ORIGINAL ARTICLE: GENETICS
Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers Tamar Perri, M.D.,a,b Dror Lifshitz, M.D.,a,b Siegal Sadetzki, M.D., M.P.H.,b,c Bernice Oberman, M.Sc.,c Dror Meirow, M.D.,b,d Gilad Ben-Baruch, M.D.,a,b Eitan Friedman, M.D., Ph.D.,b,e and Jacob Korach, M.D.a,b a Department of Gynecologic Oncology, Sheba Medical Center, Tel Hashomer; b Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; c Cancer and Radiation Epidemiology Unit, Gertner Institute, d Fertility Preservation Center and IVF Unit, and e Susanne Levy-Gertner Oncogenetics Unit, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel
Objective: To determine whether BRCA mutation carriers who undergo fertility treatments are at increased risk of developing invasive epithelial ovarian cancer (IEOC). Design: Historical cohort study. Setting: Tertiary university-affiliated medical center and the National Cancer Registry. Patient(s): A total of 1,073 Jewish Israeli BRCA mutation carriers diagnosed in a single institution between 1995 and 2013, including 164 carriers (15.2%) who had fertility treatments that included clomiphene citrate (n ¼ 82), gonadotropin (n ¼ 69), in vitro fertilization (IVF) (n ¼ 66), or a combination (n ¼ 50), and 909 carriers not treated for infertility. Intervention(s): None. Main Outcome Measure(s): Odds ratios (OR) and 95% confidence intervals (CI) for IEOC association with fertility treatments and other hormone and reproductive variables. Result(s): In 175 (16.3%) mutation carriers, IEOC was diagnosed; 139 women carried BRCA1, 33 carried BRCA2, and 3 had unknown mutations. Fertility treatments were not associated with IEOC risk (age-adjusted OR 0.63; 95% CI, 0.38–1.05) regardless of treatment type (with clomiphene citrate, OR 0.87; 95% CI, 0.46–1.63; with gonadotropin, OR 0.59; 95% CI, 0.26–1.31; with IVF, OR 1.08, 95% CI, 0.57–2.06). Multivariate analysis indicated an increased risk of IEOC with hormone-replacement therapy (OR 2.22; 95% CI, 1.33– 3.69) and a reduced risk with oral contraceptives (OR 0.19; 95% CI, 0.13–0.28) in both BRCA1 and BRCA2 mutation carriers. Parity was a risk factor for IEOC by univariate but not multivariate analysis. Conclusion(s): According to our results, treatments for infertile BRCA mutation carriers should not be contraindicated or viewed as risk modifiers for IEOC. Parity as a risk factor in BRCA muUse your smartphone tation carriers warrants further investigation. (Fertil SterilÒ 2015;-:-–-. Ó2015 by Amerto scan this QR code ican Society for Reproductive Medicine.) and connect to the Key Words: BRCA mutations, cancer risk, fertility treatment, ovarian cancer Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/perrit-fertility-treatments-cancer-risk-brca-mutations/
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nvasive epithelial ovarian cancer (IEOC), a lethal malignancy, is the fifth leading cause of cancer-
related deaths in women in the United States (1). Germline mutations in the BRCA1 and BRCA2 genes confer a sub-
Received November 9, 2014; revised February 7, 2015; accepted February 9, 2015. T.P. has nothing to disclose. D.L. has nothing to disclose. S.S. has nothing to disclose. B.O. has nothing to disclose. D.M. has nothing to disclose. G.B.-B. has nothing to disclose. E.F. has nothing to disclose. J.K. has nothing to disclose. T.P. and D.L. should be considered similar in author order. This work was performed in partial fulfillment of the M.D. thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University, Israel. Reprint requests: Tamar Perri, M.D., Department of Gynecologic Oncology, Sheba Medical Center, 52621 Tel Hashomer, Israel (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.02.011 VOL. - NO. - / - 2015
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stantially increased risk of developing IEOC, with a cumulative lifetime risk of 39% to 54% in BRCA1 mutation carriers and 11% to 23% in BRCA2 mutation carriers (2,3). In Jewish Ashkenazi women, in whom the spectrum of BRCA1 and BRCA2 mutations is limited, the risk of IEOC is reportedly as great as 58% (4). The pathogenic mechanisms associated with IEOC are still poorly understood (5). A common notion is that incessant ovulatory cycles, involving 1
ORIGINAL ARTICLE: GENETICS repeated cycles of cellular damage and repair of the ovarian surface epithelium, may lead to genetic alterations in ovarian epithelial cells, thereby facilitating malignant epithelial transformation (6,7). The ‘‘incessant ovulation’’ theory is supported by epidemiologic studies showing that factors associated with a decrease in ovulatory cycles, such as oral contraception, breastfeeding, and a relatively large number of pregnancies, lower the risk of IEOC, both in the population at average risk (8–13) and in genetically susceptible BRCA mutation carriers (14–18). Ovulation induction in the course of fertility treatments has been studied as a risk factor in research on IEOC in the general population (19–32). A meta-analysis by Rizzuto et al. (33) disclosed no convincing evidence in the average risk population of an increased risk of IEOC as a result of fertility treatment. However, there are no published data on the possible effects of fertility treatments in genetically susceptible individuals, and specifically in BRCA mutation carriers. Our study examined the possible effect of fertility treatments on the risk of IEOC in carriers of BRCA1 or BRCA2 mutations.
MATERIALS AND METHODS Study Population Included in this historical prospective study were all consecutive Jewish Israeli female patients who had undergone oncogenetic counseling because of a personal or family history of BRCA mutation-associated cancers. In these women, genotyping was performed between January 1995 and December 2011, and they had been informed that they had one of the predominant mutations known to occur in Jewish (primarily Ashkenazi) women in either the BRCA1 (185delAG, 5383InsC Tyr978X) or the BRCA2 (6174delT and 8765delAG) gene. Genotyping was performed as previously described elsewhere (34), and all nucleotide sequences were confirmed by direct DNA sequencing.
Data Collection The study was approved by the institutional review board of our medical center. All participants had provided written informed consent for genetic testing and data collection, and during the first clinic appointment had completed a questionnaire regarding family history as well as reproductive and selected lifestyle factors. Items on the questionnaire included age at menarche, oral contraception use (yes/no, duration), fertility treatments (yes/no, type), age at first pregnancy and pregnancies details (live births, abortions), duration of breastfeeding (if any, in months), hormone-replacement therapy (yes/no, type), and prior gynecologic surgeries (including risk-reducing salpingo-oophorectomy). During the follow-up period until either cancer diagnosis, death of other cause, or the end of the study, relevant data were collected from patients' files, and the participants' parameters were updated. In the ovarian cancer patients, only fertility treatments that preceded cancer diagnosis were recorded. Information on cancer diagnosis, type, and age at diagnosis was provided by the Israel National Cancer Regis2
try, updated to the end of 2013. Mortality data were updated to the end of 2013 through the national Office of Vital Records. Two groups, namely, those who had received any fertility treatment and those who had not, were defined.
Statistical Analysis For the purposes of this study, ‘‘age’’ was recorded as the age at the end of the study for living carriers without diagnosed IEOC, or age at whichever occurred first: IEOC diagnosis, prophylactic salpingo-oophorectomy, or death. Distributions of selected demographic, hormone, and fertility-related factors were compared between these two groups, and between those who had reported receiving fertility treatment and those who had not. A t test was used to check for statistically significant differences between the groups for continuous variables, and a chi-square test for categorical variables. Odds ratios for these variables were calculated using unconditional logistic regression. A multivariate analysis was performed to control for the potential confounding effects of mutation type (BRCA1/2), age at menarche (years), oral contraceptive use (ever/never), parity (yes/no and number of births), age at first pregnancy (years), and use of hormone replacement therapy (yes/no). P< .05 was considered statistically significant, and all tests were two-sided.
RESULTS Out of a total of 1,170 mutation carriers diagnosed in our institute during the study period, information about fertility treatments was available for 1,073. Of these, 718 patients (67%) had a mutation in BRCA1: 185delAG (n ¼ 502) and 5382insC (n ¼ 157) or other mutation (n ¼ 59); and 331 (31%) had a mutation in BRCA2: 6174delT (n ¼ 308) or other mutation (n ¼ 23). Three patients had both BRCA1 and BRCA2 mutations Mutation types frequencies are presented in Table 1. Primary IEOC was diagnosed in 175 mutation carriers (16.3%), 139 (79.4%) of them carrying BRCA1, 33 (18.9%) of them carrying BRCA2 mutations, and 3 (1.7%) unknown. Primary breast cancer was diagnosed in 477 (44.5%) mutation
TABLE 1 Mutation types frequencies. Mutation Total BRCA1 185delAG–106 5382iNsC–40 Other mutations BRCA2 6174delT 8765delAG Other mutations Both BRCA1 and BRCA2 185delAG, 6174delT Unknown
Ovarian cancer
No ovarian cancer
175 139 108 23 8 33 33 0 0 0 0 3
898 579 394 134 51 298 275 10 13 3 3 18
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TABLE 2 Demographic, hormone, and reproduction variables of the study population by fertility treatment. Fertility treatment Characteristic Age Mean (SD) Median (range) Mutation type, n (%) BRCA1 BRCA2 BRCA1 and BRCA2 Unknown Mutation origin, n (%) Mother Father Both NA Age at menarche Mean (SD) Median (range) Age at first pregnancy Mean (SD) Median (range) Nullipara %26, n (%) 26–30, n (%) 31–35, n (%) 36–40, n (%) >40, n (%) NA, n (%) No. of abortions Mean (SD) Median (range) Breastfeeding period (mo) Mean (SD) Median (range) OCP use (y) Mean (SD) Median (range) Never %1 y, n (%) >1–5 y, n (%) >5 y, n (%) NA HT, n (%) No Yes NA Parity Mean (SD) Median (range) 0 1, n (%) 2, n (%) 3, n (%) >3, n (%) NA, n (%) Prophylactic BSO, n (%) No Yes NA Age at prophylactic BSO Mean (SD) Median (range) Cancer diagnosis, n (%) None Breast Ovary OC and/or BC
Total (n [ 1,073)
Yes, group 1 (n [ 164)
49.9 (13.0) 49.1 (20–93)
47.1 (8.6) 46 (29–75)
50.4 (13.6) 50 (20–93)
.0001
718 (66.9) 331 (30.8) 3 (0.3) 21 (2)
105 (64) 54 (32.9) 1 (0.6) 4 (2.4)
613 (67.4) 277 (30.5) 2 (0.2) 17 (1.9)
.68
571 (53.2) 177 (16.5) 2 (0.2) 323 (30.1)
98 (59.8) 24 (14.6) 1 (0.6) 41 (25)
473 (52) 153 (16.8) 1 (0.1) 282 (31)
.13
12.93 (1.4) 13 (9–19)
12.9 (1.3) 12.5 (9–17)
12.936 (1.4) 13 (9–19)
.78
25.6 4.6 25 (14–48) 122 (11.4) 504 (47) 291 (27.1) 93 (8.7) 30 (2.8) 5 (0.5) 28 (2.6)
No, group 2 (n [ 909)
P value
29.04 (5.5) 29 (19–48) 15 (9.1) 42 (25.6) 49 (29.9) 32 (19.5) 15 (9.1) 4 (2.4) 7 (4.3)
25.02 (4.1) 24 (14–43) 107 (11.8) 462 (50.8) 242 (26.6) 61 (6.7) 15 (1.7) 1 (0.1) 21 (2.3)
< .0001
1.04 (1.5) 1 (0–11)
0.99 (1.5) 0 (0–9)
1.05 (1.5) 1 (0–11)
.65
9.45 15.3 4 (0–171)
7.86 (12.7) 3 (0–70)
9.74 (15.8) 4 (0–171)
.1
4.88 (5.97) 2 (0–30) 416 (38.8) 88 (8.2) 168 (15.7) 392 (36.5) 9 (0.8)
5.77 (5.9) 4 (0–24) 44 (26.8) 13 (7.9) 33 (20.1) 73 (44.5) 1 (0.6)
4.72 (5.98) 1.5 (0–30) 372 (40.9) 75 (8.3) 135 (14.9) 319 (35.1) 8 (0.9)
.038
936 (87.2) 105 (9.8) 32 (3)
149 (90.9) 10 (6.1) 5 (3)
787 (86.6) 95 (10.5) 27 (3)
.23
2.31 (1.5) 2 (0–13) 144 (13.4) 118 (11) 345 (32.2) 322 (30) 141 (13.1) 3 (0.3)
2.13 (1.4) 2 (0–8) 23 (14) 28 (17.1) 51 (31.1) 43 (26.2) 19 (11.6) 0
2.34 (1.5) 2 (0–13) 121 (13.3) 90 (9.9) 294 (32.3) 279 (30.7) 122 (13.4) 3 (0.3)
.11
895 (83.4) 114 (10.6) 64 (6)
131 (79.9) 22 (13.4) 11 (6.7)
764 (84.1) 92 (10.1) 53 (5.8)
.39
46.5 (7.3) 46 (31–79)
44.7 (5.8) 43 (38–58)
46.9 (7.6) 47.5 (31–79)
.2
465 (43.3) 477 (44.45) 175 (16.3) 608 (56.6)
83 (50.6) 66 (35.9) 19 (11.6) 81 (49.4)
382 (42) 411 (45.5) 156 (17.2) 527 (58)
< .0001
.01
.13
.27 .1 .05
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ORIGINAL ARTICLE: GENETICS
TABLE 2 Continued. Fertility treatment Characteristic Other cancers Uterine Uterine cervix GI Urinary tract Thyroid Lung Others
Total (n [ 1,073)
Yes, group 1 (n [ 164)
84 (7.8) 11 (1.02) 6 (0.6) 27 (2.5) 7 (0.65) 7 (0.65) 11 (1.02) 15 (1.4)
7 (4.2) 1 (0.6) 0 4 (2.4) 0 0 2 (1.2) 0
No, group 2 (n [ 909)
P value
77 (8.4) 10 (1.1) 6 (0.66) 23 (2.5) 7 (0.77) 7 (0.77) 9 (1) 15 (1.65)
Note: BSO ¼ bilateral salpingo-oophorectomy; GI ¼ gastrointestinal; HT ¼ hormone replacement therapy; NA ¼ not applicable; OCP ¼ oral contraceptive pill. Perri. BRCA mutation and fertility drugs. Fertil Steril 2015.
carriers. In 44 carriers, both breast and ovarian cancer were diagnosed, and 84 carriers had other cancers, of which 58 were additional to either breast or ovarian cancer (Table 2). All other patients (n ¼ 439) were cancer-free at the time of genetic counseling and until the end of the study. A total of 164 (15.3%, group 1) of the study participants reported undergoing fertility treatments, which included medications containing clomiphene citrate (CC) (n ¼ 82) or gonadotropin (n ¼ 69), in vitro fertilization (IVF, n ¼ 66), or some combination of these treatments (n ¼ 50). No fertility treatments were reported by the remaining 909 participants (group 2). Characteristics of the participants in the two groups are presented in Table 2. The groups did not statistically significantly differ in mutation type, mutation origin (maternal/ paternal), age at menarche, number of abortions, parity, breastfeeding duration, hormone replacement therapy, riskreducing bilateral salpingo-oophorectomy rate, or age at surgery. The groups differed in age, age at first pregnancy (older in the fertility-treated group), and oral contraceptive use. Among these patients, IEOC was diagnosed in 19 patients from group 1 (11.6%) and in 156 (17.2%) from group 2. Univariate analysis disclosed no association between fertility treatments and risk of IEOC (OR 0.63; 95% CI, 0.38–1.05), regardless of the treatment received and upon separate analysis (for CC-containing medication, OR 0.87; 95% CI, 0.46–1.63; for gonadotropin-containing medication, OR 0.59; 95% CI, 0.26–1.31; for IVF, OR 1.08, 95% CI, 0.57–2.06). There was also no association between IEOC risk and age at menarche, or between IEOC risk and breastfeeding. On the other hand, IEOC risk was associated with age at first pregnancy, parity, and hormone replacement therapy. Oral contraceptive use was associated with a reduced risk of IEOC in BRCA mutation carriers (Table 3). Among all carriers of BRCA1 and/or BRCA2 mutations, the contribution of the BRCA2 mutation to having ovarian cancer was statistically significantly smaller compared with the BRCA1 mutation (OR 0.46). On multivariate analysis only, the use of oral contraceptives and use of hormone replacement therapy (but not parity or fertility treatments) were found to alter the risk of IEOC: the risk increased with use of hormone replacement 4
therapy and decreased with oral contraceptive use (Table 4). The risk of IEOC was further reduced with longer oral contraceptive use: for its use %1 year, OR 0.36 (95% CI, 0.16–0.84); for 1–5 years, OR 0.31 (95% CI, 0.19–0.51); and for >5 years, OR 0.10 (95% CI, 0.06–0.17; data not shown). The results of the univariate and multivariate analyses were not changed when analyzed separately for BRCA1 and BRCA2 mutation carriers (Table 4).
DISCUSSION The results of our study suggest that fertility treatments in Jewish Israeli BRCA mutation carriers are not associated with an increased risk of IEOC. Incessant ovulation is one of the main factors that have been implicated in the pathogenesis of ovarian cancer (35). Fertility treatments involve ovulation-inducing drugs and thus increase the chances of multiple ovulations. An association between pharmacologic ovulation induction in the course of fertility treatments and ovarian cancers in the general population has been investigated in numerous studies. Although some early epidemiologic studies found that exposure to ovulation-stimulating drugs increases the risk of both IEOC and ovarian tumors with low malignant potential (‘‘borderline’’ tumors) (21, 26, 36, 37), most of the current data appear to exclude a clinically discernible effect of fertility drugs on the risk of ovarian tumors, and especially of high-grade IEOC in the general population (23, 24, 27–31). Recently, however, in a long-term follow-up study of 2,768 women who had undergone fertility treatment, Sanner et al. (25) reported an increased risk of ovarian cancer after treatment with gonadotropins (relative ratio 5.28; 95% CI, 1.70–16.47) and of borderline tumors after CC treatment (standardized incidence ratio 7.47; 95% CI, 1.54–21.83). Brinton et al. (19) also reported a higher risk of ovarian cancer associated with the use of ovulation-stimulating drugs during IVF, with hazard ratio (HR) 1.58 (95% CI, 0.75–3.29). These inconclusive results led Hunn et al. (5), in their recent review, to describe fertility drugs as ‘‘indeterminate’’ factors affecting ovarian cancer risk. Those observations might suggest that there is a need for long-term monitoring of patients in the general population who are undergoing fertility treatments. VOL. - NO. - / - 2015
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TABLE 3 Risk factors for developing invasive epithelial ovarian cancer, univariate analysis. Characteristic Age Mean (SD) Median (range) BRCA mutation BRCA1, n (%) BRCA2, n (%) Both, n (%) Unknown, n (%) Age at menarche Mean (SD) Median (range) Age at first pregnancy Mean (SD) Median (range) Nullipara %26, n (%) 26–30, n (%) 31–35, n (%) 36–40, n (%) >40, n (%) NA, n (%) Breastfeeding (mo) Mean (SD) Median (range) OCP Duration, mean SD Never %1 y, n (%) >1–5 y, n (%) >5 y, n (%) NA HT No Yes NA Parity 0 1, n (%) 2, n (%) 3, n (%) >3, n (%) NA, n (%) Fertility treatment No, n (%) Yes, n (%) IVF, n (%) GN, n (%) CC, n (%) Mixed
Ovarian cancer (n [ 175)
No ovarian cancer (n [ 898)
Odds ratio (95% CI)
P value
53.6 10.3 51.9 (28.7–85.2)
49.1 13.4 49 (20–93)
1.03 (1.01–1.04)
< .001
139 (79.4) 33 (18.9) 0 3 (1.7)
579 (64.5) 298 (33.2) 3 (0.3) 18 (2)
1 0.46 (0.31–0.69)a
12.9 1.36 13 (9–16.5)
12.93 1.4 13 (9–19)
0.98 (0.87–1.1)
24.31 4.5 23 (16–48) 12 (6.9) 117 (66.9) 33 (18.9) 6 (3.4) 5 (2.9) 1 (0.6) 1 (0.6)
25.91 4.57 25 (14–43) 110 (12.2) 387 (43.1) 258 (28.7) 87 (9.7) 25 (2.8) 4 (0.4) 27 (3)
1.00 2.77 (1.47–5.21) 1.17 (0.58–2.35) 0.63 (0.23–1.75) 1.83 (0.59–5.68) 2.29 (0.24–22.2)
9.54 11.6 6 (0–60)
9.43 15.95 4 (0–171)
1.0 (0.99–1.01)
1.45 3.49 123 (70.3) 14 (8) 19 (10.9) 18 (10.3) 1 (0.6)
5.55 6.13 293 (32.6) 74 (8.2) 149 (16.6) 374 (41.6)
0.82 (0.78–0.86) 1 0.45 (0.25–0.83) 0.30 (0.18–0.51) 0.11 (0.07–0.19)
136 (77.7) 32 (18.3) 7 (4)
800 (89.1) 73 (8.1) 25 (2.8)
2.58 (1.64–4.06)
13 (7.4) 15 (8.6) 61 (34.9) 60 (34.3) 26 (14.8) 0
131 (14.6) 103 (11.5) 284 (31.6) 262 (29.2) 115 (12.8) 3 (0.3)
1.00 1.47 (0.67–3.22) 2.16 (1.15–4.08) 2.31 (1.22–4.36) 2.28 (1.12–4.64) 1.00
156 (89.1) 19 (10.9) 4 (2.3) 1 (0.6) 3 (1.7) 10 (5.7)
753 (83.9) 145 (16.1) 36 (4) 22 (2.4) 37 (4.1) 40 (4.5)
0.63 (0.38–1.05)
< .001
0.69 (0.2–2.39) NS < .001
NS < .001
< .001 .03
NS
0.54 (0.19–1.53) 0.22 (0.03–1.64) 0.39 (0.12–1.29) 1.21 (0.59–2.46)
Note: BCRP ¼ breast cancer resistance protein; CC ¼ clomiphene citrate; CI ¼ confidence interval; GN ¼ gonadotropins; HT ¼ hormone replacement therapy use; NA ¼ not available; NS ¼ not statistically significant; OCP ¼ oral contraceptive use; SD ¼ standard deviation. a In comparison with BRCA1 mutation carriers. Perri. BRCA mutation and fertility drugs. Fertil Steril 2015.
In BRCA mutation carriers, the effect of fertility treatments on the risk of breast cancer was studied by Kotsopoulos et al. (38). They reported that the increased risk in users of fertility drugs was not statistically significant compared to nonusers (OR 1.21; 95% CI, 0.81–1.82). To the best of our knowledge, our study is the first to investigate the impact of ovulation induction on IEOC risk in an ethnically defined cohort of BRCA mutation carriers. It has been postulated that the association between fertility treatments and ovarian cancer merely reflects the VOL. - NO. - / - 2015
higher risk associated with the actual cause of infertility and nulliparity (or no breastfeeding, a suggested protecting factor in IEOC) (5). In the average-risk population, nulligravid women are considered to be at an increased risk of IEOC (8, 31, 37, 39, 40). In BRCA mutation carriers, however, data on the effect of parity are sparse and inconsistent. Modan et al. (15), in a study of Jewish Israeli women with ovarian cancer, reported a protective effect of each additional birth in both BRCA1 and BRCA2 mutation carriers, with a 12% reduction in the odds of ovarian cancer per birth (95% CI, 2.3–21). 5
ORIGINAL ARTICLE: GENETICS
TABLE 4 Multivariate model for impact of hormone and reproductive factors on ovarian cancer risk in BRCA-mutation carriers, adjusted for age. BRCA1 Factor Parity OCP HT Fertility treatment No Any IVF Gonadotropins CC Mixed
BRCA2
BRCA1 and BRCA2
95% CI
OR
95% CI
OR
95% CI
OR
0.81–3.33 0.14–0.33 0.89–3.08
1.64 0.21a 1.66a
– 0.09–0.61 1.19–7.8
– 0.24a 3.04a
0.95–3.61 0.14–0.31 1.21–3.25
1.85 0.21a 1.98a
0.43–1.53 0.23–2.93 0.06–4.26 – 0.78–4.15
0.81 0.82 0.50 – 1.8
0.31–3.30 0.20–16.48 – 0.57–17.14 0.09–6.95
1.01 1.81 – 3.14 0.77
0.46 0.31 0.03 0.08 0.68
Reference 0.80 0.93 0.26 0.34 1.45
Note: BCRP ¼ breast cancer resistance protein; CC ¼ clomiphene citrate; CI ¼ confidence interval; HT ¼ hormone replacement therapy use; IVF ¼ in vitro fertilization; OCP ¼ oral contraceptive use; OR ¼ odds ratio. a P< .001. Perri. BRCA mutation and fertility drugs. Fertil Steril 2015.
Milne et al. (41) reported that parity was associated with a reduced risk of ovarian cancer in carriers of BRCA1 mutations (HR 0.41, 95% CI, 0.18–0.94; P¼ .03) but not in BRCA2 mutation carriers. McLaughlin et al. (14) reported an increased risk (HR 2.74; 95% CI, 1.18–6.41; P¼ .02) for IEOC with increased parity in BRCA2 mutation carriers. We showed here that in univariate analysis, parity is a risk factor for ovarian cancer in both BRCA1 and BRCA2 mutation carriers. Those results are in line with a study encompassing 2,281 BRCA1 and 1,038 BRCA2 mutation carriers from ethnically diverse populations (17), where nulliparous women were found to be at a lower risk of ovarian cancer than women with one pregnancy; thus, overall nulliparity was associated with a slight, statistically nonsignificant reduction in the risk of ovarian cancer. These results might represent a true biologic significance or merely reflect a selection bias whereby women diagnosed with ovarian cancer are more likely to be tested for BRCA mutations if they have offspring than if they do not (17, 42). Indeed in our study, parity was not a risk factor for IEOC in multivariate analysis, supporting the selection-bias effect. Hormone replacement therapy is another risk factor for ovarian cancer that has been well studied in the general population (43–46). In contrast to our results, Kotsopoulos et al. (47) reported that hormone replacement therapy use did not adversely influence the risk of ovarian cancer in BRCA mutation carriers. There was no significant relationship with increasing duration of use. Progestin-based regimens did not have a statistically significant protecting effect on ovarian cancer (odds ratio ¼ 0.57). The relatively small number of hormone replacement therapy users and their relatively young ages warrant further studies to assess the effect of hormone replacement therapy on the incidence of IEOC in BRCA mutation carriers. Oral contraceptive pills prevent ovulation and have been reported to reduce the risk of ovarian cancer in the general population (48) as well as in BRCA mutation carriers (16, 18, 49). In a recent meta-analysis of eight studies in which ovarian cancer risk was examined in BRCA1/2 muta6
tion carriers, an inverse association was reported between oral contraceptive use and ovarian cancer (OR 0.58; 95% CI, 0.46–0.73) (18). Our results are in line with those studies: we found that the risk of ovarian cancer was reduced with any use of oral contraceptives by both BRCA1 mutation and BRCA2-mutation carriers, and we also found a statistically significant duration-dependent risk reduction. Additional factors reportedly associated with ovulation modification and hence with IEOC risk modulation, such as age at menarche, age at first pregnancy, and breastfeeding, were not associated either in our study or in those of others with risk of ovarian cancer (50). These data are consistent with the notion that in BRCA mutation carriers ovulation might not affect ovarian cancer risk. One plausible biological reason for this lack of effect is that the precursor of ovarian carcinoma in BRCA mutation carriers might be an occult intraepithelial carcinoma that originates in the fimbrial region of the fallopian tube, involving the ovary only secondarily (51, 52). One of the advantages of our study is our homogenous (Jewish Israeli) mutation-carriers population with a homogenous spectrum of BRCA gene mutations. However, our study has certain inherent limitations. Data with regard to fertility treatments were based solely on self-reporting, with no available confirmatory data on the number of treatments, dosage, or timing. Moreover, information about the cause of infertility was lacking, precluding a separate assessment of the effects of different possible causes (ovulatory, mechanical, or male factor infertility) on ovarian cancer risk. The young age of our studied population is also a limitation as IEOC risk is a function of age, with higher rates in older women. We also lacked data on borderline ovarian tumors and were thus obliged to limit our conclusion to IEOC only; however, that missing information is not particularly relevant to the present study because BRCA mutation carriers are more likely to have high-grade tumors (53). Because the ovarian cancer in most of our patients was diagnosed before the genetic counseling (and the cancer diagnosis was probably the reason for counseling), there might be VOL. - NO. - / - 2015
Fertility and Sterility® an overrepresentation of BRCA-mutation carriers who have cancer. However, it does not influence our retrospective follow-up cohort analysis of correlation between fertility treatment and ovarian cancer because in all cases the fertility treatments (exposure) preceded the cancer diagnosis. Also, because the study groups have not been matched, the results of the univariate unadjusted analysis might rather reflect the selection differences between the groups; hence, the conclusions of this study are based mainly on multivariate analysis that includes all appropriate cofactors. Despite these limitations, we believe that our study addresses an important question and is novel. It appears that fertility treatments are not associated with an increased risk of IEOC in Jewish Israeli BRCA mutation carriers, so such treatments for infertile BRCA mutation carriers should not be contraindicated. Nevertheless, the association between ovarian cancer and fertility treatments in BRCA mutation carriers should continue to be monitored. In addition, prospective cohort studies based on a more detailed collection of the type, dose, and time course of fertility treatments are clearly warranted.
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Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers Tamar Perri, M.D.,a,b Dror Lifshitz, M.D.,a,b Siegal Sadetzki, M.D., M.P.H.,b,c Bernice Oberman, M.Sc.,c Dror Meirow, M.D.,b,d Gilad Ben-Baruch, M.D.,a,b Eitan Friedman, M.D., Ph.D.,b,e and Jacob Korach, M.D.a,b a Department of Gynecologic Oncology, Sheba Medical Center, Tel Hashomer; b Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; c Cancer and Radiation Epidemiology Unit, Gertner Institute, d Fertility Preservation Center and IVF Unit, and e Susanne Levy-Gertner Oncogenetics Unit, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel
Objective: To determine whether BRCA mutation carriers who undergo fertility treatments are at increased risk of developing invasive epithelial ovarian cancer (IEOC). Design: Historical cohort study. Setting: Tertiary university-affiliated medical center and the National Cancer Registry. Patient(s): A total of 1,073 Jewish Israeli BRCA mutation carriers diagnosed in a single institution between 1995 and 2013, including 164 carriers (15.2%) who had fertility treatments that included clomiphene citrate (n ¼ 82), gonadotropin (n ¼ 69), in vitro fertilization (IVF) (n ¼ 66), or a combination (n ¼ 50), and 909 carriers not treated for infertility. Intervention(s): None. Main Outcome Measure(s): Odds ratios (OR) and 95% confidence intervals (CI) for IEOC association with fertility treatments and other hormone and reproductive variables. Result(s): In 175 (16.3%) mutation carriers, IEOC was diagnosed; 139 women carried BRCA1, 33 carried BRCA2, and 3 had unknown mutations. Fertility treatments were not associated with IEOC risk (age-adjusted OR 0.63; 95% CI, 0.38–1.05) regardless of treatment type (with clomiphene citrate, OR 0.87; 95% CI, 0.46–1.63; with gonadotropin, OR 0.59; 95% CI, 0.26–1.31; with IVF, OR 1.08, 95% CI, 0.57–2.06). Multivariate analysis indicated an increased risk of IEOC with hormone-replacement therapy (OR 2.22; 95% CI, 1.33– 3.69) and a reduced risk with oral contraceptives (OR 0.19; 95% CI, 0.13–0.28) in both BRCA1 and BRCA2 mutation carriers. Parity was a risk factor for IEOC by univariate but not multivariate analysis. Conclusion(s): According to our results, treatments for infertile BRCA mutation carriers should not be contraindicated or viewed as risk modifiers for IEOC. Parity as a risk factor in BRCA muUse your smartphone tation carriers warrants further investigation. (Fertil SterilÒ 2015;-:-–-. Ó2015 by Amerto scan this QR code ican Society for Reproductive Medicine.) and connect to the Key Words: BRCA mutations, cancer risk, fertility treatment, ovarian cancer Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/perrit-fertility-treatments-cancer-risk-brca-mutations/
I
nvasive epithelial ovarian cancer (IEOC), a lethal malignancy, is the fifth leading cause of cancer-
related deaths in women in the United States (1). Germline mutations in the BRCA1 and BRCA2 genes confer a sub-
Received November 9, 2014; revised February 7, 2015; accepted February 9, 2015. T.P. has nothing to disclose. D.L. has nothing to disclose. S.S. has nothing to disclose. B.O. has nothing to disclose. D.M. has nothing to disclose. G.B.-B. has nothing to disclose. E.F. has nothing to disclose. J.K. has nothing to disclose. T.P. and D.L. should be considered similar in author order. This work was performed in partial fulfillment of the M.D. thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University, Israel. Reprint requests: Tamar Perri, M.D., Department of Gynecologic Oncology, Sheba Medical Center, 52621 Tel Hashomer, Israel (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.02.011 VOL. - NO. - / - 2015
discussion forum for this article now.*
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stantially increased risk of developing IEOC, with a cumulative lifetime risk of 39% to 54% in BRCA1 mutation carriers and 11% to 23% in BRCA2 mutation carriers (2,3). In Jewish Ashkenazi women, in whom the spectrum of BRCA1 and BRCA2 mutations is limited, the risk of IEOC is reportedly as great as 58% (4). The pathogenic mechanisms associated with IEOC are still poorly understood (5). A common notion is that incessant ovulatory cycles, involving 1
ORIGINAL ARTICLE: GENETICS repeated cycles of cellular damage and repair of the ovarian surface epithelium, may lead to genetic alterations in ovarian epithelial cells, thereby facilitating malignant epithelial transformation (6,7). The ‘‘incessant ovulation’’ theory is supported by epidemiologic studies showing that factors associated with a decrease in ovulatory cycles, such as oral contraception, breastfeeding, and a relatively large number of pregnancies, lower the risk of IEOC, both in the population at average risk (8–13) and in genetically susceptible BRCA mutation carriers (14–18). Ovulation induction in the course of fertility treatments has been studied as a risk factor in research on IEOC in the general population (19–32). A meta-analysis by Rizzuto et al. (33) disclosed no convincing evidence in the average risk population of an increased risk of IEOC as a result of fertility treatment. However, there are no published data on the possible effects of fertility treatments in genetically susceptible individuals, and specifically in BRCA mutation carriers. Our study examined the possible effect of fertility treatments on the risk of IEOC in carriers of BRCA1 or BRCA2 mutations.
MATERIALS AND METHODS Study Population Included in this historical prospective study were all consecutive Jewish Israeli female patients who had undergone oncogenetic counseling because of a personal or family history of BRCA mutation-associated cancers. In these women, genotyping was performed between January 1995 and December 2011, and they had been informed that they had one of the predominant mutations known to occur in Jewish (primarily Ashkenazi) women in either the BRCA1 (185delAG, 5383InsC Tyr978X) or the BRCA2 (6174delT and 8765delAG) gene. Genotyping was performed as previously described elsewhere (34), and all nucleotide sequences were confirmed by direct DNA sequencing.
Data Collection The study was approved by the institutional review board of our medical center. All participants had provided written informed consent for genetic testing and data collection, and during the first clinic appointment had completed a questionnaire regarding family history as well as reproductive and selected lifestyle factors. Items on the questionnaire included age at menarche, oral contraception use (yes/no, duration), fertility treatments (yes/no, type), age at first pregnancy and pregnancies details (live births, abortions), duration of breastfeeding (if any, in months), hormone-replacement therapy (yes/no, type), and prior gynecologic surgeries (including risk-reducing salpingo-oophorectomy). During the follow-up period until either cancer diagnosis, death of other cause, or the end of the study, relevant data were collected from patients' files, and the participants' parameters were updated. In the ovarian cancer patients, only fertility treatments that preceded cancer diagnosis were recorded. Information on cancer diagnosis, type, and age at diagnosis was provided by the Israel National Cancer Regis2
try, updated to the end of 2013. Mortality data were updated to the end of 2013 through the national Office of Vital Records. Two groups, namely, those who had received any fertility treatment and those who had not, were defined.
Statistical Analysis For the purposes of this study, ‘‘age’’ was recorded as the age at the end of the study for living carriers without diagnosed IEOC, or age at whichever occurred first: IEOC diagnosis, prophylactic salpingo-oophorectomy, or death. Distributions of selected demographic, hormone, and fertility-related factors were compared between these two groups, and between those who had reported receiving fertility treatment and those who had not. A t test was used to check for statistically significant differences between the groups for continuous variables, and a chi-square test for categorical variables. Odds ratios for these variables were calculated using unconditional logistic regression. A multivariate analysis was performed to control for the potential confounding effects of mutation type (BRCA1/2), age at menarche (years), oral contraceptive use (ever/never), parity (yes/no and number of births), age at first pregnancy (years), and use of hormone replacement therapy (yes/no). P< .05 was considered statistically significant, and all tests were two-sided.
RESULTS Out of a total of 1,170 mutation carriers diagnosed in our institute during the study period, information about fertility treatments was available for 1,073. Of these, 718 patients (67%) had a mutation in BRCA1: 185delAG (n ¼ 502) and 5382insC (n ¼ 157) or other mutation (n ¼ 59); and 331 (31%) had a mutation in BRCA2: 6174delT (n ¼ 308) or other mutation (n ¼ 23). Three patients had both BRCA1 and BRCA2 mutations Mutation types frequencies are presented in Table 1. Primary IEOC was diagnosed in 175 mutation carriers (16.3%), 139 (79.4%) of them carrying BRCA1, 33 (18.9%) of them carrying BRCA2 mutations, and 3 (1.7%) unknown. Primary breast cancer was diagnosed in 477 (44.5%) mutation
TABLE 1 Mutation types frequencies. Mutation Total BRCA1 185delAG–106 5382iNsC–40 Other mutations BRCA2 6174delT 8765delAG Other mutations Both BRCA1 and BRCA2 185delAG, 6174delT Unknown
Ovarian cancer
No ovarian cancer
175 139 108 23 8 33 33 0 0 0 0 3
898 579 394 134 51 298 275 10 13 3 3 18
Perri. BRCA mutation and fertility drugs. Fertil Steril 2015.
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TABLE 2 Demographic, hormone, and reproduction variables of the study population by fertility treatment. Fertility treatment Characteristic Age Mean (SD) Median (range) Mutation type, n (%) BRCA1 BRCA2 BRCA1 and BRCA2 Unknown Mutation origin, n (%) Mother Father Both NA Age at menarche Mean (SD) Median (range) Age at first pregnancy Mean (SD) Median (range) Nullipara %26, n (%) 26–30, n (%) 31–35, n (%) 36–40, n (%) >40, n (%) NA, n (%) No. of abortions Mean (SD) Median (range) Breastfeeding period (mo) Mean (SD) Median (range) OCP use (y) Mean (SD) Median (range) Never %1 y, n (%) >1–5 y, n (%) >5 y, n (%) NA HT, n (%) No Yes NA Parity Mean (SD) Median (range) 0 1, n (%) 2, n (%) 3, n (%) >3, n (%) NA, n (%) Prophylactic BSO, n (%) No Yes NA Age at prophylactic BSO Mean (SD) Median (range) Cancer diagnosis, n (%) None Breast Ovary OC and/or BC
Total (n [ 1,073)
Yes, group 1 (n [ 164)
49.9 (13.0) 49.1 (20–93)
47.1 (8.6) 46 (29–75)
50.4 (13.6) 50 (20–93)
.0001
718 (66.9) 331 (30.8) 3 (0.3) 21 (2)
105 (64) 54 (32.9) 1 (0.6) 4 (2.4)
613 (67.4) 277 (30.5) 2 (0.2) 17 (1.9)
.68
571 (53.2) 177 (16.5) 2 (0.2) 323 (30.1)
98 (59.8) 24 (14.6) 1 (0.6) 41 (25)
473 (52) 153 (16.8) 1 (0.1) 282 (31)
.13
12.93 (1.4) 13 (9–19)
12.9 (1.3) 12.5 (9–17)
12.936 (1.4) 13 (9–19)
.78
25.6 4.6 25 (14–48) 122 (11.4) 504 (47) 291 (27.1) 93 (8.7) 30 (2.8) 5 (0.5) 28 (2.6)
No, group 2 (n [ 909)
P value
29.04 (5.5) 29 (19–48) 15 (9.1) 42 (25.6) 49 (29.9) 32 (19.5) 15 (9.1) 4 (2.4) 7 (4.3)
25.02 (4.1) 24 (14–43) 107 (11.8) 462 (50.8) 242 (26.6) 61 (6.7) 15 (1.7) 1 (0.1) 21 (2.3)
< .0001
1.04 (1.5) 1 (0–11)
0.99 (1.5) 0 (0–9)
1.05 (1.5) 1 (0–11)
.65
9.45 15.3 4 (0–171)
7.86 (12.7) 3 (0–70)
9.74 (15.8) 4 (0–171)
.1
4.88 (5.97) 2 (0–30) 416 (38.8) 88 (8.2) 168 (15.7) 392 (36.5) 9 (0.8)
5.77 (5.9) 4 (0–24) 44 (26.8) 13 (7.9) 33 (20.1) 73 (44.5) 1 (0.6)
4.72 (5.98) 1.5 (0–30) 372 (40.9) 75 (8.3) 135 (14.9) 319 (35.1) 8 (0.9)
.038
936 (87.2) 105 (9.8) 32 (3)
149 (90.9) 10 (6.1) 5 (3)
787 (86.6) 95 (10.5) 27 (3)
.23
2.31 (1.5) 2 (0–13) 144 (13.4) 118 (11) 345 (32.2) 322 (30) 141 (13.1) 3 (0.3)
2.13 (1.4) 2 (0–8) 23 (14) 28 (17.1) 51 (31.1) 43 (26.2) 19 (11.6) 0
2.34 (1.5) 2 (0–13) 121 (13.3) 90 (9.9) 294 (32.3) 279 (30.7) 122 (13.4) 3 (0.3)
.11
895 (83.4) 114 (10.6) 64 (6)
131 (79.9) 22 (13.4) 11 (6.7)
764 (84.1) 92 (10.1) 53 (5.8)
.39
46.5 (7.3) 46 (31–79)
44.7 (5.8) 43 (38–58)
46.9 (7.6) 47.5 (31–79)
.2
465 (43.3) 477 (44.45) 175 (16.3) 608 (56.6)
83 (50.6) 66 (35.9) 19 (11.6) 81 (49.4)
382 (42) 411 (45.5) 156 (17.2) 527 (58)
< .0001
.01
.13
.27 .1 .05
Perri. BRCA mutation and fertility drugs. Fertil Steril 2015.
VOL. - NO. - / - 2015
3
ORIGINAL ARTICLE: GENETICS
TABLE 2 Continued. Fertility treatment Characteristic Other cancers Uterine Uterine cervix GI Urinary tract Thyroid Lung Others
Total (n [ 1,073)
Yes, group 1 (n [ 164)
84 (7.8) 11 (1.02) 6 (0.6) 27 (2.5) 7 (0.65) 7 (0.65) 11 (1.02) 15 (1.4)
7 (4.2) 1 (0.6) 0 4 (2.4) 0 0 2 (1.2) 0
No, group 2 (n [ 909)
P value
77 (8.4) 10 (1.1) 6 (0.66) 23 (2.5) 7 (0.77) 7 (0.77) 9 (1) 15 (1.65)
Note: BSO ¼ bilateral salpingo-oophorectomy; GI ¼ gastrointestinal; HT ¼ hormone replacement therapy; NA ¼ not applicable; OCP ¼ oral contraceptive pill. Perri. BRCA mutation and fertility drugs. Fertil Steril 2015.
carriers. In 44 carriers, both breast and ovarian cancer were diagnosed, and 84 carriers had other cancers, of which 58 were additional to either breast or ovarian cancer (Table 2). All other patients (n ¼ 439) were cancer-free at the time of genetic counseling and until the end of the study. A total of 164 (15.3%, group 1) of the study participants reported undergoing fertility treatments, which included medications containing clomiphene citrate (CC) (n ¼ 82) or gonadotropin (n ¼ 69), in vitro fertilization (IVF, n ¼ 66), or some combination of these treatments (n ¼ 50). No fertility treatments were reported by the remaining 909 participants (group 2). Characteristics of the participants in the two groups are presented in Table 2. The groups did not statistically significantly differ in mutation type, mutation origin (maternal/ paternal), age at menarche, number of abortions, parity, breastfeeding duration, hormone replacement therapy, riskreducing bilateral salpingo-oophorectomy rate, or age at surgery. The groups differed in age, age at first pregnancy (older in the fertility-treated group), and oral contraceptive use. Among these patients, IEOC was diagnosed in 19 patients from group 1 (11.6%) and in 156 (17.2%) from group 2. Univariate analysis disclosed no association between fertility treatments and risk of IEOC (OR 0.63; 95% CI, 0.38–1.05), regardless of the treatment received and upon separate analysis (for CC-containing medication, OR 0.87; 95% CI, 0.46–1.63; for gonadotropin-containing medication, OR 0.59; 95% CI, 0.26–1.31; for IVF, OR 1.08, 95% CI, 0.57–2.06). There was also no association between IEOC risk and age at menarche, or between IEOC risk and breastfeeding. On the other hand, IEOC risk was associated with age at first pregnancy, parity, and hormone replacement therapy. Oral contraceptive use was associated with a reduced risk of IEOC in BRCA mutation carriers (Table 3). Among all carriers of BRCA1 and/or BRCA2 mutations, the contribution of the BRCA2 mutation to having ovarian cancer was statistically significantly smaller compared with the BRCA1 mutation (OR 0.46). On multivariate analysis only, the use of oral contraceptives and use of hormone replacement therapy (but not parity or fertility treatments) were found to alter the risk of IEOC: the risk increased with use of hormone replacement 4
therapy and decreased with oral contraceptive use (Table 4). The risk of IEOC was further reduced with longer oral contraceptive use: for its use %1 year, OR 0.36 (95% CI, 0.16–0.84); for 1–5 years, OR 0.31 (95% CI, 0.19–0.51); and for >5 years, OR 0.10 (95% CI, 0.06–0.17; data not shown). The results of the univariate and multivariate analyses were not changed when analyzed separately for BRCA1 and BRCA2 mutation carriers (Table 4).
DISCUSSION The results of our study suggest that fertility treatments in Jewish Israeli BRCA mutation carriers are not associated with an increased risk of IEOC. Incessant ovulation is one of the main factors that have been implicated in the pathogenesis of ovarian cancer (35). Fertility treatments involve ovulation-inducing drugs and thus increase the chances of multiple ovulations. An association between pharmacologic ovulation induction in the course of fertility treatments and ovarian cancers in the general population has been investigated in numerous studies. Although some early epidemiologic studies found that exposure to ovulation-stimulating drugs increases the risk of both IEOC and ovarian tumors with low malignant potential (‘‘borderline’’ tumors) (21, 26, 36, 37), most of the current data appear to exclude a clinically discernible effect of fertility drugs on the risk of ovarian tumors, and especially of high-grade IEOC in the general population (23, 24, 27–31). Recently, however, in a long-term follow-up study of 2,768 women who had undergone fertility treatment, Sanner et al. (25) reported an increased risk of ovarian cancer after treatment with gonadotropins (relative ratio 5.28; 95% CI, 1.70–16.47) and of borderline tumors after CC treatment (standardized incidence ratio 7.47; 95% CI, 1.54–21.83). Brinton et al. (19) also reported a higher risk of ovarian cancer associated with the use of ovulation-stimulating drugs during IVF, with hazard ratio (HR) 1.58 (95% CI, 0.75–3.29). These inconclusive results led Hunn et al. (5), in their recent review, to describe fertility drugs as ‘‘indeterminate’’ factors affecting ovarian cancer risk. Those observations might suggest that there is a need for long-term monitoring of patients in the general population who are undergoing fertility treatments. VOL. - NO. - / - 2015
Fertility and Sterility®
TABLE 3 Risk factors for developing invasive epithelial ovarian cancer, univariate analysis. Characteristic Age Mean (SD) Median (range) BRCA mutation BRCA1, n (%) BRCA2, n (%) Both, n (%) Unknown, n (%) Age at menarche Mean (SD) Median (range) Age at first pregnancy Mean (SD) Median (range) Nullipara %26, n (%) 26–30, n (%) 31–35, n (%) 36–40, n (%) >40, n (%) NA, n (%) Breastfeeding (mo) Mean (SD) Median (range) OCP Duration, mean SD Never %1 y, n (%) >1–5 y, n (%) >5 y, n (%) NA HT No Yes NA Parity 0 1, n (%) 2, n (%) 3, n (%) >3, n (%) NA, n (%) Fertility treatment No, n (%) Yes, n (%) IVF, n (%) GN, n (%) CC, n (%) Mixed
Ovarian cancer (n [ 175)
No ovarian cancer (n [ 898)
Odds ratio (95% CI)
P value
53.6 10.3 51.9 (28.7–85.2)
49.1 13.4 49 (20–93)
1.03 (1.01–1.04)
< .001
139 (79.4) 33 (18.9) 0 3 (1.7)
579 (64.5) 298 (33.2) 3 (0.3) 18 (2)
1 0.46 (0.31–0.69)a
12.9 1.36 13 (9–16.5)
12.93 1.4 13 (9–19)
0.98 (0.87–1.1)
24.31 4.5 23 (16–48) 12 (6.9) 117 (66.9) 33 (18.9) 6 (3.4) 5 (2.9) 1 (0.6) 1 (0.6)
25.91 4.57 25 (14–43) 110 (12.2) 387 (43.1) 258 (28.7) 87 (9.7) 25 (2.8) 4 (0.4) 27 (3)
1.00 2.77 (1.47–5.21) 1.17 (0.58–2.35) 0.63 (0.23–1.75) 1.83 (0.59–5.68) 2.29 (0.24–22.2)
9.54 11.6 6 (0–60)
9.43 15.95 4 (0–171)
1.0 (0.99–1.01)
1.45 3.49 123 (70.3) 14 (8) 19 (10.9) 18 (10.3) 1 (0.6)
5.55 6.13 293 (32.6) 74 (8.2) 149 (16.6) 374 (41.6)
0.82 (0.78–0.86) 1 0.45 (0.25–0.83) 0.30 (0.18–0.51) 0.11 (0.07–0.19)
136 (77.7) 32 (18.3) 7 (4)
800 (89.1) 73 (8.1) 25 (2.8)
2.58 (1.64–4.06)
13 (7.4) 15 (8.6) 61 (34.9) 60 (34.3) 26 (14.8) 0
131 (14.6) 103 (11.5) 284 (31.6) 262 (29.2) 115 (12.8) 3 (0.3)
1.00 1.47 (0.67–3.22) 2.16 (1.15–4.08) 2.31 (1.22–4.36) 2.28 (1.12–4.64) 1.00
156 (89.1) 19 (10.9) 4 (2.3) 1 (0.6) 3 (1.7) 10 (5.7)
753 (83.9) 145 (16.1) 36 (4) 22 (2.4) 37 (4.1) 40 (4.5)
0.63 (0.38–1.05)
< .001
0.69 (0.2–2.39) NS < .001
NS < .001
< .001 .03
NS
0.54 (0.19–1.53) 0.22 (0.03–1.64) 0.39 (0.12–1.29) 1.21 (0.59–2.46)
Note: BCRP ¼ breast cancer resistance protein; CC ¼ clomiphene citrate; CI ¼ confidence interval; GN ¼ gonadotropins; HT ¼ hormone replacement therapy use; NA ¼ not available; NS ¼ not statistically significant; OCP ¼ oral contraceptive use; SD ¼ standard deviation. a In comparison with BRCA1 mutation carriers. Perri. BRCA mutation and fertility drugs. Fertil Steril 2015.
In BRCA mutation carriers, the effect of fertility treatments on the risk of breast cancer was studied by Kotsopoulos et al. (38). They reported that the increased risk in users of fertility drugs was not statistically significant compared to nonusers (OR 1.21; 95% CI, 0.81–1.82). To the best of our knowledge, our study is the first to investigate the impact of ovulation induction on IEOC risk in an ethnically defined cohort of BRCA mutation carriers. It has been postulated that the association between fertility treatments and ovarian cancer merely reflects the VOL. - NO. - / - 2015
higher risk associated with the actual cause of infertility and nulliparity (or no breastfeeding, a suggested protecting factor in IEOC) (5). In the average-risk population, nulligravid women are considered to be at an increased risk of IEOC (8, 31, 37, 39, 40). In BRCA mutation carriers, however, data on the effect of parity are sparse and inconsistent. Modan et al. (15), in a study of Jewish Israeli women with ovarian cancer, reported a protective effect of each additional birth in both BRCA1 and BRCA2 mutation carriers, with a 12% reduction in the odds of ovarian cancer per birth (95% CI, 2.3–21). 5
ORIGINAL ARTICLE: GENETICS
TABLE 4 Multivariate model for impact of hormone and reproductive factors on ovarian cancer risk in BRCA-mutation carriers, adjusted for age. BRCA1 Factor Parity OCP HT Fertility treatment No Any IVF Gonadotropins CC Mixed
BRCA2
BRCA1 and BRCA2
95% CI
OR
95% CI
OR
95% CI
OR
0.81–3.33 0.14–0.33 0.89–3.08
1.64 0.21a 1.66a
– 0.09–0.61 1.19–7.8
– 0.24a 3.04a
0.95–3.61 0.14–0.31 1.21–3.25
1.85 0.21a 1.98a
0.43–1.53 0.23–2.93 0.06–4.26 – 0.78–4.15
0.81 0.82 0.50 – 1.8
0.31–3.30 0.20–16.48 – 0.57–17.14 0.09–6.95
1.01 1.81 – 3.14 0.77
0.46 0.31 0.03 0.08 0.68
Reference 0.80 0.93 0.26 0.34 1.45
Note: BCRP ¼ breast cancer resistance protein; CC ¼ clomiphene citrate; CI ¼ confidence interval; HT ¼ hormone replacement therapy use; IVF ¼ in vitro fertilization; OCP ¼ oral contraceptive use; OR ¼ odds ratio. a P< .001. Perri. BRCA mutation and fertility drugs. Fertil Steril 2015.
Milne et al. (41) reported that parity was associated with a reduced risk of ovarian cancer in carriers of BRCA1 mutations (HR 0.41, 95% CI, 0.18–0.94; P¼ .03) but not in BRCA2 mutation carriers. McLaughlin et al. (14) reported an increased risk (HR 2.74; 95% CI, 1.18–6.41; P¼ .02) for IEOC with increased parity in BRCA2 mutation carriers. We showed here that in univariate analysis, parity is a risk factor for ovarian cancer in both BRCA1 and BRCA2 mutation carriers. Those results are in line with a study encompassing 2,281 BRCA1 and 1,038 BRCA2 mutation carriers from ethnically diverse populations (17), where nulliparous women were found to be at a lower risk of ovarian cancer than women with one pregnancy; thus, overall nulliparity was associated with a slight, statistically nonsignificant reduction in the risk of ovarian cancer. These results might represent a true biologic significance or merely reflect a selection bias whereby women diagnosed with ovarian cancer are more likely to be tested for BRCA mutations if they have offspring than if they do not (17, 42). Indeed in our study, parity was not a risk factor for IEOC in multivariate analysis, supporting the selection-bias effect. Hormone replacement therapy is another risk factor for ovarian cancer that has been well studied in the general population (43–46). In contrast to our results, Kotsopoulos et al. (47) reported that hormone replacement therapy use did not adversely influence the risk of ovarian cancer in BRCA mutation carriers. There was no significant relationship with increasing duration of use. Progestin-based regimens did not have a statistically significant protecting effect on ovarian cancer (odds ratio ¼ 0.57). The relatively small number of hormone replacement therapy users and their relatively young ages warrant further studies to assess the effect of hormone replacement therapy on the incidence of IEOC in BRCA mutation carriers. Oral contraceptive pills prevent ovulation and have been reported to reduce the risk of ovarian cancer in the general population (48) as well as in BRCA mutation carriers (16, 18, 49). In a recent meta-analysis of eight studies in which ovarian cancer risk was examined in BRCA1/2 muta6
tion carriers, an inverse association was reported between oral contraceptive use and ovarian cancer (OR 0.58; 95% CI, 0.46–0.73) (18). Our results are in line with those studies: we found that the risk of ovarian cancer was reduced with any use of oral contraceptives by both BRCA1 mutation and BRCA2-mutation carriers, and we also found a statistically significant duration-dependent risk reduction. Additional factors reportedly associated with ovulation modification and hence with IEOC risk modulation, such as age at menarche, age at first pregnancy, and breastfeeding, were not associated either in our study or in those of others with risk of ovarian cancer (50). These data are consistent with the notion that in BRCA mutation carriers ovulation might not affect ovarian cancer risk. One plausible biological reason for this lack of effect is that the precursor of ovarian carcinoma in BRCA mutation carriers might be an occult intraepithelial carcinoma that originates in the fimbrial region of the fallopian tube, involving the ovary only secondarily (51, 52). One of the advantages of our study is our homogenous (Jewish Israeli) mutation-carriers population with a homogenous spectrum of BRCA gene mutations. However, our study has certain inherent limitations. Data with regard to fertility treatments were based solely on self-reporting, with no available confirmatory data on the number of treatments, dosage, or timing. Moreover, information about the cause of infertility was lacking, precluding a separate assessment of the effects of different possible causes (ovulatory, mechanical, or male factor infertility) on ovarian cancer risk. The young age of our studied population is also a limitation as IEOC risk is a function of age, with higher rates in older women. We also lacked data on borderline ovarian tumors and were thus obliged to limit our conclusion to IEOC only; however, that missing information is not particularly relevant to the present study because BRCA mutation carriers are more likely to have high-grade tumors (53). Because the ovarian cancer in most of our patients was diagnosed before the genetic counseling (and the cancer diagnosis was probably the reason for counseling), there might be VOL. - NO. - / - 2015
Fertility and Sterility® an overrepresentation of BRCA-mutation carriers who have cancer. However, it does not influence our retrospective follow-up cohort analysis of correlation between fertility treatment and ovarian cancer because in all cases the fertility treatments (exposure) preceded the cancer diagnosis. Also, because the study groups have not been matched, the results of the univariate unadjusted analysis might rather reflect the selection differences between the groups; hence, the conclusions of this study are based mainly on multivariate analysis that includes all appropriate cofactors. Despite these limitations, we believe that our study addresses an important question and is novel. It appears that fertility treatments are not associated with an increased risk of IEOC in Jewish Israeli BRCA mutation carriers, so such treatments for infertile BRCA mutation carriers should not be contraindicated. Nevertheless, the association between ovarian cancer and fertility treatments in BRCA mutation carriers should continue to be monitored. In addition, prospective cohort studies based on a more detailed collection of the type, dose, and time course of fertility treatments are clearly warranted.
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