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Fertility drug use was not associated with an increased risk of breast cancer
REPRODUC TIVE ENDOCRINOLOGY&INFERTILIT Y
Fertility drug use was not associated with an increased risk of breast cancer Burkman RT, Tang MTC, Malone KE, Marchbanks PA, McDonald JA, Folger SG. Infertility drugs and the risk of breast cancer: findings from the National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences Study. Fertil Steril 2003; 79: 844 ^ 851.
OBJECTIVE To determine if there is an association between the use of fertility drugs and the risk of breast cancer. DESIGN Multicentre, case-control study. SETTING Population-based study in ¢ve cities in the USA. SUBJECTS Cases were 4575 women, aged 35^64 years, with histologically con¢rmed primary invasive breast cancer diagnosed in 1994^1998. Controls were 4682 women without breast cancer, matched to cases by city, race, and age. METHODS Cases were identi¢ed mainly through the national cancer register and controls were recruited through random-digit dialling. All women were interviewed in person to obtain information about history of infertility, fertility drug use, and other factors. MAIN OUTCOME MEASURES Odds ratio (OR, 95% CI) for breast cancer in women who had used fertility drugs, compared to those who had not, adjusted for age, race, and city.
doi:10.1016/j.ebobgyn.2004.05.003
MAIN RESULTS A similar proportion of cases and controls (9.1and 9.2%) had had testing for infertility and 5.0 and 5.7%, respectively, had been diagnosed with a speci¢c female fertility problem. Some type of fertility drug had been taken by 184 cases (4.0%) and 200 controls (4.3%); the OR for breast cancer was 0.9 (0.8^ 1.2). The risk was not a¡ected by duration of use or age at ¢rst use.The most commonly used drug, clomiphene citrate, had been used by 141 cases (3.1%) and 145 controls (3.1%); the OR was 1.0 (0.8^1.3), again with no e¡ect of duration of use. Human menopausal gonadotropins (hMG) had been used by 38 cases (0.8%) and 28 controls (0.6%); the OR was 1.5 (0.9^2.4). There was no signi¢cant increase in risk for women who had used hMG for o6 cycles (OR 1.2, CI 0.7^2.3, 22 cases and 19 controls), but the risk was signi¢cantly elevated for women who had used hMG for 6 cycles (OR 2.7, CI 1.0^6.9, 15 cases and 6 controls). Among women who had never taken infertility drugs, a history of infertility was not a risk factor for breast cancer (OR 0.9, CI 0.7^1.1). CONCLUSION A history of fertility drug use, in general, and clomiphene citrate, in particular, was not associated with an increased risk of breast cancer. Based on a small number of cases, a signi¢cantly increased risk was observed in women who had used hMG for 6 cycles or more.
Evidence-based Obstetrics and Gynecology (2004) 6,137^138
137
Commentary Studies of subfertility in relation to breast cancer risk show inconsistent results, partly caused by methodological differences in the assessment of cause of subfertility and the control of various confounders, i.e. nulliparity. Both Klip et al1 and Venn et al2 in their extensive reviews could not identify an infertility risk factor associated with breast cancer risk in case-control as well as cohort studies. Case-control and cohort studies have shown that the overall risk of breast cancer in fertility drug users is similar to that of the general female population.1, 2 The authors of the present study found no overall increased risk of breast cancer after fertility drug use; however, in a subgroup of women who underwent 6 or more cycles (or 6 or more months) of human menopausal gonadotropins (hMG) treatment, the risk was significantly increased. As stressed by the authors, the numbers of both cases and controls who had long-term exposure to hMG are small and, consequently, the 95% confidence interval is wide. We encounter the same problems in all observational studies of fertility drugs and cancer: the follow-up period is relatively short and the number of exposed women with cancer is low. Analyzing subgroups, clomiphene citrate and hMG are recognized as potential risk factors. Rossing et al3 found no increased breast cancer risk with clomiphene citrate, whereas Potashnik et al4 found a significantly increased risk with a cumulative dose of less than1000mg clomiphene citrate.This result is rather confusing, since, from a biological point of view, clomiphene citrate might be expected to be protective against breast cancer because of its structural similarity with tamoxifen. Besides the present study, no other authors have found an increased risk of breast cancer with hMG use.Venn et al5 found indirect proof of increased breast cancer risk with hMG or clomiphene citrate use, because they calculated that the retrieval of 3^ 6 oocytes per cycle coincided with an increased risk of breast cancer. Strangely enough, it was not correlated with retrieval of more than 6 oocytes per cycle. However, subgroup analysis did not reveal an increased risk with use of either clomiphene citrate or hMG. These results are very suggestive that the increased risk with
138
Evidence-based Obstetrics and Gynecology (2004) 6,137^138
3^ 6 oocytes per cycle was merely a chance correlation. Again no consistency is present. Ovulation induction temporarily exposes women to higher estrogen concentrations than occur in natural menstrual cycles, sometimes for prolonged times. Is it possible that these higher levels provide a carcinogenic stimulus to the breast? All present data do not indicate that fertility drugs induce breast cancer, although we cannot exclude a promotional effect of hormones on an already present ‘silent breast cancer’. It is also important to mention that progestins are more harmful to the breast than was thought. Most assisted reproduction protocols include luteal phase support for at least two weeks by way of exogenous administration of progestins. This aspect is relevant, since there is some evidence that prolonged exposure to progestins may increase breast cancer risk. What must we conclude from this study and others? As yet, based on data available in the literature, we do not have to advise our patients to undergo breast screening after using fertility drugs. Curt W. Burger MD, PhD Division of Gynecology and Gynecologic Oncology, Erasmus University Medical Centre, Rotterdam, The Netherlands
Literature cited 1. Klip H, Burger CW, Kenemans P, van Leeuwen FE.Cancer risk associated with subfertility and ovulation induction: a review. Cancer Causes Control 2000; 11: 319^344. 2. Venn A. Cancer risk associated with diagnosis of infertility. Best Pract Res Clin Obstet Gynaecol 2003; 17: 343^367. 3. Rossing MA, Daling JR,Weiss NS, et al. Risk of breast cancer in a cohort in infertile women.Gynecol Oncol1996; 60: 300 ^303. 4. Potashnik G, Lerner-Geva L, Genkin L, et al. Fertility drugs and the risk of breast and ovarian cancers: results of a longterm follow-up study. Fertil Steril 1999; 71: 853^ 859. 5. Venn A,Watson L, Bruinsma F, et al. Risk of cancer after use of fertility drugs with in-vitro fertilization. Lancet 1999; 354: 1586 ^1590.
Fertility drug use was not associated with an increased risk of breast cancer Burkman RT, Tang MTC, Malone KE, Marchbanks PA, McDonald JA, Folger SG. Infertility drugs and the risk of breast cancer: findings from the National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences Study. Fertil Steril 2003; 79: 844 ^ 851.
OBJECTIVE To determine if there is an association between the use of fertility drugs and the risk of breast cancer. DESIGN Multicentre, case-control study. SETTING Population-based study in ¢ve cities in the USA. SUBJECTS Cases were 4575 women, aged 35^64 years, with histologically con¢rmed primary invasive breast cancer diagnosed in 1994^1998. Controls were 4682 women without breast cancer, matched to cases by city, race, and age. METHODS Cases were identi¢ed mainly through the national cancer register and controls were recruited through random-digit dialling. All women were interviewed in person to obtain information about history of infertility, fertility drug use, and other factors. MAIN OUTCOME MEASURES Odds ratio (OR, 95% CI) for breast cancer in women who had used fertility drugs, compared to those who had not, adjusted for age, race, and city.
doi:10.1016/j.ebobgyn.2004.05.003
MAIN RESULTS A similar proportion of cases and controls (9.1and 9.2%) had had testing for infertility and 5.0 and 5.7%, respectively, had been diagnosed with a speci¢c female fertility problem. Some type of fertility drug had been taken by 184 cases (4.0%) and 200 controls (4.3%); the OR for breast cancer was 0.9 (0.8^ 1.2). The risk was not a¡ected by duration of use or age at ¢rst use.The most commonly used drug, clomiphene citrate, had been used by 141 cases (3.1%) and 145 controls (3.1%); the OR was 1.0 (0.8^1.3), again with no e¡ect of duration of use. Human menopausal gonadotropins (hMG) had been used by 38 cases (0.8%) and 28 controls (0.6%); the OR was 1.5 (0.9^2.4). There was no signi¢cant increase in risk for women who had used hMG for o6 cycles (OR 1.2, CI 0.7^2.3, 22 cases and 19 controls), but the risk was signi¢cantly elevated for women who had used hMG for 6 cycles (OR 2.7, CI 1.0^6.9, 15 cases and 6 controls). Among women who had never taken infertility drugs, a history of infertility was not a risk factor for breast cancer (OR 0.9, CI 0.7^1.1). CONCLUSION A history of fertility drug use, in general, and clomiphene citrate, in particular, was not associated with an increased risk of breast cancer. Based on a small number of cases, a signi¢cantly increased risk was observed in women who had used hMG for 6 cycles or more.
Evidence-based Obstetrics and Gynecology (2004) 6,137^138
137
Commentary Studies of subfertility in relation to breast cancer risk show inconsistent results, partly caused by methodological differences in the assessment of cause of subfertility and the control of various confounders, i.e. nulliparity. Both Klip et al1 and Venn et al2 in their extensive reviews could not identify an infertility risk factor associated with breast cancer risk in case-control as well as cohort studies. Case-control and cohort studies have shown that the overall risk of breast cancer in fertility drug users is similar to that of the general female population.1, 2 The authors of the present study found no overall increased risk of breast cancer after fertility drug use; however, in a subgroup of women who underwent 6 or more cycles (or 6 or more months) of human menopausal gonadotropins (hMG) treatment, the risk was significantly increased. As stressed by the authors, the numbers of both cases and controls who had long-term exposure to hMG are small and, consequently, the 95% confidence interval is wide. We encounter the same problems in all observational studies of fertility drugs and cancer: the follow-up period is relatively short and the number of exposed women with cancer is low. Analyzing subgroups, clomiphene citrate and hMG are recognized as potential risk factors. Rossing et al3 found no increased breast cancer risk with clomiphene citrate, whereas Potashnik et al4 found a significantly increased risk with a cumulative dose of less than1000mg clomiphene citrate.This result is rather confusing, since, from a biological point of view, clomiphene citrate might be expected to be protective against breast cancer because of its structural similarity with tamoxifen. Besides the present study, no other authors have found an increased risk of breast cancer with hMG use.Venn et al5 found indirect proof of increased breast cancer risk with hMG or clomiphene citrate use, because they calculated that the retrieval of 3^ 6 oocytes per cycle coincided with an increased risk of breast cancer. Strangely enough, it was not correlated with retrieval of more than 6 oocytes per cycle. However, subgroup analysis did not reveal an increased risk with use of either clomiphene citrate or hMG. These results are very suggestive that the increased risk with
138
Evidence-based Obstetrics and Gynecology (2004) 6,137^138
3^ 6 oocytes per cycle was merely a chance correlation. Again no consistency is present. Ovulation induction temporarily exposes women to higher estrogen concentrations than occur in natural menstrual cycles, sometimes for prolonged times. Is it possible that these higher levels provide a carcinogenic stimulus to the breast? All present data do not indicate that fertility drugs induce breast cancer, although we cannot exclude a promotional effect of hormones on an already present ‘silent breast cancer’. It is also important to mention that progestins are more harmful to the breast than was thought. Most assisted reproduction protocols include luteal phase support for at least two weeks by way of exogenous administration of progestins. This aspect is relevant, since there is some evidence that prolonged exposure to progestins may increase breast cancer risk. What must we conclude from this study and others? As yet, based on data available in the literature, we do not have to advise our patients to undergo breast screening after using fertility drugs. Curt W. Burger MD, PhD Division of Gynecology and Gynecologic Oncology, Erasmus University Medical Centre, Rotterdam, The Netherlands
Literature cited 1. Klip H, Burger CW, Kenemans P, van Leeuwen FE.Cancer risk associated with subfertility and ovulation induction: a review. Cancer Causes Control 2000; 11: 319^344. 2. Venn A. Cancer risk associated with diagnosis of infertility. Best Pract Res Clin Obstet Gynaecol 2003; 17: 343^367. 3. Rossing MA, Daling JR,Weiss NS, et al. Risk of breast cancer in a cohort in infertile women.Gynecol Oncol1996; 60: 300 ^303. 4. Potashnik G, Lerner-Geva L, Genkin L, et al. Fertility drugs and the risk of breast and ovarian cancers: results of a longterm follow-up study. Fertil Steril 1999; 71: 853^ 859. 5. Venn A,Watson L, Bruinsma F, et al. Risk of cancer after use of fertility drugs with in-vitro fertilization. Lancet 1999; 354: 1586 ^1590.