Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non-Small Cell Lung Cancer
Jia-Tao Zhang, Si-Yang Liu, Wei Gao, Si-Yang Maggie Liu, Hong-Hong Yan, Liyan Ji, Yu Chen, Yuhua Gong, Hong-Lian Lu, Jun-Tao Lin, Kai Yin, Ben-Yuan Jiang, Qiang Nie, Ri-Qiang Liao, Song Dong, Yanfang Guan, Pingping Dai, Xu-Chao Zhang, Jin-Ji Yang, Hai-Yan Tu, Xuefeng Xia, Xin Yi, Qing Zhou, Wen-Zhao Zhong, Xue-Ning Yang, Yi-Long Wu, Jia-Tao Zhang, Si-Yang Liu, Wei Gao, Si-Yang Maggie Liu, Hong-Hong Yan, Liyan Ji, Yu Chen, Yuhua Gong, Hong-Lian Lu, Jun-Tao Lin, Kai Yin, Ben-Yuan Jiang, Qiang Nie, Ri-Qiang Liao, Song Dong, Yanfang Guan, Pingping Dai, Xu-Chao Zhang, Jin-Ji Yang, Hai-Yan Tu, Xuefeng Xia, Xin Yi, Qing Zhou, Wen-Zhao Zhong, Xue-Ning Yang, Yi-Long Wu
Abstract
The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non-small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC.
Significance: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599.
©2022 The Authors; Published by the American Association for Cancer Research.
Figures
References
- Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. . Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552–9.
- Burdett S, Rydzewska L, Tierney JF, Fisher DJ, PORT Meta-analysis Trialist Group. A closer look at the effects of postoperative radiotherapy by stage and nodal status: updated results of an individual participant data meta-analysis in non–small-cell lung cancer. Lung Cancer 2013;80:350–2.
- Le Pechoux C, Pourel N, Barlesi F, Faivre-Finn C, Lerouge D, Zalcman G, et al. . LBA3_PR An international randomized trial, comparing postoperative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non–small cell lung cancer (NSCLC) and mediastinal N2 involvement: primary end-point analysis of LungART (IFCT-0503, UK NCRI, SAKK) NCT00410683. Ann Oncol 2020;31:S1178.
- Wu YL, Tsuboi M, He J, John T, Grohe C, Majem M, et al. . Osimertinib in resected EGFR-mutated non–small-cell lung cancer. N Engl J Med 2020;383:1711–23.
- Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, et al. . Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021;398:1344–57.
- Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, et al. . An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 2014;20:548–54.
- Zviran A, Schulman RC, Shah M, Hill STK, Deochand S, Khamnei CC, et al. . Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med 2020;26:1114–24.
- Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F, et al. . Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol 2016;34:547–55.
- Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, et al. . Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 2017;545:446–51.
- Chae YK, Oh MS. Detection of minimal residual disease using ctDNA in lung cancer: current evidence and future directions. J Thorac Oncol 2019;14:16–24.
- Pantel K, Alix-Panabières C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol 2019;16:409–24.
- Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, et al. . Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov 2017;7:1394–403.
- Moding EJ, Liu Y, Nabet BY, Chabon JJ, Chaudhuri AA, Hui AB, et al. . Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non–small-cell lung cancer. Nat Cancer 2020;1:176–83.
- Qiu B, Guo W, Zhang F, Lv F, Ji Y, Peng Y, et al. . Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC. Nat Commun 2021;12:6770.
- Abbosh C, Birkbak NJ, Swanton C. Early stage NSCLC - challenges to implementing ctDNA-based screening and MRD detection. Nat Rev Clin Oncol 2018;15:577–86.
- Powles T, Assaf ZJ, Davarpanah N, Banchereau R, Szabados BE, Yuen KC, et al. . ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 2021;595:432–7.
- Chouaid C, Danson S, Andreas S, Siakpere O, Benjamin L, Ehness R, et al. . Adjuvant treatment patterns and outcomes in patients with stage IB-IIIA non-small cell lung cancer in France, Germany, and the United Kingdom based on the LuCaBIS burden of illness study. Lung Cancer 2018;124:310–6.
- Buck PO, Saverno KR, Miller PJ, Arondekar B, Walker MS. Treatment patterns and health resource utilization among patients diagnosed with early stage resected non-small cell lung cancer at US community oncology practices. Clin Lung Cancer 2015;16:486–95.
- Wu YL, John T, Grohe C, Majem M, Goldman JW, Kim SW, et al. . Postoperative chemotherapy and outcomes from ADAURA: osimertinib as adjuvant therapy for resected EGFR-Mutated NSCLC. J Thorac Oncol 2021;17:423–33.
- Garcia-Murillas I, Chopra N, Comino-Méndez I, Beaney M, Tovey H, Cutts RJ, et al. . Assessment of molecular relapse detection in early-stage breast cancer. JAMA Oncol 2019;5:1473–8.
- Li YS, Jiang BY, Yang JJ, Zhang XC, Zhang Z, Ye JY, et al. . Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy. Ann Oncol 2018;29:945–52.
- De Mattos-Arruda L, Mayor R, Ng CKY, Weigelt B, Martínez-Ricarte F, Torrejon D, et al. . Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun 2015;6:8839.
- Seoane J, De Mattos-Arruda L, Le Rhun E, Bardelli A, Weller M. Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases. Ann Oncol 2019;30:211–8.
- Dudley JC, Schroers-Martin J, Lazzareschi DV, Shi WY, Chen SB, Esfahani MS, et al. . Detection and surveillance of bladder cancer using urine tumor DNA. Cancer Discov 2019;9:500–9.
- Razavi P, Li BT, Brown DN, Jung B, Hubbell E, Shen R, et al. . High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Nat Med 2019;25:1928–37.
- Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. . Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014;371:2477–87.
- Thompson JC, Yee SS, Troxel AB, Savitch SL, Fan R, Balli D, et al. . Detection of therapeutically targetable driver and resistance mutations in lung cancer patients by next-generation sequencing of cell-free circulating tumor DNA. Clin Cancer Res 2016;22:5772–82.
- Jiang J, Adams HP, Yao L, Yaung S, Lal P, Balasubramanyam A, et al. . Concordance of genomic alterations by next-generation sequencing in tumor tissue versus cell-free DNA in stage I–IV non–small cell lung cancer. J Mol Diagn 2020;22:228–35.
- Guo Q, Wang J, Xiao J, Wang L, Hu X, Yu W, et al. . Heterogeneous mutation pattern in tumor tissue and circulating tumor DNA warrants parallel NGS panel testing. Mol Cancer 2018;17:131.
- Jamal-Hanjani M, Wsilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. . Tracking the evolution of non–small-cell lung cancer. N Engl J Med 2017;376:2109–21.
- Zhang Y, Yao Y, Xu Y, Li L, Gong Y, Zhang K, et al. . Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients. Nat Commun 2021;12:11.
- Lin G, Li C, Li PS, Fang WZ, Xu HP, Gong YH, et al. . Genomic origin and EGFR-TKI treatments of pulmonary adenosquamous carcinoma. Ann Oncol 2020;31:517–24.
- Xu ST, Xi JJ, Zhong WZ, Mao WM, Wu L, Shen Y, et al. . The unique spatial-temporal treatment failure patterns of adjuvant gefitinib therapy: a post hoc analysis of the ADJUVANT trial (CTONG 1104). J Thorac Oncol 2019;14:503–12.
Source: PubMed