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Mutational analysis and clinical correlation of metastatic colorectal cancer.

ABSTRACT: Early identification of mutations may guide patients with metastatic colorectal cancer toward targeted therapies that may be life prolonging. The authors assessed tumor genotype correlations with clinical characteristics to determine whether mutational profiling can account for clinical similarities, differences, and outcomes.Under Institutional Review Board approval, 222 patients with metastatic colon adenocarcinoma (n = 158) and rectal adenocarcinoma (n = 64) who underwent clinical tumor genotyping were reviewed. Multiplexed tumor genotyping screened for >150 mutations across 15 commonly mutated cancer genes. The chi-square test was used to assess genotype frequency by tumor site and additional clinical characteristics. Cox multivariate analysis was used to assess the impact of genotype on overall survival.Broad-based tumor genotyping revealed clinical and anatomic differences that could be linked to gene mutations. NRAS mutations were associated with rectal cancer versus colon cancer (12.5% vs 0.6%; P

SUBMITTER: Russo AL

PROVIDER: S-EPMC4327902 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Mutational analysis and clinical correlation of metastatic colorectal cancer.

Russo Andrea L AL Borger Darrell R DR Szymonifka Jackie J Ryan David P DP Wo Jennifer Y JY Blaszkowsky Lawrence S LS Kwak Eunice L EL Allen Jill N JN Wadlow Raymond C RC Zhu Andrew X AX Murphy Janet E JE Faris Jason E JE Dias-Santagata Dora D Haigis Kevin M KM Ellisen Leif W LW Iafrate Anthony J AJ Hong Theodore S TS

Cancer 20140205 10

<h4>Background</h4>Early identification of mutations may guide patients with metastatic colorectal cancer toward targeted therapies that may be life prolonging. The authors assessed tumor genotype correlations with clinical characteristics to determine whether mutational profiling can account for clinical similarities, differences, and outcomes.<h4>Methods</h4>Under Institutional Review Board approval, 222 patients with metastatic colon adenocarcinoma (n = 158) and rectal adenocarcinoma (n = 64) ...[more]

PMID: 24500602

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Project description:BackgroundWe previously reported that loss of KRAS mutations ("regressive" mutational trajectories) from primary tumors to metastases associated with the oligo-metastatic status in colorectal cancer (CRC). The present study was undertaken in order to analyze the mutational trajectories of KRAS in a well-characterized cohort of CRC patients who developed poly- or oligo-metastatic disease.Material and methodsPatients were treated and followed-up according to European Society of Medical Oncology guidelines. Primary CRC FFPE tissue and metastatic circulating-free DNA were extracted using the QIAamp DNA specific kits (Qiagen, Hilden, Germany). Samples were sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Plasma collection for liquid biopsy was done from 1 to 14 days before starting first-line chemotherapy. Analysis of the prognostic power of KRAS evolutionary trajectories was done with uni- and multivariate analyses.ResultsOne-hundred-fourteen patients were enrolled. Sixty-three patients presented with mutated KRAS (mutKRAS) and 51 with wild-type KRAS (wtKRAS). KRAS mutational concordance was high (70.1%).Two divergent subsets were identified: mutKRAS in primary tumors and wtKRAS in metastatic ones (regressive: mutKRAS → wtKRAS in 8.8% of patients), and vice versa (progressive: wtKRAS → mutKRAS in 21.1% of patients). An association between KRAS regressive trajectory and the oligo-metastatic status (P <0.0001) was found. At multivariate analysis, regressive and progressive mutational trajectories emerged as independent prognostic factors for survival, with Hazard Ratios of 0.22 (CI 95%: 0.08-0.61; median survival: not reached) and 2.70 (CI 95%: 1.11-6.56, median survival: 12.1 months), respectively.ConclusionsOur data provide evidence that the evolutionary trajectories of KRAS can have a strong clinical prognostic role and that they can be involved in discriminating between poly-metastatic aggressive vs oligo-metastatic indolent CRC.

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Mutational analysis and clinical correlation of metastatic colorectal cancer.

Publications

Mutational analysis and clinical correlation of metastatic colorectal cancer.

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