Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2 - Overexpressing locally advanced breast cancers

Bhuvanesh Dave, Ilenia Migliaccio, M. Carolina Gutierrez, Meng Fen Wu, Gary C. Chamness, Helen Wong, Archana Narasanna, Anindita Chakrabarty, Susan G. Hilsenbeck, Jian Huang, Mothaffar Rimawi, Rachel Schiff, Carlos Arteaga, C. Kent Osborne, Jenny C. Chang

Research output: Contribution to journalArticle

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Abstract

Purpose: Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods: We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results: Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion: Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

Original languageEnglish (US)
Pages (from-to)166-173
Number of pages8
JournalJournal of Clinical Oncology
Volume29
Issue number2
DOIs
StatePublished - Jan 10 2011

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Phosphoric Monoester Hydrolases
Phosphotransferases
Breast Neoplasms
docetaxel
Clinical Trials
Mutation
human ERBB2 protein
Trastuzumab
Tensins
lapatinib
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Therapeutics
Immunohistochemistry
Monoclonal Antibodies
Apoptosis
Cell Line
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2 - Overexpressing locally advanced breast cancers. / Dave, Bhuvanesh; Migliaccio, Ilenia; Gutierrez, M. Carolina; Wu, Meng Fen; Chamness, Gary C.; Wong, Helen; Narasanna, Archana; Chakrabarty, Anindita; Hilsenbeck, Susan G.; Huang, Jian; Rimawi, Mothaffar; Schiff, Rachel; Arteaga, Carlos; Osborne, C. Kent; Chang, Jenny C.

In: Journal of Clinical Oncology, Vol. 29, No. 2, 10.01.2011, p. 166-173.

Research output: Contribution to journalArticle

Dave, B, Migliaccio, I, Gutierrez, MC, Wu, MF, Chamness, GC, Wong, H, Narasanna, A, Chakrabarty, A, Hilsenbeck, SG, Huang, J, Rimawi, M, Schiff, R, Arteaga, C, Osborne, CK & Chang, JC 2011, 'Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2 - Overexpressing locally advanced breast cancers', Journal of Clinical Oncology, vol. 29, no. 2, pp. 166-173. https://doi.org/10.1200/JCO.2009.27.7814
Dave, Bhuvanesh ; Migliaccio, Ilenia ; Gutierrez, M. Carolina ; Wu, Meng Fen ; Chamness, Gary C. ; Wong, Helen ; Narasanna, Archana ; Chakrabarty, Anindita ; Hilsenbeck, Susan G. ; Huang, Jian ; Rimawi, Mothaffar ; Schiff, Rachel ; Arteaga, Carlos ; Osborne, C. Kent ; Chang, Jenny C. / Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2 - Overexpressing locally advanced breast cancers. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 2. pp. 166-173.
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abstract = "Purpose: Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods: We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results: Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion: Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.",
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AU - Dave, Bhuvanesh

AU - Migliaccio, Ilenia

AU - Gutierrez, M. Carolina

AU - Wu, Meng Fen

AU - Chamness, Gary C.

AU - Wong, Helen

AU - Narasanna, Archana

AU - Chakrabarty, Anindita

AU - Hilsenbeck, Susan G.

AU - Huang, Jian

AU - Rimawi, Mothaffar

AU - Schiff, Rachel

AU - Arteaga, Carlos

AU - Osborne, C. Kent

AU - Chang, Jenny C.

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Y1 - 2011/1/10

N2 - Purpose: Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods: We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results: Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion: Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

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