The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers

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1 Gynecologic Oncology 96 (2005) The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers Kelly A. Metcalfe a,b, *, Henry T. Lynch c, Parviz Ghadirian d, Nadine Tung e, Ivo A. Olivotto f, William D. Foulkes g, Ellen Warner h, Olufunmilayo Olopade i, Andrea Eisen h, Barbara Weber j, Jane McLennan k, Ping Sun b, Steven A. Narod b a Faculty of Nursing, University of Toronto, Toronto, ON, Canada b The Centre for Research in Women s Health, Sunnybrook and Women s College Health Sciences Centre, Toronto, ON, Canada c Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE 68178, USA d Epidemiology Research Unit, Centre Hopital de Université de Montreal, Montreal, Quebec, Canada e Beth Israel Deaconess Medical Center, Boston, MA 02215, USA f BC Cancer Agency, Victoria, BC, Canada g Program in Cancer Genetics, McGill University, Montreal, Quebec, Canada h Sunnybrook and Women s College Health Sciences Centre, Toronto, ON, Canada i University of Chicago, Chicago, IL 60637, USA j Department of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA k University of California-San Francisco, CA , USA Received 23 July 2004 Abstract Objective. To estimate the risk of ovarian cancer after a primary diagnosis of breast cancer among women with a BRCA1 or BRCA2 mutation and to identify host and treatment-related factors that might modify the risk. Patients and methods. Patients were 491 women with stage I or stage II breast cancer, diagnosed from 1975 to 2000 and for whom a BRCA1 or BRCA2 mutation had been identified. Patients were followed from the initial diagnosis of breast cancer until either ovarian cancer, prophylactic oophorectomy, death, or The medical treatment records and pathology documents were reviewed. Information that was abstracted from the medical charts included date of breast cancer diagnosis, stage of disease, use of chemotherapy, use of radiation therapy, usage of tamoxifen, oophorectomy, recurrence, second malignancy, and vital status. Results. The 10-year actuarial risk of ovarian cancer after breast cancer was 12.7% for BRCA1 carriers and 6.8% for BRCA2 carriers (P = 0.03). The use of tamoxifen (OR = 1.79; P = 0.16) and chemotherapy (OR = 0.59; P = 0.15) did not significantly impact on the risk of subsequent ovarian cancer. Twenty-five percent of the deaths in women with stage I breast cancer were due to a subsequent ovarian cancer. Conclusions. The high incidence of ovarian cancer suggests that oophorectomy should be recommended in female BRCA1 and BRCA2 mutation carriers with a diagnosis of breast cancer, especially those with stage I disease. Breast cancer systemic therapy did not significantly alter the risk of ovarian cancer. D 2004 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Breast cancer; BRCA1; BRCA2 Introduction Women with a genetic mutation in either BRCA1 or BRCA2 have an increased risk of developing breast and * Corresponding author. Faculty of Nursing, University of Toronto, 50 St. George Street, Toronto, ON, Canada, M5S 3H4. Fax: ovarian cancer. The lifetime risk of breast cancer for these women has been estimated to be 82%, and the lifetime risk of ovarian cancer is 54% for BRCA1 carriers and 23% for BRCA2 carriers [1]. In BRCA1 and BRCA2 mutation carriers, breast cancer typically presents earlier than ovarian cancer and there is a significant probability that ovarian /$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi: /j.ygyno

2 K.A. Metcalfe et al. / Gynecologic Oncology 96 (2005) cancer will be diagnosed after breast cancer. Early studies quantified the risk of ovarian cancer after breast cancer [2]; however, no study has examined whether breast cancer treatment modalities modify the risk of ovarian cancer after breast cancer. In non-familial breast cancer patients, an increased risk of ovarian cancer following a diagnosis of breast cancer has not been observed [3]. However, for women with a family history of breast cancer, a twofold increased risk of ovarian cancer following breast cancer has been observed [4]. This risk was greatest for women with early-onset breast cancer (younger than age 40 years at diagnosis) or with a family history of breast or ovarian cancer. SEER data from 1992 to 1999 estimate the 5-year survival rate for breast cancer to be 87.9% and for ovarian cancer to be 52.4% [5]. If ovarian cancer could be prevented in BRCA1 or BRCA2 mutation carriers following a diagnosis of breast cancer, then the overall risk of death due to cancer would be reduced. In women with breast cancer who develop ovarian cancer, there are competing causes of mortality and one of the goals of the study is to quantify the relative contribution of each malignancy to death rates. It is not clear to what extent the risk of ovarian cancer varies with age at diagnosis of breast cancer and if the ovarian cancer risks are equivalent for carriers of BRCA1 and BRCA2 mutations. Additionally, few data are available to examine the influence of breast cancer treatments on the risk of ovarian cancer for BRCA1 and BRCA2 mutation carriers. Here we present data from a large-scale historical cohort study designed to generate estimates of the risk of ovarian cancer after a primary diagnosis of breast cancer among women with a BRCA1 or BRCA2 mutation and to identify host and treatment-related factors that might modify the risk. Methods Study subjects Pedigrees of cancer families followed at 10 participating cancer genetics clinics were reviewed. A family was considered to be eligible for the study when a BRCA1 or a BRCA2 mutation was documented in the family and at least one case of invasive breast cancer was recorded. Eligible study subjects included all women from these families who were diagnosed with stage I or stage II breast cancer at age 65 or below, from 1975 to Living and deceased women were eligible, but those with a prior diagnosis of cancer (including breast cancer before 1975) or those who resided outside of North America were excluded. It was not necessary that the woman was a proven carrier of the mutation found in the family to be included in the study; however, affected women who were known to be noncarriers were excluded. We identified a total of 1139 breast cancer cases in 337 families. Pedigree review indicated that 647 of these were currently alive and that 492 were deceased. From the 1139 cases of breast cancer, 320 women were excluded because the date of diagnosis was before 1975 and 50 women were excluded because the age of diagnosis was above 65 years. An additional 19 women were non-carriers of the familial mutation and were therefore excluded. Ten women were excluded because they had a diagnosis of cancer (including ovarian) prior to breast cancer and 11 women were excluded because they were treated outside of North America. We were able to obtain identifying information for 587 of the remaining 729 women (80.5%). An attempt was made to contact each of these or her next-of-kin to obtain permission to review the medical records. Thirteen women (or their next of kin) refused to provide consent for the release of the medical records. The medical record was requested from the hospital where treatment was received for the remaining 574 women. In 54 cases, the hospital was not able to locate the record or did not forward the requested documents. The medical record was obtained on the remaining 520 women (91%). After review of the medical records, an additional 29 women were excluded. Of these, 22 women were excluded because the tumour stage was stage III or IV; six women were excluded because the tumour was non-invasive (DCIS or LCIS) and one woman was excluded because she refused treatment. The remaining 491 women were included in the analysis. Study protocol The medical treatment records and pathology documents were reviewed. Information that was abstracted from the medical charts included date and age at time of breast cancer diagnosis, stage of disease, use of chemotherapy (yes/no), use of radiation therapy (yes/no), usage of tamoxifen (yes/ no, dosage, duration), oophorectomy (yes/no, date, indication), recurrence (date and location), second malignancy (type and date), mode of ovarian cancer detection (screen detected or clinically detected) and current vital status (living/deceased, cause of death). Statistical analysis All data was analyzed using the SAS software program. Univariate analyses were conducted using t tests and chisquared tests. Cox regression analyses were used for multivariate analyses. A survival analysis was performed. We considered the woman to be at risk for ovarian cancer from the date of the first surgical procedure for breast cancer until oophorectomy, a diagnosis of ovarian cancer, death from any cause, or date of last follow-up. Kaplan Meier survival curves were constructed using log rank statistics and compared for subgroups of women defined by age (analyzed as a

3 224 K.A. Metcalfe et al. / Gynecologic Oncology 96 (2005) continuous variable) and by mutation status (BRCA1 vs. BRCA2). We also compared the rate of ovarian cancer for subgroups defined by each of the breast cancer treatments (i.e., tamoxifen vs. no tamoxifen, chemotherapy vs. no chemotherapy, etc). Results There were 491 women who were treated for stage I or II breast cancer between 1975 and 2000 and who had a known mutation or were from a family with a documented mutation (BRCA1, n = 327; BRCA2, n = 152; both BRCA1 and BRCA2, n = 12). The objective of this study was to estimate the risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 mutation carriers; therefore, women who did not have at least one intact ovary at the time of breast cancer diagnosis were excluded. Of the 491 women, 42 women had a bilateral oophorectomy prior to, or at the time of breast cancer diagnosis. These women were excluded, leaving a sample of 449 women with at least one intact ovary at the time of breast cancer diagnosis. The mean age of breast cancer diagnosis was 41.7 years (range years). The mean period of follow-up was 9.6 years (SD = 5.5, range from 0.23 to 26.0 years). After being diagnosed with breast cancer, 40 women (8.9%) developed ovarian cancer, one woman (0.2%) developed cancer of the omentum, two women (0.4%) developed peritoneal cancer, and three women (0.6%) developed fallopian tube cancer. These women (n = 46, 10.2%) were all identified as cases (ovarian cancers). The mean age at time of ovarian cancer diagnosis was 51.7 years (range years); BRCA1 carriers were diagnosed at a mean age of 51.0 years and BRCA2 carriers at 54.8 years (P = 0.36). The mean period of time from breast cancer to ovarian cancer in the cases was 8.1 years (range years). The annual and actuarial risks of developing ovarian cancer after breast cancer for BRCA1 and BRCA2 mutation carriers are presented in Table 1 and Fig. 1. The risk of ovarian cancer was estimated for patient subgroups defined by age (analyzed as a continuous variable), gene status (BRCA1 vs. BRCA2) and by treatment received (chemotherapy, tamoxifen). The univariate and multivariate relative risks associated with each of these factors are presented in Table 2. After adjusting for time and treatment type, gene (BRCA1 or BRCA2) was the only significant predictor of ovarian cancer after breast cancer. Table 1 Five- and 10-year risks of ovarian cancer after breast cancer Annual risk a Actuarial 5-year cumulative risk BRCA1 1.3% 4.5% 12.7% BRCA2 0.8% 5.3% 6.8% a Calculated over 10 years. Actuarial 10-year cumulative risk BRCA2 carriers had less than half of the risk of developing ovarian cancer after breast cancer compared to BRCA1 carriers (OR = 0.41; 95% CI ; P = 0.026) (Table 2). Although not statistically significant, the use of tamoxifen and chemotherapy showed a trend towards higher risks of ovarian cancer. Tamoxifen usage was associated with a nonsignificant modest increase in the risk of ovarian cancer (OR = 1.79; 95% CI ; P = 0.16). The use of chemotherapy decreased the risk of ovarian cancer by about one-half (OR = 0.59; 95% CI ; P = 0.15), but again, this was not statistically significant. In the cohort of 449 women, 83 women (18.5%) died of either breast (n = 75) or ovarian (n = 8) cancers (Table 3). Of the women with stage I breast cancer (n = 201), 21 of the women (10.4%) died of breast cancer, and 7 (3.5%) died of ovarian cancer. Of the women with stage II breast cancer (n = 248), 54 (21.8%) died of breast cancer and 1 (0.4%) died of ovarian cancer. Eight women died of ovarian cancer; seven with stage I breast cancer (87.5%) and one with stage II breast cancer (12.5%). Among women diagnosed with stage I breast cancer, 25% of the deaths in this group were attributed to ovarian cancer, compared to the women with stage II breast cancer where 1.8% of the deaths were the result of ovarian cancer. Discussion This paper is the first cohort study to examine the risk of ovarian cancer after breast cancer in BRCA1 and BRCA2. The current study has several strengths, including a large sample size. All women with breast cancer in the families were identified and all those who had been diagnosed with breast cancer (from 1975 to 2000) at age 65 or younger were eligible. Some women with breast cancer who had not received a test result were included, but women who had tested negative were excluded. We included untested and deceased women in the study in order to avoid the survivorship bias that would arise if only tested women were included. The actuarial cumulative risk of developing ovarian cancer after breast cancer in BRCA1 mutation carriers was 4.5% at 5 years after the diagnosis of breast cancer and 12.7% at 10 years; for BRCA2 carriers, it was 5.3% at 5 years and 6.8% at 10 years. For BRCA1 and BRCA2 mutation carriers without breast cancer, the lifetime risks of developing ovarian cancer have been estimated to be 50% [6] and 27% [7], respectively. Although these risks are not as high as the risks for breast cancer in this population, they are many times higher than the risk of ovarian cancer in the general population. In the United States, the lifetime risk of ovarian cancer is 1.7% [8]. There is the possibility that some of the untested women included in this study did not have the known family mutation. Although this number would be small, there is the possibility that the risks of ovarian cancer are slightly underestimated.

4 K.A. Metcalfe et al. / Gynecologic Oncology 96 (2005) Fig. 1. The risk of ovarian cancer following breast cancer in BRCA mutation carriers. It was hypothesized that breast cancer treatments might affect the risk of ovarian cancer. Women who received adjuvant chemotherapy had a lower risk of developing ovarian cancer as compared to women who did not receive chemotherapy, although the difference was not statistically significant. We previously reported in this cohort that chemotherapy for invasive breast cancer offered a 68% reduction in risk of ipsilateral breast cancer in BRCA1 and BRCA2 carriers (RR = 0.32; 95% CI ), but not of contralateral breast cancer [9]. In addition, preliminary research has suggested that there is a specific chemosensitivity profile of BRCA1 defective cells in vitro [10]. Although not statistically significant, we found that tamoxifen use was associated with a modestly increased Table 2 Cox s PH regression on the relative risk (RR) of ovarian cancer Variable Univariate RR (95% CI) P value Multivariate OR (95% CI) P value Mutation BRCA1 1 1 BRCA ( ) ( ) 0.03 a Age at breast cancer 1.03 ( ) ( ) 0.14 b Tamoxifen No 1 1 Yes 1.28 ( ) ( ) 0.16 c Chemotherapy No 1 1 Yes 0.61 ( ) ( ) 0.15 d a Adjusted for age, tamoxifen, chemotherapy. b Adjusted for mutation, tamoxifen, chemotherapy. c Adjusted for mutation, age, chemotherapy. d Adjusted for mutation, age, tamoxifen. risk of ovarian cancer after breast cancer (OR = 1.79). An increased risk of ovarian cancer associated with tamoxifen has not been described before. The tamoxifen trials have not reported an increased risk of ovarian cancer [11,12]. This preliminary finding warrants further investigation. Our research suggests that mutation carriers should be encouraged to consider prophylactic oophorectomy after a diagnosis of breast cancer. Prophylactic oophorectomy has been shown to be effective in BRCA1 or BRCA2 mutation carriers for the prevention of ovarian cancer [13], the prevention of a contralateral breast cancer [9] and the prevention of primary breast cancer [14]. In the cohort of women that we followed, 43 of the 46 ovarian cancers potentially could have been prevented by prophylactic bilateral salpingo-oophorectomy. The other three cancers developed in the peritoneum and omentum, and prophylactic oophorectomy would not have been protective. Our previous research has demonstrated that the strongest (negative) predictor of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers was oophorectomy [9]. Oophorectomy was associated with a 59% reduction in Table 3 Deaths: breast and ovarian cancers Cause of death Breast cancer Ovarian cancer Stage I breast cancer (n = 201) Stage II breast cancer (n = 248) Total deaths Total deaths

5 226 K.A. Metcalfe et al. / Gynecologic Oncology 96 (2005) the risk of contralateral breast cancer (HR = 0.41; 95% CI ). The magnitude of the risk reduction observed with oophorectomy was greater for women aged less than 50 at diagnosis (HR = 0.24; 95% CI 0.07 to 0.77; P = 0.02) than for women aged 50 or above (HR = 0.91; 95% CI ). Although to our knowledge, there has been no research published on the impact of oophorectomy on survival in BRCA1 and BRCA2 mutation carriers after breast cancer, data from sporadic breast cancer patients suggests that there is a protective effect of oophorectomy on survival. The Early Breast Cancer Trialists Collaborative Group has presented a systematic review of randomized control trials of ovarian ablation in pre-menopausal women by irradiation or surgery, which began before 1980 [15]. After 15 years of follow-up among 2102 women, the 15-year overall survival was highly significantly improved among women who underwent ovarian ablation (P = 0.001), as was recurrence-free survival (P = ). As expected, a greater number of women died of breast cancer who were diagnosed with stage II disease compared to those with stage I breast cancer. However, the number of deaths did increase in the group of women with stage I breast as a result of ovarian cancer. Women who are diagnosed with stage I breast cancer have high rates of breast cancer survival. This group of women appear to have the most to gain from prophylactic oophorectomy. Twenty-five percent of the deaths in the group of women with stage I breast cancer were due to ovarian cancer. Although we do not have statistical evidence that the death rate would be decreased if women had bilateral oophorectomy, this study provides evidence that bilateral oophorectomy might have prevented 25% of the deaths that occurred in women with stage I breast cancer. Women with breast cancer who are BRCA1 or BRCA2 mutation carriers should be counseled accordingly. In conclusion, women with a BRCA1 or BRCA2 mutation who have been diagnosed with and treated for breast cancer continue to have a high risk of developing ovarian cancer. Women should be aware that their ovarian cancer risk remains elevated despite having received for treatment for breast cancer. Prophylactic measures for the prevention of ovarian cancer should be considered, especially for women with stage I breast cancer. References [1] King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003; 302(5645): [2] Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast cancer linkage consortium. Am J Hum Genet 1995;56(1): [3] Levi F, Te VC, Randimbison L, La Vecchia C. Cancer risk in women with previous breast cancer. Ann Oncol 2003;14(1):71 3. [4] Bergfeldt K, Rydh B, Granath F, Gronberg H, Thalib L, Adami HO, et al. Risk of ovarian cancer in breast-cancer patients with a family history of breast or ovarian cancer: a population-based cohort study. Lancet 2002;360(9337): [5] Ries L, Eisner M, Kosary C, Hankey B, Miller B, Clegg L, et al. SEER cancer statistics review, Bethesda, MD7 National Cancer Institute; [6] Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 2002; 94(18): [7] Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The breast cancer linkage consortium. Am J Hum Genet 1998;62(3): [8] Ries L, Eisner M, Kosary C, Hankey B, Miller B, Clegg L, et al. SEER cancer statistics review, National Cancer Institute [9] Metcalfe K, Lynch H, Ghadirian P, Tung N, Olivotto I, Foulkes W, et al. The risk of contralateral breast cancer in BRCA1 and BRCA2 carriers. J Clin Oncol 2004 [in press]. [10] Tassone P, Tagliaferri P, Perricelli A, Blotta S, Quaresima B, Martelli ML, et al. BRCA1 expression modulates chemosensitivity of BRCA1- defective HCC937 human breast cancer cells. Br J Cancer 2003; 88(8): [11] Stewart HJ, Prescott RJ, Forrest AP. Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst 2001; 93(6): [12] Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah WM, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90(18): [13] Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van t Veer L, Garber JE, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346(21): [14] Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Cannon- Albright L, et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 1999;91(17): [15] Ovarian ablation in early breast cancer: overview of the randomised trials. Early breast cancer trialists collaborative group. Lancet 1996;348(9036):