Overall Survival with Circulating Tumor DNA-guided Therapy in Advanced Non-small-cell Lung Cancer

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

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References

Bolton K, Koh Y, Foote M, Im H, Jee J, Sun C . Clonal hematopoiesis is associated with risk of severe Covid-19. Nat Commun. 2021; 12(1):5975. PMC: 8514469. DOI: 10.1038/s41467-021-26138-6. View

Howlader N, Forjaz G, Mooradian M, Meza R, Kong C, Cronin K . The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med. 2020; 383(7):640-649. PMC: 8577315. DOI: 10.1056/NEJMoa1916623. View

Li B, Daly B, Gospodarowicz M, Bertagnolli M, Brawley O, Chabner B . Reimagining patient-centric cancer clinical trials: a multi-stakeholder international coalition. Nat Med. 2022; 28(4):620-626. DOI: 10.1038/s41591-022-01775-6. View

Bettegowda C, Sausen M, Leary R, Kinde I, Wang Y, Agrawal N . Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014; 6(224):224ra24. PMC: 4017867. DOI: 10.1126/scitranslmed.3007094. View

Brannon A, Jayakumaran G, Diosdado M, Patel J, Razumova A, Hu Y . Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS. Nat Commun. 2021; 12(1):3770. PMC: 8213710. DOI: 10.1038/s41467-021-24109-5. View

Rolfo C, Russo A, de Miguel-Perez D . Speeding tumor genotyping during the SARS-CoV-2 outbreak through liquid biopsy. Cancer. 2020; 126(18):4089-4091. PMC: 7300674. DOI: 10.1002/cncr.32983. View

Pasche B, Grant S . Non-small cell lung cancer and precision medicine: a model for the incorporation of genomic features into clinical trial design. JAMA. 2014; 311(19):1975-6. DOI: 10.1001/jama.2014.3742. View

Mack P, Banks K, Espenschied C, Burich R, Zill O, Lee C . Spectrum of driver mutations and clinical impact of circulating tumor DNA analysis in non-small cell lung cancer: Analysis of over 8000 cases. Cancer. 2020; 126(14):3219-3228. PMC: 7383626. DOI: 10.1002/cncr.32876. View

Razavi P, Li B, Brown D, Jung B, Hubbell E, Shen R . High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Nat Med. 2019; 25(12):1928-1937. PMC: 7061455. DOI: 10.1038/s41591-019-0652-7. View

10.

Shen R, Seshan V . FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res. 2016; 44(16):e131. PMC: 5027494. DOI: 10.1093/nar/gkw520. View

11.

Paweletz C, Sacher A, Raymond C, Alden R, OConnell A, Mach S . Bias-Corrected Targeted Next-Generation Sequencing for Rapid, Multiplexed Detection of Actionable Alterations in Cell-Free DNA from Advanced Lung Cancer Patients. Clin Cancer Res. 2015; 22(4):915-22. PMC: 4755822. DOI: 10.1158/1078-0432.CCR-15-1627-T. View

12.

Bardelli A, Pantel K . Liquid Biopsies, What We Do Not Know (Yet). Cancer Cell. 2017; 31(2):172-179. DOI: 10.1016/j.ccell.2017.01.002. View

13.

Coombs C, Zehir A, Devlin S, Kishtagari A, Syed A, Jonsson P . Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell. 2017; 21(3):374-382.e4. PMC: 5591073. DOI: 10.1016/j.stem.2017.07.010. View

14.

Chaudhuri A, Chabon J, Lovejoy A, Newman A, Stehr H, Azad T . Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling. Cancer Discov. 2017; 7(12):1394-1403. PMC: 5895851. DOI: 10.1158/2159-8290.CD-17-0716. View

15.

Li B, Janku F, Jung B, Hou C, Madwani K, Alden R . Ultra-deep next-generation sequencing of plasma cell-free DNA in patients with advanced lung cancers: results from the Actionable Genome Consortium. Ann Oncol. 2019; 30(4):597-603. PMC: 6503621. DOI: 10.1093/annonc/mdz046. View

16.

Morbelli S, Alama A, Ferrarazzo G, Coco S, Genova C, Rijavec E . Circulating Tumor DNA Reflects Tumor Metabolism Rather Than Tumor Burden in Chemotherapy-Naive Patients with Advanced Non-Small Cell Lung Cancer: F-FDG PET/CT Study. J Nucl Med. 2017; 58(11):1764-1769. DOI: 10.2967/jnumed.117.193201. View

17.

Rothwell D, Ayub M, Cook N, Thistlethwaite F, Carter L, Dean E . Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nat Med. 2019; 25(5):738-743. DOI: 10.1038/s41591-019-0380-z. View

18.

Sabari J, Offin M, Stephens D, Ni A, Lee A, Pavlakis N . A Prospective Study of Circulating Tumor DNA to Guide Matched Targeted Therapy in Lung Cancers. J Natl Cancer Inst. 2018; 111(6):575-583. PMC: 6579739. DOI: 10.1093/jnci/djy156. View

19.

Alix-Panabieres C, Pantel K . Liquid Biopsy: From Discovery to Clinical Application. Cancer Discov. 2021; 11(4):858-873. DOI: 10.1158/2159-8290.CD-20-1311. View

20.

Karachaliou N, Mayo-de las Casas C, Queralt C, de Aguirre I, Melloni B, Cardenal F . Association of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial. JAMA Oncol. 2015; 1(2):149-57. DOI: 10.1001/jamaoncol.2014.257. View