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)

Charehbili, Ayoub; Ven, Saskia van de; Smit, Vincent T.H.B.M.; Kranenbarg, Elma Meershoek-Klein; Hamdy, N.A.T.; Putter, Hein; Heijns, Joan B.; Warmerdam, L. J. C. van; Kessels, Lonneke W.; Dercksen, M. Wouter; Pepels, M.J.A.E.; Maartense, E.; Laarhoven, Hanneke W. M. van; Vriens, B.E.P.J.; Wasser, Martin; Leeuwen-Stok, A. Elise van; Liefers, Gerrit‐Jan; Velde, C. J. H. van de; Nortier, J. W. R.; Kroep, Judith R.

doi:10.1093/annonc/mdu102

Cited by 36 publications

(35 citation statements)

References 32 publications

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“…From December 2010 until May 2012, 81 patients were recruited from the NEOZOTAC trial (14). Only patients with both EpCAM and MCAM enumerations available were used in the analyses, leaving 68 evaluable patients at baseline-thus meeting our power calculations-and 39 patients after one NAC cycle (Fig.…”

Section: Resultsmentioning

confidence: 99%

Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

Onstenk

Kraan

Mostert

et al. 2015

Molecular Cancer Therapeutics

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Circulating tumor cells (CTC) are detected by the CellSearch System in 20% to 25% of patients with primary breast cancer (pBC). To improve CTC detection, we investigated melanoma cell adhesion molecule (MCAM) as enrichment marker next to epithelial cell adhesion molecule (EpCAM) and tested the clinical relevance of MCAM-positive CTCs in patients with HER2-negative stage II/III pBC starting neoadjuvant chemotherapy (NAC) in the NEOZOTAC trial. Using the CellSearch System, EpCAM-positive and MCAM-positive CTCs were separately enriched from 7.5 mL blood, at baseline and after the first NAC cycle. Circulating endothelial cells (CEC) were measured using flow cytometry. Primary objective was to improve the CTC detection rate to !40% combining EpCAM/MCAM. Correlations of CTC and CEC counts and pathologic complete response (pCR) were also explored. At baseline, we detected EpCAM-positive and MCAM-positive CTCs in 12 of 68 (18%) and 8 of 68 (12%) patients, respectively. After one cycle, this was 7 of 44 (16%) and 7 of 44 (16%) patients, respectively. The detection rate improved from 18% at baseline and 16% after one cycle with EpCAM to 25% (P ¼ 0.08) and 30% (P ¼ 0.02), respectively, with EpCAM/ MCAM. No patients with MCAM-positive CTCs versus 23% of patients without MCAM-positive CTCs at baseline achieved pCR (P ¼ 0.13). EpCAM-positive CTCs and CEC counts were not correlated to pCR. Combined EpCAM/MCAM CellSearch enrichment thus increased the CTC detection rate in stage II/III pBC. We found no associations of CTC and CEC counts with pCR to NAC. The clinical relevance of MCAM-positive CTCs deserves further study.

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Section: Resultsmentioning

confidence: 99%

Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

Onstenk

Kraan

Mostert

et al. 2015

Molecular Cancer Therapeutics

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“…The main results of the two studies on impact of type of chemotherapy and role of zoledronic acid as an adjunct to neoadjuvant chemotherapy on pathologic complete remission rate in the breast and/or breast and lymph nodes have been reported before [1, 7]. In the two studies, the timing of axillary staging was largely depended on the baseline clinical nodal status, although in patients with clinical node-negative disease the sentinel node procedure was increasingly used post-neoadjuvant chemotherapy in later years.…”

Section: Discussionmentioning

confidence: 99%

“…Patients were enrolled in two sequentially conducted phase III trials on neoadjuvant chemotherapy under auspices of the Dutch Breast Cancer Research Group (BOOG), the INTENS and the NEOZOTAC study [1, 7]. In the INTENS study, patients were randomized between TAC and AC-T neoadjuvant chemotherapy (doxorubicin (A), cyclophosphamide (C) and docetaxel (T)) [1].…”

Section: Methodsmentioning

confidence: 99%

“…Especially patients with nodal low-volume disease may achieve a pathologic complete remission in the lymph nodes. Therefore, we re-analyzed the data from two Dutch randomized phase III breast cancer studies on neoadjuvant chemotherapy with regard to final pathologic nodal status related to baseline clinical lymph node status and related to timing of axillary staging [1, 7]. …”

Section: Introductionmentioning

confidence: 99%

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Axillary staging in breast cancer patients treated with neoadjuvant chemotherapy in two Dutch phase III studies

et al. 2017

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BackgroundPrimary aim of our study was to assess the impact of timing of sentinel node procedure, pre- versus post-neoadjuvant chemotherapy, on final pathologic node-negative rate (pN0) in patients with clinically node-negative (cN0) breast cancer. Secondary endpoint was the usability of the sentinel node procedure in patients with clinically node-positive disease that converted to cN0 after neoadjuvant chemotherapy.Patients and MethodsPatients were enrolled in two sequentially conducted Dutch phase III trials, studying the impact of two neoadjuvant chemotherapy schedules and use of zoledronic acid on complete pathologic response rate. For the present analyses, patients were excluded if they had not undergone surgical axillary staging.ResultsIn total 439 patients were included, of whom 230 (52%) had pre-treatment cN0. In this group, pN0 status was seen in 58% (N = 23) of patients with a sentinel node biopsy post-neoadjuvant chemotherapy compared to 51% (N = 83) pre-neoadjuvant chemotherapy, including the axillary lymph node dissection whenever performed. In multivariable analysis, timing of sentinel node procedure (pre- versus post- neoadjuvant chemotherapy) was, however, not significantly associated with final pN0/pN0(i+) status, with an odds ratio of 1.18 (95% CI 0.64 - 2.18) after correction for age, clinical tumor status, histology, grade, hormone- and HER2 receptor. Of patients with clinically node-positive disease only 15% had a final pN0 status, with a false-negative rate of the sentinel node of 30%.ConclusionIn breast cancer patients with cN0 disease, sentinel node procedure performed post-neoadjuvant chemotherapy led to nodal down staging, although not statistically significant after multivariate correction for patient and tumor characteristics.

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“…A subgroup analysis in patients being postmenopausal for more than 5 years showed an increase in disease free survival from 71% to 78.2% (adjusted HR 0.75; 95% CI 0.59 to 0.96; P = 0.02) 5 years after randomization. In the NEO-ZOTAC study, among 250 human epidermal growth factor receptor (HER)2 negative breast cancer patients, no difference in pathologic response rate was seen with or without zoledronic acid, administered in the neo-adjuvant setting (Charehbili et al, 2014). A meta-analysis among 17,751 from 41 randomized clinical trials compared outcome of breast cancer patients with and without adjuvant bisphosphonate treatment and found reduction of breast cancer mortality and bone recurrence in postmenopausal patients (Coleman et al, 2013).…”

Section: Tgfβ -Clinical Datamentioning

confidence: 99%

Targeting breast cancer through its microenvironment: Current status of preclinical and clinical research in finding relevant targets

Nienhuis

Gaykema

Timmer‐Bosscha

et al. 2015

Pharmacology & Therapeutics

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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)

Abstract: Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment.

Cited by 36 publications

References 32 publications

Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

Axillary staging in breast cancer patients treated with neoadjuvant chemotherapy in two Dutch phase III studies

Targeting breast cancer through its microenvironment: Current status of preclinical and clinical research in finding relevant targets

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