title: Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites.
abstract: Metastatic colorectal cancer (mCRC) carries a poor prognosis with an overall 5-year survival of 13.1%. Therapies guided by tumor profiling have suggested benefit in advanced cancer. We used a multiplatform molecular profiling (MP) approach to identify key molecular changes that may provide therapeutic options not typically considered in mCRC. We evaluated 6892 mCRC referred to Caris Life Sciences by MP including sequencing (Sanger/NGS), immunohistochemistry (IHC) and in-situ hybridization (ISH). mCRC metastases to liver, brain, ovary or lung (n = 1507) showed differential expression of markers including high protein expression of TOPO1 (52%) and/or low RRM1 (57%), TS (71%) and MGMT (39%), suggesting possible benefit from irinotecan, gemcitabine, 5FU/capecitabine and temozolomide, respectively. Lung metastases harbored a higher Her2 protein expression than the primary colon tumors (4% vs. 1.8%, p = 0.028). Brain and lung metastases had higher KRAS mutations than other sites (65% vs 59% vs 47%, respectively, p = 0.07, <0.01), suggesting poor response to anti-EGFR therapies. BRAF-mutated CRC (n = 455) showed coincident high protein expression of RRM1 (56%), TS (53%) and low PDGFR (22%) as compared with BRAF wild-type tumors. KRAS-mutated mCRC had higher protein expression of c-MET (47% vs. 36%) and lower MGMT (56% vs. 63%), suggesting consideration of c-MET inhibitors and temozolomide. KRAS-mutated CRC had high TUBB3 (42% vs. 33%) and low Her2 by IHC (0.5%) and HER2 by FISH (3%, p <0.05). CRC primaries had a lower incidence of PIK3CA and BRAF mutations in rectal cancer versus colon cancer (10% and 3.3%, respectively). MP of 6892 CRCs identified significant differences between primary and metastatic sites and among BRAF/KRAS sub-types. Our findings are hypothesis generating and need to be examined in prospective studies. Specific therapies may be considered for different actionable targets in mCRC as revealed by MP.
authors.affiliation: a Fox Chase Cancer Center ; Philadelphia , PA , 19111 , USA.|c Penn State Hershey Cancer Institute ; Hershey , PA , 17033 , USA.
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
authors.affiliation: a Fox Chase Cancer Center ; Philadelphia , PA , 19111 , USA.
authors.forename: Namrata
authors.initials: N
authors.lastname: Vijayvergia
authors.affiliation: b Caris Life Sciences ; Phoenix , AZ , 85040 , USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Xiu
authors.affiliation: c Penn State Hershey Cancer Institute ; Hershey , PA , 17033 , USA.
authors.forename: Angelique
authors.initials: A
authors.lastname: Scicchitano
authors.affiliation: c Penn State Hershey Cancer Institute ; Hershey , PA , 17033 , USA.|d MD Anderson Cancer Center ; Houston , TX , 77030 , USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Lim
authors.affiliation: c Penn State Hershey Cancer Institute ; Hershey , PA , 17033 , USA.
authors.forename: Nelson S
authors.initials: NS
authors.lastname: Yee
authors.affiliation: c Penn State Hershey Cancer Institute ; Hershey , PA , 17033 , USA.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Harvey
authors.affiliation: b Caris Life Sciences ; Phoenix , AZ , 85040 , USA.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.affiliation: b Caris Life Sciences ; Phoenix , AZ , 85040 , USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Reddy
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000556:secondary
chemical_list: D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II
keywords: APC; BRAF; Cox2; ERCC1; Her2; KRAS; TP53; Topo1; c-MET; colorectal cancer; irinotecan; metastasis; molecular profiling; oxaliplatin; peritoneal cancer; precision medicine