Circulating Tumor Cell-Free DNA As Prognostic Biomarker in Non-Small Cell Lung Cancer Patients Undergoing Immunotherapy: The CORELAB Experience

Overview

Journal Int J Mol Sci

Publisher MDPI

Date 2025 Jan 25

PMID 39859325

Authors

Stefania Gelmini

Adele Calabri

Irene Mancini

Camilla Eva Comin

Valeria Pasini

Marco Banini

Vieri Scotti

Pamela Pinzani

Affiliations

Soon will be listed here.

Abstract

The expression level of Programmed Death-Ligand 1 (PD-L1) determined by the immunohistochemical method is currently approved to test the potential efficacy of immune-checkpoint inhibitors and to candidate patients with Non-Small Cell Lung Cancer (NSCLC) for treatment with immunotherapeutic drugs. As part of the CORELAB (New prediCtivebiOmaRkers of activity and Efficacy of immune checkpoint inhibitors in advanced non-small cell Lung cArcinoma) project, aimed at identifying new predictive and prognostic biomarkers in NSCLC patients receiving immunotherapeutic drugs, we investigated the role of circulating tumor DNA (ctDNA) molecular characterization as an additional predictive biomarker. We analyzed plasma ctDNA by targeted Next Generation Sequencing in a subset of 50 patients at different time points. ctDNA content was inversely correlated with the clinical outcome both at a baseline and after 2 months of treatment. OS was significantly higher in patients with ≥50% ctDNA reduction. and were the most frequently mutated genes, and patients with and/or mutations showed worse outcomes than patients without detectable variants or with mutations in other genes. Fewer common variants were found in , , , , , and genes. Our data demonstrated that molecular characterization of ctDNA and also its quantitative evaluation could serve as a dynamic, real-time prognostic, and predictive biomarker, enabling regular molecular monitoring of therapy efficacy in support of other medical examinations.

References

Dong Z, Zhong W, Zhang X, Su J, Xie Z, Liu S . Potential Predictive Value of and Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma. Clin Cancer Res. 2017; 23(12):3012-3024. DOI: 10.1158/1078-0432.CCR-16-2554. View

Zhang Q, Luo J, Wu S, Si H, Gao C, Xu W . Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade. Cancer Discov. 2020; 10(12):1842-1853. PMC: 8358981. DOI: 10.1158/2159-8290.CD-20-0047. View

Yang Y, Liu H, Chen Y, Xiao N, Zheng Z, Liu H . Liquid biopsy on the horizon in immunotherapy of non-small cell lung cancer: current status, challenges, and perspectives. Cell Death Dis. 2023; 14(3):230. PMC: 10066332. DOI: 10.1038/s41419-023-05757-5. View

Schwarzenbach H, Hoon D, Pantel K . Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011; 11(6):426-37. DOI: 10.1038/nrc3066. View

Lahiri A, Maji A, Potdar P, Singh N, Parikh P, Bisht B . Lung cancer immunotherapy: progress, pitfalls, and promises. Mol Cancer. 2023; 22(1):40. PMC: 9942077. DOI: 10.1186/s12943-023-01740-y. View

Haghighat Jahromi A, Zabel M, Okamura R, Hoh C, Kurzrock R . Variant allele fraction of genomic alterations in circulating tumor DNA (%ctDNA) correlates with SUV in PET scan. Am J Nucl Med Mol Imaging. 2021; 11(4):307-312. PMC: 8414395. View

Alama A, Coco S, Genova C, Rossi G, Fontana V, Tagliamento M . Prognostic Relevance of Circulating Tumor Cells and Circulating Cell-Free DNA Association in Metastatic Non-Small Cell Lung Cancer Treated with Nivolumab. J Clin Med. 2019; 8(7). PMC: 6679117. DOI: 10.3390/jcm8071011. View

Ricciuti B, Jones G, Severgnini M, Alessi J, Recondo G, Lawrence M . Early plasma circulating tumor DNA (ctDNA) changes predict response to first-line pembrolizumab-based therapy in non-small cell lung cancer (NSCLC). J Immunother Cancer. 2021; 9(3). PMC: 7996662. DOI: 10.1136/jitc-2020-001504. View

Goh K, Cheng T, Tham S, Lim D . Circulating Biomarkers for Prediction of Immunotherapy Response in NSCLC. Biomedicines. 2023; 11(2). PMC: 9953588. DOI: 10.3390/biomedicines11020508. View

10.

Peng W, Liu Y, Sha H, Wen S, Fang Y, Zhou G . Relationship between plasma circulating cell-free DNA concentration and treatment outcomes including prognosis in patients with advanced non-small cell lung cancer. BMC Pulm Med. 2023; 23(1):348. PMC: 10503004. DOI: 10.1186/s12890-023-02586-2. View

11.

Tang S, Qin C, Hu H, Liu T, He Y, Guo H . Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Progress, Challenges, and Prospects. Cells. 2022; 11(3). PMC: 8834198. DOI: 10.3390/cells11030320. View

12.

Aggarwal C, Leighl N . Next-generation ctDNA-driven clinical trials in precision immuno-oncology. J Immunother Cancer. 2023; 11(1). PMC: 9853228. DOI: 10.1136/jitc-2022-006397. View

13.

Liu B, Hu Z, Ran J, Xie N, Tian C, Tang Y . The circulating tumor DNA (ctDNA) alteration level predicts therapeutic response in metastatic breast cancer: Novel prognostic indexes based on ctDNA. Breast. 2022; 65:116-123. PMC: 9356206. DOI: 10.1016/j.breast.2022.07.010. View

14.

Frost N, Kollmeier J, Vollbrecht C, Grah C, Matthes B, Pultermann D . KRAS/TP53 co-mutations identify long-term responders to first line palliative treatment with pembrolizumab monotherapy in PD-L1 high (≥50%) lung adenocarcinoma. Transl Lung Cancer Res. 2021; 10(2):737-752. PMC: 7947421. DOI: 10.21037/tlcr-20-958. View

15.

Guibert N, Jones G, Beeler J, Plagnol V, Morris C, Mourlanette J . Targeted sequencing of plasma cell-free DNA to predict response to PD1 inhibitors in advanced non-small cell lung cancer. Lung Cancer. 2019; 137:1-6. DOI: 10.1016/j.lungcan.2019.09.005. View

16.

Cisneros-Villanueva M, Hidalgo-Perez L, Rios-Romero M, Cedro-Tanda A, Ruiz-Villavicencio C, Page K . Cell-free DNA analysis in current cancer clinical trials: a review. Br J Cancer. 2022; 126(3):391-400. PMC: 8810765. DOI: 10.1038/s41416-021-01696-0. View

17.

Pavan A, Boscolo Bragadin A, Calvetti L, Ferro A, Zulato E, Attili I . Role of next generation sequencing-based liquid biopsy in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: impact of STK11, KRAS and TP53 mutations and co-mutations on outcome. Transl Lung Cancer Res. 2021; 10(1):202-220. PMC: 7867770. DOI: 10.21037/tlcr-20-674. View

18.

Izevbaye I . RELAY phase 3 randomized study: a step closer to the clinic for ctDNA in non-small cell lung cancer treatment monitoring?. Transl Lung Cancer Res. 2023; 12(11):2151-2156. PMC: 10713271. DOI: 10.21037/tlcr-23-684. View

19.

Salvianti F, Gelmini S, Mancini I, Pazzagli M, Pillozzi S, Giommoni E . Circulating tumour cells and cell-free DNA as a prognostic factor in metastatic colorectal cancer: the OMITERC prospective study. Br J Cancer. 2021; 125(1):94-100. PMC: 8257609. DOI: 10.1038/s41416-021-01399-6. View

20.

Alix-Panabieres C, Marchetti D, Lang J . Liquid biopsy: from concept to clinical application. Sci Rep. 2023; 13(1):21685. PMC: 10709452. DOI: 10.1038/s41598-023-48501-x. View