Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Abbosh, C; Frankell, AM; Harrison, T; Kisistok, J; Garnett, A; Johnson, L; Veeriah, S; Moreau, M; Chesh, A; Chaunzwa, TL; Weiss, J; Schroeder, MR; Ward, S; Grigoriadis, K; Shahpurwalla, A; Litchfield, K; Puttick, C; Biswas, D; Karasaki, T; Black, JRM; Martinez-Ruiz, C; Al Bakir, M; Pich, O; Watkins, TBK; Lim, EL; Huebner, A; Moore, DA; Godin-Heymann, N; L&#39;Hernault, A; Bye, H; Odell, A; Roberts, P; Gomes, F; Patel, AJ; Manzano, E; Hiley, CT; Carey, N; Riley, J; Cook, DE; Hodgson, D; Stetson, D; Barrett, JC; Kortlever, RM; Evan, GI; Hackshaw, A; Daber, RD; Shaw, JA; Aerts, HJWL; Licon, A; Stahl, J; Jamal-Hanjani, M; TRACERx Consortium; Birkbak, NJ; McGranahan, N; Swanton, C

Author(s): Abbosh, C; Frankell, AM; Harrison, T; Kisistok, J; Garnett, A; Johnson, L; Veeriah, S; Moreau, M; Chesh, A; Chaunzwa, TL; Weiss, J; Schroeder, MR; Ward, S; Grigoriadis, K; Shahpurwalla, A; Litchfield, K; Puttick, C; Biswas, D; Karasaki, T; Black, JRM; Martinez-Ruiz, C; Al Bakir, M; Pich, O; Watkins, TBK; Lim, EL; Huebner, A; Moore, DA; Godin-Heymann, N; L'Hernault, A; Bye, H; Odell, A; Roberts, P; Gomes, F; Patel, AJ; Manzano, E; Hiley, CT; Carey, N; Riley, J; Cook, DE; Hodgson, D; Stetson, D; Barrett, JC; Kortlever, RM; Evan, GI; Hackshaw, A; Daber, RD; Shaw, JA; Aerts, HJWL; Licon, A; Stahl, J; Jamal-Hanjani, M; TRACERx Consortium; Birkbak, NJ; McGranahan, N; Swanton, C;
Details: Publication Year 2023,Volume 616,Issue #7957,Page 553-562
Journal Title: Nature
Publication Type: Research article
Abstract: Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy(1). The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study(2). A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.
Keywords: Humans; *Biomarkers, Tumor/blood/genetics; *Carcinoma, Non-Small-Cell Lung/blood/genetics/pathology; *Circulating Tumor DNA/blood/genetics; Cohort Studies; *Lung Neoplasms/blood/genetics/pathology; *Mutation; *Neoplasm Metastasis/diagnosis/genetics/pathology; Neoplasm Recurrence, Local/diagnosis/genetics/pathology; Phylogeny; *Small Cell Lung Carcinoma/pathology; Liquid Biopsy
Department(s): Laboratory Research
PubMed ID: 37055640
Publisher's Version: https://doi.org/10.1038/s41586-023-05776-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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