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Cited by 114Colorectal Cancer Treatments and StudiesCancer Genomics and DiagnosticsGenetic factors in colorectal cancer

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Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer

Open access
Osumi, Hiroki, Shinozaki, Eiji, Yamaguchi, Kensei, Zembutsu, Hitoshi·2019·Scientific Reports
DOI 10.1038/s41598-019-53711-3PMC PMC6874682
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Abstract

The impact of ctDNA changes after chemotherapy on the clinical outcomes of patients with metastatic colorectal cancer (mCRC) remains unclear. The present study evaluated the clinical implications of the early change in ctDNA levels as a predictor of objective response and clinical outcome in mCRC patients who received chemotherapy. We investigated the effects of after/before ratio of ctDNA levels 2 and 8 weeks after initiation of second-line chemotherapy, on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). ctDNA was detected using amplicon-based deep sequencing with a molecular barcode encompassing >240 hotspot mutations in 14 colon cancer-related genes. In multivariate analysis, as compared to baseline, patients with lower ctDNA level (≤50%) 8 weeks after initiation of chemotherapy showed significantly longer PFS and OS than the patients with higher (>50%) ctDNA level. In patients achieving a partial response or stable disease, the after/before ratio of ctDNA level 8 weeks after initiation of chemotherapy was significantly lower than those in patients with progressive disease. The present study suggests that an early change in the ctDNA level might serve as a biomarker to predict the chemotherapeutic efficacy and clinical outcomes in patients with mCRC.

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Figure 1 Mutant allele frequencies in cell-free DNA (cfDNA) of metastatic colorectal cancer (mCRC) patients. Genomic landscape of the mutations detected in the plasma of 29 patients with mCRC. The numbers and frequencies of the mutant alleles in 8 genes detected in 29 patients are shown. Grey panel, no mutation detected; White panel, not tested.
Figure 1 Mutant allele frequencies in cell-free DNA (cfDNA) of metastatic colorectal cancer (mCRC) patients. Genomic landscape of the mutations detected in the plasma of 29 patients with mCRC. The numbers and frequencies of the mutant alleles in 8 genes detected in 29 patients are shown. Grey panel, no mutation detected; White panel, not tested.CC BY · PubMed Central
Figure 2 Changes in ctDNA levels in mCRC patients treated with second-line chemotherapy. ctDNA analysis at baseline, 2 weeks and 8 weeks after initiation of second-line chemotherapy in all the patients (A) and the patients with PD and SD or PR (B). Treatment responses were evaluated by CT images.
Figure 2 Changes in ctDNA levels in mCRC patients treated with second-line chemotherapy. ctDNA analysis at baseline, 2 weeks and 8 weeks after initiation of second-line chemotherapy in all the patients (A) and the patients with PD and SD or PR (B). Treatment responses were evaluated by CT images.CC BY · PubMed Central
Figure 3 Kaplan-Meier estimates of PFS and OS with respect to ctDNA levels in mCRC patients treated with second-line chemotherapy. Comparison of PFS (A) and OS (B) in patients with after/before ratio of ctDNA level >50% and ≤50% at 2 weeks after initiation of the second-line chemotherapy. Comparison of PFS (C) and OS (D) in patients with after/before ratio of ctDNA level >50% and ≤50% 8 weeks after initiation of the second-line chemotherapy. P values were calculated using log-rank test.
Figure 3 Kaplan-Meier estimates of PFS and OS with respect to ctDNA levels in mCRC patients treated with second-line chemotherapy. Comparison of PFS (A) and OS (B) in patients with after/before ratio of ctDNA level >50% and ≤50% at 2 weeks after initiation of the second-line chemotherapy. Comparison of PFS (C) and OS (D) in patients with after/before ratio of ctDNA level >50% and ≤50% 8 weeks after initiation of the second-line chemotherapy. P values were calculated using log-rank test.CC BY · PubMed Central
Figure 4 Association between ctDNA response and clinical response after chemotherapy. (A) ctDNA response (after/before ratios of ctDNA levels 8 weeks after initiation of the chemotherapy) is significantly associated with objective response in mCRC patients treated with second-line chemotherapy (P = 0.006). (B) ctDNA response strongly correlated with the tumor shrinkage ratio 8 weeks after initiation of the chemotherapy (r = 0.52, P = 0.006). P values were calculated by Spearman correlation method and linear regression was performed.
Figure 4 Association between ctDNA response and clinical response after chemotherapy. (A) ctDNA response (after/before ratios of ctDNA levels 8 weeks after initiation of the chemotherapy) is significantly associated with objective response in mCRC patients treated with second-line chemotherapy (P = 0.006). (B) ctDNA response strongly correlated with the tumor shrinkage ratio 8 weeks after initiation of the chemotherapy (r = 0.52, P = 0.006). P values were calculated by Spearman correlation method and linear regression was performed.CC BY · PubMed Central

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Metadata

Authors
Osumi, H., Shinozaki, E., Yamaguchi, K., & Zembutsu, H.
Affiliations
Japanese Foundation For Cancer Research (JP)
Corresponding author
Zembutsu, Hitoshi
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-11-22
Volume
9
Issue
1
Pages
17358-17358
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-019-53711-3
PMC
PMC6874682
OpenAlex
W2991166240
Cited by
114
References
46
Citations by year
2026: 10 · 2025: 13 · 2024: 9 · 2023: 17 · 2022: 21 · 2021: 21 · 2020: 23
FWCI
6.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Japan Society for the Promotion of Science (18K07310)
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
circulating tumor DNA, metastatic colorectal cancer, second-line chemotherapy, objective response rate, predictive biomarkers, progression-free survival, overall survival, mutational hotspots, treatment response prediction
MeSH terms
Liquid Biopsy, Circulating Tumor DNA, Adenocarcinoma, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Predictive Value of Tests, Prognosis, Biomarkers, Tumor, Colorectal Neoplasms, Early Diagnosis, Biomarkers, Pharmacological, High-Throughput Nucleotide Sequencing

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