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Clinical Trial
. 2015 Dec 3;10(12):e0143643.
doi: 10.1371/journal.pone.0143643. eCollection 2015.

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

Yoshie Hasegawa  1 , Hirokazu Tanino  2 , Jun Horiguchi  3 , Daishu Miura  4 , Takashi Ishikawa  5 , Mitsuhiro Hayashi  6 , Shintaro Takao  7 , Seung Jin Kim  8 , Kazuhiko Yamagami  9 , Masaru Miyashita  10 , Muneharu Konishi  11 , Yasushi Shigeoka  12 , Masato Suzuki  13 , Tetsuya Taguchi  14 , Tomoyuki Kubota  15 , Kouhei Akazawa  16 , Norio Kohno  17 ; JONIE Study Group
Collaborators, Affiliations
Clinical Trial

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

Yoshie Hasegawa et al. PLoS One. .

Abstract

Purpose: Zoledronic 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).

Methods: Asian 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.

Results: This 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 registration: University Hospital Medical Information Network. UMIN000003261.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. CONSORT diagram for JONIE Study.
See this image and copyright information in PMC

References

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    1. Charehbili A, van de Ven S, Smit VT, Meershoek-Klein Kranenbarg E, Hamdy NA, Putter H, Heijns JB, et al. Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010–01). Ann Oncol. 2014;25:998–1004. 10.1093/annonc/mdu102 - DOI - PubMed
    1. Coleman R, de Boer R, Eidtmann H, Llombart A, Davidson N, Neven P, et al. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol. 2013;24:398–405. 10.1093/annonc/mds277 - DOI - PubMed
    1. Coleman R, Gnant M, Paterson A, Powles T, von Minckwitz G, Pritchard K, et al. Abstract S4-07: Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomised trials. Cancer Res. 2013;73:S4–07. 10.1158/0008-5472.sabcs13-s4-07 - DOI

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