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Colorectal Cancer Treatments and Studies / Colorectal Cancer Surgical Treatments / Genetic Factors in Colorectal Cancer · Review
Medical Oncology · August 7, 2026
A consensus or society position rather than new primary data.
This narrative review synthesizes evidence on tumor-intrinsic genomic, transcriptomic, and circulating biomarkers associated with neoadjuvant therapy response in locally advanced rectal cancer. The authors conclude that dynamic ctDNA clearance, transcriptomic signatures, and MMR status show the most promise for personalizing treatment selection, but prospective validation and standardization are needed before clinical implementation.
Narrative review. Patients with locally advanced rectal cancer receiving neoadjuvant therapy (conventional chemoradiotherapy or total neoadjuvant therapy).
KRAS mutations recurrently associated with lower pathological complete response (pCR) rates in chemoradiotherapy-era cohorts Individual somatic mutations (KRAS, TP53, BRAF) demonstrated limited reproducibility as predictive biomarkers Transcriptomic biomarkers showed greater biological coherence, with proliferative, epithelial-mesenchymal transition, and metabolic signatures frequently associated with treatment resistance
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Clinicians should consider that MMR status, transcriptomic signatures, and dynamic ctDNA monitoring during treatment show greater promise than baseline single-gene mutations for predicting response and guiding personalized neoadjuvant therapy selection. However, prospective validation in contemporary total neoadjuvant therapy cohorts is required before routine clinical incorporation.
A narrative review synthesizing current evidence on genomic and molecular biomarkers for neoadjuvant therapy response in rectal cancer, offering recommendations for future clinical integration without reporting original trial data.
As stated by the source record.
Clinicians should consider that MMR status, transcriptomic signatures, and dynamic ctDNA monitoring during treatment show greater promise than baseline single-gene mutations for predicting response and guiding personalized neoadjuvant therapy selection. However, prospective validation in contemporary total neoadjuvant therapy cohorts is required before routine clinical incorporation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
Total neoadjuvant therapy (TNT) has emerged as a key treatment paradigm for locally advanced rectal cancer, reducing distant metastasis rates and facilitating organ preservation in selected patients. However, treatment response remains heterogeneous, highlighting the need for biomarkers that can guide treatment selection and optimise outcomes. This narrative review synthesises the current evidence regarding tumour-intrinsic genomic biomarkers associated with response to neoadjuvant therapy, encompassing somatic mutations, germline polymorphisms, gene expression profiles, mismatch repair (MMR) status, protein expression, epigenetic markers, and circulating tumour-derived biomarkers across conventional chemoradiotherapy (CRT) and TNT paradigms. Across the reviewed literature, individual somatic mutations, including KRAS, TP53, and BRAF, demonstrated limited reproducibility as predictive biomarkers, although KRAS mutations were recurrently associated with lower pathological complete response (pCR) rates in CRT-era cohorts. Germline polymorphisms in DNA repair (XRCC1) and folate metabolism (MTHFR) genes showed inconsistent associations with treatment response. In contrast, transcriptomic biomarkers demonstrated greater biological coherence, with proliferative, epithelial-mesenchymal transition, and metabolic signatures frequently associated with treatment resistance, while multi-gene classifiers generally outperformed single-gene markers. Among currently available tumour-intrinsic biomarkers, MMR deficiency was the most consistently reported biomarker associated with reduced response to fluoropyrimidine-based regimens, including TNT, although TNT-specific evidence remains comparatively limited. Dynamic circulating tumour DNA (ctDNA) monitoring, particularly ctDNA clearance during or after therapy, was consistently associated with pathological response and long-term oncologic outcomes across reviewed studies, whereas baseline ctDNA levels showed limited predictive value. Overall, the reviewed literature suggests that biomarker research in rectal cancer has evolved from single-gene analyses towards pathway-level and dynamic biomarkers. The integration of transcriptomic signatures, MMR status, and dynamic ctDNA monitoring may represent a promising strategy for personalising neoadjuvant therapy, improving patient selection for organ-preserving approaches, and enhancing oncologic outcomes in locally advanced rectal cancer. Nevertheless, the evidence base remains heterogeneous, and further prospective validation, assay standardisation, and evaluation within contemporary TNT cohorts are required before these biomarkers can be routinely incorporated into clinical decision-making.
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