Bisphosphonates, bone, and breast cancer recurrence

Bisphosphonates reduce bone turnover by inhibiting osteoclast maturation and function, and are important in the prevention of age-related osteoporosis and bone fracture, in the prevention of complications of bone metastases, and in the prevention of osteopenia and osteoporosis resulting from adjuvant aromatase inhibitor therapy of breast cancer. Over 125 years ago, in The Lancet, Paget hypothesised that the “soil” in which a tumour resides would be important for tumour propagation and growth. Interruption of the interaction of tumour micrometastases with their microenvironmental “soil” is now a subject of intense investigation. Bone is an active microenvironment, and, in bone with high turnover, excess osteoclastic activity could potentially lead to excess production of growth factors, which could aff ect survival of micrometastases. Bisphosphonates, by reducing osteoclast activity, could in theory reduce expression of these factors, thereby preventing establishment of micrometastatic disease. Clinical trials of bisphosphonates as adjuvant therapy for breast cancer have had mixed results. Clodronate, an oral fi rst-generation bisphosphonate, showed a disease-free survival benefi t versus placebo in one large randomised trial, but not in another. An early trial of zoledronic acid, a more powerful third-generation aminobisphosphonate, added to adjuvant aromatase inhibitor therapy for postmenopausal women to prevent bone loss, showed a non-signifi cant improve ment in disease-free survival, a secondary endpoint. Larger trials comparing zoledronic acid to no therapy in postmenopausal women, or in premenopausal women made menopausal with gonadotropin-releasing hormone agonists, showed signifi cant disease-free survival benefi ts, but no benefi t was seen in a large randomised trial of both premenopausal and postmenopausal women. In The Lancet, the Early Breast Cancer Trialists’ Collaborative Group presents a meta-analysis of randomised trials of bisphosphonates as adjuvant systemic therapy for breast cancer. This meta-analysis is comprised of individual patient data derived from randomised adjuvant bisphosphonate trials in breast cancer done over the past 20 years. The analysis received data on 18 766 women (18 206 in randomised trials of 2–5 years of adjuvant bisphosphonate vs control), with a median follow-up of 5·6 years, 3453 fi rst recurrences, and 2106 deaths. For all patients, there were borderline signifi cant reductions with the addition of bisphosphonates at 10 years for distant recurrence (20·4% vs 21·8%, rate ratio [RR]=0·92, 95% CI 0·85–0·99; 2p=0·03), bone recurrence (7·8% vs 9·0%, RR=0·83, 0·73–0·94; 2p=0·004), breast cancer mortality (16·6% vs 18·4%, RR=0·91, 0·83–0·99; 2p=0·04), and all-cause mortality (20·8% vs 22·3%, RR=0·92, 0·85–1·00; 2p=0·06). 8 Davies C, Pan H, Godwin J, et al. Long-term eff ects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013; 381: 805–16. 9 Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated fi ndings from NCIC CTG MA.17. J Natl Cancer Inst 2005; 16: 707–15. 10 Sestak I, Dowsett M, Zabaglo L, et al. Factors predicting late recurrence for estrogen receptor-positive breast cancer. J Natl Cancer Inst 2013; 105: 1504–11. 11 Viale G, Regan MM, Dell’Orto P, et al. Which patients benefi t most from adjuvant aromatase inhibitors? Results using a composite measure of prognostic risk in the BIG 1-98 randomized trial. Ann Oncol 2011; 22: 2201–07. 12 Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–91. 13 Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2015; 372: 436–46. 14 Aiello Bowles EJ, Boudreau DM, Chubak J, et al. Patient-reported discontinuation of endocrine therapy and related adverse eff ects among women with early-stage breast cancer. J Oncol Pract 2012; 8: 149–57. 15 Hadji P, Jackisch C, Bolten W, et al. COMPliance and Arthralgia in Clinical Therapy: the COMPACT trial, assessing the incidence of arthralgia, and compliance within the fi rst year of adjuvant anastrozole therapy. Ann Oncol 2014; 25: 372–77.