Using plasma cell-free DNA to monitor the chemoradiotherapy course of cervical cancer

Jichao Tian, Yan Geng, Dekang Lv, Peiying Li, Miguel Cordova, Yuwei Liao, Xiaoyuan Tian, Xiaolong Zhang, Qingzheng Zhang, Kun Zou, Yu Zhang, Xia Zhang, Yulong Li, Jian Zhang, Zhaokui Ma, Yanyan Shao, Luyao Song, Gareth I Owen, Tingting Li, Ruimei Liu, Quentin Liu, Lijuan Zou, Zhuo Zhang, Zhiguang Li, Jichao Tian, Yan Geng, Dekang Lv, Peiying Li, Miguel Cordova, Yuwei Liao, Xiaoyuan Tian, Xiaolong Zhang, Qingzheng Zhang, Kun Zou, Yu Zhang, Xia Zhang, Yulong Li, Jian Zhang, Zhaokui Ma, Yanyan Shao, Luyao Song, Gareth I Owen, Tingting Li, Ruimei Liu, Quentin Liu, Lijuan Zou, Zhuo Zhang, Zhiguang Li

Abstract

The liquid biopsy is being integrated into cancer diagnostics and surveillance. However, critical questions still remain, such as how to precisely evaluate cancer mutation burden and interpret the corresponding clinical implications. Herein, we evaluated the role of peripheral blood cell-free DNA (cfDNA) in characterizing the dynamic mutation alterations of 48 cancer driver genes from cervical cancer patients. We performed targeted deep sequencing on 93 plasma cfDNA from 57 cervical cancer patients and from this developed an algorithm, allele fraction deviation (AFD), to monitor in an unbiased manner the dynamic changes of genomic aberrations. Differing treatments, including chemotherapy (n = 22), radiotherapy (n = 14) and surgery (n = 15), led to a significant decrease in AFD values (Wilcoxon, p = 0.029). The decrease of cfDNA AFD values was accompanied by shrinkage in the size of the tumor in most patients. However, in a subgroup of patients where cfDNA AFD values did not reflect a reduction in tumor size, there was a detection of progressive disease (metastasis). Furthermore, a low AFD value at diagnosis followed a later increase of AFD value also successfully predicted relapse. These results show that plasma cfDNA, together with targeted deep sequencing, may help predict treatment response and disease development in cervical cancer.

Keywords: allele fraction deviation; cell-free DNA; cervical cancer; chemoradiotherapy; targeted sequencing.

© 2019 UICC.

References

    1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.
    1. Petignat P, Roy M. Diagnosis and management of cervical cancer. BMJ 2007;335:765-8.
    1. Xu JZ, Wen F, Wang XR. The eIF3a Arg803Lys genetic polymorphism is associated with susceptibility to and chemoradiotherapy efficacy in cervical carcinoma. Kaohsiung J Med Sci 2017;33:187-94.
    1. Tewari KS, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;370:734-43.
    1. Lo YM, Chan KC, Sun H, et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med 2010;2:61ra91.
    1. Fan HC, Blumenfeld YJ, Chitkara U, et al. Analysis of the size distributions of fetal and maternal cell-free DNA by paired-end sequencing. Clin Chem 2010;56:1279-86.
    1. Thierry AR, El Messaoudi S, Gahan PB, et al. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev 2016;35:347-76.
    1. Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med 2008;14:985-90.
    1. Yung TK, Chan KC, Mok TS, et al. Single-molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non-small cell lung cancer patients. Clin Cancer Res 2009;15:2076-84.
    1. Burgener JM, Rostami A, De Carvalho DD, et al. Cell-free DNA as a post-treatment surveillance strategy: current status. Semin Oncol 2017;44:330-46.
    1. Alix-Panabieres C, Pantel K. Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov 2016;6:479-91.
    1. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014;6:224ra224.
    1. Jahr S, Hentze H, Englisch S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 2001;61:1659-65.
    1. Page K, Guttery DS, Fernandez-Garcia D, et al. Next generation sequencing of circulating cell-free DNA for evaluating mutations and gene amplification in metastatic breast cancer. Clin Chem 2017;63:532-41.
    1. Bohers E, Viailly PJ, Dubois S, et al. Somatic mutations of cell-free circulating DNA detected by next-generation sequencing reflect the genetic changes in both germinal center B-cell-like and activated B-cell-like diffuse large B-cell lymphomas at the time of diagnosis. Haematologica 2015;100:e280-4.
    1. Chicard M, Colmet-Daage L, Clement N, et al. Whole-exome sequencing of cell-free DNA reveals temporo-spatial heterogeneity and identifies treatment-resistant clones in neuroblastoma. Clin Cancer Res 2018;24:939-49.
    1. Shen S, Wei Y, Zhang R, et al. Mutant-allele fraction heterogeneity is associated with non-small cell lung cancer patient survival. Oncol Lett 2018;15:795-802.
    1. Kalatskaya I, Trinh QM, Spears M, et al. ISOWN: accurate somatic mutation identification in the absence of normal tissue controls. Genome Med 2017;9:59.
    1. Kamps R, Brandao RD, Bosch BJ, Paulussen AD, Xanthoulea S, Blok MJ, Romano A. Next-generation sequencing in oncology: genetic diagnosis, risk prediction and cancer classification. Int J Mol Sci 2017;18.
    1. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 2010;26:589-95.
    1. Koboldt DC, Zhang Q, Larson DE, et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 2012;22:568-76.
    1. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164.
    1. Karczewski KJ, Weisburd B, Thomas B, et al. The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res 2017;45(D1):D840-5.
    1. Genomes Project Consortium, Abecasis GR, Auton A, et al. An integrated map of genetic variation from 1,092 human genomes. Nature 2012;491:56-65.
    1. Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 2013;31:213-9.
    1. Larson DE, Harris CC, Chen K, et al. SomaticSniper: identification of somatic point mutations in whole genome sequencing data. Bioinformatics 2012;28:311-7.
    1. Supek F, Minana B, Valcarcel J, et al. Synonymous mutations frequently act as driver mutations in human cancers. Cell 2014;156:1324-35.
    1. Guo N, Lou F, Ma Y, et al. Circulating tumor DNA detection in lung cancer patients before and after surgery. Sci Rep 2016;6:33519.
    1. Ng SB, Chua C, Ng M, et al. Individualised multiplexed circulating tumour DNA assays for monitoring of tumour presence in patients after colorectal cancer surgery. Sci Rep 2017;7:40737.
    1. Parkinson CA, Gale D, Piskorz AM, et al. Exploratory analysis of TP53 mutations in circulating tumour DNA as biomarkers of treatment response for patients with relapsed high-grade serous ovarian carcinoma: a retrospective study. PLoS Med 2016;13:e1002198.
    1. Marcus CD, Ladam-Marcus V, Cucu C, et al. Imaging techniques to evaluate the response to treatment in oncology: current standards and perspectives. Crit Rev Oncol Hematol 2009;72:217-38.
    1. Suzuki C, Jacobsson H, Hatschek T, et al. Radiologic measurements of tumor response to treatment: practical approaches and limitations. Radiographics 2008;28:329-44.
    1. Strickler JH, Loree JM, Ahronian LG, et al. Genomic landscape of cell-free DNA in patients with colorectal cancer. Cancer Discov 2018;8:164-73.
    1. Barbano R, Pasculli B, Coco M, et al. Competitive allele-specific TaqMan PCR (cast-PCR) is a sensitive, specific and fast method for BRAF V600 mutation detection in melanoma patients. Sci Rep 2015;5:18592.
    1. Zonta E, Garlan F, Pecuchet N, et al. Multiplex detection of rare mutations by picoliter droplet based digital PCR: sensitivity and specificity considerations. PLoS One 2016;11:e0159094.
    1. Ashida A, Sakaizawa K, Mikoshiba A, et al. Quantitative analysis of the BRAF (V600E) mutation in circulating tumor-derived DNA in melanoma patients using competitive allele-specific TaqMan PCR. Int J Clin Oncol 2016;21:981-8.
    1. Siravegna G, Marsoni S, Siena S, et al. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol 2017;14:531-48.
    1. Reis-Filho JS. Next-generation sequencing. Breast Cancer Res 2009;11(Suppl 3):S12.
    1. Hung SS, Meissner B, Chavez EA, et al. Assessment of capture and amplicon-based approaches for the development of a targeted next-generation sequencing pipeline to personalize lymphoma management. J Mol Diagn 2018;20:203-14.
    1. Betge J, Kerr G, Miersch T, et al. Amplicon sequencing of colorectal cancer: variant calling in frozen and formalin-fixed samples. PLoS One 2015;10:e0127146.
    1. Yan B, Hu Y, Ng C, et al. Coverage analysis in a targeted amplicon-based next-generation sequencing panel for myeloid neoplasms. J Clin Pathol 2016;69:801-4.
    1. Jennings LJ, Arcila ME, Corless C, et al. Guidelines for validation of next-generation sequencing-based oncology panels: a Joint Consensus Recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagn 2017;19:341-65.
    1. Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 2016;8:346ra392.
    1. Shoda K, Ichikawa D, Fujita Y, et al. Monitoring the HER2 copy number status in circulating tumor DNA by droplet digital PCR in patients with gastric cancer. Gastric Cancer 2017;20:126-35.
    1. Tjensvoll K, Lapin M, Buhl T, et al. Clinical relevance of circulating KRAS mutated DNA in plasma from patients with advanced pancreatic cancer. Mol Oncol 2016;10:635-43.
    1. Chung TKH, Cheung TH, Yim SF, et al. Liquid biopsy of PIK3CA mutations in cervical cancer in Hong Kong Chinese women. Gynecol Oncol 2017;146:334-9.
    1. Schou JV, Larsen FO, Sorensen BS, et al. Circulating cell-free DNA as predictor of treatment failure after neoadjuvant chemo-radiotherapy before surgery in patients with locally advanced rectal cancer. Ann Oncol 2018;29:610-5.
    1. Vandekerkhove G, Todenhofer T, Annala M, et al. Circulating tumor DNA reveals clinically actionable somatic genome of metastatic bladder cancer. Clin Cancer Res 2017;23:6487-97.
    1. Bottini A, Berruti A, Bersiga A, et al. Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer. Br J Cancer 2001;85:1106-12.
    1. Ball D, Mitchell A, Giroux D, et al. Effect of tumor size on prognosis in patients treated with radical radiotherapy or chemoradiotherapy for non-small cell lung cancer. An analysis of the staging project database of the International Association for the Study of Lung Cancer. J Thorac Oncol 2013;8:315-21.
    1. Abel EJ, Culp SH, Tannir NM, et al. Early primary tumor size reduction is an independent predictor of improved overall survival in metastatic renal cell carcinoma patients treated with sunitinib. Eur Urol 2011;60:1273-9.
    1. Suzuki C, Blomqvist L, Sundin A, et al. The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy. Ann Oncol 2012;23:948-54.
    1. Garcia-Saenz JA, Ayllon P, Laig M, et al. Tumor burden monitoring using cell-free tumor DNA could be limited by tumor heterogeneity in advanced breast cancer and should be evaluated together with radiographic imaging. BMC Cancer 2017;17:210.
    1. Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013;368:1199-209.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe