Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor

Maurizio Scaltriti, Sarat Chandarlapaty, Ludmila Prudkin, Claudia Aura, José Jimenez, Pier Davide Angelini, Gertrudis Sánchez, Marta Guzman, Josep Lluis Parra, Catherine Ellis, Robert Gagnon, Maria Koehler, Henry Gomez, Charles Geyer, David Cameron, Joaquin Arribas, Neal Rosen, José Baselga

Research output: Contribution to journalArticle

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Abstract

Purpose: A subgroup of human epidermal growth factor receptor 2 (HER2)-overexpressing breast tumors coexpresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting. Experimental Design: Two different p95HER2 animal models were used for preclinical studies. Expression of p95HER2 was analyzed in HER2-overexpressing breast primary tumors from a firstline lapatinib monotherapy study (EGF20009) and a second-line lapatinib in combination with capecitabine study (EGF100151). p95HER2 expression was correlated with overall response rate (complete + partial response), clinical benefit rate (complete response + partial response + stable disease ≥24 wk), and progression-free survival using logistic regression and Cox proportional hazard models. Results: Lapatinib inhibited tumor growth and the HER2 downstream signaling of p95HER2-expressing tumors. A total of 68 and 156 tumors from studies EGF20009 and EGF100151 were evaluable, respectively, for p95HER2 detection. The percentage of p95HER2-positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In both studies, there was no statistically significant difference in progression-free survival, clinical benefit rate, and overall response rate between p95HER2-positive and p95HER2-negative tumors. Conclusions: Lapatinib as a monotherapy or in combination with capecitabine seems to be equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors.

Original languageEnglish (US)
Pages (from-to)2688-2695
Number of pages8
JournalClinical Cancer Research
Volume16
Issue number9
DOIs
StatePublished - May 1 2010

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Breast Neoplasms
Neoplasms
Therapeutics
Disease-Free Survival
human ERBB2 protein
lapatinib
Proportional Hazards Models
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Research Design
Animal Models
Logistic Models
Growth
Capecitabine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. / Scaltriti, Maurizio; Chandarlapaty, Sarat; Prudkin, Ludmila; Aura, Claudia; Jimenez, José; Angelini, Pier Davide; Sánchez, Gertrudis; Guzman, Marta; Parra, Josep Lluis; Ellis, Catherine; Gagnon, Robert; Koehler, Maria; Gomez, Henry; Geyer, Charles; Cameron, David; Arribas, Joaquin; Rosen, Neal; Baselga, José.

In: Clinical Cancer Research, Vol. 16, No. 9, 01.05.2010, p. 2688-2695.

Research output: Contribution to journalArticle

Scaltriti, M, Chandarlapaty, S, Prudkin, L, Aura, C, Jimenez, J, Angelini, PD, Sánchez, G, Guzman, M, Parra, JL, Ellis, C, Gagnon, R, Koehler, M, Gomez, H, Geyer, C, Cameron, D, Arribas, J, Rosen, N & Baselga, J 2010, 'Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor', Clinical Cancer Research, vol. 16, no. 9, pp. 2688-2695. https://doi.org/10.1158/1078-0432.CCR-09-3407
Scaltriti, Maurizio ; Chandarlapaty, Sarat ; Prudkin, Ludmila ; Aura, Claudia ; Jimenez, José ; Angelini, Pier Davide ; Sánchez, Gertrudis ; Guzman, Marta ; Parra, Josep Lluis ; Ellis, Catherine ; Gagnon, Robert ; Koehler, Maria ; Gomez, Henry ; Geyer, Charles ; Cameron, David ; Arribas, Joaquin ; Rosen, Neal ; Baselga, José. / Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 9. pp. 2688-2695.
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abstract = "Purpose: A subgroup of human epidermal growth factor receptor 2 (HER2)-overexpressing breast tumors coexpresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting. Experimental Design: Two different p95HER2 animal models were used for preclinical studies. Expression of p95HER2 was analyzed in HER2-overexpressing breast primary tumors from a firstline lapatinib monotherapy study (EGF20009) and a second-line lapatinib in combination with capecitabine study (EGF100151). p95HER2 expression was correlated with overall response rate (complete + partial response), clinical benefit rate (complete response + partial response + stable disease ≥24 wk), and progression-free survival using logistic regression and Cox proportional hazard models. Results: Lapatinib inhibited tumor growth and the HER2 downstream signaling of p95HER2-expressing tumors. A total of 68 and 156 tumors from studies EGF20009 and EGF100151 were evaluable, respectively, for p95HER2 detection. The percentage of p95HER2-positive patients was 20.5{\%} in the EGF20009 study and 28.5{\%} in the EGF100151 study. In both studies, there was no statistically significant difference in progression-free survival, clinical benefit rate, and overall response rate between p95HER2-positive and p95HER2-negative tumors. Conclusions: Lapatinib as a monotherapy or in combination with capecitabine seems to be equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors.",
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AU - Scaltriti, Maurizio

AU - Chandarlapaty, Sarat

AU - Prudkin, Ludmila

AU - Aura, Claudia

AU - Jimenez, José

AU - Angelini, Pier Davide

AU - Sánchez, Gertrudis

AU - Guzman, Marta

AU - Parra, Josep Lluis

AU - Ellis, Catherine

AU - Gagnon, Robert

AU - Koehler, Maria

AU - Gomez, Henry

AU - Geyer, Charles

AU - Cameron, David

AU - Arribas, Joaquin

AU - Rosen, Neal

AU - Baselga, José

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