Finasteride and potential risk of male breast cancer
HSA would like to bring to the attention of healthcare professionals the potential risk of male breast cancer associated with finasteride.
Finasteride is a competitive and specific inhibitor of Type II 5α-reductase, an intracellular enzyme which metabolises testosterone into the more potent androgen dihydrotestosterone (DHT). The inhibition of Type II 5α-reductase results in a decrease in serum and tissue DHT concentrations.
Finasteride 5mg is indicated for the treatment and control of benign prostatic hyperplasia (BPH) by causing the regression of enlarged prostate thereby improving urinary flow and symptoms associated with BPH. At a lower strength of 1mg, it is indicated for androgenetic alopecia to increase hair growth and prevent hair loss. Finasteride has been licensed in Singapore since 1998 and is available under these brands: Proscar® and Propecia® (MSD); Finast® (Zyfas Medical Co) and Finasteride Mevon® (Novem Healthcare Pte Ltd).
UK Medicines and Healthcare products Regulatory Agency (MHRA)
In December 2009, the UK MHRA completed a review on the risk of breast cancer in men taking different strengths of finasteride for the various medical conditions, and concluded that an increased risk of male breast cancer associated with finasteride use cannot be excluded.1,2 As a precaution, the package inserts of all finasteride-containing products in the UK were updated to include a warning on the risk of breast cancer.
UK MHRA's assessment
UK MHRA's review took into consideration data from clinical trials as well as post-marketing reports of male breast cancer associated with finasteride. In addition, the review also considered whether there was a plausible biological mechanism for male breast cancer to occur with the use of finasteride.
(i) Clinical trial data analysis
Data from studies of 5mg finasteride were reviewed and these include three placebo-controlled clinical trials of at least four years in duration, uncontrolled open-label extension studies and one short-term (less than one year) placebo-controlled clinical trial. From the data, 11 cases of male breast cancer were observed, of which three occurred in patients treated with placebo. Of the remaining eight cases, there was a case of male breast cancer recurrence in a patient treated with 5mg finasteride during the short-term clinical trial, two cases of male breast cancer in trials of at least one year in duration and five cases of male breast cancer in patients treated with 5mg finasteride during the placebo-controlled clinical trials of at least four years in duration.
In an analysis that included the 10 cases of male breast cancer observed in both controlled and uncontrolled trials of at least one year in duration, although the overall incidence of male breast cancer in patients who received 5mg finasteride was not significantly different compared to patients who received placebo (7.8 per 100,000 patient-years vs. 3.8 per 100,000 patient-years; p=0.328), the data showed that there was a trend towards male breast cancer occurring more frequently in patients who had received finasteride, than in those who did not.
No cases of breast cancer were reported in men treated with 1mg finasteride in controlled trials up to five years in duration as well as in open-extension studies up to six years in duration.
(ii) Post-marketing reports of male breast cancer
As of November 2009, 53 worldwide cases of male breast cancer in patients treated with finasteride have been received by the drug manufacturer, MSD. Of these, 50 occurred in patients aged between 54 to 88 years (mean age: 71 years) treated with Proscar® 5mg while the remaining three cases occurred in patients treated with Propecia® 1mg.
Of the 50 cases of male breast cancer reported with Proscar® 5mg, 14 (28%) reports could not be properly evaluated due to inadequate information, in particular the time to onset of breast cancer. The time to onset of breast cancer was estimated to be approximately 44.4 months (median duration: 36 months), based on 36 (72%) reports. Out of these 36 reports, 27 (75%) cases occurred after at least one year of finasteride treatment and nine (25%) cases occurred after less than one year of finasteride treatment.
Of the three cases of male breast cancer reported with Propecia® 1mg, inadequate information and the relatively short times to onset in these cases makes the causal association between male breast cancer and finasteride unlikely. The time to onset of event was three months and six months respectively for two cases but was not known for the third case.
In addition, although finasteride was not approved for use in females, four case reports of female breast cancer were received with “off-label” use of finasteride in the United States. The time to onset in the female breast cancer cases ranged from 6 to 12 months, which were relatively short periods of exposure. It is also important to recognise that under-reporting of adverse drug reactions (ADR) is a recognised limitation as with all ADR-reporting schemes.
(iii) Possible biological mechanism
A possible mechanism to the increased risk of breast cancer with finasteride use could be related to its ability to increase endogenous testosterone and thus oestradiol levels. By inhibiting Type II 5α-reductase, the conversion of testosterone to DHT is prevented, thereby resulting in an increase in testosterone level. As oestrogens in men are derived from the conversion of testosterone to oestradiol and androstenedione to oestrone, an increase in testosterone with finasteride use may lead to a rise in oestradiol levels.
To date, HSA has not received any local reports of male breast cancer associated with finasteride. HSA is currently working with the companies to update the local package inserts of finasteride to include warnings to reflect the above safety issue. Healthcare professionals are advised to inform their patients taking finasteride to promptly report any changes in their breast tissue such as lumps, pain, gynaecomastia or nipple discharge to their doctors.
Healthcare professionals are also strongly encouraged to report any adverse reactions suspected to be associated with finasteride to the Vigilance Branch of HSA.
1. UK MHRA Public Assessment Report
2. UK MHRA Drug Safety Update: Volume 3, Issue 5, December 2009
Healthcare professional, Industry member, Therapeutic Products