Long-term relationship of ovulation-stimulating drugs to breast cancer risk.
BACKGROUND
Although fertility drugs stimulate ovulation and raise estradiol levels, their effect on breast cancer risk remains unresolved.


METHODS
An extended follow-up was conducted among a cohort of 12,193 women evaluated for infertility between 1965 and 1988 at five U.S. sites. Follow-up through 2010 was achieved for 9,892 women (81.1% of the eligible population) via passive as well as active (questionnaires) means. Cox regression determined HRs and 95% confidence intervals (CI) for fertility treatments adjusted for breast cancer risk factors and causes of infertility.


RESULTS
During 30.0 median years of follow-up (285,332 person-years), 749 breast cancers were observed. Ever use of clomiphene citrate among 38.1% of patients was not associated with risk (HR = 1.05; 95% CI, 0.90-1.22 vs. never use). However, somewhat higher risks were seen for patients who received multiple cycles, with the risk for invasive cancers confirmed by medical records being significantly elevated (HR = 1.69; 95% CI, 1.17-2.46). This risk remained relatively unchanged after adjustment for causes of infertility and multiple breast cancer predictors. Gonadotropins, used by 9.6% of patients, mainly in conjunction with clomiphene, showed inconsistent associations with risk, although a significant relationship of use with invasive cancers was seen among women who remained nulligravid (HR = 1.98; 95% CI, 1.04-3.60).


CONCLUSIONS
Although the increased breast cancer risk among nulligravid women associated with gonadotropins most likely reflects an effect of underlying causes of infertility, reasons for the elevated risk associated with multiple clomiphene cycles are less clear.


CONCLUSIONS
Given our focus on a relatively young population, additional evaluation of long-term fertility drug effects on breast cancer is warranted.
Authors' Affiliations: Division of Cancer Epidemiology and Genetics, National Cancer Institute; Westat, Inc.; IMS, Inc., Rockville, Maryland; Department of Obstetrics and Gynecology, University of Illinois, Chicago, Illinois; Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan; Department of Obstetrics and Gynecology, Columbia University, New York, New York; and Stanford University, Stanford, California.
Louise A
LA
Brinton
Bert
B
Scoccia
Kamran S
KS
Moghissi
Carolyn L
CL
Westhoff
Shelley
S
Niwa
David
D
Ruggieri
Britton
B
Trabert
Emmet J
EJ
Lamb
D000328:Adult; D001943:Breast Neoplasms / Q000139:chemically induced / Q000453:epidemiology*; D002996:Clomiphene / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D005260:Female; D005300:Fertility Agents, Female / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D010060:Ovulation / Q000187:drug effects*; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D055815:Young Adult
D005300:Fertility Agents, Female; D002996:Clomiphene