Next generation sequencing identifies ‘interactome’ signatures in relapsed and refractory metastatic colorectal cancer
AffiliationUniv Arizona, Ctr Canc
KeywordsMetastatic colorectal cancer (mCRC)
next generation sequencing (NGS)
MetadataShow full item record
PublisherPIONEER BIOSCIENCE PUBL CO
CitationNext generation sequencing identifies ‘interactome’ signatures in relapsed and refractory metastatic colorectal cancer 2017, 8 (1):20-31 Journal of Gastrointestinal Oncology
Rights© Journal of Gastrointestinal Oncology. All rights reserved.
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AbstractBackground: In the management of metastatic colorectal cancer (mCRC), KRAS, NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making. Methods: Relapsed and refractory mCRC pts (N=32) were molecularly profiled utilizing commercially available next generation sequencing (NGS) platforms. Web-based bioinformatics tools (Reactome/Enrichr) were utilized to elucidate mutational profile linked pathways-networks that have the potential to guide therapy. Results: Pts had progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab and/or panitumumab. Most common histology was adenocarcinoma (colon N=29; rectal N=3). Of the mutations TP53 was the most common, followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average had >= 5 unique mutations. The most frequent activated signaling pathways were: HER2, fibroblast growth factor receptor (FGFR), p38 through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2. Conclusions: Dominant driver oncogene mutations do not always equate to oncogenic dependence, hence understanding pathogenic ` interactome(s)' in individual pts is key to both clinically relevant targets and in choosing the next best therapy. Mutational signatures derived from corresponding ` pathway-networks' represent a meaningful tool to (I) evaluate functional investigation in the laboratory; (II) predict response to drug therapy; and (III) guide rational drug combinations in relapsed and refractory mCRC pts.
NoteOpen Access Journal.
VersionFinal published version
SponsorsThe West Cancer Center; University of Tennessee Health Science Center (UTHSC); UTHSC research grant
- KRAS Testing for Anti-EGFR Therapy in Advanced Colorectal Cancer: An Evidence-Based and Economic Analysis.
- Authors: Health Quality Ontario.
- Issue date: 2010
- Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy?
- Authors: Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.
- Issue date: 2013 Jul
- Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial.
- Authors: Ciardiello F, Normanno N, Maiello E, Martinelli E, Troiani T, Pisconti S, Giuliani F, Barone C, Cartenì G, Rachiglio AM, Montesarchio V, Tonini G, Rizzi D, Cinieri S, Bordonaro R, Febbraro A, De Vita F, Orditura M, Fenizia F, Lambiase M, Rinaldi A, Tatangelo F, Botti G, Colucci G
- Issue date: 2014 Sep
- Phase II trial of cetuximab plus irinotecan for oxaliplatin- and irinotecan-based chemotherapy-refractory patients with advanced and/or metastatic colorectal cancer: evaluation of efficacy and safety based on KRAS mutation status (T-CORE0801).
- Authors: Soeda H, Shimodaira H, Gamoh M, Ando H, Isobe H, Suto T, Takahashi S, Kakudo Y, Amagai K, Mori T, Watanabe M, Yamaguchi T, Kato S, Ishioka C
- Issue date: 2014
- Worse prognosis of KRAS c.35 G > A mutant metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx).
- Authors: Bruera G, Cannita K, Di Giacomo D, Lamy A, Frébourg T, Sabourin JC, Tosi M, Alesse E, Ficorella C, Ricevuto E
- Issue date: 2013 Mar 4