence on breast cancer risk in BRCA1 mutation cancers. Because BRCA1-associated breast cancers are commonly negative for estrogen and progesterone receptors (17), they are potentially less likely to be under hormonal influence. The apparent paradox of reduction in breast cancer risk following oophorectomy in BRCA1 mutation carriers has been addressed in preclinical studies that suggest that BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating estrogen receptor 
expression (18), leading to a hypothesis that these tumors follow a pathway in which hormone stimulation is required early followed by loss of hormone receptors later. Finally, the apparent association between relatively short-term use of estrogen plus progestin and lower breast cancer incidence could represent a false-positive finding because in the WHI randomized trial, combined hormone use was associated with fewer breast cancers during the first several years, a finding that was likely related to interference with breast cancer detection rather then a true reduction in incidence (6).
In summary, the results presented by Eisen et al. (3) regarding hormone therapy use in postmenopausal BRCA1 mutation carriers provide some evidence for safety but are insufficient to reliably inform routine clinical practice. Decision making regarding menopausal therapies in women at increased risk of breast cancer is complex (19). The current regulatory agency label identifies climacteric symptoms as the main indication of hormone therapy use at the lowest dose and shortest duration consistent with therapeutic goals. How many postmenopausal women with BRCA1 mutations have limiting symptoms of hot flashes, vaginal/vulvar problems, and sexual dysfunction that cannot be addressed using nonhormonal approaches, and what should be the definition of the term "limiting" providing a threshold for hormone use? To address these issues, the editorial comments of Garber and Hartman of 4 years ago (20) are still true today: "many aspects of the effects of ‘menopausal hormone therapy’ on breast cancer risk in mutation carriers are unknown." As a result, continued caution in prescribing hormone therapy to women with BRCA1 mutations who are at high risk for breast cancers remains prudent.
NOTES
R. T. Chlebowski has been a consultant for AstraZeneca, Novartis Pharmaceuticals Corp, Eli Lilly & Co, Pfizer Inc, and Wyeth and is on the speaker's bureau for AstraZeneca and Novartis.
REFERENCES
1. Eisen A, Lubinski J, Kliijn J, et al. Breast cancer risk following bilateral oopherctomy in BRCA1 and BRCA2 mutation carriers: an international case-control study. J Clin Oncol (2005) 23(30):7491–7496.
2. Rebbeck TR, Friebel T, Wagner T, et al. 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.
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(19):1361–1367.
4. Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol (1998) 16(12):3115–3120.
5. Chlebowski RT, Hendrix SL, Langer RD, et al. for the WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative randomized trial. JAMA (2003) 289(24):3243–3253.
6. Chlebowski RT, Anderson G, Pettinger M, et al. Estrogen plus progestin and breast cancer detection with mammography and breast biopsy. Arch Intern Med (2008) 168(4):382–391.
7. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet (1997) 350(9084):1047–1059.[CrossRef][Web of Science][Medline]
8. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy: the Women's Health Initiative randomized trial. JAMA (2006) 295(14):1647–1657.
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11. Von Schoultz E, Rutqvist LE. Menopausal hormone therapy after breast cancer: the Stockholm Randomized Trial. J Natl Cancer Inst (2005) 97:533–535.
12. http://www.drugs.com/news/tibolone-study-breast-cancer-patients-close-ahead-schedule-6164.html. Accessed August 6, 2008.
13. Chlebowski RT, Anderson G. Progestins and recurrence in breast cancer survivors. J Natl Cancer Inst (2005) 97(7):471–472.
14. Pritchard KI. Should observational studies be a thing of the past? J Natl Cancer Inst (2008) 100(7):451–452.
15. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA (2002) 288(3):321–333.
16. Ravdin PM, Cronin KA, Howlander B, et al. The decrease in breast cancer incidence in 2003 in the United States. N Engl J Med (2007) 356(16):1670–1674.
17. Foulkes WD, Metcalfe K, Sun P, et al. Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res. (2004) 10(6):2029–2034.
18. Hosey AM, Gorski JJ, Murray MM, et al. Molecular basis for estrogen receptor alpha deficiency in BRCA1-linked breast cancer. J Natl Cancer Inst (2007) 99(22):1683–1694.
19. Col NF, Chlebowski RT. Risks and benefits of therapy with menopausal hormones versus selective estrogen receptor modulators in peri- and postmenopausal women at increased breast cancer risk. Menopause (2008) 15(4):804–809.[CrossRef][Web of Science][Medline]
20. Garber JE, Hartman AR. Prophylactic oophorectomy and hormone replacement therapy: protection at what price? J Clin Oncol (2004) 22(6):978–980.
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