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

Abstract

Background
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.

Methods
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.

Results
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.

Conclusions
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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