Pharmaceuticals that cause mammary gland tumors in animals: findings in women

Abstract

Risk of breast cancer in women was assessed for eight pharmaceuticals that produce mammary tumors in experimental animals, using nested case-control analyses in two cohorts with prescription records in a comprehensive medical care program. The two cohorts were: 1) earlier cohort: 78,118 female members who received prescriptions in 1969-1973, of whom 2,467 developed breast cancer, and 2) later cohort: 3,289,408 female members who received prescriptions in 1994-2006 of whom 24,528 developed breast cancer. Longest follow-up was until June 30, 2006. Ten randomly selected concurrent control women were age-matched to almost every case. Relative risks were estimated by conditional logistic regression. Case ascertainment was lagged by two years, or unlagged and subdivided by number of prescriptions received. Some analyses were controlled for hormone use and sensitivity analyses were conducted to estimate the effects of uncontrolled confounding. In the later cohort furosemide, and metronidazole showed statistically significant but very small increases in relative risk (ranging from 1.07 to 1.13). Of these, only furosemide showed increased risk in the earlier cohort: 2-year lag relative risk 1.66 (95% confidence interval 1.23-2.24) or as low as 0.97, assuming uncontrolled positive confounding. Griseofulvin showed significant increases in the later cohort: relative risk for three or more prescriptions 1.48 (1.08-2.03) or as low as 1.23 assuming uncontrolled positive confounding and non-significant increases were noted in the earlier cohort. Our findings are limited by their inconsistency across the two cohorts and our inability to directly control for most established breast cancer risk factors. Although inconclusive, our findings suggest a need for more research on furosemide and griseofulvin. Recently, Rudel et al. provided a comprehensive review of chemicals found to cause mammary tumors in animals (1). The review identified 216 chemicals associated with an increase in mammary tumors in at least one study. Of these, 47 were pharmaceuticals.As part of a project to screen pharmaceutical drugs for possible carcinogenicity (2,3) we have examined data in a large group of women to determine whether use of some pharmaceuticals among these substances is associated with an increased risk of developing breast cancer. We here report findings for cyclophosphamide, furosemide, griseofulvin, indomethacin, isoniazid, metronidazole, nitrofurantoin and reserpine. These were the only drugs listed in the review (1) on which we had sufficient data, and on which study in our setting was appropriate as explained below.Cyclophosphamide is used for treatment of some cancers and auto-immune disorders and to prevent rejection of transplanted organs. Furosemide is a diuretic used for treatment of hypertension and fluid retention due to congestive heart failure or liver or kidney disease. Griseofulvin is used to treat fungal infections of the skin, hair and nails. Indomethacin is an anti-inflammatory drug used to treat rheumatoid disorders...

Epidemiologic evaluation of pharmaceuticals with limited evidence of carcinogenicity

“…Of the previously-reported cancer sites, increased risk for breast cancer noted previously in this setting (17) was confirmed, but increased risk for liver cancer and thyroid cancer were not. However, the small number of cases and wide confidence intervals did not provide reliable evidence against those associations ( Table 3).…”

Randomized controlled trials of the efficacy of lung cancer screening by sputum cytology revisited

“…Of the previously‐reported cancer sites, increased risk for breast cancer noted previously in this setting17 was confirmed, but increased risk for liver cancer and thyroid cancer were not. However, the small number of cases and wide confidence intervals did not provide reliable evidence against those associations (Table III).…”

Metronidazole affects breast cancer cell lines

“…Moreover, the knowledge about the drugs with carcinogenic potential is still poor. When carcinogenicity is found in animal models, it is important to determine whether it is also true for humans, as not all chemicals known to cause tumors in animals also induce tumors in humans [15].…”

“…Friedman et al [15] assessed the risk of breast cancer among 8 drugs that induce mammary tumors in experimental animals. In their cohort, MTZ showed statistically significant yet very small increases in relative risk (1.07 to 1.13) [15]. In the next study, performed on animal models the authors attempted to link the old and new cancer cases with the drug.…”