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Utility of exome sequencing in routine care for metastatic colorectal cancer.

ABSTRACT: Metastatic colorectal cancer (mCRC) is a heterogenous disease and its prognosis depends on clinical features, such as tumor sidedness, and whether it is metachronous or synchronous. However, little is known about the overall genomic characterization of mCRC in these clinical subtypes. This single-center observational study included 77 patients with mCRC who underwent somatic and germline exome analysis during the first or second line of therapy in 2018. Somatic and germline variants were determined in addition to tumor mutational burden, ploidy, clonality, human leucocyte antigen typing, neoantigens, and mutational and copy number signatures. Variables associated with sidedness, synchronous status and RAS status were determined using Fisher's test; and variables associated with overall survival were determined using univariate Cox survival models. The present study successfully generated whole exome sequencing analysis in 77 mCRC cases. Among them, 50 were left- and rectal-sided, while 27 were right-sided. Furthermore, 27 were metachronous and 46 were RAS-mutated. The median OS was 3.75 years. It was observed that signature single nucleotide variation (SNV) 26, oncogenic alterations in receptor tyrosine kinase and nucleotide excision repair pathways were associated with tumor sidedness. SNV signature 3, Hedgehog signaling and mismatch repair pathways were associated with synchronous status. Phosphatidylinositol signaling system, ERK signaling and chromatin organization pathways were associated with RAS mutant status. In the whole cohort, metachronous metastasis was associated with improved survival. On gene variation, PTEN, PDGFRA, MYCN and SMAD4 were associated with poor prognosis, as was SNV signature 15. In conclusion, this study highlighted that structural and pathway genomic features are associated with sidedness, synchronous status, RAS status and overall survival and could be helpful to improve the stratification of patients with colorectal cancer.

SUBMITTER: D'Agay MG

PROVIDER: S-EPMC8461624 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceUnderstanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer.ObjectiveTo understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response.Design, setting, and patientsPatients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response.Main outcomes and measuresFeasibility, use of WES for decision making, and identification of novel biomarkers.ResultsA total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95X and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was identified who harbored a somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response.Conclusions and relevanceThe majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for WES of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.

Project description:BackgroundGenomically-guided clinical trials are performed across different tumor types sharing genetic mutations, but trial organization remains complex. Here we address the feasibility and utility of routine somatic and constitutional exome analysis in metastatic cancer patients.MethodsExoma trial (NCT02840604) is a multicenter, prospective clinical trial. Eligible patients presented a metastatic cancer progressing after at least one line of systemic therapy. Constitutional genetics testing required geneticist consultation. Somatic and germline exome analysis was restricted to 317 genes. Variants were classified and molecular tumor board made therapeutic recommendations based on ESMO guidelines. Primary endpoint was the feasibility of the approach evaluated by the proportion of patient that received a therapeutic proposal.FindingsBetween May 2016 and October 2018, 506 patients were included. Median time required for tumor sample reception was 8 days. Median time from sample reception to results was 52 days. Somatic analysis was performed for 456 patients (90.1%). Both somatic and constitutional analyses were successfully performed for 386 patients (76.3%). In total, 342 patients (75%) received a therapeutic proposal. Genetic susceptibility to cancer was found in 35 (9%) patients. Only, 79 patients (23.1%) were treated with NGS matched therapy mainly PI3K/AKT/mTOR inhibitors 22 (27.8%), followed by PARP inhibitors 19 (24.1%), antiangiogenics 17 (21.5%), MEK inhibitors 7 (8.9%) and immunotherapy 5 (6.3%). Matched treatment was finally stopped because of disease progression 50 (63%), treatment toxicity 18 (23%), patients' death 4 (5%). PFS2/PFS1 ratio was > 1,3 for 23,5% of patients treated with the NGS matched therapy and 23,7% of patients treated with standard therapy.InterpretationStudy shows that exome analysis is feasible in cancer routine care. This strategy improves detection of genetic predispositions and enhances access to target therapies. However, no differences were observed between PFS ratios of patients treated with matched therapy versus standard therapy.FundingThis work was funding by the centre Georges Francois Leclerc.

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Utility of exome sequencing in routine care for metastatic colorectal cancer.

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