Fertility Drugs and the Risk of Breast and Ovarian Cancers

Liat Lerner-Geva, M.D.
Department of Clinical Epidemiology
Chaim Sheba Medical Center, Tel-Hashomer, Israel

Potashnik Gad, M.D.
Fertility & IVF Unit, Department of Obstetrics & Gynecology
Soroka Medical Center of Kupat Cholim & Faculty of Health Sciences
Ben-Gurion University of the Negev, Beer-Sheba, Israel

INTRODUCTION

Breast and ovarian malignancies have been associated with numerous risk factors. Infertility is one of these factors. A linkage between exposure to fertility drugs and the risk for developing ovarian and breast cancers has also been suggested. The difficulties in establishing such a linkage include small number of cancer cases reported for women receiving infertility treatment, and the role of other risk factors such as infertility by itself, age at first childbirth and family history of cancer. However, a consensus does exist that this issue can be further clarified by retrospective studies with long latency periods and well-documented data regarding type of infertility, dosage and duration fertility drugs used, and a high degree of cancer ascertainment.

The present study was undertaken to evaluate the incidence of cancer in general and of breast and ovarian cancers in particular, among 1197 infertile women attending our infertility clinic between 1960 and 1984 and the possible role of fertility drugs in the development of breast and ovarian cancers.

STUDY DESIGN

Our study included 1197 files of all infertile women attending the fertility clinic of the Soroka University Medical centre in Beer-Sheba during the period 1960 through 1984. Demographic, personal and clinical data were extracted. Type of infertility, dosage and duration of drugs used were also obtained. The study cohort computer file was then linked to the Israel National Cancer Registry to identify cancer cases that developed through the end of 1994. The Registry receives notification of all malignancies from hospital discharge reports as well as from oncology and pathology departments throughout the country, with a very high degree of ascertainment.

STUDY RESULTS

Women in the study were followed for a mean period of 18 years (range 2-35). Their mean age at the end of follow-up was 44.8 years. Seven hundred and eighty (65.2%) women were exposed to fertility drugs and the other 417 (34.8%) did not receive fertility drugs as part of their treatment. The fertility drugs that were used to stimulate follicular growth comprised of Clomiphene Citrate (CC) and Human Menopausal Gonadotropins (HMG). Altogether, 38 cancers of various origins were identified, with no evidence of an increased incidence among the whole cohort or the groups exposed and unexposed to fertility drugs, as compared with the expected number of cancers in the general population. Of these, 20 were cases of breast cancers were observed, indicating a non-significant increased incidence of this cancer in the entire cohort of 1197 women in comparison to the general population.

Similarly, only 2 cases of ovarian cancer were observed (one in the exposed group), with no evidence of increased incidence of this cancer when compared to the general population.

Of the 3978 treatment cycles given to 780 women, no cancers were observed among patients treated with HMG only. A significant increase for breast cancers that was detected in patients treated with only 1 or 2 CC treatment cycles. Also, 82% of the breast cancers were observed in women who had been exposed to no more than 5 treatment cycles with CC and a cumulative dose of less than 2000 mg. These findings exclude a possible causal linkage between the use of fertility drugs and excessive risk for development of breast cancer.

DISCUSSION

Results of the present study indicate that the use of fertility drugs was not associated with an increased risk of breast and ovarian cancers as compared with infertile women not receiving these drugs or to the general population. Thus, a causal linkage between infertility, fertility drugs usage and the development of these cancers was not confirmed in the current long-term follow-up study of an average 18 years and more.

Family history, nulliparity and late age at first childbirth are well-defined risk factors for breast cancer. The results of the present long-term follow-up study of up to 35 years in some cases indicate no excessive risk of developing breast and ovarian cancer among infertile women treated with CC when compared to those not treated or to the general population. Furthermore, since most of these cancers (82%) were observed in women treated with less than 5 CC cycles, it is very unlikely that the use of fertility drugs might have contributed to the development of the disease. These findings are in agreement with previous studies where elevated (non-significant) risk of breast cancer was found to be associated with hormonal infertility with no additional risk following the use of fertility drugs.

The incidence of ovarian cancer in the whole cohort, regardless of exposure category and type of infertility was not different from that in the general population. We found no evidence to suggest an association between increased risk of ovarian cancer and infertility and the use of fertility drugs.

The strengths of the study include: long-latency period required to observe potential harmful effects of fertility drugs; accurate data on diagnosis, number of treatments and dosage of fertility drugs which were obtained accurately from patients' records; and complete ascertainment and verification of cancer diagnoses achieved by reviewing the original pathological reports of all the cancer cases. A limitation of this study is the fact that since the mean age of patients at the last follow-up date was 44 years, it is possible that this population may have not yet surpassed the period in life of greatest risk for developing breast cancer. Further follow-up of these women well into their sixties, will contribute in large toward a definitive conclusion about the risk of ovarian and breast cancers among infertile women and following the use of fertility drugs.

SUMMARY

No excessive risk of breast and ovarian cancer was observed among 1,197 infertile women treated with fertility drugs after an average follow-up period of 18 years (and in some cases up to 35 years) since last use of these drugs. An association between the use of fertility drugs and an increased risk of breast and ovarian cancers has not been confirmed. Correspondence to: Gad Potashnik M.D. Director, Fertility and In-Vitro Fertilisation Unit, Department of Obstetrics and Gynaecology, Soroka Medical Centre, Beer-Sheba, Israel.
Fax 972-7-6403057
Tel. 972-7-6400562
E-mail - GadP@bgumail.bgu.ac.il