Abstract 2619: Genetic landscape of KRAS-NRAS-BRAF-PIK3CA wild type metastatic colorectal cancer patients enrolled in the CAPRI clinical trial
Authors: Rachiglio Anna Maria , Lambiase Matilde , Fenizia Francesca , Iannaccone Alessia , Roma Cristin , Cardone Claudia , Luca Antonella De , Martinelli Erika , Maiello Evaristo , Ciardiello Fortunato , Normanno Nicola 
Published: August 2018

Introduction: The Cetuximab After Progression in KRAS wild type colorectal cancer patients (CAPRI) study enrolled KRAS exon 2 wild-type (wt) metastatic colorectal cancer (mCRC) patients who received first-line FOLFIRI-cetuximab. Retrospective analysis showed that mCRC patients with KRAS/NRAS/BRAF/PIK3CA wt (quadruple-wt) tumors had an excellent prognosis when treated with anti-EGFR agents. In order to identify additional mechanisms that might allow to better select patients who benefit of anti-EGFR monoclonal antibodies, we analyzed quadruple-wt tumors from the CAPRI clinical trial with a large targeted sequencing panel and correlated results with patients' outcome.

Materials and methods: NGS analysis was performed using the Oncomine Comprehensive v.2 panel from Thermofisher on Ion Torrent PGM. The panel covers 143 cancer genes providing information on hotspot mutations of 73 oncogenes, copy number variation (CNV) of 49 genes, full-length sequence of 26 tumor suppressor genes, and sequence of 22 fusion driver genes. Data analysis was carried out using Ion Reporter™ Software v5.0.

Results: Complete data of the first cohort of 17 patients are summarized. These patients had a median progression-free survival (mPFS) of 12,3 months (m) and median overall survival (mOS) of 34,03 mos. The analysis revealed in all 17 tumors the presence of at least one mutation, and in 9/17 showed the presence of at least one CNV. Variants were detected in the following genes: TP53 (17 mutations), APC (16), FBXW7 (2), MAP2K1 (1), PTPN11 (1), PTCH1 (1), ATM (1), CTNNB1 (1), PIK3R1 (1), PTEN (1), CDKN2A (1), KRAS (1). CNVs were found in APC (2 deletions), TP53 (1 deletion), PIK3R1 (1 deletion), BCL2L1 (4 amplifications), GAS6 (3 amplifications), MYC (2 amplifications), ZNF217 (2 amplifications), FLT3 (1 amplification), ERBB2 (1 amplification), APEX 1 (1 amplification). The 3 patients with the shortest PFS and OS had peculiar genetic alterations that might be associated with resistance to EGFR targeting drugs. Case #980 (PFS 3,93 m; OS 9,2 m) carried a KRAS p.Gln61His variant at a low allelic frequency (0,38%) that was confirmed by plasma testing with BEAMing. Case #4120 (PFS 5,77 m; OS 25,33 m) had a loss of function PTCH1 variant (p.Tyr1316fs) leading to activation of the sonic hedgehog (SHH) pathway. Case #1491 (PFS 6,63 m; OS 19,03 m) carried a p.Lys57Glu mutations in the MAP2K1 gene that causes constitutive activation of the corresponding protein.

Conclusions: These preliminary data show that quadruple-wt CRC carry genetic alterations that potentially can drive resistance to anti-EGFR monoclonal antibodies. While the significance of the identified variants needs to be explored in experimental models, these findings do suggest that wide genetic profiling of CRC might improve our ability to select patients who are highly sensitive to EGFR inhibition.

Citation Format: Anna Maria Rachiglio, Matilde Lambiase, Francesca Fenizia, Alessia Iannaccone, Cristin Roma, Claudia Cardone, Antonella De Luca, Erika Martinelli, Evaristo Maiello, Fortunato Ciardiello, Nicola Normanno. Genetic landscape of KRAS-NRAS-BRAF-PIK3CA wild type metastatic colorectal cancer patients enrolled in the CAPRI clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2619.