D. Dodwell

Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial

BACKGROUNDnThe role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer.nnnMETHODSnIn the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3-4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020.nnnFINDINGSn3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0·94, 95% CI 0·82-1·06; p=0·30). IDFS (HR 0·93, 95% CI 0·82-1·05; p=0·22), overall survival (0·93, 0·81-1·08; p=0·37), and distant recurrences (0·93, 0·81-1·07; p=0·29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0·78, 95% CI 0·63-0·96; p=0·020) and at any time during follow-up (0·81, 0·68-0·97; p=0·022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0·77, 95% CI 0·63-0·96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1·03, 95% CI 0·89-1·20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1·7%, 95% CI 1·0-2·4).nnnINTERPRETATIONnThese results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes.nnnFUNDINGnNovartis Global and NIHR Cancer Research Network.

Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel

Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus. The panel recommended that bisphosphonates should be considered as part of routine clinical practice for the prevention of CTIBL in all patients with a T score of <-2.0 or ≥2 clinical risk factors for fracture. Compelling evidence from a meta-analysis of trial data of >18,000 patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breast cancer mortality in post-menopausal women or those receiving ovarian suppression therapy. Therefore, the panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients.

Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4xa0mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60xa0months post-randomisation (six doses in the first 6xa0months, eight doses in the following 24xa0months and five doses in the final 30xa0months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36xa0months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3–1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

Phase I/II evaluation of effervescent and enteric coated oral pamidronate for bone metastases.

THE DISCOVERY of the action of bisphosphonates on osteoclast activity led to study of their role in the management of tumourinduced osteolysis aad hypercalcaemia [ 11. These encouraging preliminary results have been confirmed by many groups and bisphosphonates are now considered the treatment of choice for hypercalcaemia [2]. Most studies have been performed with intravenous bisphosphonates, as this class of compounds is poorly absorbed from the gut, with an average bioavailability of 1% [3]. Although large doses, relative to those used parenterally, have to be administered, oral pamidronate has been shown to reduce skeletal morbidity in patients with breast cancer and established bone metastases [4] and attention is now turning to the possibility of preventing metastatic bone disease. However, in addition to the problems of absorption, gastrointestinal toxicity secondary to the locally irritant effect of pamidronate on the gut mucosa occurs. For long-term administration, particularly adjuvant use, the level of toxicity with the current non-proprietary formulation of oral pamidronate is considered too high. We have studied the toxicity and efficacy of two new oral formulations: an effervescent tablet and an enteric-coated capsule (Ciba-Geigy, Basle), in patients with bone metastases. 79 patients were treated with oral pamidronate at six hospitals. The median age was

Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04)

6 years and all but 3 patients had advanced breast cancer. Eligibility required radiographically confirmed bone metastases and during the 1 month trial period patients received no other anticancer drug therapy. The exceptions to this were patients on endocrine treatment, providing this had not been changed in the previous 4 months, who continued with this treatment for the month to exclude the possibility of a withdrawal response. In addition, a raised level of urinary calcium excretion was necessary. This was defined as a urinary calcium/creatinine ratio (UCCR) of more than 0.4 (mmol/mmol) in fasting morning spot urine samples taken on two occasions during the week before trial entry. Patients receiving medication known to affect bone meta-

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

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. Patients and methods 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapyu202f+/− intravenous ZOL 4u202fmg every 3–4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. Results With a median follow up of 117 months [IQR 70.4–120.4), DFS and IDFS were similar in both arms (HRDFSu202f=u202f0.94, 95%CIu202f=u202f0.84–1.06, pu202f=u202f0.340; HRIDFSu202f=u202f0.91, 95%CIu202f=u202f0.82–1.02, pu202f=u202f0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFSu202f=u202f0.82, 95%CIu202f=u202f0.67–1.00; HRIDFSu202f=u202f0.78, 95%CIu202f=u202f0.64–0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFSu202f=u202f0.75, 95%CIu202f=u202f0.58–0.97) and OS HROSu202f=u202f0.69, 95%CIu202f=u202f0.50–0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISHu202f+u202ftumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFSu202f=u202f0.76, 95%CIu202f=u202f0.63–0.92, pu202f=u202f0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. Conclusions Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial

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 °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.