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

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number97
JournalBreast Cancer Research
Volume21
Issue number1
DOIs
Publication statusPublished - 28 Aug 2019
Externally publishedYes

Cite this

de Groot, Stefanie ; Pijl, Hanno ; Charehbili, Ayoub ; van de Ven, Saskia ; Smit, Vincent T. H. B. M. ; Meershoek-Klein Kranenbarg, Elma ; Heijns, Joan B. ; van Warmerdam, Laurence J. C. ; Kessels, Lonneke W. ; Dercksen, M. Wouter ; Pepels, Manon J. A. E. ; van Laarhoven, Hanneke W. M. ; Vriens, Birgit E. P. J. ; Putter, Hein ; Fiocco, Marta ; Liefers, Gerrit-Jan ; van der Hoeven, Jacobus J. M. ; Nortier, Johan W. R. ; Kroep, Judith R. / 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). In: Breast Cancer Research. 2019 ; Vol. 21, No. 1.
@article{dd9e12f9029a46d9bfe12afb32d5e303,
title = "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)",
abstract = "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.",
author = "{de Groot}, Stefanie and Hanno Pijl and Ayoub Charehbili and {van de Ven}, Saskia and Smit, {Vincent T. H. B. M.} and {Meershoek-Klein Kranenbarg}, Elma and Heijns, {Joan B.} and {van Warmerdam}, {Laurence J. C.} and Kessels, {Lonneke W.} and Dercksen, {M. Wouter} and Pepels, {Manon J. A. E.} and {van Laarhoven}, {Hanneke W. M.} and Vriens, {Birgit E. P. J.} and Hein Putter and Marta Fiocco and Gerrit-Jan Liefers and {van der Hoeven}, {Jacobus J. M.} and Nortier, {Johan W. R.} and Kroep, {Judith R.}",
year = "2019",
month = "8",
day = "28",
doi = "10.1186/s13058-019-1180-6",
language = "English",
volume = "21",
journal = "Breast Cancer Research",
issn = "1465-542X",
publisher = "BioMed Central",
number = "1",

}

de Groot, S, Pijl, H, Charehbili, A, van de Ven, S, Smit, VTHBM, Meershoek-Klein Kranenbarg, E, Heijns, JB, van Warmerdam, LJC, Kessels, LW, Dercksen, MW, Pepels, MJAE, van Laarhoven, HWM, Vriens, BEPJ, Putter, H, Fiocco, M, Liefers, G-J, van der Hoeven, JJM, Nortier, JWR & Kroep, JR 2019, '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)' Breast Cancer Research, vol. 21, no. 1, 97. https://doi.org/10.1186/s13058-019-1180-6

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

In: Breast Cancer Research, Vol. 21, No. 1, 97, 28.08.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - 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)

AU - de Groot, Stefanie

AU - Pijl, Hanno

AU - Charehbili, Ayoub

AU - van de Ven, Saskia

AU - Smit, Vincent T. H. B. M.

AU - Meershoek-Klein Kranenbarg, Elma

AU - Heijns, Joan B.

AU - van Warmerdam, Laurence J. C.

AU - Kessels, Lonneke W.

AU - Dercksen, M. Wouter

AU - Pepels, Manon J. A. E.

AU - van Laarhoven, Hanneke W. M.

AU - Vriens, Birgit E. P. J.

AU - Putter, Hein

AU - Fiocco, Marta

AU - Liefers, Gerrit-Jan

AU - van der Hoeven, Jacobus J. M.

AU - Nortier, Johan W. R.

AU - Kroep, Judith R.

PY - 2019/8/28

Y1 - 2019/8/28

N2 - 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.

AB - 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31455425

U2 - 10.1186/s13058-019-1180-6

DO - 10.1186/s13058-019-1180-6

M3 - Article

VL - 21

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-542X

IS - 1

M1 - 97

ER -