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

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Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusion

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.

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Data Availability

The datasets generated and analyzed during the current study are available from the corresponding authors on reasonable request.

Abbreviations

AMP:

Association for Molecular Pathology

ASCO:

American Society of Clinical Oncology

CAP:

College of American Pathologists

cfDNA:

Circulating cell-free DNA

CNV:

Copy number variation

CUP:

Cancer of unknown primary

evDNA:

Extracellular vesicle DNA

NGS:

Next-generation sequencing

PBMC:

Peripheral blood mononuclear cells

SNV:

Single-nucleotide variant

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Acknowledgements

We thank our patients and their families. We dedicate this study to the memory of our beloved colleague Dr. Gauri R. Varadhachary who was responsible for initiating this study and was always there for her patients.

Funding

A.M. is supported by the MD Anderson Pancreatic Cancer Moon Shot Program, the Sheikh Khalifa bin Zayed Al-Nahyan Foundation, and the NIH (R01CA218230, U01CA196403, U01CA200468, and P50CA221707). V. Bernard is supported by the NIH (U54CA096300, U54CA096297, and T32CA217789). J.J.L. is supported by the NIH (T32CA009599). A.S. is supported by the German Research Foundation (SE-2616/2–1).

Author information

Authors and Affiliations

  1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Fiona R. Kolbinger, Vincent Bernard, Jaewon J. Lee, Bret M. Stephens, Vittorio Branchi, Anirban Maitra, Paola A. Guerrero & Alexander Semaan

  2. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Kanwal P. S. Raghav

Authors
  1. Fiona R. Kolbinger
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  2. Vincent Bernard
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Contributions

F.R.K. performed experiments and data analysis and wrote the manuscript, B.M.S. performed experiments, V. Branchi conducted data analysis, V. Bernard and J.J.L. edited the manuscript. K.P.S.R. helped with clinical annotations, A.M. provided funding and scientific guidance and edited the manuscript. A.S. and P.A.G, conceptualized and guided the work and edited the manuscript. All authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Paola A. Guerrero or Alexander Semaan.

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Competing Interests

A.M. receives royalties for a pancreatic cancer biomarker test from Cosmos Wisdom Biotechnology, and this financial relationship is managed and monitored by the UTMDACC Conflict of Interest Committee. A.M. is also listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection (an Exact Sciences Company). A.M. is a consultant for Freenome and Tezcat. All other authors declare no conflicts of interests.

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Significance

Analysis of genomic variants in liquid biopsies has potential as a diagnostic tool for CUP samples. We compared cfDNA and evDNA by a targeted NGS approach and identified druggable targets that could help to stratify patients for inclusion into clinical trials.

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Kolbinger, F.R., Bernard, V., Lee, J.J. et al. Significance of Distinct Liquid Biopsy Compartments in Evaluating Somatic Mutations for Targeted Therapy Selection in Cancer of Unknown Primary. J Gastrointest Canc 54, 1276–1285 (2023). https://doi.org/10.1007/s12029-023-00922-7

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