Mutational evolution after chemotherapy-progression in metastatic colorectal cancer revealed by circulating tumor DNA analysis
Sheehyun Kim
Department of Genomic Medicine, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorYongjun Cha
Center for Colorectal Cancer, National Cancer Center, Research Institute and Hospital, Goyang, South Korea
Search for more papers by this authorYoojoo Lim
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorKyung-Hun Lee
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
Cancer Research Institute, Seoul National University, Seoul, South Korea
Search for more papers by this authorMin Jung Kim
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorJi Won Park
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorSeung-Bum Ryoo
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorSeung-Yong Jeong
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorKyu Joo Park
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorCorresponding Author
Sae-Won Han
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
Cancer Research Institute, Seoul National University, Seoul, South Korea
Correspondence
Sae-Won Han, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
Email: [email protected]
Search for more papers by this authorTae-You Kim
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
IMBdx, Inc., Seoul, South Korea
Cancer Research Institute, Seoul National University, Seoul, South Korea
Search for more papers by this authorSheehyun Kim
Department of Genomic Medicine, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorYongjun Cha
Center for Colorectal Cancer, National Cancer Center, Research Institute and Hospital, Goyang, South Korea
Search for more papers by this authorYoojoo Lim
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorKyung-Hun Lee
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
Cancer Research Institute, Seoul National University, Seoul, South Korea
Search for more papers by this authorMin Jung Kim
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorJi Won Park
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorSeung-Bum Ryoo
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorSeung-Yong Jeong
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorKyu Joo Park
Department of Surgery, Seoul National University Hospital, Seoul, South Korea
Search for more papers by this authorCorresponding Author
Sae-Won Han
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
Cancer Research Institute, Seoul National University, Seoul, South Korea
Correspondence
Sae-Won Han, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
Email: [email protected]
Search for more papers by this authorTae-You Kim
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
IMBdx, Inc., Seoul, South Korea
Cancer Research Institute, Seoul National University, Seoul, South Korea
Search for more papers by this authorSheehyun Kim and Yongjun Cha contributed equally to this work.
Abstract
Emerging new mutations after treatment can provide clues to acquired resistant mechanisms. Circulating tumor DNA (ctDNA) sequencing has enabled noninvasive repeated tumor mutational profiling. We aimed to investigate newly emerging mutations in ctDNA after disease progression in metastatic colorectal cancer (mCRC). Blood samples were prospectively collected from mCRC patients receiving palliative chemotherapy before treatment and at radiological evaluations. ctDNA from pretreatment and progressive disease (PD) samples were sequenced with a next-generation sequencing panel targeting 106 genes. A total of 712 samples from 326 patients were analyzed, and 381 pretreatment and PD pairs (163 first-line, 85 second-line and 133 later-line [≥third-line]) were compared. New mutations in PD samples (mean 2.75 mutations/sample) were observed in 49.6% (189/381) of treatments. ctDNA samples from later-line had more baseline mutations (P = .002) and were more likely to have new PD mutations (adjusted odds ratio [OR] 2.27, 95% confidence interval [CI]: 1.40-3.69) compared to first-line. RAS/BRAF wild-type tumors were more likely to develop PD mutations (adjusted OR 1.87, 95% CI: 1.22-2.87), independent of cetuximab treatment. The majority of new PD mutations (68.5%) were minor clones, suggesting an increasing clonal heterogeneity after treatment. Pathways involved by PD mutations differed by the treatment received: MAPK cascade (Gene Ontology [GO]: 0000165) in cetuximab and regulation of kinase activity (GO: 0043549) in regorafenib. The number of mutations revealed by ctDNA sequencing increased during disease progression in mCRC. Clonal heterogeneity increased after chemotherapy progression, and pathways involved were affected by chemotherapy regimens.
Graphical Abstract
What's new?
Mutations that arise during treatment for metastatic colorectal cancer (mCRC) can fuel the development of treatment-resistant tumors. Tracking the mutational evolution of mCRC, however, is challenged by limitations in existing approaches. Here, the authors investigated newly emerging mutations by sequencing circulating tumor DNA (ctDNA) from progressive mCRC patients following conventional treatments. Mutations that emerged in association with treatment were identified in half of progressive disease samples. New mutations were dominantly subclonal variants and were more frequently observed in later-line treatments and RAS/BRAF wild-type tumors. The findings cast new light on relationships between emergent mutations and treatment in progressive mCRC.
CONFLICT OF INTEREST STATEMENT
Yongjun Cha received consulting fees from IMBdx; Yoojoo Lim, Hanseong Roh and Jun-Kyu Kang are employees of IMBdx; Hwang-Phill Kim is an employee and stock owner of IMBdx; Sae-Won Han received honoraria and a research fund from IMBdx and Tae-You Kim is a co-founder and stock owner of IMBdx. The other authors declare no competing interest.
Open Research
DATA AVAILABILITY STATEMENT
All the NGS data of ctDNA sequencing are available on the NCBI Sequence Read Archive (SRA) database with links to BioProject (https://www.ncbi.nlm.nih.gov/bioproject/) accession number PRJNA933526. The data that support the findings of our study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ijc34558-sup-0001-Supinfo.pdfPDF document, 713.6 KB | Data S1. Supporting Information. |
| ijc34558-sup-0002-TableS2.xlsxExcel 2007 spreadsheet , 67.6 KB | Table S2. Sequencing statistics of study samples. |
| ijc34558-sup-0003-TableS3.xlsxExcel 2007 spreadsheet , 36.7 KB | Table S3. Treatment information with date of blood sampling. |
| ijc34558-sup-0004-TableS4.xlsxExcel 2007 spreadsheet , 68.2 KB | Table S4. List of newly emerging PD mutations. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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