Evaluation of molecular residual disease in operable non-small cell lung cancer with gene fusions, MET exon skipping or de novo MET amplification

Abstract

Gene fusions and MET alterations are rare and difficult to detect in plasma samples. The clinical detection efficacy of molecular residual disease (MRD) based on circulating tumor DNA (ctDNA) in patients with non-small cell lung cancer (NSCLC) with these mutations remains unknown. This prospective, non-intervention study recruited 49 patients with operable NSCLC with actionable gene fusions (ALK, ROS1, RET, and FGFR1), MET exon 14 skipping or de novo MET amplification. We analyzed 43 tumor tissues and 111 serial perioperative plasma samples using 1021- and 338-gene panels, respectively. Detectable MRD correlated with a significantly higher recurrence rate (P < 0.001), yielding positive predictive values of 100% and 90.9%, and negative predictive values of 82.4% and 86.4% at landmark and longitudinal time points, respectively. Patients with detectable MRD showed reduced disease-free survival (DFS) compared to those with undetectable MRD (P < 0.001). Patients who harbored tissue-derived fusion/MET alterations in their MRD had reduced DFS compared to those who did not (P = 0.05). To our knowledge, this is the first comprehensive study on ctDNA-MRD clinical detection efficacy in operable NSCLC patients with gene fusions and MET alterations. Patients with detectable tissue-derived fusion/MET alterations in postoperative MRD had worse clinical outcomes.

Keywords

ctDNA / molecular residual disease / operable NSCLC / gene fusion / MET exon skipping / MET amplification

References

[1] Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, Dunant A, Torri V, Rosell R, Seymour L, Spiro SG, Rolland E, Fossati R, Aubert D, Ding K, Waller D, Le Chevalier T; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26(21): 3552–3559

[2] NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014; 383(9928): 1561–1571

[3] Zhang JT, Liu SY, Gao W, Liu SM, Yan HH, Ji L, Chen Y, Gong Y, Lu HL, Lin JT, Yin K, Jiang BY, Nie Q, Liao RQ, Dong S, Guan Y, Dai P, Zhang XC, Yang JJ, Tu HY, Xia X, Yi X, Zhou Q, Zhong WZ, Yang XN, Wu YL. Longitudinal undetectable molecular residual disease defines potentially cured population in localized non-small cell lung cancer. Cancer Discov 2022; 12(7): 1690–1701

[4] Fu R, Huang J, Tian X, Liang C, Xiong Y, Zhang JT, Jiang B, Dong S, Gong Y, Gao W, Li F, Shi Y, Liu Z, Gao X, Chen R, Zhong W, Zhang Y. Postoperative circulating tumor DNA can refine risk stratification in resectable lung cancer: results from a multicenter study. Mol Oncol 2023; 17(5): 825–838

[5] Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Grönroos E, Zambrana F, Endozo R, Bi WL, Fennessy FM, Sponer N, Johnson D, Laycock J, Shafi S, Czyzewska-Khan J, Rowan A, Chambers T, Matthews N, Turajlic S, Hiley C, Lee SM, Forster MD, Ahmad T, Falzon M, Borg E, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Hafez D, Naik A, Ganguly A, Kareht S, Shah R, Joseph L, Marie Quinn A, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Oukrif D, Akarca AU, Hartley JA, Lowe HL, Lock S, Iles N, Bell H, Ngai Y, Elgar G, Szallasi Z, Schwarz RF, Herrero J, Stewart A, Quezada SA, Peggs KS, Van Loo P, Dive C, Lin CJ, Rabinowitz M, Aerts HJWL, Hackshaw A, Shaw JA, Zimmermann BG; TRACERx consortium; PEACE consortium; Swanton C. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 2017; 545(7655): 446–451

[6] Xia L, Mei J, Kang R, Deng S, Chen Y, Yang Y, Feng G, Deng Y, Gan F, Lin Y, Pu Q, Ma L, Lin F, Yuan Y, Hu Y, Guo C, Liao H, Liu C, Zhu Y, Wang W, Liu Z, Xu Y, Li K, Li C, Li Q, He J, Chen W, Zhang X, Kou Y, Wang Y, Wu Z, Che G, Chen L, Liu L. Perioperative ctDNA-based molecular residual disease detection for non-small cell lung cancer: A prospective multicenter cohort study (LUNGCA-1). Clin Cancer Res 2022; 28(15): 3308–3317

[7] Tie J, Cohen JD, Lahouel K, Lo SN, Wang Y, Kosmider S, Wong R, Shapiro J, Lee M, Harris S, Khattak A, Burge M, Harris M, Lynam J, Nott L, Day F, Hayes T, McLachlan SA, Lee B, Ptak J, Silliman N, Dobbyn L, Popoli M, Hruban R, Lennon AM, Papadopoulos N, Kinzler KW, Vogelstein B, Tomasetti C, Gibbs P; DYNAMIC Investigators. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med 2022; 386(24): 2261–2272

[8] Pascual J, Attard G, Bidard FC, Curigliano G, De Mattos-Arruda L, Diehn M, Italiano A, Lindberg J, Merker JD, Montagut C, Normanno N, Pantel K, Pentheroudakis G, Popat S, Reis-Filho JS, Tie J, Seoane J, Tarazona N, Yoshino T, Turner NC. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol 2022; 33(8): 750–768

[9] Gawroński AR, Lin YY, McConeghy B, LeBihan S, Asghari H, Koçkan C, Orabi B, Adra N, Pili R, Collins CC, Sahinalp SC, Hach F. Structural variation and fusion detection using targeted sequencing data from circulating cell free DNA. Nucleic Acids Res 2019; 47(7): e38

[10] 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, Martínez-Ruiz C, Bakir MA, 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. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. Nature 2023; 616(7957): 553–562

[11] Chen S, Zhou Y, Chen Y, Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 2018; 34(17): i884–i890

[12] Li J, Lupat R, Amarasinghe KC, Thompson ER, Doyle MA, Ryland GL, Tothill RW, Halgamuge SK, Campbell IG, Gorringe KL. CONTRA: copy number analysis for targeted resequencing. Bioinformatics 2012; 28(10): 1307–1313

[13] Ai X, Cui J, Zhang J, Chen R, Lin W, Xie C, Liu A, Zhang J, Yang W, Hu X, Hu X, Zhao Q, Rao C, Zang YS, Ning R, Li P, Chang L, Yi X, Lu S. Clonal architecture of EGFR mutation predicts the efficacy of EGFR-tyrosine kinase inhibitors in advanced NSCLC: a prospective multicenter study (NCT03059641). Clin Cancer Res 2021; 27(3): 704–712

[14] Zhang Y, Yao Y, Xu Y, Li L, Gong Y, Zhang K, Zhang M, Guan Y, Chang L, Xia X, Li L, Jia S, Zeng Q. Pan-cancer circulating tumor DNA detection in over 10 000 Chinese patients. Nat Commun 2021; 12(1): 11

[15] Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, Knudsen M, Nordentoft I, Wu HT, Tin AS, Heilskov Rasmussen M, Vang S, Shchegrova S, Frydendahl Boll Johansen A, Srinivasan R, Assaf Z, Balcioglu M, Olson A, Dashner S, Hafez D, Navarro S, Goel S, Rabinowitz M, Billings P, Sigurjonsson S, Dyrskjøt L, Swenerton R, Aleshin A, Laurberg S, Husted Madsen A, Kannerup AS, Stribolt K, Palmelund Krag S, Iversen LH, Gotschalck Sunesen K, Lin CJ, Zimmermann BG, Lindbjerg Andersen C. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol 2019; 5(8): 1124–1131

[16] Tie J, Cohen JD, Wang Y, Christie M, Simons K, Lee M, Wong R, Kosmider S, Ananda S, McKendrick J, Lee B, Cho JH, Faragher I, Jones IT, Ptak J, Schaeffer MJ, Silliman N, Dobbyn L, Li L, Tomasetti C, Papadopoulos N, Kinzler KW, Vogelstein B, Gibbs P. Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol 2019; 5(12): 1710–1717

[17] Gou LY, Wu YL. Prevalence of driver mutations in non-small-cell lung cancers in the People’s Republic of China. Lung Cancer (Auckl) 2014; 5: 1–9

[18] Vuong HG, Ho ATN, Altibi AMA, Nakazawa T, Katoh R, Kondo T. Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer—a systematic review and meta-analysis. Lung Cancer 2018; 123: 76–82

[19] Drilon A, Cappuzzo F, Ou SI, Camidge DR. Targeting MET in lung cancer: will expectations finally be MET?. J Thorac Oncol 2017; 12(1): 15–26

[20] Rolfo C, Mack P, Scagliotti GV, Aggarwal C, Arcila ME, Barlesi F, Bivona T, Diehn M, Dive C, Dziadziuszko R, Leighl N, Malapelle U, Mok T, Peled N, Raez LE, Sequist L, Sholl L, Swanton C, Abbosh C, Tan D, Wakelee H, Wistuba I, Bunn R, Freeman-Daily J, Wynes M, Belani C, Mitsudomi T, Gandara D. Liquid biopsy for advanced NSCLC: a consensus statement from the international association for the study of lung cancer. J Thorac Oncol 2021; 16(10): 1647–1662

[21] Gale D, Heider K, Ruiz-Valdepenas A, Hackinger S, Perry M, Marsico G, Rundell V, Wulff J, Sharma G, Knock H, Castedo J, Cooper W, Zhao H, Smith CG, Garg S, Anand S, Howarth K, Gilligan D, Harden SV, Rassl DM, Rintoul RC, Rosenfeld N. Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer. Ann Oncol 2022; 33(5): 500–510

[22] Chen K, Yang F, Shen H, Wang C, Li X, Chervova O, Wu S, Qiu F, Peng D, Zhu X, Chuai S, Beck S, Kanu N, Carbone D, Zhang Z, Wang J. Individualized tumor-informed circulating tumor DNA analysis for postoperative monitoring of non-small cell lung cancer. Cancer Cell 2023; 41(10): 1749–1762.e6

[23] Qiu B, Guo W, Zhang F, Lv F, Ji Y, Peng Y, Chen X, Bao H, Xu Y, Shao Y, Tan F, Xue Q, Gao S, He J. Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC. Nat Commun 2021; 12(1): 6770

[24] Hellmann MD, Nabet BY, Rizvi H, Chaudhuri AA, Wells DK, Dunphy MPS, Chabon JJ, Liu CL, Hui AB, Arbour KC, Luo J, Preeshagul IR, Moding EJ, Almanza D, Bonilla RF, Sauter JL, Choi H, Tenet M, Abu-Akeel M, Plodkowski AJ, Perez Johnston R, Yoo CH, Ko RB, Stehr H, Gojenola L, Wakelee HA, Padda SK, Neal JW, Chaft JE, Kris MG, Rudin CM, Merghoub T, Li BT, Alizadeh AA, Diehn M. Circulating tumor DNA analysis to assess risk of progression after long-term response to PD-(L)1 blockade in NSCLC. Clin Cancer Res 2020; 26(12): 2849–2858

[25] Tang W, Lei Y, Su J, Zhang C, Fu R, Kang J, Yan H, Yang X, Tu H, Wu Y, Zhong W. TNM stages inversely correlate with the age at diagnosis in ALK-positive lung cancer. Transl Lung Cancer Res 2019; 8(2): 144–154

Acknowledgements

This research was supported by funding from the National Natural Science Foundation of China Major Joint Project on Key Scientific Issues of Lung Cancer (No. 82241235), the National Natural Science Foundation of China (No. 81872510), Guangdong Provincial People’s Hospital Young Talent Project (No. GDPPHYTP201902), Guangdong Basic and Applied Basic Research Foundation (No. 2019B1515130002), High-level Hospital Construction Project (No. DFJH201801), and Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer (No. 2017B030314120).

We would like to thank Editage for English language editing.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1060-z and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Wenzhao Zhong declares speaker fees from AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hengrui, Merck Sharp & Dohme, Pfizer, Roche, Sanofi. Yilong Wu declares advisory services for AstraZeneca, Boehringer Ingelheim, Novartis, and Takeda; speaker fees from AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hengrui, Merck Sharp & Dohme, Pfizer, Roche, Sanofi; and grants from AstraZeneca, Boehringer Ingelheim, BMS, Pfizer and Roche outside the submitted work. Yuanyuan Xiong, Miao Cai, Fang Li, and Rongrong Chen are current employees of Geneplus-Beijing Ltd. All financial interests are unrelated to this study. Rui Fu declares that he has no conflict of interest. This study was approved by the Institutional Review Board of the Guangdong Provincial People’s Hospital (No. GDREC2018115H) and the study was performed in accordance with the ethical standards as laid down in the 1975 Declaration of Helsinki and its later amendments. Informed consent was obtained from all patients for being included in the study.

RIGHTS & PERMISSIONS

2024 Higher Education Press