Englander Institute for Precision Medicine

Circulating Tumor DNA Enables Sensitive Detection of Actionable Gene Fusions and Rearrangements Across Cancer Types.

TitleCirculating Tumor DNA Enables Sensitive Detection of Actionable Gene Fusions and Rearrangements Across Cancer Types.
Publication TypeJournal Article
Year of Publication2024
AuthorsKasi PM, Lee JK, Pasquina LW, Decker B, Borre PVanden, Pavlick DC, Allen JM, Parachoniak C, Quintanilha JCF, Graf RP, Schrock AB, Oxnard GR, Lovly CM, Tukachinsky H, Subbiah V
JournalClin Cancer Res
Date Published2024 Feb 16
KeywordsCarcinoma, Non-Small-Cell Lung, Circulating Tumor DNA, Gene Fusion, Gene Rearrangement, Genomics, Humans, Lung Neoplasms, Male

PURPOSE: Genomic rearrangements can generate potent oncogenic drivers or disrupt tumor suppressor genes. This study examines the landscape of fusions and rearrangements detected by liquid biopsy (LBx) of circulating tumor DNA (ctDNA) across different cancer types.

EXPERIMENTAL DESIGN: LBx from 53,842 patients with 66 solid tumor types were profiled using FoundationOneLiquid CDx, a hybrid-capture sequencing platform that queries 324 cancer-related genes. Tissue biopsies (TBx) profiled using FoundationOneCDx were used as a comparator.

RESULTS: Among all LBx, 7,377 (14%) had ≥1 pathogenic rearrangement detected. A total of 3,648 (6.8%) LBx had ≥1 gain-of-function (GOF) oncogene rearrangement, and 4,428 (8.2%) LBx had ≥1 loss-of-function rearrangement detected. Cancer types with higher prevalence of GOF rearrangements included those with canonical fusion drivers: prostate cancer (19%), cholangiocarcinoma (6.4%), bladder (5.5%), and non-small cell lung cancer (4.4%). Although the prevalence of driver rearrangements was lower in LBx than TBx overall, the frequency of detection was comparable in LBx with a tumor fraction (TF) ≥1%. Rearrangements in FGFR2, BRAF, RET, and ALK, were detected across cancer types, but tended to be clonal variants in some cancer types and potential acquired resistance variants in others.

CONCLUSIONS: In contrast to some prior literature, this study reports detection of a wide variety of rearrangements in ctDNA. The prevalence of driver rearrangements in tissue and LBx was comparable when TF ≥1%. LBx presents a viable alternative when TBx is not available, and there may be less value in confirmatory testing when TF is sufficient.

Alternate JournalClin Cancer Res
PubMed ID38060240
PubMed Central IDPMC10870120
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