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Annals of Oncology Advance Access published online on July 31, 2008
Annals of Oncology, doi:10.1093/annonc/mdn541
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

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

F. Perrone1,{dagger}, A. Lampis1,{dagger}, M. Orsenigo1, M. Di Bartolomeo2, A. Gevorgyan2, M. Losa1, M. Frattini3, C. Riva1, S. Andreola1, E. Bajetta2, L. Bertario4, E. Leo5, M. A. Pierotti6 and S. Pilotti1,*

1 Experimental Molecular Pathology, Department of Pathology
2 Medical Oncology Unit 2, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
3 Laboratory of Molecular Diagnostics, Institute of Pathology, Locarno, Switzerland
4 Preventive-Predictive Medicine Unit
5 Colorectal Surgery Unit
6 Scientific Management, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

* Correspondence to: Dr S. Pilotti MD, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Tel: +39-02-2390-2293; Fax: +39-02-2390-2198; E-mail: silvana.pilotti{at}istitutotumori.mi.it

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.

cetuximab, KRAS, metastatic colorectal cancer, PI3KCA, PTEN

{dagger} Both authors contributed equally to this work.

Received for publication March 7, 2008. Revision received July 3, 2008. Accepted for publication July 4, 2008.


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