Hormone Replacement Therapy in Breast Cancer Survivors

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Hormone Replacement Therapy in Breast Cancer Survivors W.R. Brewster University of California, Irvine. Orange California, U.S.A. The prevalence of breast cancer and the large numbers of survivors make quality of life issues exceedingly important in the management of breast cancer. Breast cancer survivors appear to attain maximum recovery from the physical and psychological trauma of cancer treatment by one year after surgery.1 However, several aspects of quality of life may be disrupted or worsen over time. Women who have undergone chemotherapy have shown more sexual dysfunction, poorer body image, and more psychological distress compared to those treated with hormonal therapy and radiation therapy.2 Similarly, women who have received chemotherapy are especially susceptible to adverse changes in psychosexual functioning, which includes weight changes, hot flashes, mood swings, vaginal dryness, decreased libido, dyspareunia, and difficulty with orgasm.3 Menopausal symptoms are common among breast cancer patients and, in fact, are probably more common than in the general population because of the current treatments for breast cancer. The relationships between the treatment of breast cancer and menopausal symptoms have only recently been studied. In a study of hot flashes among 114 post-menopausal women who had completed their primary therapy for breast cancer and were clinically disease-free, there was a 65% prevalence of hot flashes within two weeks of the interview.4 Greater body mass, age at diagnosis, and use of tamoxifen therapy were associated with greater severity in multivariate analyses. In a mail survey of 190 post-menopausal women who had been treated for insitu or invasive loco-regional breast cancer 65% reported hot flashes (65%), 44% night sweats, 48% vaginal dryness, 26% dyspareunia, 44% disrupted sleep 44%), noted symptoms of depression.5 The prevalence and severity of these symptoms clearly warrant the search for safe actions that lead to relief of menopausal symptoms. Wile suggested that, in the absence of a prospective study of HRT in patients with breast cancer, one should analyze situations in which patients were exposed to high levels of female hormones at times when they might have been harboring an occult breast cancer.6 Was there evidence that, in these situations, the outcome for the patients so exposed was adversely effected? Situations that were chosen were the following: 1) pregnancy coincident with breast cancer, 2) pregnancy subsequent to breast cancer, 3) breast cancer in both previous and current users of oral contraceptives, and 4) breast cancer in post- menopausal women receiving HRT at diagnosis. Pregnancy coincident with, or subsequent to, the detection of breast cancer provides an excellent opportunity to evaluate the outcome of breast cancer patients inadvertently exposed to high levels of estrogen at times when they are harboring occult disease. It's been estimated that the average breast cancer is within the breast some five to eight years as an occult lesion before becoming clinically detectable; thus, there is ample opportunity for exposure. During pregnancy, the serum levels of estriol increase 50-fold. The outcome in women with subclinical breast cancers exposed to elevated levels of progesterone and estrogen under these circumstances should provide insight into the influence of these hormones on the malignant disease process. Comparisons to non- pregnant women matched for similar age and stage of breast cancer do not suggest a worse prognosis for pregnant patients with breast cancer.7 Von Schoultz performed a comparison of women diagnosed with breast cancer five years before pregnancy to 055a6a21953dc01003fe033c70967f14.doc women without a pregnancy during the same period of time.8 There was no survival disadvantage to the women who were pregnant years prior to the diagnosis of breast cancer. This and other studies have discouraged the practice of prohibiting breast cancer survivors from becoming pregnant on clinical grounds. Subsequent pregnancies do not seem to negatively impact survival outcomes. Anderson reported their experience with breast cancer in women less than 30 years of age.9 Two hundred twenty seven cases were identified, of whom 22 had pregnancy- associated breast cancer. The authors confirmed that pregnancy-associated breast cancers were usually larger and present in a more advanced stage at the time of diagnosis, compared to a similar group who were not pregnant. However, the survival probability for the women with early stage disease was independent of pregnancy status. Others have analyzed the experience of women who have completed term pregnancies after treatment of antecedent breast cancer. Clark reported a 71 percent five-year survival in a series of 136 women with pregnancies after breast cancer (Stages I - III).10 Once again given the long natural history of this neoplasm, it is certain that a large number of patients subsequently diagnosed with breast cancer have used oral contraceptive pills (OCP) during the genesis and progression of their malignant disease process; they're another group that deserves careful examination. Schonborn evaluated the influence of a positive history of OCP use on survival.11 Four hundred and seventy- one breast cancer patients were investigated. Two hundred and ninety-seven patients (63 percent) had used OCP during their lifetime, and 92 (20 percent) were still using them at the time of diagnosis. Sixty months after diagnosis, the OCP users had a significantly increased overall survival (p =.037). Survival rates amounted to 79.5 percent and 70.3 percent for OCP users and nonusers, respectively. Sauerbrei investigated the relationship between OCP use and standard prognostic factors, and the effect of OCP use on disease-free survival and overall survival, in 422 pre- menopausal node-positive patients from two trials of the German Breast Cancer Study Group.12 One hundred and thirty-seven OCP users (32.5 percent) were younger than those who did not use OCP (mean age 41.5 years versus 45 years). Noteworthy was the fact that the percentage of patients with smaller tumors was higher in the group of OCP users. No significant effect of OCP use on ether disease-free or overall survival could be demonstrated in univariate and multivariate analyses after adjustment for tumor size and other prognostic factors. Bergkvist compared 261 women who developed breast cancer in a population-based cohort of estrogen-treated women with 6617 breast cancer patients who had no recorded estrogen treatment.13 Complete follow-up was achieved during a period up to nine years. The relative survival rate was significantly higher, by about ten percent at eight years, in patients who had received estrogen treatment, corresponding to an approximately 40 percent reduction in excess mortality. The time from the use of estrogens to diagnosis and the total duration of estrogen medication were unrelated to survival when the effect of recent use was taken into account in a multivariate analysis. It seems reasonable to assume that women diagnosed with breast cancer while taking HRT have a lesion in the breast that has had years of exposure to hormone therapy ("fuel on the fire" theory). These women do not demonstrate an adverse effect on their survival from this exposure. 055a6a21953dc01003fe033c70967f14.doc

Most of the studies that have carefully examined the breast cancer mortality rates of women using post-menopausal hormone therapy at the time of their diagnosis of breast cancer have documented improved survival rates.14 Even studies that detect an increased risk of breast cancer in hormone users indicate a paradoxical better outcome. This may reflect earlier diagnosis in users because the recovery rate in current users is associated with a lower frequency. It would appear that recent users of hormone replacement therapy develop localized breast cancer. There is also evidence to suggest that estrogen users develop smaller, better-differentiated neoplastic lesions. These biological differences imply that hormone treatment promotes the growth of a malignant locus already in place, and it presents clinically with a more favorable biology. This conclusion is consistent with the fact that virtually all the positive studies find that any increase in risk disappears within five years of discontinuing therapy. Estrogen-Replacement Therapy in Breast Cancer Survivors DiSaia reported on 71 breast cancer survivors who received ERT. There was no exclusion based on time interval from diagnosis, stage, age, receptor status, or lymph node status.15 Women received combination therapy with progestin only if they had not previously undergone hysterectomy. Later, the author reported a comparison of 41 of these ERT survivors to 82 non-ERT breast cancer subjects, matched for both age and stage of disease.16 Survival analyses did not indicate a significant difference between the two groups. DiSaia and Brewster published a matched case-control study comparing the survival of 125 breast cancer patients who took HRT subsequent to their cancer with the survival of breast cancer patients who had not taken HRT after their diagnosis.17 Cases used various HRT regimens. The median duration of HRT use was 22 months. Controls were selected from a population-based cancer registry and were matched to cases by age at diagnosis, no worse stage of breast cancer, year of diagnosis and survival as long as the time between diagnosis and HRT use for the matched case. On average, 3 controls were selected per case (125 versus 362). Survival curves were estimated using the Kaplan- Meier method. At 15 years of survival, there was a statistically significant difference (88% versus 63%, p = 0.003) in favor the HRT group. There was almost a 70% reduction in the risk of death among HRT users as calculated by using a Cox proportional hazards model. The OR was 0.28 (95% CI = 0.11 – 0.71). It should be noted that 6 endometrial cancers were found among the HRT users, while none were found among the controls. Forty-four (35%) of the 125 cases used estrogen only. All 6 of the subjects who developed endometrial cancer had been on the estrogen only therapy. Other authors have reported their experience of ERT in breast cancer survivors. Eden reported six recurrences among 90 women receiving ERT.18 These ERT users were matched two to one with control subjects with no history of hormone use after diagnosis of breast cancer. The recurrence rate was 7 percent in the ERT users and 30 percent in the non-ERT users. Bluming reported on 155 breast cancer patients who received ERT for between one and 56 months, among whom seven recurrences were identified.19 The only published prospective randomized trial is being undertaken by Vassilopoulou-Sellin.20 Subjects are randomized to either a placebo or ERT without a progestational agent. Ninety women have been randomized and 49 have received ERT for a minimum of two years. No breast cancer recurrences have been observed in the ERT arm. The single recurrence was in the placebo arm. 055a6a21953dc01003fe033c70967f14.doc

Marsden conducted a pilot 6-month study to evaluate the feasibility of conducting a large clinical trial in Great Britain.21 Eligible patients were post-menopausal and had been treated for either in situ or stage I/II breast cancer. Subjects were randomized to either HRT or no HRT therapy within strata of current or no current use of tamoxifen. One hundred women consented to participate. Participants particularly appreciated the information provided concerning the estrogen deficiency side effects of their breast cancer therapy and the concern for their symptoms expressed by the medical staff. The increase in follow-up for breast cancer recurrence was seen as lessening the risk of an adverse outcome that might come from taking HRT. Six months after enrollment onto the study only 3 (7%) of the 41 patients in the HRT arm were not compliant, as judged from having serum estradiol levels below 50 pmol/L. Seventy-six percent (76%, 31 of 41) of the HRT patients wanted to continue use of HRT and 50%, (21 of 42) of women in the non-HRT arm wanted to crossover to the HRT arm. Follow-up has now been extended to around 5 years for those recruited at the beginning of the study. Two (2) women in the HRT arm and 1 woman in the non-HRT arm developed recurrent breast cancer. O’Meara studied 174 users of HRT subsequent to treatment for initial invasive breast cancer, identified between 1977 and 1994 at the Group Health Cooperative of Puget Sound. Identification was through pharmacy records.22 These patients were matched to 4 randomly selected non-HRT users, with the matching based on age, disease stage, and year of diagnosis. The subjects were recurrence free at the time of initiation of HRT or the equivalent time since diagnosis for the controls. Recurrence and/or death were determined through 1996. The adjusted relative risk for recurrence was 0.50 (95% CI = 0.3 to 0.85), based on 17 recurrences per 1000 person years in the HRT user group and 33 recurrences per 1000 person years in the control group. The adjusted breast cancer mortality relative risk was 0.34 (95% CI = 0.13 to 0.91). The adjusted overall mortality relative risk was 0.48 (95% CI = 0.29 to 0.78). Adjustment variables were bilateral oophorectomy, hysterectomy, mastectomy, tamoxifen, body mass index, and positive lymph nodes at diagnosis, as appropriate for each analysis. It should be noted that the HRT user group had more frequency used HRT prior to their initial breast cancer diagnosis, 68% versus 48%. The series discussed above are representative of the reported experience of ERT in 779 female breast cancer survivors. This group of women is very heterogeneous with respect to breast cancer stage, the interval between diagnosis of breast cancer and initiation of ERT, the hormonal combinations prescribed, estrogen-receptor status, and finally in the duration of use of estrogen. Despite these limitations, it remains obvious that the use of estrogen is not associated with a rash of occurrences. Overall, the data do not suggest that ERT has an adverse effect on breast cancer outcome. References 1 Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339:1-15, 71-85. 2 Schover LR, Yetman RJ, Tuason LJ, Meisler E, Esselstyn CB, Hermann RE, Grundfest- Broniatowski S, Dowden RV. Partial mastectomy and breast reconstruction. A comparison of their effects on psychosocial adjustment, body image, and sexuality. Cancer 1995;75:54-64 3 Ganz PA, Rowland JH, Desmond K, Meyerowitz BE, Wyatt GE. Life after breast cancer: Understanding women’s health-related quality of life and sexual functioning. J Clin Oncol 1998;16:501-14 4 Carpenter JS, Andrykowski MA, Cordova M, Cunningham L, Studts J, McGrath P, Kenady D, Sloan D, Munn R. Hot flashes in postmenopausal women treated for breast carcinoma. Cancer 1998;82:1682-1691 5 Couzi RJ, Helzlsouer KJ, Fetting JH. Prevalence of menopausal symptoms among women with a history of breast cancer and attitudes toward estrogen replacement therapy. J Clin Oncol 1995;13:2737-2744 6 Wile AG, DiSaia PJ. Hormones and breast cancer. Am J Surg 1989;157:438-42 7 Nugent P, O'Connell TX. Breast cancer and pregnancy. Arch Surg 1985;120:1221-4 8 von Schoultz E, Johansson H, Wilking N, Rutqvist LE. Influence of prior and subsequent pregnancy on breast cancer prognosis. J Clin Oncol 1995;13:430-4 9 Anderson BO, Petrek JZ, Byrd DR, et al. Pregnancy influences breast cancer stage at diagnosis in women 30 years of age and younger. Ann Surg Oncol 1996;3:204 10 Clark RM, Chua T. Breast cancer and pregnancy: the ultimate challenge. Clin Oncol (R Coll Radiol) 1989;1:11-8 11 Schonborn I, Nischan P, Ebeling K. Oral contraceptive use and the prognosis of breast cancer. Breast Cancer Res Treat 1994;30:283-92 12 Sauerbrei W, Blettner M, Schmoor C, et al. The effect of oral contraceptive use on the prognosis of node positive breast cancer patients. German Breast Cancer Study Group. Eu J Cancer 1998 Aug;34(9):1348-51 13 Bergkvist L, Adami H-O, Persson I, et al. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989;130:221- 8 14 Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. New Engl J Med. 336:1769-1775, 1997 15 DiSaia PJ, Odicino F, Grosen EA, et al. Hormone replacement therapy in breast cancer [letter]. Lancet 1993; 342:1232 16 DiSaia PJ, Grosen EA, Kurosaki T, et al. Hormone replacement therapy in breast cancer survivors. A cohort study. Am J Obstet Gynecol 1996;174:1494-8 17 DiSaia PJ, Brewster WR, Ziogas A, Anton-Culver, H. Breast Cancer Survival and Hormone Replacement Therapy. A Cohort Analysis. Am J Clin Oncol 2000;23(6): 541-545 18 Eden JA, Bush T, Nand S, Wren BG. A case control study of combined continuous estrogen progestin replacement therapy among women with a personal history of breast cancer. Menopause 1995;2:67-72 19 Bluming AZ, Waisman JR, Dosik GM. Hormone replacement therapy (HRT) in women with previously treated primary breast cancer. Update III. Proc Am Soc Clin Oncol 1997;16A:463, 131a 20 Vassilopoulou-Sellin R, Rherriault R, Klein MY. Estrogen replacement therapy in women with prior diagnosis and treatment for breast cancer. Gynecol Oncol 1997;65:89 21 Marsden J, Whitehead M, Hern RA, Baum M, Sacks N. Are randomized trials of hormone replacement therapy in symptomatic women with breast cancer feasible? Fertility Sterility 2000;73:292-299 22 O’Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone Replacement Therapy after a Diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst 2001: 93: 754-62