The effect of metformin vs placebo on sex hormones in CCTG MA.32.

BACKGROUND Metformin has been associated with lower breast cancer risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones (SHs). We evaluated the effect of metformin on SHs in MA.32, a phase III trial of nondiabetic BC subjects randomized to metformin or placebo. METHODS We studied the subgroup of post-menopausal hormone receptor negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after randomization. Sex hormone binding globulin (SHBG), bioavailable testosterone (BT) and estradiol levels were assayed using ECLIA (electrochemiluminescense immunoassay). Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. RESULTS 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2 negative BC and had received (neo)adjuvant chemotherapy. Mean age ± SD was 58.1±6.9 vs 57.5±7.9 years, mean BMI was 27.3±5.2 vs 28.9±6.4 kg/m2 for metformin vs placebo respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; p < 0.001) in univariable analysis and after controlling for baseline BMI and BMI change (p < 0.001). There was no change in SHBG or BT. CONCLUSION Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers

A multi-centre study comparing granulocyte-colony stimulating factors to antibiotics for primary prophylaxis of docetaxel-cyclophosphamide induced febrile neutropenia

Background: Primary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted. Methods: EBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective. Results: 458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = −6.7%, 95%CI = −13.5%–0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p < 0.001). Non-FN treatment-related hospitalisation occurred in 40/228 (17.5%) of ciprofloxacin patients vs 28/230 (12.2%) of G-CSF patients (p = 0.12). There were no differences in other secondary outcomes. G-CSF was associated with an incremental cost-effectiveness ratio of C$1,760,796 per one quality-adjusted life year gained. Conclusion: The primary endpoint of superiority of G-CSF over ciprofloxacin was not demonstrated. While there were reduced FN rates with G-CSF, there were no differences in chemotherapy dose delays/reductions or discontinuations. With the commonly used willingness to pay value of C$50,000/QALY, G-CSF use was not cost-effective compared to ciprofloxacin and deserves scrutiny from the payer perspective