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© 2001 American Society for Clinical Oncology
Menopause and Breast Cancer: Addressing the Secondary Health Effects of Adjuvant ChemotherapyUniversity of California, Los Angeles Schools of Public Health and Medicine, Jonsson Comprehensive Cancer Center, Los Angeles, CA IN RECENT YEARS there has been a significant decrease in breast cancer mortality.1 The reasons for this welcome improvement in survival are probably multifactorial, reflecting the more widespread utilization of mammography as well as the successful dissemination and utilization of adjuvant therapy. According to the recommendations of the National Institutes of Health Consensus Conference on Adjuvant Therapy of Breast Cancer,2 chemotherapy should be considered in all women with invasive breast cancer, and women with hormone receptor–positive tumors should be receiving adjuvant tamoxifen for 5 years’ duration. The value of such therapy in very small tumors is being actively debated3,4 and will not be discussed further in this editorial. Although the relative and absolute survival benefits of adjuvant chemotherapy and adjuvant endocrine therapy are well documented in the serial reports from the Oxford Overview,5,6 few data are available on other noncancer health effects from such treatments. For example, few individual randomized treatment trials have prospectively examined the incidence of oligomenorrhea or menopause after adjuvant therapy,7 both of which may have other health effects, such as premature bone loss and increased risk of subsequent fractures. These late health effects take on increasing importance, given the long-term survival expected for most women with early-stage breast cancer. A large body of data supports the direct relationship between markers of cumulative endogenous and exogenous estrogen exposure, such as age at menopause or use of postmenopausal hormone therapy, and radiographically measured bone density.8 Perhaps the most dramatic illustration of the importance of ovarian function to bone health comes from studies of women undergoing surgical oophorectomy, which leads to a dramatic decrease in bone mineral density (BMD).9 In contrast, epidemiologic studies demonstrate that survivors of breast cancer have higher bone densities than women without a history of this disease, suggesting a causative role for estrogen for both situations.10,11 In women, bone density reaches its peak in the third and fourth decades of life and, without bone-compromising illnesses, is maintained throughout adulthood. Recent data suggest that the onset of perimenopause12 may usher in a relatively rapid phase of bone loss, the rate of which may subsequently decline in severity several years after the menopause. Thus, women diagnosed with breast cancer in the fourth or fifth decade of life may already be experiencing rapid bone loss. What are the consequences of chemotherapy-induced oligomenorrhea or menopause in this setting?
In this issue of the Journal of Clinical Oncology, Shapiro et al13 report on the results of a small, prospective study designed to examine the bone metabolism effects of ovarian failure in women presumed to be pre- or perimenopausal at the start of adjuvant chemotherapy. Eligibility criteria for the study included a menstrual period within the past 3 months, a negative serum pregnancy test, and a physician recommendation for adjuvant therapy. Appropriately, women with underlying conditions affecting bone metabolism were excluded. Baseline evaluations took place within 4 weeks before the start of adjuvant chemotherapy and included ionized calcium, estradiol, follicle-stimulating hormone (FSH), markers of bone metabolism, and bone densitometry. Of note, the authors do not describe whether reproductive hormone levels were measured in the early follicular phase of the menstrual cycle, which limits our ability to interpret their meaning. "Ovarian failure" at 12 months was defined as 3 or more months of amenorrhea and an FSH Of the 64 women initially enrolled onto the study,13 only 49, or 77%, were assessable at 1 year, which underscores the challenges of conducting this type of study in parallel with standard treatment. Nevertheless, this report provides important preliminary information about the pattern of reproductive hormone and bone metabolism changes associated with adjuvant chemotherapy. As defined in this study, women who experienced ovarian failure at 12 months had significant bone loss at each of the measurements after baseline. In addition, the authors observed parallel changes in markers of bone metabolism in the ovarian failure group, with a suggestion of significant changes at 6 months in the non–ovarian failure group. Although 22% of the study sample received tamoxifen, the sample size is too small to comment on whether tamoxifen in this setting was beneficial or detrimental. The study by Shapiro et al13 provides further evidence of compromise in BMD associated with ovarian dysfunction in the setting of adjuvant therapy for breast cancer. What are the long-term consequences of adjuvant therapy on women’s health? To study this problem in greater detail, we examined the late reproductive health effects of adjuvant chemotherapy in a large cohort of breast cancer survivors who were 50 years or younger at the time of diagnosis and were between 2 and 10 years after diagnosis at the time of assessment.15 We obtained information about their reproductive and menopausal history, treatments for breast cancer, and current health-related quality of life, and we have measured reproductive hormones, cardiovascular lipids, blood pressure, bone density, and body composition in a large subsample.16 The cohort is composed of four groups: no adjuvant therapy (control for breast cancer only), tamoxifen alone, chemotherapy alone, and chemotherapy followed by tamoxifen. In our recent analysis of BMD measurements in a total of 350 survivors,17 we found that currently pre- and perimenopausal breast cancer survivors who had received no adjuvant therapy had whole-body bone density values that were 0.8 SD greater than age- and race-matched population referents.18 Postmenopausal breast cancer survivors with no adjuvant treatment in our study had whole-body BMD values that were 0.5 SDs higher than the population referent. Within our breast cancer cohort, pre-, peri-, and postmenopausal women who received chemotherapy demonstrated significant decrements in bone density compared with the cohort controls who had not received any adjuvant treatment, although the absolute value of their BMDs was greater than the non–cancer population referents. This is likely due to starting out with a higher peak bone mass, as evidenced by the high BMDs of the untreated survivors. The early findings from our ongoing cohort study, as well of those of Shapiro et al,13 suggest that strategies to prevent accelerated bone loss in perimenopausal breast cancer patients are needed. The higher BMD measurements of breast cancer survivors who have not received any adjuvant treatment underscores the need to use the appropriate referent group: a comparison of the BMDs of breast cancer survivors treated with chemotherapy to those of the United States population referent would be negatively biased. Given the availability of nonhormonal pharmacologic agents that prevent bone loss, appropriate intervention may prevent long-term risk of fractures and should be considered in breast cancer survivors. Future clinical trials of adjuvant chemotherapy in pre- and perimenopausal women should consider the prospective monitoring of BMD, with clinical evaluation of interventions to reduce or ameliorate the impact of treatment-related bone loss. REFERENCES
1.
Wingo PA, Ries LA, Giovino GA, et al: Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 91: 675-690, 1999 2. NIH Consensus Development Program: Adjuvant Therapy for Breast Cancer. National Institutes of Health Consensus Development Statement, November 1-3, 2000. Http://odp.od.nih.gov/consensus/cons/114/114_statement.htm
3.
Fisher B, Dignam J, Tan-Chiu E, et al: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93: 112-120, 2001
4.
Lippman ME, Hayes DF: Adjuvant therapy for all patients with breast cancer? J Natl Cancer Inst 93: 80-82, 2001 5. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998 6. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998
7.
Bines J, Oleske DM, Cobleigh MA: Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 14: 1718-1729, 1996 8. Cauley JA, Salamone LM, Lucas FL: Postmenopausal endogenous and exogenous hormones, degree of obesity, thiazide diuretics, and risk of osteoporosis, in Marcus R, Feldman D, Kelsey J (eds): Osteoporosis. San Diego, CA, Academic Press, 1996, pp 551-570 9. Aitken JM, Hart DM, Lindsay R, et al: Prevention of bone loss following oophorectomy in premenopausal women: A retrospective assessment of the effects of oophorectomy and a prospective controlled trial of the effects of mestranol therapy. Isr J Med Sci 12: 607-614, 1976[Medline] 10. Cauley JA, Lucas FL, Kuller LH, et al: Bone mineral density and risk of breast cancer in older women: The study of osteoporotic fractures—Study of Osteoporotic Fractures Research Group. JAMA 276: 1404-1408, 1996[Abstract]
11.
Zhang Y, Kiel DP, Kreger BE, et al: Bone mass and the risk of breast cancer among postmenopausal women. N Engl J Med 336: 611-617, 1997 12. Sowers MF: Lower peak bone mass and its decline. Baillieres Best Pract Res Clin Endocrinol Metab 14: 317-329, 2000[Medline]
13.
Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early stage breast cancer. J Clin Oncol 19: 3306-3311, 2001 14. Burger HG: The endocrinology of the menopause. Maturitas 23: 129-136, 1996[Medline] 15. Pakilit AT, Kahn BA, Petersen L, et al: Making effective use of tumor registries for cancer survivorship research. Cancer (in press) 16. Ganz PA, Greendale GA, Petersen L: Reproductive health effects of breast cancer treatment. Proceedings of the Dept Defense Breast Cancer Res Program Era of Hope Mtg, Atlanta, GA, June 8-11, 2000, vol II, p 778 17. Greendale GA, Petersen L, Ganz PA: Bone density in breast cancer survivors. Presented at the 4th Int Symp Women’s Health and Menopause, Washington, DC, May 21, 2001 18. Looker AC, Johnston CC Jr, Wahner HW, et al: Prevalence of low femoral bone density in older US women from NHANES III. J Bone Miner Res 10: 796-802, 1995[Medline] This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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30 MIU/mL in the presence of a negative pregnancy test. Recent insights from longitudinal studies of the menopause transition underscore that the perimenopause/menopause transition is a time of "endocrine chaos" and that an FSH of 30 MIU/mL alone does not indicate the cessation of ovarian function.
