Testosterone Undecanoate Treatment Reduces Joint Morbidities Induced by Anastrozole Therapy in Postmenopausal Women with Breast Cancer: Results of a Double-Blind, Randomized Phase II Trial.
Background: Approximately 50% of women taking 3rd generation aromatase inhibitors (AI) for adjuvant breast cancer therapy develop arthralgia, tenosynovitis or arthritis. In many women, the morbidity is significant and affects therapy compliance. The pathology of AI-induced joint morbidity is poorly understood, but clinical features in severe cases mimic rheumatoid arthritis. Afflicted women are treated with anti-inflammatory medication, but this does not address the etiology, which appears to involve steroid hormone imbalance. Testosterone can be metabolised to estrogen or the more potent androgen, 5alpha-dihydrotestosterone (DHT). Androgen levels decrease with age and this may be exacerbated by chemotherapy and, paradoxically, aromatase inhibition. We hypothesise that AI-associated joint morbidities are the result of testosterone deficiency and that testosterone treatment during AI therapy will be beneficial. Testosterone replacement had been contraindicated in women with breast cancer until the advent of powerful 3rd generation aromatase inhibitors that are highly efficacious in blocking conversion of testosterone to estrogen, thus allowing the examination of combinations of drugs such as anastrozole and testosterone.Materials and Methods: 90 women taking Arimidex® 1mg daily and registering a visual analogue scale (VAS) pain or stiffness score of ≥ 40mm on a 100mm scale, were randomized into 3 equal arms: placebo, 40 mg or 80 mg testosterone undecanoate daily, with follow-up at 1 and 3 months. The primary efficacy endpoint was reduction in pain at 3 months and the primary safety endpoints were signs of androgen excess with secondary safety endpoints being serum hormone levels, serum lipids and bone absorption markers.Results: The VAS scores at 3 months fell for all groups, with a marked placebo effect of 35% compared with 43% and 70% for the 40 and 80mg treatment arms (p=0.06 and p=0.04, respectively). No significant androgenic side-effects (hirsutism, alopecia and acne) were observed and serum lipids remained unaltered. Serum total testosterone and free-testosterone levels stabilized at 3 months in a dose-dependent fashion into a physiological range. There was no elevation in serum estradiol in either treatment arm and the serum sex hormone binding globulin level fell significantly in the 80mg treatment group (p=0.03). There was no significant change in bone absorption markers in any of the patient groups.Discussion: This study has demonstrated for the first time that testosterone replacement may be a viable option in the management of AI-induced arthralgia, tenosynovitis and arthritis with good tolerability and safety, without adversely reducing aromatase inhibitor efficacy (as indicated by serum estradiol levels).This study was supported AstraZeneca (UK). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 804.