Rossing, M. A., Daling, J. R., Weiss, N. S., Moore, D. E., & Self, S. G. (1994). Ovarian tumors in a cohort of infertile women. The New England journal of medicine, 331(12), 771-776. https://doi.org/10.1056/NEJM199409223311204
Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med. 1994;331(12):771-776. doi:10.1056/NEJM199409223311204
Rossing, M. A., et al. "Ovarian tumors in a cohort of infertile women." The New England journal of medicine, vol. 331, no. 12, 1994, pp. 771-776.
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Case reports and the results of a recent case-control study have raised questions about the potential neoplastic effects of medications used as treatment for infertility.
Methods
We examined the risk of ovarian tumors in a cohort of 3837 women evaluated for infertility between 1974 and 1985 in Seattle. Computer linkage with a population-based tumor registry was used to identify women in whom tumors were diagnosed before January 1, 1992. Data on infertility testing and treatment were abstracted from the medical records of women who had ovarian cancer and those of a randomly selected comparison group. The risk of ovarian tumors associated with exposure to ovulation-inducing medications was assessed through an age-standardized comparison with the rate of ovarian tumors in the general population, and Cox regression analysis was used to compare the risk of cancer among women who received these medications with the risk among infertile women who did not receive them.
Results
There were 11 invasive or borderline malignant ovarian tumors, as compared with an expected number of 4.4 (standardized incidence ratio, 2.5; 95 percent confidence interval, 1.3 to 4.5). Nine of the women in whom ovarian tumors developed had taken clomiphene; the adjusted relative risk among these women, as compared with that among infertile women who had not taken this drug, was 2.3 (95 percent confidence interval, 0.5 to 11.4). Five of the nine women had taken the drug during 12 or more monthly cycles. This period of treatment was associated with an increased risk of ovarian tumors among both women with ovarian abnormalities and those without apparent abnormalities (relative risk, 11.1; 95 percent confidence interval, 1.5 to 82.3), whereas treatment with the drug for less than one year was not associated with an increased risk.
Conclusions
Prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.
Babic A et al., 2020·JAMA oncology·Free full text on PubMed Central
Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent. To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype. DESIGN, SETTING, A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019. Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies. Diagnosis of epithelial ovarian cancer. A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02). Breastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.
Beaber EF et al., 2014·Cancer Epidemiol Biomarkers Prev·Free full text on PubMed Central
Evidence suggests that recent oral contraceptive (OC) use is associated with a small increased breast cancer risk; yet risks associated with contemporary OC preparations and by molecular subtype are not well characterized. We conducted a population-based case-control study of invasive breast cancer among women ages 20 to 44 residing in the Seattle-Puget Sound area from 2004 to 2010 (985 cases and 882 controls). We collected information on contraceptive use and participant characteristics via an in-person interview. Multivariable-adjusted logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Lifetime duration of OC use for ≥ 15 years was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.1-2.2). Current OC use (within 1 year of reference date) for ≥ 5 years was associated with an increased risk (OR, 1.6; 95% CI, 1.1-2.5) and there were no statistically significant differences in risk by OC preparation. Risk magnitudes were generally greater among women ages 20 to 39, and for estrogen receptor-negative (ER(-)) and triple-negative breast cancer (current use for ≥ 5 years among ages 20-39: ER(-) OR, 3.5; 95% CI, 1.3-9.0; triple-negative OR, 3.7; 95% CI, 1.2-11.8), although differences between groups were not statistically significant. Long-term use of contemporary OCs and current use for ≥ 5 years was associated with an increased breast cancer risk among women ages 20 to 44. Risk may be greater among younger women and for ER(-) and triple-negative breast cancer, but these findings require confirmation. Continued surveillance and pooled analyses of OC use and breast cancer risk by molecular subtype are needed as OC preparations evolve.
Li CI et al., 2012·Cancer Res·Free full text on PubMed Central
Depo-medroxyprogesterone acetate (DMPA) is an injectable contraceptive that contains the same progestin as the menopausal hormone therapy regimen found to increase breast cancer risk among postmenopausal women in the Women's Health Initiative clinical trial. However, few studies have evaluated the relationship between DMPA use and breast cancer risk. Here, we conducted a population-based case-control study among 1,028 women ages 20 to 44 years to assess the association between DMPA use and breast cancer risk. Detailed information on DMPA use and other relevant covariates was obtained through structured interviewer-administered in-person questionnaires, and unconditional logistic regression was used to evaluate associations between various aspects of DMPA use and breast cancer risk. We found that recent DMPA use for 12 months or longer was associated with a 2.2-fold [95% confidence interval (CI), 1.2-4.2] increased risk of invasive breast cancer. This risk did not vary appreciably by tumor stage, size, hormone receptor expression, or histologic subtype. Although breast cancer is rare among young women and the elevated risk of breast cancer associated with DMPA appears to dissipate after discontinuation of use, our findings emphasize the importance of identifying the potential risks associated with specific forms of contraceptives given the number of available alternatives.
Dolle JM et al., 2009·Cancer Epidemiol Biomarkers Prev·Free full text on PubMed Central
Little is known about the etiologic profile of triple-negative breast cancer (negative for estrogen receptor/progesterone receptor/human epidermal growth factor), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook this study to assess the risk for triple-negative breast cancer among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive use. Study participants were ascertained in two previous population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20 to 45 years in the Seattle-Puget Sound area, diagnosed between January 1983 and December 1992, for whom complete data was obtained for estrogen receptor, progesterone receptor, and human epidermal growth factor status (n = 897; including n = 187 triple-negative breast cancer cases). Controls were age matched and ascertained via random digit dialing. Oral contraceptive use > or =1 year was associated with a 2.5-fold increased risk for triple-negative breast cancer (95% confidence interval, 1.4-4.3) and no significantly increased risk for non-triple-negative breast cancer (P(heterogeneity) = 0.008). Furthermore, the risk among oral contraceptive users conferred by longer oral contraceptive duration and by more recent use was significantly greater for triple-negative breast cancer than non-triple-negative breast cancer (P(heterogeneity) = 0.02 and 0.01, respectively). Among women < or =40 years, the relative risk for triple-negative breast cancer associated with oral contraceptive use > or =1 year was 4.2 (95% confidence interval, 1.9-9.3), whereas there was no significantly increased risk with oral contraceptive use for non-triple-negative breast cancer among women < or =40 years, nor for triple-negative breast cancer or non-triple-negative breast cancer among women 41 to 45 years of age. In conclusion, significant heterogeneity exists for the association of oral contraceptive use and breast cancer risk between triple-negative breast cancer and non-triple-negative breast cancer among young women, lending support to a distinct etiology.
Related research
Cancer and Fertility · Hormone Sensitive Cancer and Reproductive Care
To investigate a possible linkage between the use of fertility drugs for infertility and the risk of breast and ovarian cancers. Long-term, historic-prospective study. Fertility clinic in a university hospital. PATIENT(S): Files of 1,197 infertile women with a mean (+/- SD) follow-up of 17.9+/-5 years (21,407 person-years) were reviewed. Diagnoses, number of courses, and dosage of fertility drugs were extracted from the files. INTERVENTION(S): Cancers were identified by record linkage to the National Cancer Registry. Histopathologic reports and data on estrogen and progesterone receptors in breast cancer tissue were also reviewed. MAIN OUTCOME MEASURE(S): Standardized incidence ratio with 95% confidence interval (CI) were used for risk assessment. RESULT(S): Of 20 breast cancers (standardized incidence ratio, 1.40 [95% CI, 0.83-2.10]), 16 were detected among 780 women who had been exposed to 3,978 cycles of clomiphene citrate (CC) and/or hMG (standardized incidence ratio, 1.65 [95% CI, 0.94-2.68]). The standardized incidence ratio for this cancer was significantly increased only in patients with one or two CC treatments and a dose of < or =1,000 mg (2.6 [1.19-5.0] and 2.52 [1.21-4.64], respectively). Two cases of ovarian cancer (1 patient unexposed) were observed with no evidence of excessive risk. Six of the eight patients with data on estrogen and progesterone receptors were exposed to CC, and all tested positive for these receptors. CONCLUSION(S): An association between the use of fertility drugs and an increased risk of breast and ovarian cancers has not been confirmed.
Cancer and Fertility · Hormone Sensitive Cancer and Reproductive Care
The possibility that ovulation induction increases the risk of ovarian cancer remains unproven. However, recent studies suggest that both infertility and endometriosis may be independent risk factors. Despite the various case reports and epidemiological studies performed the association between the use of infertility drugs and ovarian cancer remains weak. The fact that the women who were the first to use ovulation agents are now reaching mid-life means that future studies should show whether any association exists. Hence, there is a need now for large prospective trials to be performed to establish whether an association between ovulation induction agents and ovarian cancer truly exists.
Cancer and Fertility · Hormone Sensitive Cancer and Reproductive Care
Controversy surrounds the relations among infertility, fertility drug use, and the risk of ovarian cancer. The authors pooled interview data on infertility and fertility drug use from eight case-control studies conducted between 1989 and 1999 in the United States, Denmark, Canada, and Australia. Odds ratios and 95% confidence intervals were calculated, adjusting for age, race, family history of ovarian cancer, duration of oral contraception use, tubal ligation, gravidity, education, and site. Included in the analysis were 5,207 cases and 7,705 controls. Among nulligravid women, attempts for more than 5 years to become pregnant compared with attempts for less than 1 year increased the risk of ovarian cancer 2.67-fold (95% confidence interval (CI): 1.91, 3.74). Among nulliparous, subfertile women, neither any fertility drug use (odds ratio (OR) = 1.60, 95% CI: 0.90, 2.87) nor more than 12 months of use (OR = 1.54, 95% CI: 0.45, 5.27) was associated with ovarian cancer. Fertility drug use in nulligravid women was associated with borderline serous tumors (OR = 2.43, 95% CI: 1.01, 5.88) but not with any invasive histologic subtypes. Endometriosis (OR = 1.73, 95% CI: 1.10, 2.71) and unknown cause of infertility (OR = 1.19, 95% CI: 1.00, 1.40) increased cancer risk. These data suggest a role for specific biologic causes of infertility, but not for fertility drugs in overall risk for ovarian cancer.
Cancer and Fertility · Hormone Sensitive Cancer and Reproductive Care
Concern has been expressed that exposure to fertility drugs might be associated with a risk of ovarian cancer. We have examined the incidence of breast and ovarian cancer in a cohort of 10,358 women referred for in-vitro fertilisation (IVF) treatment in Victoria, Australia, between 1978 and 1992. The "exposed" group (n = 5564) had had ovarian stimulation to induce multiple folliculogenesis and the "unexposed" group (n = 4794) had been referred for IVF but were untreated or had had "natural cycle" treatment without ovarian stimulation. Duration of follow-up ranged from 1 to 15 years. Cases of cancer were determined by record linkage with data from population-based cancer registries. 34 cases of invasive breast cancer and 6 of invasive ovarian cancer were observed. A comparison with the expected numbers, derived by applying age-standardised general population rates to the cohort gave standardised incidence ratios (SIR) for breast cancer of 0.89 (95% CI 0.55-1.46) in the exposed group and 0.98 (0.62-1.56) in the unexposed group, and for ovarian cancer SIRs were 1.70 (0.55-5.27) and 1.62 (0.52-5.02), respectively. Rates of all cancers were not significantly different from general population rates. The relative risk (RR) of cancer, adjusted for age and infertility type, was, in the treated group compared with the untreated group, 1.11 (95% CI 0.56-2.20) for breast cancer and 1.45 (0.28-7.55) for ovarian cancer. The risk of body of uterus cancer was increased in the exposed and unexposed groups combined (SIR 2.84 [1.18-6.81]). Women with unexplained infertility, independent of IVF exposure, had significantly increased risks of ovarian cancer (RR = 19.19 [2.23-165.0]) and body of uterus cancer (RR = 6.34 [1.06-38.0]) compared with women with known causes of infertility. This relatively short-term follow-up suggests that ovarian stimulation with IVF is not associated with an increased risk of breast cancer. Although there was no significantly increased risk of ovarian cancer after ovarian stimulation with IVF the small number of cases limits the conclusions that can be drawn. Longer-term follow-up of large cohorts of women who have been in IVF programmes will be necessary.
General Gynecology › Cancer and Fertility › Hormone Sensitive Cancer and Reproductive Care · Therapeutics › Ovulation Agents › Selective Estrogen Receptor Modulators
Janet R Daling
J Daling
PMID 8065405 8065405 DOI 10.1056/NEJM199409223311204 10.1056/NEJM199409223311204 Rossing et al. 1994, Rossing 1994
Cite this article
Rossing, M. A., Daling, J. R., Weiss, N. S., Moore, D. E., & Self, S. G. (1994). Ovarian tumors in a cohort of infertile women. The New England journal of medicine, 331(12), 771-776. https://doi.org/10.1056/NEJM199409223311204
Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med. 1994;331(12):771-776. doi:10.1056/NEJM199409223311204
Rossing, M. A., et al. "Ovarian tumors in a cohort of infertile women." The New England journal of medicine, vol. 331, no. 12, 1994, pp. 771-776.
