Cancer Res Treat.  2022 Jul;54(3):753-766. 10.4143/crt.2021.905.

The Feasibility of Using Biomarkers Derived from Circulating Tumor DNA Sequencing as Predictive Classifiers in Patients with Small-Cell Lung Cancer

Affiliations
  • 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
  • 2Medical Center, Geneplus-Beijing, Beijing, China
  • 3Department of Medical Oncology, The People's Hospital of Tangshan city, Tangshan, China
  • 4Department of Respiratory and Critical Care Medicine, Beijing Luhe Hospital, Capital Medical University, Beijing, China
  • 5Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China

Abstract

Purpose
To investigate the feasibility of biomarkers based on dynamic circulating tumor DNA (ctDNA) to classify small cell lung cancer (SCLC) into different subtypes.
Materials and Methods
Tumor and longitudinal plasma ctDNA samples were analyzed by next-generation sequencing of 1,021 genes. PyClone was used to infer the molecular tumor burden index (mTBI). Pre-treatment tumor tissues [T1] and serial plasma samples were collected (pre-treatment [B1], after two [B2], six [B3] cycles of chemotherapy and at progression [B4]).
Results
Overall concordance between T1 and B1 sequencing (n=30) was 66.5%, and 89.5% in the gene of RB1. A classification method was designed according to the changes of RB1 mutation, named as subtype Ⅰ (both positive at B1 and B2), subtype Ⅱ (positive at B1 but negative at B2), and subtype Ⅲ (both negative at B1 and B2). The median progressive-free survival for subtype Ⅰ patients (4.5 months [95%CI: 2.6-5.8]) was inferior to subtype Ⅱ (not reached, p<0.0001) and subtype Ⅲ (10.8 months [95%CI: 6.0-14.4], p=0.002). The median overall survival for subtype Ⅰ patients (16.3 months [95%CI: 5.3-22.9]) was inferior to subtype Ⅱ (not reached, p=0.01) and subtype Ⅲ (not reached, p=0.02). Patients with a mTBI dropped to zero at B2 had longer median overall survival (not reached vs. 19.5 months, p=0.01). The changes of mTBI from B4 to B1 were sensitive to predict new metastases, with a sensitivity of 100% and a specificity of 85.7%.
Conclusion
Monitoring ctDNA based RB1 mutation and mTBI provided a feasible tool to predict the prognosis of SCLC.

Keyword

Circulating tumor DNA; Molecular tumor burden index; Overall survival; Progression-free survival; mutation; Small-cell lung cancer; Subtype

Figure

  • Fig. 1 Mutational concordance between tumor DNA and circulating tumor DNA (ctDNA) sequencing. (A) Somatic mutation profiles of paired tumor and ctDNA samples. (B) The number of shared, tissue only, blood only mutations and concordance rate for each individual. (C) Venn diagrams demonstrated the concordance rate between tumor tissue and ctDNA sequencing in terms of all mutations and mutations in TP53, RB1, LRP1B, and FAT1.

  • Fig. 2 Detection rate of TP53 and RB1 mutations at different time points and patients’ survival for different molecular subtypes based RB1 mutation. (A) Proportion of SCLC patients with RB1 from B1 to B4 time points. (B) Proportion of SCLC patients with TP53 mutations from B1 to B4 time points. (C) Classification of molecular groups according to the dynamic changes of TP53 and RB1 mutation from B1 to B2. (D) Kaplan-Meier curves for progression-free survival of patients in different subtypes according to the dynamic changes of RB1 mutation. (E) Kaplan-Meier curves for overall survival of patients in different subtypes according to the dynamic changes of RB1 mutation. CI, confidence interval; mOS, median overall survival; mPFS, median progression-free survival; NR, not reached; SCLC, small cell lung cancer.

  • Fig. 3 The performance of molecular tumor burden index (mTBI) with computed tomography (CT) for evaluating therapeutic response. (A) Evaluation of therapeutic response in 18 patients using mTBI were consistent with CT. (B) Progressive disease was identified earlier using mTBI than by using tumor size. (C) Evaluations in two patients were inconsistent between mTBI and CT.

  • Fig. 4 Changing in circulating tumor DNA and imaging during progressive disease in patients P35. CT (computed tomography): Imaging shows new metastases on right adrenal gland and enlargement of primary lesion. mTBI: Values of molecular tumor burden index at B1, B2 and B4, respectively. C, cycle of first-line chemotherapy; VAF, variant allele frequency.


Reference

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