Reproductive hormone analyses and effects of adjuvant zoledronic acid in early breast cancer - An AZURE (BIG 01/04) sub-study

Purpose: Adjuvant bisphosphonates have been shown to improve disease outcomes in early breast cancer in women who are postmenopausal at the start of treatment. We explored the influence of pretreatment serum levels of reproductive hormones in the hypothalamic-pituitary-gonadal (HPG) axis from a subset of patients included in the AZURE trial to investigate their impact on disease recurrence and whether reproductive hormone measurements are of value in selecting patients for treatment with adjuvant zoledronic acid. Patients and methods; The AZURE trial is an academic, multi-centre, international phase III trial that randomised patients to standard adjuvant therapy (chemotherapy and/or endocrine therapy) +/- intravenous zoledronic acid, 4 mg for 5 years. Serum from 865 patients taken at randomisation was stored at -80 degrees C prior to central batch analysis for inhibin A, oestradiol and follicle stimulating hormone (FSH). We assessed the clinical value of pretreatment hormone levels for predicting invasive disease free survival (IDFS), skeletal recurrence and distant recurrence and response to treatment with zoledronic acid. Results: Oestradiol in the postmenopausal range (<50 pmol/l) was associated with a significantly shorter IDFS (HR 1.36 95% CI: 1.05-1.78 p=0.022), predominantly due to distant recurrence (HR 1.33 95% CI: 0.98-1.81 p=0.065), compared to oestradiol >= 50pmol/l. In contrast, FSH in the postmenopausal range (>26 IU/l) was associated with a longer time to bone as first recurrence (HR 0.66 95% CI: 0.41-1.04 p=0.072) compared to an FSH <= 26 IU/l. When all 3 hormone levels were within the assay specified postmenopausal range, a trend to improved IDFS was seen with addition of zoledronic acid in biochemically postmenopausal women only (postmenopausal HR=0.81; 95% CI: 0.54-1.22, non-postmenopausal HR=0.99; 95% CI: 0.69-1.39) with risk reductions that mirrored the results of the main AZURE study, although the interaction between menopausal status and treatment effect was not statistically significant (p=0.47). Conclusion: Oestradiol and FSH may influence the pattern of disease recurrence with postmenopausal levels possibly creating a less conducive environment for the formation of bone metastases, therefore disseminated tumour cells could seek alternative niches outside of bone. Biochemical evaluation of a panel of reproductive hormones may be helpful to assist selection of patients for adjuvant zoledronic acid when menopausal status is unknown.