Significance of Distinct Liquid Biopsy Compartments in Evaluating Somatic Mutations for Targeted Therapy Selection in Cancer of Unknown Primary

Fiona R Kolbinger; Vincent Bernard; Jaewon J Lee; Bret M Stephens; Vittorio Branchi; Kanwal P S Raghav; Anirban Maitra; Paola A Guerrero; Alexander Semaan

doi:10.1007/s12029-023-00922-7

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Significance of Distinct Liquid Biopsy Compartments in Evaluating Somatic Mutations for Targeted Therapy Selection in Cancer of Unknown Primary

Journal article

Peer reviewed

Significance of Distinct Liquid Biopsy Compartments in Evaluating Somatic Mutations for Targeted Therapy Selection in Cancer of Unknown Primary

Fiona R Kolbinger, Vincent Bernard, Jaewon J Lee, Bret M Stephens, Vittorio Branchi, Kanwal P S Raghav, Anirban Maitra, Paola A Guerrero and Alexander Semaan

Journal of gastrointestinal cancer, Vol.54(4), pp.1276-1285

12/2023

DOI: 10.1007/s12029-023-00922-7

PMID: 36862364

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Abstract

Cancer of unknown primary (CUP) accounts for 2-5% of all cancer diagnoses, wherein standard investigations fail to reveal the original tumor site. Basket trials allocate targeted therapeutics based on actionable somatic mutations, independent of tumor entity. These trials, however, mostly rely on variants identified in tissue biopsies. Since liquid biopsies (LB) represent the overall tumor genomic landscape, they may provide an ideal diagnostic source in CUP patients. To identify the most informative liquid biopsy compartment, we compared the utility of genomic variant analysis for therapy stratification in two LB compartments (circulating cell-free (cf) and extracellular vesicle (ev) DNA). CfDNA and evDNA from 23 CUP patients were analyzed using a targeted gene panel covering 151 genes. Identified genetic variants were interpreted regarding diagnostic and therapeutic relevance using the MetaKB knowledgebase. LB revealed a total of 22 somatic mutations in evDNA and/or cfDNA in 11/23 patients. Out of the 22 identified somatic variants, 14 are classified as Tier I druggable somatic variants. Comparison of variants identified in evDNA and cfDNA revealed an overlap of 58% of somatic variants in both LB compartments, whereas over 40% of variants were only found in one or the other compartment. We observed substantial overlap between somatic variants identified in evDNA and cfDNA of CUP patients. Nonetheless, interrogation of both LB compartments can potentially increase the rate of druggable alterations, stressing the significance of liquid biopsies for possible primary-independent basket and umbrella trial inclusion.

Cell-Free Nucleic Acids

DNA, Neoplasm - genetics

Humans

Liquid Biopsy

Mutation

Neoplasms, Unknown Primary - drug therapy

Neoplasms, Unknown Primary - genetics

Details

Title: Subtitle: Significance of Distinct Liquid Biopsy Compartments in Evaluating Somatic Mutations for Targeted Therapy Selection in Cancer of Unknown Primary
Creators: Fiona R Kolbinger - The University of Texas MD Anderson Cancer Center
Vincent Bernard - The University of Texas MD Anderson Cancer Center
Jaewon J Lee - The University of Texas MD Anderson Cancer Center
Bret M Stephens - The University of Texas MD Anderson Cancer Center
Vittorio Branchi - The University of Texas MD Anderson Cancer Center
Kanwal P S Raghav - The University of Texas MD Anderson Cancer Center
Anirban Maitra - The University of Texas MD Anderson Cancer Center
Paola A Guerrero - The University of Texas MD Anderson Cancer Center
Alexander Semaan - The University of Texas MD Anderson Cancer Center
Resource Type: Journal article
Publication Details: Journal of gastrointestinal cancer, Vol.54(4), pp.1276-1285
DOI: 10.1007/s12029-023-00922-7
PMID: 36862364
NLM abbreviation: J Gastrointest Cancer
ISSN: 1941-6628
eISSN: 1941-6636
Grant note: T32CA009599 / NIH HHS R01CA218230 / NIH HHS U54CA096300 / NIH HHS
Language: English
Date published: 12/2023
Academic Unit: Surgery
Record Identifier: 9985240990102771

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