SABCS 2011 Report – The role of adjuvant bisphosphonates in breast cancer: The mist has started to clear

by Dr Sunil Upadhyay – The role of bisphosphonates in the management of breast cancer with bone metastases is well established. However, their benefit in the adjuvant setting remains questionable. Zoledronic acid has been studied widely and the results are conflicting. The 84 months follow-up results from the ABCSG-12 trial at SABCS 2011, presented by Professor Michael Gnant from the Medical University of Vienna, confirmed the benefits for DFS (HR 0.71; p=0.011) in early stage I and II, oestrogen receptor positive breast cancer patients. The pre-menopausal age group of patients were randomised to adjuvant goserlin for three years in combination with tamoxifen or anastrozole with or without zoledronic acid in this trial. The addition of zoledronic acid reduced the incidence of disease recurrence not only in the bones but also at all sites compared to endocrine therapy alone arms. This benefit was larger in patients over the age of 40 years due to presumed complete ovarian blockade. The addition of zoledronic acid improved the overall survival compared to endocrine therapy alone (HR 0.61; P=0.033), again particularly in women above 40 years of age (HR 0.57; p=0.042). Stratification according to age shows that the benefits were pronounced in women over the age of 40 years, suggesting the anticancer effects may be greatest in women achieving complete postmenopausal status. This hypothesis was confirmed in the subgroup analysis of the AZURE trial.

The 5-year follow-up results of the ZO-FAST trial, a multicentre, global study presented by de Boer from Australia on the use of adjuvant letrozole with immediate (IM-ZOL) versus delayed zoledronic acid (D-ZOL) (4mg once every 6 months) in postmenopausal, oestrogen receptor positive women with early stage breast cancer (n=1065) provides extra support to the above hypothesis. The patients in the delayed arm were allowed zoledronic acid if their BMD fell below –2, they developed a clinical fracture or if an asymptomatic fracture was diagnosed on plain x-ray at 36 months. The primary end point was BMD changes at 12 months and the secondary endpoints were BMD changes at 36 and 60 months, disease recurrence, fracture and safety.

As anticipated, the primary characteristics between the two arms were well balanced. The results showed that the primary endpoint benefits (median change in the lumbar spine BMD) in the immediate zoledronic acid group occurred early and continued after 5 years with a net difference of 10% in the BMD favouring the immediate arm. The secondary endpoint of improvement in BMD of the total hip also favoured the immediate group. The DFS in the intention to treat population (HR 0.66; p=0.0375) as well as the censored analysis (HR 0.62; p=0.024) also favoured immediate use. As far as the site of recurrence was concerned, similar to ABCSG-12 results, the immediate zoledronic acid group did better for local, contralateral and distant recurrence in all organs, including bones. The overall survival favoured the IM-ZOL arm (HR 0.69) though not significantly (p=0.196).

Stratification factors consisted of recent postmenopausal, defined as “chemotherapy or ovarian suppression induced premature menopause” (n=177) in patients who were pre- or peri-menopausal at the time of the diagnosis, and truly postmenopausal defined as “naturally occurring menopause” prior to diagnosis of the breast cancer (n=888). Among the women who were postmenopausal for >5 years or >60 years old at the time of randomisation (n=670), IM-ZOL prolonged the DFS (HR 0.63; p=0.52) as well as OS (HR 0.50; p=0.22). There were no unexpected safety concerns observed in this trial. Putting together the results of three zoledronic acid trials, ABCSG-12, AZURE and ZO-FAST, a clearer picture emerges showing superiority of adjuvant zoledronic acid in postmenopausal women with a hazard ratio closer to 0.70. These data support the hypothesis that the anticancer potential of zoledronic acid might be best realised in a low oestrogen environment. Abstract S-1-3. SABCS 2011