Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: A single center s
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RESEARCH
Open Access
Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: A single center study 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*
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. Keywords: Metastatic colorectal cancer, Cetuximab, KRAS, BRAF, PIK3CA, PTEN
Background Colorectal cancer (CRC) is the third most common form of cancer and the second leading cause of cancer-related death. Although early diagnosis may allow radical surgery to be performed and result in a complete cure, about 25% of patients present with metastatic disease at diagnosis and about 40-50% of resected patients will develop distant metastases and die [1]. There is evidence that the use of polychemotherapy with fluoropyrimidines, oxaliplatin * Correspondence: [email protected] 2 Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Via Maroncelli 40, 47014 Meldola (FC), Italy Full list of author information is available at the end of the article
and irinotecan can significantly improve overall survival (OS) in patients with metastatic CRC (mCRC) with respect to those who do not receive all three drugs. The use of bevacizumab in association with chemotherapy has also been shown to prolong OS [2]. Current treatment options for
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