Addition of Zoledronic Acid to Neoadjuvant Chemotherapy Is Not Beneficial in Patients With HER2-negative Stage II/III Breast Cancer

5-Year Survival Analysis of the NEOZOTAC Trial (BOOG 2010-01)

Stefanie de Groot; Hanno Pijl; Ayoub Charehbili; Saskia van de Ven; Vincent T. H. B. M. Smit; Elma Meershoek-Klein Kranenbarg; Joan B. Heijns; Laurence J. C. van Warmerdam; Lonneke W. Kessels; M. Wouter Dercksen; Manon J. A. E. Pepels; Hanneke W. M. van Laarhoven; Birgit E. P. J. Vriens; Hein Putter; Marta Fiocco; Gerrit-Jan Liefers; Jacobus J. M. van der Hoeven; Johan W. R. Nortier; Judith R. Kroep


Breast Cancer Res. 2019;21(97) 

In This Article

Abstract and Introduction


Background: Adjuvant bisphosphonates are associated with improved breast cancer survival in postmenopausal patients. Addition of zoledronic acid (ZA) to neoadjuvant chemotherapy did not improve pathological complete response in the phase III NEOZOTAC trial. Here we report the results of the secondary endpoints, disease-free survival, (DFS) and overall survival (OS).

Patients and methods: Patients with HER2-negative, stage II/III breast cancer were randomized to receive the standard 6 cycles of neoadjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy with or without 4 mg intravenous (IV) ZA administered within 24 h of chemotherapy. This was repeated every 21 days for 6 cycles. Cox regression models were used to evaluate the effect of ZA and covariates on DFS and OS. Regression models were used to examine the association between insulin, glucose, insulin growth factor-1 (IGF-1) levels, and IGF-1 receptor (IGF-1R) expression with survival outcomes.

Results: Two hundred forty-six women were eligible for inclusion. After a median follow-up of 6.4 years, OS for all patients was significantly worse for those who received ZA (HR 0.468, 95% CI 0.226–0.967, P = 0.040). DFS was not significantly different between the treatment arms (HR 0.656, 95% CI 0.371–1.160, P = 0.147). In a subgroup analysis of postmenopausal women, no significant difference in DFS or OS was found for those who received ZA compared with the control group (HR 0.464, 95% CI 0.176–1.222, P = 0.120; HR 0.539, 95% CI 0.228–1.273, P = 0.159, respectively). The subgroup analysis of premenopausal patients was not significantly different for DFS and OS ((HR 0.798, 95% CI 0.369–1.725, P = 0.565; HR 0.456, 95% CI 0.156–1.336, P = 0.152, respectively). Baseline IGF-1R expression was not significantly associated with DFS or OS. In a predefined additional study, lower serum levels of insulin were associated with improved DFS (HR 1.025, 95% CI 1.005–1.045, P = 0.014).

Conclusions: Our results suggest that ZA in combination with neoadjuvant chemotherapy was associated with a worse OS in breast cancer (both pre- and postmenopausal patients). However, in a subgroup analysis of postmenopausal patients, ZA treatment was not associated with DFS or OS. Also, DFS was not significantly different between both groups. IGF-1R expression in tumor tissue before and after neoadjuvant treatment did not predict survival.


Bisphosphonates (BPs) act to suppress bone resorption by inducing osteoclast apoptosis.[1,2] BPs are indicated for treatment and prevention of osteoporosis and prevention of skeletal-related events due to metastasis of solid tumors or multiple myeloma.[3] Results of the meta-analysis of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that adjuvant BPs were associated with decreased fracture rate, as well as improved breast cancer survival and bone metastasis risk. These benefits were only found in postmenopausal (natural or induced) women in a subgroup analysis.[4] The benefits may be explained by the increased bone resorption in postmenopausal patients, as BP prevented tumor growth in bone in a postmenopausal model but not in a premenopausal model.[5] Currently, BPs are considered as a part of the adjuvant breast cancer treatment in postmenopausal patients and patients receiving ovarian suppression therapy.[6] The exact mechanism of the anti-tumor effect of BPs is unknown. However, the following mechanisms have been proposed,[7] BPs may (1) prevent tumors cells from metastasizing to the bone by decreasing bone turnover,[8] (2) change the bone micro-environment by reducing growth factors such as insulin-like growth factor-1 (IGF-1) and insulin and thereby inhibit proliferation,[9–12] (3) have immunomodulatory properties by activating γδ T cells[13,14] and recruiting tumor-associated macrophages,[15,16] (4) reduce angiogenic factors,[17,18] and/or (5) kill dormant disseminated tumor cells.[19,20] BP was reported to improve the tumor response when combined with doxorubicin in an experimental breast cancer model.[21] Moreover, adding a BP to neoadjuvant chemotherapy in breast cancer patients resulted in a significantly lower residual invasive tumor size and a non-significantly higher pathological complete response (pCR) rate in an exploratory evaluation of the AZURE trial.[22]

Clinically, in our phase III randomized NEOZOTAC study examining the effect of zolendronic acid (ZA) in addition to neoadjuvant TAC chemotherapy in HER2 negative early breast cancer, ZA did not improve the primary endpoint, pathological complete response (pCR).[23] A subsequent meta-analysis did not show a significant increase in pCR rate when adding a BP to neoadjuvant chemotherapy in patients with early breast cancer.[16,24] In this paper, we report the secondary endpoints of disease-free survival (DFS) and overall survival (OS) from the NEOZOTAC study.[23]

Additionally, we report associations between the IGF-1 receptor (IGF-1R) expression and the concentrations of circulating growth factors such as insulin and IGF-1, and survival. IGF-1R and insulin receptor isoform A (IR-A) are frequently upregulated in breast cancer.[25,26] Both receptors activate the Ras/mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways, through which cell proliferation is stimulated and apoptosis is inhibited.[27]