Theranostics 2017; 7(19):4753-4762. doi:10.7150/thno.21687 This issue Cite

Research Paper

Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC

Tao Jiang1*, Xuefei Li2*, Jianfei Wang3*, Chunxia Su1, Wenbo Han3, Chao Zhao2, Fengying Wu1, Guanghui Gao1, Wei Li1, Xiaoxia Chen1, Jiayu Li1, Fei Zhou1, Jing Zhao1, Weijing Cai1, Henghui Zhang3, Bo Du3, Jun Zhang4✉, Shengxiang Ren1✉, Caicun Zhou1✉, Hui Yu5, Fred R. Hirsch5

1. Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, P.R. China;
2. Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P.R. China;
3. Beijing Genecast Biotechnology Co., Beijing, P.R. China;
4. Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA, USA;
5. Department of Medicine, Division of Medical Oncology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, USA.
* These authors make the same contributions to this paper.

Citation:
Jiang T, Li X, Wang J, Su C, Han W, Zhao C, Wu F, Gao G, Li W, Chen X, Li J, Zhou F, Zhao J, Cai W, Zhang H, Du B, Zhang J, Ren S, Zhou C, Yu H, Hirsch FR. Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC. Theranostics 2017; 7(19):4753-4762. doi:10.7150/thno.21687. https://www.thno.org/v07p4753.htm
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Abstract

Graphic abstract

Rationale To investigate whether the mutational landscape of circulating cell-free DNA (cfDNA) could predict and dynamically monitor the response to first-line platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).

Methods Eligible patients were included and blood samples were collected from a phase III trial. Both cfDNA fragments and fragmented genomic DNA were extracted for enrichment in a 1.15M size panel covering exon regions of 1,086 genes. Molecular mutational burden (MMB) was calculated to investigate the relationship between molecular features of cfDNA and response to chemotherapy.

Results In total, 52 eligible cases were enrolled and their blood samples were prospectively collected at baseline, every cycle of chemotherapy and time of disease progression. At baseline, alterations of 17 genes were found. Patients with partial response (PR) had significantly lower baseline MMB of these genes than those patients with either stable disease (SD) (P = 0.0006) or progression disease (PD) (P = 0.0074). Further analysis revealed that the mutational landscape of cfDNA from pretreatment blood samples were distinctly different among patients with PR vs. SD/PD. For patients with baseline TP53 mutation, those with PR experienced a significant reduction in MMB whereas patients with SD or PD experienced an increase after two, three or four cycles of chemotherapy. Furthermore, patients with low MMB had superior response rate and significantly longer progression-free survival than those with high MMB.

Conclusion This study indicated that the mutational landscape of cfDNA has potential clinical value to predict the therapeutic response to first-line platinum-based doublet chemotherapy in NSCLC patients. At the single gene level, dynamic change of molecular mutational burden of TP53 is valuable to monitor efficacy (and, therefore, might aid in early recognition of resistance and relapse) in patients harboring this mutation at baseline.

Keywords: Non-small-cell lung cancer, circulating cell-free DNA, chemotherapy, molecular mutational burden


Citation styles

APA
Jiang, T., Li, X., Wang, J., Su, C., Han, W., Zhao, C., Wu, F., Gao, G., Li, W., Chen, X., Li, J., Zhou, F., Zhao, J., Cai, W., Zhang, H., Du, B., Zhang, J., Ren, S., Zhou, C., Yu, H., Hirsch, F.R. (2017). Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC. Theranostics, 7(19), 4753-4762. https://doi.org/10.7150/thno.21687.

ACS
Jiang, T.; Li, X.; Wang, J.; Su, C.; Han, W.; Zhao, C.; Wu, F.; Gao, G.; Li, W.; Chen, X.; Li, J.; Zhou, F.; Zhao, J.; Cai, W.; Zhang, H.; Du, B.; Zhang, J.; Ren, S.; Zhou, C.; Yu, H.; Hirsch, F.R. Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC. Theranostics 2017, 7 (19), 4753-4762. DOI: 10.7150/thno.21687.

NLM
Jiang T, Li X, Wang J, Su C, Han W, Zhao C, Wu F, Gao G, Li W, Chen X, Li J, Zhou F, Zhao J, Cai W, Zhang H, Du B, Zhang J, Ren S, Zhou C, Yu H, Hirsch FR. Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC. Theranostics 2017; 7(19):4753-4762. doi:10.7150/thno.21687. https://www.thno.org/v07p4753.htm

CSE
Jiang T, Li X, Wang J, Su C, Han W, Zhao C, Wu F, Gao G, Li W, Chen X, Li J, Zhou F, Zhao J, Cai W, Zhang H, Du B, Zhang J, Ren S, Zhou C, Yu H, Hirsch FR. 2017. Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC. Theranostics. 7(19):4753-4762.

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