Reply: Do drugs that stimulate ovulation increase the risk for endometrial stromal sarcoma?
1 National Cancer Institute, Bethesda, MD, 2 University of Illinois, Chicago, IL, 3 Wayne State University, Detroit, MI, 4 Columbia University, New York, NY, 5 Georgetown University, Washington, DC 6 Stanford University, Stanford, CA, USA
7 To whom correspondence should be addressed. Email: brinton{at}nih.gov
Sir,
Reich and Regauer (2004) have made an intriguing observation regarding a preponderance of histories of in vitro fertilization among patients developing endometrial stromal sarcomas (ESS). Although the absence of information as to how long these patients were followed or what types and dosages of drugs they received limits the extent to which a biological connection can be made, we agree that the effects of fertility drugs on uterine cancers is an issue that deserves further pursuit, particularly given the well-recognized role of hormonal factors in the etiology of these tumors. Clomiphene is of particular interest, given that it is a selective estrogen receptor modulator (SERM), structurally similar to tamoxifen, a drug which has been linked with >2-fold increases in the risk of uterine cancers and even higher risks for certain rare tumor histologies (Curtis et al., 2004
). Of note in this regard are several reports of ESS among tamoxifen-treated women (Liao and Lin, 2001; Saga et al., 2003).
Despite biological plausibility, few previous investigations have assessed the effects of usage of fertility drugs on the risk of uterine cancers. One previous study in Israel noted a 2-fold increased risk of endometrial cancer among women exposed to fertility drugs, although based on only 21 cancers (Modan et al., 1998). In our cohort study of infertile women, from which we recently reported results regarding breast cancer risk (Brinton et al., 2004), we also found an 
2-fold increased risk of uterine cancers associated with clomiphene use, with even further elevations in risk among women with higher doses or those followed for longer periods of time (Althuis et al., in press). However, of the 39 observed uterine carcinomas, we did not observe any ESS, with the majority of cancers for which we were able to derive pathological details reflecting the more common diagnosis of endometrial adenocarcinoma.
Although the rate reported by Reich and Regauer (2004) of 12.5% of previous in vitro fertilization among women with ESS appears high, a contributing factor may be that ESS often arise among patients with endometriosis (Corpa et al., 2004), who would be at high risk of being infertile. Clarification of the true nature of a relationship between fertility treatment and ESS would require use of appropriate comparison groups and adequate adjustment for other predictors of risk. However, as emphasized by the absence of any ESS in our investigation of >12 000 women, this will be an extremely difficult issue to study in cohort studies. Assembling a large series of cancers for a case-control study will also be difficult, given that ESS is an extremely rare tumor, having an incidence rate among females during the period 1992–2001 in the US of 0.34 per 100 000 women [Surveillance, Epidemiology and End Results (SEER) Program SEER & Stat Database].
We agree that effects of ovulation induction should continue to be investigated for a variety of cancers. However, in order for results not to cause unnecessary alarm, it is important that they be carefully communicated. We therefore caution against our findings for breast cancer being communicated as a significant increase, since the only statistically significant increase pertained to a relatively small subgroup, namely clomiphene users who developed invasive cancers after 20 or more years of follow-up (Brinton et al., 2004). The results, however, support the need for further evaluation of long-term effects of fertility drugs.
References
Althuis MD, Moghissi KS, Westhoff CL, Scoccia B, Lamb EJ, Lubin JH and Brinton LA. Endometrial cancer after use of clomiphene citrate for ovulation-induction. Am J Epidemiol (in press).
Brinton LA, Scoccia B, Moghissi KS, Westhoff CL, Althuis MD, Mabie JE and Lamb EJ (2004) Breast cancer risk associated with ovulation-stimulating drugs. Hum Reprod 19, 2005–2013.
Corpa MV, Serafini EP and Bacchi CE (2004) Low-grade endometrial stromal sarcoma presenting as vaginal nodule. Ann Diagn Pathol 8, 295–298.[CrossRef][Medline]
Curtis RE, Freedman DM, Sherman ME and Fraumeni JF Jr (2004) Risk of malignant mixed mullerian tumors after tamoxifen therapy for breast cancer. J Natl Cancer Inst 96, 70–74.
Liao JB and Lin JY (2001) Estrogen receptor expression in an endometrial stromal sarcoma after tamoxifen therapy. Eur J Gynaecol Oncol 22, 417–419.[Web of Science][Medline]
Modan B et al. (1998) Cancer incidence in a cohort of infertile women. Am J Epidemiol 147, 1038–1042.
Reich O and Regauer S. Do drugs that stimulate ovulation increase the risk for endometrial stromal sarcoma? Hum Reprod (in press).
Saga Y, Ohwada M, Kohno T, Takayashiki N and Suzuki M (2003) High-grade endometrial stromal sarcoma after treatment with tamoxifen in a patient treated for breast cancer. Int J Gynecol Cancer 13, 690–692.[CrossRef][Web of Science][Medline]
Surveillance, Epidemiology and End Results (SEER) Program SEER*Stat Database: Incidence–SEER 11 Regs + AK Public-Use (www.seer.cancer.gov). National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch. Release date of 2004, based on November 2003 submission.
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