S2-4: GAIN Study: A Phase III Trial To Compare ETC vs. EC-TX and Ibandronate vs. Observation in Patients with Node-Positive Primary Breast Cancer – 1st Interim Efficacy Analysis.

Abstract

Background: We previously showed that intense dose-dense (idd) epirubicin (E), paclitaxel (T), cyclophosphamide (C) results in a superior DFS and OS compared to conventionally dosed EC-T in pts with primary breast cancer (PBC) and ≥4 involved lymph nodes (LN) (Möbus et al JCO 2010). In the GAIN study, the intense dose-dense strategy has been further investigated as well as the adjuvant application of ibandronate (I). We here report on the planned interim efficacy analysis after 50% (N>401) of the required events have occurred. Methods: A prospective, multi-center, controlled, non-blinded, randomized phase III trial investigating ETC (E: 150 mg/m2, T:225 mg/m2, C:2500–2000 mg/m2, i.v. day 1, q15 for 3 cycles each: A1); or EC→TX (E: 112.5 mg/m2 + C: 600 mg/m2, i.v. day 1, q 15 for 4 cycles→T: 67.5 mg/m2 i.v. day 1, q 8 for 10 weeks + X: 2000 mg/m2 p. o. day 1–14, q 22 for 4 cycles: A2). Pts were further randomized in a 2:1 ratio to receive ibandronate: 50 mg/day p.o. for 2 years (B1) or observation (B2). Pts received a primary prophylaxis with either epoetin β or darbepoetin α and pegfilgrastim during ETC or EC. After recruitment of 1500 pts prophylactic ciprofloxacin was implemented and the dose of C was reduced to 2000 mg/m2. Eligibility: Females ≥18 and <65 years, histologically confirmed LN positive uni- or bilateral PBC; adequate surgery, ≥1 pos.LN; ECOG ≤2; written informed consent. Primary objective:compare DFS A1 vs. A2 and B1 vs.B2. Secondary objectives: OS, safety, incidence of secondary primaries, and EFS in subgroups of hormone sensitivity and number of pos. LN between arms; assessment of compliance; determine prognostic factors. 3000 pts with 801 events were needed to show an increase of 5-year DFS from 75% to 79% for pts receiving EC→TX and 728 events to show an increase of 5-year DFS from 75% to 79.5% for pts receiving I, assuming a drop-out rate of 5%, α=0.05 (two-sided)and 1-β =80%. An interim analysis for both primary objectives was planned after 50% of the expected events occurred. Safety results have been reported previously (Möbus et al. SABCS 2009). Results: 3023 patients were randomized between 06/2004 and 08/2008.1512 received ETC and 1511 EC→TX. 29pts never started therapy, 14 in ETC, 15 in EC→TX. Median follow-up is 38.7 months. Median age was 50 years; pN1 (37.7%), pN2 (35.4%); pN3 (26.9%); 77.4% had ductal invasive carcinoma, 46.6% were grade 3; 76.7% had hormone receptor-positive tumors, 22% were HER2−positive. 405 events have occurred by 12.05.2011.380pts relapsed and 25pts. died w/o relapse. The interim futility boundary for chemotherapy was not crossed. For the ibandronate question the futility boundary was reached. There was no difference in DFS and OS between the patients with and without ibandronate (DFS log-rank p=0.593; HR 1.059; 95%CI 0.861−1.301; OS log-rank p=0.801 HR 0.961; 95% CI 0.705−1.31). Conclusion: The GAIN study demonstrated that adjuvant ibandronate does neither improve DFS nor OS in primary node positive breast cancer after treatment with dose-intensified chemotherapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-4.

Cancer-associated bone disease

“…Similarly, in the study GAIN, 3,023 women with lymph node positive breast cancer were randomized to either oral ibandronate or placebo. There was equal disease free and overall survival in the two groups [134]. In another phase III study, patients were randomized to clodronate, ibandronate or zoledronic acid (without control or placebo arm).…”

Adjuvant bisphosphonate treatment for breast cancer: Why did something so elegant become so complicated?

“…This trial compared oral clodronate to placebo and while the results showed no difference between the two arms for breast cancer outcomes, a subgroup analysis suggested that benefit was seen in women aged over 60. Finally, the German Adjuvant Intergroup Node Positive (GAIN) study using the oral bisphosphonate ibandronate was recently presented by Mobus et al [11]. In this study 50 % of participants were premenopausal and 75 % were hormone positive.…”

“…With their demonstrated activity and anti-tumour effects in preclinical studies it was natural to assess these agents in the adjuvant clinical setting. Surprisingly, the results of adjuvant breast cancer trials have shown either modest [6,8,9,15] or no benefit [4,10,11,14], or even harm [17]. Given these conflicting clinical outcomes and the extensive preclinical data that was supposed to support the adjuvant development of these agents, one has to ask why did something so elegant become so complicated?…”

“…Thus correctly interpreting the current clinical results and identifying the treatment population and strategy most likely to achieve benefit are critically important. The results of the current trials that were appropriately powered and designed with the primary objective of answering the role of adjuvant bisphosphonate therapy have all been negative [4,8,9,11]. While the suggestion that certain subpopulations of breast cancer patients may derive more benefit from bisphosphonate treatment than others has been made, future preclinical and clinical studies should be designed with this in mind.…”

ecancermedicalscience

“…Similarly, in an exploratory analysis of data from the ZO-FAST study, initiation of ZOL concurrent with standard adjuvant therapy significantly improved survival (HR = 0.50, P = 0.0224) in early stage BC patients who were >5 years post-menopause or >60 years of age [7]. In the GAIN study, a similar trend toward improved survival was noted in ibandronate-treated patients ≥60 years of age (HR = 0.746, P = 0.172) [4]. …”