Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab

M. Bates, J. Sperinde, W. J. Köstler, S. M. Ali, K. Leitzel, E. M. Fuchs, A. Paquet, Y. Lie, T. Sherwood, R. Horvat, C. F. Singer, J. Winslow, J. M. Weidler, W. Huang, A. Lipton

Research output: Contribution to journalArticle

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Abstract

Background: Patients with metastatic breast cancer (MBC) overexpressing HER2 (human epidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond. Patients and methods: Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab-based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T ≥ 68.5), and H2T intermediate (13.8 ≤ H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results. Results: TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2T low tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results. Conclusions: MBC patients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts.

Original languageEnglish (US)
Pages (from-to)2014-2020
Number of pages7
JournalAnnals of Oncology
Volume22
Issue number9
DOIs
StatePublished - Sep 1 2011

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Breast Neoplasms
Kaplan-Meier Estimate
Neoplasms
Survival Analysis
human ERBB2 protein
Trastuzumab
Paraffin
Formaldehyde
Therapeutics
Multivariate Analysis
Survival
Population
Proteins

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Cite this

Bates, M. ; Sperinde, J. ; Köstler, W. J. ; Ali, S. M. ; Leitzel, K. ; Fuchs, E. M. ; Paquet, A. ; Lie, Y. ; Sherwood, T. ; Horvat, R. ; Singer, C. F. ; Winslow, J. ; Weidler, J. M. ; Huang, W. ; Lipton, A. / Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab. In: Annals of Oncology. 2011 ; Vol. 22, No. 9. pp. 2014-2020.
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title = "Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab",
abstract = "Background: Patients with metastatic breast cancer (MBC) overexpressing HER2 (human epidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond. Patients and methods: Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab-based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T ≥ 68.5), and H2T intermediate (13.8 ≤ H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results. Results: TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2T low tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results. Conclusions: MBC patients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts.",
author = "M. Bates and J. Sperinde and K{\"o}stler, {W. J.} and Ali, {S. M.} and K. Leitzel and Fuchs, {E. M.} and A. Paquet and Y. Lie and T. Sherwood and R. Horvat and Singer, {C. F.} and J. Winslow and Weidler, {J. M.} and W. Huang and A. Lipton",
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Bates, M, Sperinde, J, Köstler, WJ, Ali, SM, Leitzel, K, Fuchs, EM, Paquet, A, Lie, Y, Sherwood, T, Horvat, R, Singer, CF, Winslow, J, Weidler, JM, Huang, W & Lipton, A 2011, 'Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab', Annals of Oncology, vol. 22, no. 9, pp. 2014-2020. https://doi.org/10.1093/annonc/mdq706

Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab. / Bates, M.; Sperinde, J.; Köstler, W. J.; Ali, S. M.; Leitzel, K.; Fuchs, E. M.; Paquet, A.; Lie, Y.; Sherwood, T.; Horvat, R.; Singer, C. F.; Winslow, J.; Weidler, J. M.; Huang, W.; Lipton, A.

In: Annals of Oncology, Vol. 22, No. 9, 01.09.2011, p. 2014-2020.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab

AU - Bates, M.

AU - Sperinde, J.

AU - Köstler, W. J.

AU - Ali, S. M.

AU - Leitzel, K.

AU - Fuchs, E. M.

AU - Paquet, A.

AU - Lie, Y.

AU - Sherwood, T.

AU - Horvat, R.

AU - Singer, C. F.

AU - Winslow, J.

AU - Weidler, J. M.

AU - Huang, W.

AU - Lipton, A.

PY - 2011/9/1

Y1 - 2011/9/1

N2 - Background: Patients with metastatic breast cancer (MBC) overexpressing HER2 (human epidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond. Patients and methods: Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab-based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T ≥ 68.5), and H2T intermediate (13.8 ≤ H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results. Results: TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2T low tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results. Conclusions: MBC patients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts.

AB - Background: Patients with metastatic breast cancer (MBC) overexpressing HER2 (human epidermal growth factor receptor 2) are currently selected for treatment with trastuzumab, but not all patients respond. Patients and methods: Using a novel assay, HER2 protein expression (H2T) was measured in formalin-fixed, paraffin-embedded primary breast tumors from 98 women treated with trastuzumab-based therapy for MBC. Using subpopulation treatment effect pattern plots, the population was divided into H2T low (H2T < 13.8), H2T high (H2T ≥ 68.5), and H2T intermediate (13.8 ≤ H2T < 68.5) subgroups. Kaplan-Meier (KM) analyses were carried out comparing the groups for time to progression (TTP) and overall survival (OS). Cox multivariate analyses were carried out to identify correlates of clinical outcome. Bootstrapping analyses were carried out to test the robustness of the results. Results: TTP improved with increasing H2T until, at the highest levels of H2T, an abrupt decrease in the TTP was observed. KM analyses demonstrated that patients with H2T low tumors [median TTP 4.2 months, hazard ratio (HR) = 3.7, P < 0.0001] or H2T high tumors (median TTP 4.6 months, HR = 2.7, P = 0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate (median TTP 12 months). OS analyses yielded similar results. Conclusions: MBC patients with very high levels of H2T may represent a subgroup with de novo resistance to trastuzumab. These results are preliminary and require confirmation in larger controlled clinical cohorts.

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U2 - 10.1093/annonc/mdq706

DO - 10.1093/annonc/mdq706

M3 - Article

C2 - 21289364

AN - SCOPUS:80051550763

VL - 22

SP - 2014

EP - 2020

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 9

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