Gain of ALK Gene Copy Number May Predict Lack of Benefit from Anti-EGFR Treatment in Patients with Advanced Colorectal Cancer and RAS-RAF-PI3KCA Wild-Type Status

Filippo Pietrantonio,Adele Testi,Roberto Iacovelli,Giuseppe Pelosi,Federica Perrone,Filippo De Braud,Claudia Maggi,Maria Grazia Facciorusso,Ilaria Bossi,Massimo Milione,Rosalba Miceli,Giorgia Leone,Maria Di Bartolomeo,John Souglakos

doi:10.1371/journal.pone.0092147

Filippo Pietrantonio, Adele Testi + Show 12 more

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https://doi.org/10.1371/journal.pone.0092147

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Journal: PloS one	Publication Date: Apr 1, 2014
Citations: 46	License type: CC BY 4.0

Affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori

Abstract

IntroductionAlthough cetuximab and panitumumab show an increased efficacy for patients with KRAS-NRAS-BRAF and PI3KCA wild-type metastatic colorectal cancer, primary resistance occurs in a relevant subset of molecularly enriched populations.Patients and MethodsWe evaluated the outcome of 68 patients with advanced colorectal cancer and RAS, BRAF and PI3KCA status according to ALK gene status (disomic vs. gain of ALK gene copy number – defined as mean of 3 to 5 fusion signals in ≥10% of cells). All consecutive patients received cetuximab and irinotecan or panitumumab alone for chemorefractory disease.ResultsNo ALK translocations or amplifications were detected. ALK gene copy number gain was found in 25 (37%) tumors. Response rate was significantly higher in patients with disomic ALK as compared to those with gain of gene copy number (70% vs. 32%; p = 0.0048). Similarly, progression-free survival was significantly different when comparing the two groups (6.7 vs. 5.3 months; p = 0.045). A trend was observed also for overall survival (18.5 vs. 15.6 months; p = 0.885).ConclusionGain of ALK gene copy number might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy.

Highlights

Cetuximab and panitumumab show an increased efficacy for patients with KRAS-NRAS-BRAF and PI3KCA wild-type metastatic colorectal cancer, primary resistance occurs in a relevant subset of molecularly enriched populations
In cases where clusters were observed, we reported the percentage of cells with clusters and considered amplified cases with $10% of Anaplastic lymphoma kinase (ALK) clusters [18] (Figure 1)
RAF-PI3KCA colorectal cancer (CRC) were included in this prospective dataset at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan

Summary

Introduction

Cetuximab and panitumumab show an increased efficacy for patients with KRAS-NRAS-BRAF and PI3KCA wild-type metastatic colorectal cancer, primary resistance occurs in a relevant subset of molecularly enriched populations. Treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies - cetuximab and panitumumab - improved the outcome of patients with advanced KRAS wild-type colorectal cancer (CRC) in combination with first- or second-line fluoropyrimidine-based chemotherapy or in the setting of chemorefractory disease [1,2,3,4,5,6]. The identification of additional resistance biomarkers is an unmet clinical need for anti-EGFR treatment personalization in this setting. Oncogenic ALK may activate independently downstream pathways including the PI3KCA/Akt and RAS-RAF-MAPK, even in presence of EGFR blockage [12]

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Conclusion