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Kinase Fusions in Colorectal Cancers: A Unique Biologic Subset

Date

21 Oct 2018

Session

Poster Discussion session - Gastrointestinal tumours, colorectal 2

Presenters

Russell Madison

Citation

Annals of Oncology (2018) 29 (suppl_8): viii150-viii204. 10.1093/annonc/mdy281

Authors

R. Madison1, F. Pietrantonio2, L. Juckett1, C. Cremolini3, J. Chung4, L.A. Albacker5, V.A. Miller4, S.J. Klempner6, M.B. Resnick7, E. Yakirevich7, S.I. Ou8, M. Fakih9, A.B. Schrock1, J.S. Ross4, S.M. Ali4

Author affiliations

  • 1 Genetics, Foundation Medicine, Inc., 02141 - Cambridge/US
  • 2 Oncology And Hemato-oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milan/IT
  • 3 Polo Oncologico, Azienda Ospedaliera Universitaria S.Chiara, 56100 - Pisa/IT
  • 4 Genetics, Foundation Medicine, Inc., Cambridge/US
  • 5 Cancer Genomics, Foundation Medicine, Inc., 02141 - Cambridge, MA/US
  • 6 Medical Oncology, The Angeles Clinic and Research Institute, 90025 - Los Angeles/US
  • 7 Pathology, Rhode Island Hospital & Alpert Medical School of Brown University, 02903 - Providence/US
  • 8 Medicine, Chao Family Comprehensive Cancer Center, 92697 - Irvine/US
  • 9 Medical Oncology & Therapeutics Research, City of Hope, 91010 - Duarte/US
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Resources

Abstract 3509

Background

In a subset of colorectal carcinomas (CRC), fusion genes resulting from genomic rearrangements of protein kinases have been previously reported. Anecdotal responses to matched therapy support clinical relevance but larger description is lacking.

Methods

18,407 tissue specimens and 513 ctDNA specimens from patients with CRC were assayed using hybrid-capture based comprehensive genomic profiling (CGP) of 63, 186, or 315 genes plus introns from 6, 14 or 28 genes commonly rearranged in cancer. Tumor mutational burden (TMB) was assessed on solid tumor cases on 0.83 or 1.1 Mb of DNA and is reported as mutations per megabase (m/mb). Microsatellite instability (MSI) was assessed across 114 homopolymeric loci.

Results

Kinase rearrangements (KRE) were identified in 126 CRC tissue specimens (0.68%) and 7 CRC ctDNA samples (1.36%). The most frequently altered kinases were RET (22%), BRAF (22%), NTRK1 (16%), and ALK (13%). KRE of EGFR, FGFR3, FGFR1, ROS1, RAF1, FGFR2, NTRK3, PDGFRB, MET, and NTRK2 occurred in 5 or less cases each. Patients with tumors harboring KRE were 52% female (69/133) and had a median age of 62 years. Among cases with KRE, the non-kinase genes most frequently altered were TP53 (67.7%), APC (39.1%), RNF43 (30.1%), and MLL2 (21.1%), and KRAS was wildtype in 90% of these cases. Cases with KRE had a median TMB of 6.96 m/mb, relative to a median TMB of 3.60 m/mb for all CRC cases in the database. Of cases assessed for MSI status, 38% (41/107) were MSI high with a median TMB of 42.8 m/mb (range 20.9-118.3 m/mb). Of all KRE cases, NTRK1 and RET KRE cases were 86% and 45% MSI high, respectively. MSI Status by Kinase.Table: 457PD

KinaseTotalMSI StatusCases% MSI-H
ALK14MSI-H214.29%
MSS12
BRAF23MSI-H417.39%
MSI-L1
MSS18
FGFR23MSI-H3100.00%
NTRK122MSI-H1986.36%
MSS3
NTRK33MSI-H3100.00%
RET22MSI-H1045.45%
MSS12

Conclusions

Among KRE CRC, the enrichment of MSI high status in NTRK1 KRE cases, and to a lesser extent RET, FGFR2, and NTRK2, suggests these patients may benefit from both TKIs and checkpoint inhibitors either as respective monotherapies or in combination. No MS stable KRE cases had high TMB, suggesting further investigation of the observed intersection of MSI-high and KRE is warranted as a unique biologic subset.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine Inc.

Funding

Foundation Medicine Inc.

Editorial Acknowledgement

Disclosure

R. Madison, L. Juckett, J. Chung, L.A. Albacker, V.A. Miller, A.B. Schrock, J.S. Ross, S.M. Ali: Employee, Equity interest: FMI. All other authors have declared no conflicts of interest.

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