Mutational evolution after chemotherapy‐progression in metastatic colorectal cancer revealed by circulating tumor DNA analysis

• Published in: International journal of cancer Vol. 153; no. 3; pp. 571 - 583
• Main Authors: Kim, Sheehyun, Cha, Yongjun, Lim, Yoojoo, Roh, Hanseong, Kang, Jun‐Kyu, Lee, Kyung‐Hun, Kim, Min Jung, Park, Ji Won, Ryoo, Seung‐Bum, Kim, Hwang‐Phill, Jeong, Seung‐Yong, Park, Kyu Joo, Han, Sae‐Won, Kim, Tae‐You
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.08.2023; Wiley Subscription Services, Inc
• Subjects: Biomarkers, Tumor - genetics; Cancer; Cetuximab - therapeutic use; Chemotherapy; circulating tumor DNA; Circulating Tumor DNA - genetics; Colonic Neoplasms; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Disease Progression; DNA Mutational Analysis; DNA sequencing; Humans; Kinases; MAP kinase; Medical research; Metastases; Metastasis; metastatic colorectal cancer; Mutation; mutational evolution; Rectal Neoplasms; Tumors; metastatic colorectal cancer; mutational evolution; chemotherapy; circulating tumor DNA
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.34558

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. 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.