Paola Ulivi et al., Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: A single center study. Journal of Translational Medicine

Paola Ulivi1, Laura Capelli1, Martina Valgiusti2, Wainer Zoli1, Emanuela Scarpi3, Elisa Chiadini1, Paola Rosetti2, Sara Bravaccini1, Daniele Calistri1, Luca Saragoni4, Andrea Casadei Gardini2, Angela Ragazzini1, Giovanni Luca Frassineti2, Dino Amadori2 and Alessandro Passardi2

1Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.)
2Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.)
3Unit of Biostatistics and Clinical Trials, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.)
4Pathology Unit, Morgagni-Pierantoni Hospital


KRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC) patients. As only 20% of KRAS wild type (WT) patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. We retrospectively analyzed objective tumor response rate, (ORR) progression-free (PFS) and overall survival (OS) with respect to the mutational status of KRAS, BRAF, PIK3CA and PTEN expression in mCRC patients treated with a cetuximab-based regimen.

67 mCRC patients were enrolled onto the study. DNA was extracted from paraffin-embedded sections derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were analyzed by direct sequencing, PIK3CA was evaluated by pyrosequencing and PTEN expression by immunohistochemistry.

BRAF and PIK3CA mutations were independently associated with worse PFS (p?=?0.006 and p?=?0.028, respectively) and OS (p?=?0.008 and p?=?0.029, respectively). No differences in clinical outcome were found between patients who were positive or negative for PTEN expression. Conversely, patients negative for KRAS, BRAF and PIK3CA mutations were characterized by significantly better ORR, PFS and OS than patients with at least one of these mutations.

BRAF and PIK3CA mutations would seem to be independent predictors of anti-EGFR therapy effectiveness and could be taken into consideration during treatment decision making.

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