NCCN clinical practice guidelines in oncology: colon cancer (version 1. 2026): a comprehensive analysis of molecular testing_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YAO Ziyi ^1,2 , YAO Lin ¹ , CHEN Peng ¹ ,  WANG Xiaodong ¹ , LI Li ³

1. Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. West China School of Medicine, Sichuan University, Chengdu 610041, P. R. China;
3. Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding?author：

WANG Xiaodong, Email: wangxiaodong@wchscu.cn

Keywords：

colon cancer; NCCN guidelines; molecular testing; multigene panel testing; molecular biomarker; pharmacogenetics

DOI：

10.7507/1007-9424.202604010

Video：

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Colon cancer exhibits marked molecular heterogeneity, and molecular testing has become a central component throughout screening, diagnosis, treatment, and prognostic management, while also playing a pivotal role in surgical decision-making. The “NCCN clinical practice guidelines in oncology: colon cancer (version 1. 2026)”, systematically update the molecular testing framework and its clinical applications. The guidelines establish multigene panel testing as a standardized testing strategy based on next-generation sequencing platforms, promoting a transition in colon cancer molecular testing from single-gene, single-site detection toward comprehensive molecular profiling. Multigene panel testing enables the simultaneous detection of key molecular targets including RAS mutations, BRAF mutations, HER2 amplification, mismatch repair deficiency/microsatellite instability, and rare targetable alterations such as POLE/POLD1, RET, and NTRK mutations. In addition, the guidelines recognize the clinical value of circulating tumor DNA testing using peripheral blood as an alternative approach in cases of limited tissue availability. The guidelines further standardize routine biomarker testing workflows and clarify the principles for precise matching between distinct molecular subtypes and targeted therapeutic strategies. Stratified targeted treatment approaches for patients with BRAF V600E mutations and HER2 amplification have been continuously refined. The clinical application of immunotherapy-related biomarkers has been substantially advanced and that is no longer limited to later-line salvage treatment in the metastatic setting. Results of microsatellite instability-high/mismatch repair-deficient and POLE/POLD1 mutation testing have also been incorporated into the decision-making process for neoadjuvant therapy and perioperative stratified treatment for stage Ⅱ/Ⅲ colon cancer. The guidelines first incorporate PI3K pathway testing into routine evaluation for stage Ⅱ/Ⅲ colon cancer and recommend aspirin as a prognostic intervention strategy. In the field of pharmacogenomics, DPYD testing has been included as a pre-treatment screening requirement prior to fluoropyrimidine administration in order to improve the safety management system for chemotherapy. Meanwhile, the guidelines clearly define local treatment strategies for oligometastatic liver and lung lesions, emphasizing the rational selection of surgery, ablation, and radiotherapy. Overall, this update expands the role of molecular testing from treatment guidance to comprehensive whole-course management and promotes its deep integration with surgical practice, thereby providing an important foundation for precise, standardized, and safe treatment of colon cancer.

Citation： YAO Ziyi, YAO Lin, CHEN Peng, WANG Xiaodong, LI Li. NCCN clinical practice guidelines in oncology: colon cancer (version 1. 2026): a comprehensive analysis of molecular testing. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2026, 33(7): 875-882. doi: 10.7507/1007-9424.202604010 Copy

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4.	中國醫師協會外科醫師分會, 中華醫學會外科學分會胃腸外科學組, 中華醫學會外科學分會結直腸外科學組, 等. 結直腸癌肝轉移診斷和綜合治療指南(2025版). 中國臨床醫學, 2026, 33(1): 160-190.
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15.	Li J, Liang Y. The research progress of neurotrophic tyrosine receptor kinase (NTRK) gene fusions and tropomyosin receptor kinase (TRK) inhibitors: a narrative review. Iran J Public Health, 2025, 54(4): 710-722.
16.	Xu J, Meng Q, Sun H, et al. HER2-specific chimeric antigen receptor-T cells for targeted therapy of metastatic colorectal cancer. Cell Death Dis, 2021, 12(12): 1109. doi: 10.1038/s41419-021-04100-0.
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34.	Fenizia F, Wolstenholme N, Fairley JA, et al. Tumor mutation burden testing: a survey of the International Quality Network for Pathology (IQN Path). Virchows Arch, 2021, 479(6): 1067-1072.
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37.	Kelly RJ, Bever K, Chao J, et al. Society for immunotherapy of cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gastrointestinal cancer. J Immunother Cancer, 2023, 11(6): e006658. doi: 10.1136/jitc-2022-006658.
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1. Ca?ellas-Socias A, Sancho E, Batlle E. Mechanisms of metastatic colorectal cancer. Nat Rev Gastroenterol Hepatol, 2024, 21(9): 609-625.
2. Zygulska AL, Pierzchalski P. Novel diagnostic biomarkers in colorectal cancer. Int J Mol Sci, 2022, 23(2): 852. doi: 10.3390/ijms23020852.
3. Marisa L, de Reyniès A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med, 2013, 10(5): e1001453. doi: 10.1371/journal.pmed.1001453.
4. 中國醫師協會外科醫師分會, 中華醫學會外科學分會胃腸外科學組, 中華醫學會外科學分會結直腸外科學組, 等. 結直腸癌肝轉移診斷和綜合治療指南(2025版). 中國臨床醫學, 2026, 33(1): 160-190.
5. Zhu G, Pei L, Xia H, et al. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Mol Cancer, 2021, 20(1): 143. doi: 10.1186/s12943-021-01441-4.
6. Goldstein J, Tran B, Ensor J, et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol, 2014, 25(5): 1032-1038.
7. Tommasi S, Pinto R, Petriella D, et al. Oncosuppressor methylation: a possible key role in colon metastatic progression. J Cell Physiol, 2011, 226(7): 1934-1939.
8. Tuteja S, Cayabyab MAS, Hoffecker G, et al. Implementation of DPYD and UGT1A1 testing in patients with GI cancer: a prospective, nonrandomized clinical trial. JCO Precis Oncol, 2025, 9: e2500086. doi: 10.1200/PO-25-00086.
9. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: colon cancer. Version 1. 2026. Plymouth Meeting (PA): National Comprehensive Cancer Network, 2026.National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: colon cancer. Version 1. 2026. Plymouth Meeting (PA): National Comprehensive Cancer Network, 2026.
10. Pearlman R, Frankel WL, Swanson BJ, et al. Prospective statewide study of universal screening for hereditary colorectal cancer: the Ohio colorectal cancer prevention initiative. JCO Precis Oncol, 2021, 5: PO. 20.00525. doi: 10.1200/PO.20.00525.
11. Nakamura Y, Watanabe J, Akazawa N, et al. ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nat Med, 2024, 30(11): 3272-3283.
12. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol, 2010, 28(20): 3219-3226.
13. Parsons MT, Buchanan DD, Thompson B, et al. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet, 2012, 49(3): 151-157.
14. 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(346): 346ra92. doi: 10.1126/scitranslmed.aaf6219.
15. Li J, Liang Y. The research progress of neurotrophic tyrosine receptor kinase (NTRK) gene fusions and tropomyosin receptor kinase (TRK) inhibitors: a narrative review. Iran J Public Health, 2025, 54(4): 710-722.
16. Xu J, Meng Q, Sun H, et al. HER2-specific chimeric antigen receptor-T cells for targeted therapy of metastatic colorectal cancer. Cell Death Dis, 2021, 12(12): 1109. doi: 10.1038/s41419-021-04100-0.
17. 趙龍, 楊長江, 葉穎江, 等. POLE/POLD1突變對結直腸癌預后及免疫治療影響的生物信息學分析. 腫瘤學雜志, 2024, 30(6): 439-448.
18. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med, 2013, 369(11): 1023-1034.
19. Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol, 2008, 26(3): 374-379.
20. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol, 2023, 41(18): 3278-3286.
21. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol, 2008, 26(35): 5705-5712.
22. Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer, 2015, 51(5): 587-594.
23. Ciardiello D, Martinelli E, Troiani T, et al. Anti-EGFR rechallenge in patients with refractory ctDNA RAS/BRAF wt metastatic colorectal cancer: a nonrandomized controlled trial. JAMA Netw Open, 2024, 7(4): e245635. doi: 10.1001/jamanetworkopen.2024.5635.
24. Kopetz S, Wasan HS, Yoshino T, et al. BREAKWATER: primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). J Clin Oncol, 2026, 44(2_suppl): 13. doi: 10.1200/JCO.2026.44.2_suppl.13.
25. Alcaide-Garcia J, Pereda T, Perez-Ruiz E, et al. Concordance of KRAS, NRAS and BRAF status between primary colorectal tumors and paired metastasis (mts). Ann Oncol, 2016, 27(suppl_6): 535P. doi: 10.13140/RG.2.2.10421.88804.
26. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol, 2016, 17(6): 738-746.
27. Valtorta E, Martino C, Sartore-Bianchi A, et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol, 2015, 28(11): 1481-1491.
28. Hashimoto T, Takayanagi D, Yonemaru J, et al. A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer. Br J Cancer, 2023, 129(7): 1176-1183.
29. Das S, Allen A, Berlin J. Immunotherapy after immunotherapy: response rescue in a patient with microsatellite instability-high colorectal cancer post-pembrolizumab. Clin Colorectal Cancer, 2020, 19(2): 137-140.
30. Sinicrope FA, Ou FS, Arnold D, et al. Atezolizumab plus FOLFOX for stage Ⅲ mismatch repair-deficient colon cancer. N Engl J Med, 2026, 394(12): 1155-1166.
31. Kciuk M, Wanke K, Kruczkowska W, et al. Focus on PD-1/PD-L1-targeting antibodies in colorectal cancer: are there options beyond dostarlimab, nivolumab, and pembrolizumab? A comprehensive review. Molecules, 2025, 30(13): 2686. doi: 10.3390/molecules30132686.
32. Mur P, García-Mulero S, Del Valle J, et al. Role of POLE and POLD1 in familial cancer. Genet Med, 2020, 22(12): 2089-2100.
33. Palles C, Cazier JB, Howarth KM, et al. Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature Genetics, 2013, 45(2): 136-144.
34. Fenizia F, Wolstenholme N, Fairley JA, et al. Tumor mutation burden testing: a survey of the International Quality Network for Pathology (IQN Path). Virchows Arch, 2021, 479(6): 1067-1072.
35. Domingo E, Freeman-Mills L, Rayner E, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol, 2016, 1(3): 207-216.
36. Garmezy B, Gheeya J, Lin HY, et al. Clinical and molecular characterization of POLE mutations as predictive biomarkers of response to immune checkpoint inhibitors in advanced cancers. JCO Precis Oncol, 2022, 6: e2100267. doi: 10.1200/PO.21.00267.
37. Kelly RJ, Bever K, Chao J, et al. Society for immunotherapy of cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gastrointestinal cancer. J Immunother Cancer, 2023, 11(6): e006658. doi: 10.1136/jitc-2022-006658.
38. Martling A, Hed Myrberg I, Nilbert M, et al. Low-dose aspirin for PI3K-altered localized colorectal cancer. N Engl J Med, 2025, 393(11): 1051-1064.
39. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med, 2012, 367(17): 1596-1606.
40. Amstutz U, Henricks LM, Offer SM, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther, 2018, 103(2): 210-216.
41. Meulendijks D, Henricks LM, Sonke GS, et al. Clinical relevance of DPYD variants c. 1679T>G, c. 1236G>A/HapB3, and c. 1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol, 2015, 16(16): 1639-1650.
42. Reizine NM, Danahey K, Truong TM, et al. Clinically actionable genotypes for anticancer prescribing among >1 500 patients with pharmacogenomic testing. Cancer, 2022, 128(8): 1649-1657.
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CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

NCCN clinical practice guidelines in oncology: colon cancer (version 1. 2026): a comprehensive analysis of molecular testing

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