PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients

F. Perrone, A. Lampis, M. Orsenigo, M. Di Bartolomeo, A. Gevorgyan, M. Losa, M. Frattini, C. Riva, S. Andreola, E. Bajetta, L. Bertario, E. Leo, M. A. Pierotti, Silvana Pilotti

Research output: Contribution to journalArticle

Abstract

Background: It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear. Patients and methods: We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing. Results: Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not [nonresponder (NR)]. EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs. Conclusion: These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin.

Original languageEnglish
Pages (from-to)84-90
Number of pages7
JournalAnnals of Oncology
Volume20
Issue number1
DOIs
Publication statusPublished - 2009

Keywords

  • Cetuximab
  • KRAS
  • Metastatic colorectal cancer
  • PI3KCA
  • PTEN

ASJC Scopus subject areas

  • Oncology
  • Hematology

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  • Cite this

    Perrone, F., Lampis, A., Orsenigo, M., Di Bartolomeo, M., Gevorgyan, A., Losa, M., Frattini, M., Riva, C., Andreola, S., Bajetta, E., Bertario, L., Leo, E., Pierotti, M. A., & Pilotti, S. (2009). PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Annals of Oncology, 20(1), 84-90. https://doi.org/10.1093/annonc/mdn541