Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study)

Yoshie Hasegawa,Norio Kohno,Tomoyuki Kubota,Mitsuhiro Hayashi,Yasushi Shigeoka,Tetsuya Taguchi,Kouhei Akazawa,Takashi Ishikawa,Masaru Miyashita,Muneharu Konishi,Hirokazu Tanino,Daishu Miura,Masato Suzuki,Kazuhiko Yamagami,Seung Jin Kim,Shintaro Takao,Jun Horiguchi,Daniele Santini

doi:10.1371/journal.pone.0143643

Abstract

PurposeZoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT).MethodsAsian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four 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 three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug.ResultsThis randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted.Trial RegistrationUniversity Hospital Medical Information Network. UMIN000003261.

Highlights

Bisphosphonates have a high affinity for hydroxyapatite on the bone surface and inhibit osteoclastic bone resorption [1]
Safety was assessed in all patients who received at least one dose of the study drug. This randomized controlled trial indicated that the rates of pathological complete response (pCR) in CTZ group (14.8%) was doubled to CT group (7.7%), respectively, though the additional efficacy of zoledronic acid was not demonstrated statistically
We planned a new trial to define additional efficacy of zoledronic acid onto standard neo-adjuvant chemotherapy using FEC100 followed by weekly paclitaxel for HER2 negative breast cancer

Summary

Introduction

Bisphosphonates have a high affinity for hydroxyapatite on the bone surface and inhibit osteoclastic bone resorption [1]. Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that powerfully suppresses bone resorption. In 2005, Kohno et al [3] performed a randomized placebo-controlled clinical trial of ZOL in patients with metastasis of breast cancer to bone and reported both an analgesic effect and significant reduction in the frequency of skeletal-related events. Clinical recurrence of breast cancer was reportedly less frequent when ZOL was added to postoperative adjuvant endocrine therapy for premenopausal patients with breast cancer receiving ovarian suppression therapy [5]. The efficacy of ZOL did not improve when used in combination with chemotherapy (CT), benefits were seen in the subset of women who were postmenopausal at the time of diagnosis [6]. Clinical trials have reported conflicting results on whether oral clodronic acid therapy improves survival in patients with breast cancer. The anticancer efficacy of bisphosphonates has not yet been clinically proven

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