Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.
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Abbosh Christopher, Frankell Alexander M, Harrison Thomas, Kisistok Judit, Garnett Aaron, Johnson Laura, Veeriah Selvaraju, Moreau Mike, Chesh Adrian, Chaunzwa Tafadzwa L, Weiss Jakob, Schroeder Morgan R, Ward Sophia, Grigoriadis Kristiana, Shahpurwalla Aamir, Litchfield Kevin, Puttick Clare, Biswas Dhruva, Karasaki Takahiro, Black James R M, Martínez-Ruiz Carlos, Bakir Maise Al, Pich Oriol, Watkins Thomas B K, Lim Emilia L, Huebner Ariana, Moore David A, Godin-Heymann Nadia, L'Hernault Anne, Bye Hannah, Odell Aaron, Kalavakur Paula, Gomes Fabio, Patel Akshay J, Manzano Elizabeth, Hiley Crispin T, Carey Nicolas, Riley Joan, Cook Daniel E, Hodgson Darren, Stetson Daniel, Barrett J Carl, Kortlever Roderik M, Evan Gerard I, Hackshaw Allan, Daber Robert D, Shaw Jacqui A, Aerts Hugo J W L, Licon Abel, Stahl Josh, Jamal-Hanjani Mariam, TRACERx Consortium, Birkbak Nicolai J, McGranahan Nicholas, Swanton Charles
Аннотация
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. 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 study2. 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.