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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
Open accessAbstract
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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“Patients with ‘hot spot’ PIK3CA mutations and undetectable or low PTEN measured by IHC, exhibited a poorer outcome after treatment with chemotherapy and trastuzumab compared to patients without those alterations (Berns et al., 2007; Dave et al., 2011; Esteva et al., 2010).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Dave et al., 2011
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Metadata
- Authors
- Dave, B., Migliaccio, I., Gutierrez, M. C., Wu, M.-F., Chamness, G. C., Wong, H., Narasanna, A., Chakrabarty, A., Hilsenbeck, S. G., Huang, J., Rimawi, M., Schiff, R., Arteaga, C., Osborne, C. K., & Chang, J. C.
- Affiliations
- Houston Methodist (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2011-01-10
- Volume
- 29
- Issue
- 2
- Pages
- 166-173
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC3058274
- OpenAlex
- W2109189228
- Cited by
- 252
- References
- 28
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 7 · 2023: 15 · 2022: 10 · 2021: 7 · 2020: 12 · 2019: 14 · 2018: 10 · 2017: 17 · 2016: 15 · 2015: 32 · 2014: 21 · 2013: 34 · 2012: 21
- FWCI
- 12.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Breast Cancer Research Foundation
- GlaxoSmithKline
- National Cancer Institute (P50 CA 50183, R01CA112305)
- Medical Research and Materiel Command
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- PTEN loss, PIK3CA mutation, trastuzumab resistance, lapatinib, HER2-positive breast cancer, locally advanced breast cancer, PI3 kinase pathway, MAPK signaling, Akt phosphorylation, pathological complete response, neoadjuvant therapy
- MeSH terms
- Trastuzumab, Docetaxel, Lapatinib, Adult, Aged, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Enzyme Activation, Female, Humans, Middle Aged, Mutation, Quinazolines, Transfection, Clinical Trials, Phase II as Topic, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Phosphatidylinositol 3-Kinases, Neoadjuvant Therapy, RNA, Small Interfering, Taxoids, Cell Line, Tumor, PTEN Phosphohydrolase, Class I Phosphatidylinositol 3-Kinases, Antibodies, Monoclonal, Humanized
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