Circulating tumor DNA serial monitoring of relapse and responses to tislelizumab immunotherapy as second‑line monotherapy for metastatic esophageal squamous cell carcinoma: A prospective study

He,Qiong; He,Qiong; Shi,Xun; Shi,Xun; Yan,Junrong; Yan,Junrong; Wu,Mengmeng; Wu,Mengmeng; Gu,Cuiping; Gu,Cuiping; Yu,Xinmin; Yu,Xinmin

doi:10.3892/mco.2024.2727

Circulating tumor DNA serial monitoring of relapse and responses to tislelizumab immunotherapy as second‑line monotherapy for metastatic esophageal squamous cell carcinoma: A prospective study

Authors:
- Qiong He
- Xun Shi
- Junrong Yan
- Mengmeng Wu
- Cuiping Gu
- Xinmin Yu
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Affiliations: Department of Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China, Medical Department, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu 210032, P.R. China
Published online on: February 9, 2024 https://doi.org/10.3892/mco.2024.2727
Article Number: 29
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Anti‑programmed cell death 1 immuno‑monotherapy has become the second‑line standard treatment for advanced esophageal squamous cell carcinoma (ESCC) after the failure of first‑line chemotherapy. However, new biomarkers are still needed to identify patients at risk of tumor progression and to select patients with advanced ESCC who are likely to benefit from immunotherapy. A total of 12 patients with advanced ESCC treated with tislelizumab were prospectively enrolled and endoscopic biopsy samples were collected. Plasma was obtained prior to and after every 2‑3 treatment cycles with tislelizumab and when disease progression occurred. Targeted sequencing of 425 genes from plasma cell‑free DNA, DNA from leukocytes and fixed esophageal tumor biopsies was performed. The patients underwent imaging analyses every 6‑8 weeks until disease progression. The association between status of circulating tumor DNA (ctDNA) or changes in ctDNA following tislelizumab immunotherapy and response, tumor progression and survival was determined. All patients had evaluable next‑generation sequencing results at the time of analysis. The results showed that patients with ESCC with liver metastasis had a significantly shorter median progression‑free survival (mPFS: 1.4 vs. 11.7 months; P=0.037). TSC complex subunit 2 [11.7 months vs. not reached (NR); P=0.004] and zinc finger protein 217 (11.7 months vs. NR; P=0.022) gene mutations were the independent and negative prognostic factors for median overall survival (OS), respectively. Of note, ctDNA dynamic changes expressed as ∆ mutant molecules per milliliter of plasma (∆MMPM; MMPM detected at the first monitoring time‑point after the first infusion of tislelizumab as baseline MMPM) predicted progression‑free survival (PFS) and OS more accurately compared to the ctDNA change of an individual gene. ∆MMPM <20% was an independent predictor of PFS (2.8 vs. 14.6 months; P=0.029), although there was no significant difference for OS (16.7 vs. 17.6 months; P=0.830). In conclusion, changes in ctDNA levels were associated with anti‑tumor effects, progression and disease‑specific survival. ctDNA sequencing is promising for predicting response and progression after tislelizumab immunotherapy as second‑line monotherapy for advanced ESCC [the present study was part of the RATIONALE‑302 study (ClinicalTrials.gov identifier no. NCT03430843; 29.01.2018)].

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1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021.PubMed/NCBI View Article : Google Scholar
2	Arnold M, Soerjomataram I, Ferlay J and Forman D: Global incidence of oesophageal cancer by histological subtype in 2012. Gut. 64:381–387. 2015.PubMed/NCBI View Article : Google Scholar
3	Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al: Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 373:1627–1639. 2015.PubMed/NCBI View Article : Google Scholar
4	Asaoka Y, Ijichi H and Koike K: PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 373(1979)2015.PubMed/NCBI View Article : Google Scholar
5	Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, Berry S, Chartash EK, Daud A, Fling SP, et al: PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 374:2542–2552. 2016.PubMed/NCBI View Article : Google Scholar
6	Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, et al: Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 20:1506–1517. 2019.PubMed/NCBI View Article : Google Scholar
7	Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, et al: Randomized Phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol. 38:4138–4148. 2020.PubMed/NCBI View Article : Google Scholar
8	Huang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, Chen J, Zhang H, Niu Z, Fan Q, et al: Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): A multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 21:832–842. 2020.PubMed/NCBI View Article : Google Scholar
9	Schneider PRM, Metzger R, Schaefer H, Baumgarten F, Vallbohmer D, Brabender J, Wolfgarten E, Bollschweiler E, Baldus SE, Dienes HP and Hoelscher AH: Response evaluation by endoscopy, rebiopsy, and endoscopic ultrasound does not accurately predict histopathologic regression after neoadjuvant chemoradiation for esophageal cancer. Ann Surg. 248:902–908. 2008.PubMed/NCBI View Article : Google Scholar
10	Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, et al: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 373:23–34. 2015.PubMed/NCBI View Article : Google Scholar
11	Bidard FC, Weigelt B and Reis-Filho JS: Going with the flow: From circulating tumor cells to DNA. Sci Transl Med. 5(207ps14)2013.PubMed/NCBI View Article : Google Scholar
12	Diaz LA Jr and Bardelli A: Liquid biopsies: Genotyping circulating tumor DNA. J Clin Oncol. 32:579–586. 2014.PubMed/NCBI View Article : Google Scholar
13	Alix-Panabières C and Pantel K: Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov. 6:479–491. 2016.PubMed/NCBI View Article : Google Scholar
14	Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, et al: Circulating mutant DNA to assess tumor dynamics. Nat Med. 14:985–990. 2008.PubMed/NCBI View Article : Google Scholar
15	Lu J, Zhong H, Wu J, Chu T, Zhang L, Li H, Wang Q, Li R, Zhao Y, Gu A, et al: Circulating DNA-Based sequencing guided anlotinib therapy in non-small cell lung cancer. Adv Sci (Weinh). 6(1900721)2019.PubMed/NCBI View Article : Google Scholar
16	Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, Ponzetti A, Cremolini C, Amatu A, Lauricella C, et al: Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 21:795–801. 2015.PubMed/NCBI View Article : Google Scholar
17	Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, et al: Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 40:3065–3076. 2022.PubMed/NCBI View Article : Google Scholar
18	Schwartz LH, Seymour L, Litière S, Ford R, Gwyther S, Mandrekar S, Shankar L, Bogaerts J, Chen A, Dancey J, et al: RECIST 1.1-Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group. Eur J Cancer. 62:138–145. 2016.PubMed/NCBI View Article : Google Scholar
19	Bosman FT, Carneiro F, Hruban RH and Theise ND: WHO classification of tumours of 485 the Digestive System, 4th edition. Lyon, IARC, Chapter 2, pp15-37, 2010.
20	Yang Z, Yang N, Ou Q, Xiang Y, Jiang T, Wu X, Bao H, Tong X, Wang X, Shao YW, et al: Investigating novel resistance mechanisms to Third-Generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients. Clin Cancer Res. 24:3097–3107. 2018.PubMed/NCBI View Article : Google Scholar
21	Fang W, Ma Y, Yin JC, Hong S, Zhou H, Wang A, Wang F, Bao H, Wu X, Yang Y, et al: Comprehensive genomic profiling identifies novel genetic predictors of response to Anti-PD-(L)1 therapies in non-small cell lung cancer. Clin Cancer Res. 25:5015–5026. 2019.PubMed/NCBI View Article : Google Scholar
22	Max MX, Bendell JC, Hurwitz HI, Ju C, Lee JJ, Lovejoy A, Mancao C, Nicholas A, Price R, Sommer N, et al: Disease monitoring using Post-induction circulating tumor DNA analysis following First-Line therapy in patients with metastatic colorectal cancer. Clin Cancer Res. 26:4010–4017. 2020.PubMed/NCBI View Article : Google Scholar
23	Herrera AF, Tracy S, Croft B, Opat S, Ray J, Lovejoy AF, Musick L, Paulson JN, Sehn LH and Jiang Y: Risk profiling of patients with relapsed/refractory diffuse large B-cell lymphoma by measuring circulating tumor DNA. Blood Adv. 6:1651–1660. 2022.PubMed/NCBI View Article : Google Scholar
24	Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET and Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 5:649–655. 1982.PubMed/NCBI
25	Xu J, Li Y, Fan Q, Shu Y, Yang L, Cui T, Gu K, Tao M, Wang X, Cui C, et al: Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: A randomized, open-label phase 2 study (ORIENT-2). Nat Commun. 13(857)2022.PubMed/NCBI View Article : Google Scholar
26	Zhou YX, Chen P, Sun YT, Zhang B and Qiu MZ: Comparison of PD-1 inhibitors in patients with advanced esophageal squamous cell carcinoma in the Second-Line setting. Front Oncol. 11(698732)2021.PubMed/NCBI View Article : Google Scholar
27	Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, et al: Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st randomized clinical trial. JAMA. 326:916–925. 2021.PubMed/NCBI View Article : Google Scholar
28	Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, et al: Nivolumab combination therapy in advanced esophageal Squamous-Cell carcinoma. N Engl J Med. 386:449–462. 2022.PubMed/NCBI View Article : Google Scholar
29	Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, Yang S, Fan Y, Shi J, Zhang X, et al: Toripalimab plus chemotherapy in treatment-naive, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell. 40:277–288.e3. 2022.PubMed/NCBI View Article : Google Scholar
30	Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges JP, Li Z, Kim SB, et al: Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet. 398:759–771. 2021.PubMed/NCBI View Article : Google Scholar
31	Thuss-Patience P and Stein A: Immunotherapy in squamous cell cancer of the esophagus. Curr Oncol. 29:2461–2471. 2022.PubMed/NCBI View Article : Google Scholar
32	Chen G, Zhu YJ, Chen J, Miao F, Wu N, Song Y, Mao BB, Wang SZ, Xu F and Chen ZM: Mutational landscape of DNA damage response deficiency-related genes and its association with immune biomarkers in esophageal squamous cell carcinoma. Neoplasma. 69:1314–1321. 2022.PubMed/NCBI View Article : Google Scholar
33	He Q and Yu X: P14.15 Circulating Tumor DNA Predict the response and survival after tislelizumab immunotherapy for advanced esophageal squamous cell carcinoma. J Thoracic Oncol. 16 (Suppl)(S336)2021.