Abstract BACKGROUND and AIM: Findings from a randomized phase 2 JONIE1 trial in women with HER2-negative early breast cancer have shown that the addition of zoledronic acid (ZOL) to neoadjuvant chemotherapy (CT) has potential anticancer benefits in postmenopausal and triple-negative breast cancer patients. We report the data for the prespecified secondary endpoint of disease-free survival (DFS). METHODS: We enrolled women with HER2-negative early breast cancer and randomly assigned them to receive CT or CT+ZOL (CTZ). All patients received 4 cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered 3-4 times weekly for 7 weeks to the CTZ group patients. Definitive surgery was performed 3-4 weeks after the last paclitaxel dose. The primary endpoint was pathological complete response (pCR). The secondary endpoints were the clinical response rates, rate of breast-conserving surgery, safety, and DFS (defined as the time from randomization to disease occurrence or death). The trial is registered as UMIN000003261 (www.umin.ac.jp/english/) with ongoing follow-up. FINDINGS: Of the 188 patients enrolled, 95 were assigned to the CT group and 93 to the CTZ group. The mean (95% CI) DFS time of the CT group was 5.15 years (4.83-5.47) and that of the CTZ group was 5.38 years (5.11-5.66). The 3-year DFS rate was 84.6% (95% CI 77.2-92.0) in the CT group and 90.7% (84.6-96.8) in the CTZ group with no significant difference (p = 0.120). The particular benefit from ZOL for the neoadjuvant CT seen as improvement of the pCR rate was indicated in the 3-year DFS period for triple-negative cancer cases (CT vs CTZ: 70.6% vs 94.1%), but not for postmenopausal cases. CONCLUSIONS: ZOL slightly improved DFS when combined with CT. Although a significant difference was not found in this study, plans are underway for conducting a combined analysis of 3 neoadjuvant CT trials together with ZOL. The improvement of the pCR rate may be associated with DFS in triple-negative cases. Previous studies have shown that ZOL was more efficacious in an estrogen-suppressed condition. However, the short-term application of ZOL in this study may not be sufficient to improve the outcome in postmenopausal patients. Citation Format: Ishikawa T, Akazawa K, Hasegawa Y, Tanino H, Horiguchi J, Miura D, Hayashi M, Takao S, Kim SJ, Yamagami K, Miyashita M, Konishi M, Shigeoka Y, Suzuki M, Taguchi T, Kubota T, Kohno N. Zoledronic acid combined with neoadjuvant chemotherapy for HER2-negative early breast cancer (JONIE 1 trial): Survival outcomes of a randomized multicenter phase 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-10.

Abstract Background: Zoledronic acid (ZOL) has been found to have a synergistic anti-proliferative effect when used in combination with antitumor drugs. We suggested that the addition of ZOL to neoadjuvant chemotherapy (CT) has potential anti-cancer benefit in postmenopausal patients with triple-negative breast cancer in JONIE-1 Trial (50% pCR rate in ZOL+CT: CTZ versus 0% in CT, p = 0.029). We analyzed the disease-free survival (DFS) as a secondary endpoint and baseline Ki67 levels between two groups. Methods: Women with Stage IIA-IIIB HER-2-negative breast cancer were randomly assigned 1:1 to CTZ group or CT group, CT was FEC100 q3w × 4 cycles followed by weekly paclitaxel for 12 cycles and ZOL 4mg was administered every 3-4 weeks. Among 188 patients recruited between March 2010 and April 2012 excluding 10 from the primary assessment, 178 patients were assessed. The aims of this study were to compare the relative efficacy or CTZ with the efficacy of CT in prolonging DFS in all patients and also to compare the pCR rates between baseline Ki67 high (20% and >20%) with Ki67 low (<20%) in ER positive cohort. Results: During a mean follow-up period of 34.4 months, breast cancer specific events (recurrence and death) occurred 17 participants, 7 in CTZ group and 10 in CT group. The 1-year, 2-year, and 3-year DFS rates were 97.7%, 88.4%, and 88.4% in CTZ versus 100%, 84.8%, and 81.1% in CT, respectively. In the ER positive cohort studied for Ki67 consist of 109 patients, 40 were in Ki67 low group and 69 were in Ki67 high group. Among Ki67 low group, number of pCR was none out of 18 in CTZ and 1 out of 22 in CT (p = .550). Among Ki high group, that was 6 out of 38 in CTZ and 3 out of 31 (p = .352). Conclusion: We could not find a modest improvement in disease-free survival compared the addition of ZOL to neoadjuvant CT with CT alone. Ki67 study for central analysis has been under investigation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-7.