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Metastatic Colorectal Cancer

1. Disease Information (overview and definitions)

2026-05-10
Falcon MONDO:0005575 Model: Edison Scientific Literature 45 citations

1. Disease Information (overview and definitions)

Metastatic colorectal cancer (mCRC) refers to colorectal carcinoma that has spread beyond the primary colon/rectal site to distant organs (stage IV disease in TNM/AJCC frameworks). NCCN Colon Cancer v3.2024 frames management of “disseminated metastatic CRC” as dependent on therapy goals, prior therapy, tumor mutational profile, and toxicity profiles, underscoring that mCRC is both a systemic disease and a biomarker-stratified therapeutic entity in contemporary care (benson2024coloncancerversion pages 2-3).

A key current concept is that mCRC is not a single disease, but rather a collection of molecularly defined subgroups (e.g., MSI‑H/dMMR, BRAF V600E, KRAS G12C, HER2‑amplified) that map to distinct, actionable treatment paths in guidelines and in clinical practice algorithms (benson2024coloncancerversion pages 2-3, benson2024coloncancerversion pages 15-16, benson2024coloncancerversion media afa7e635).

2. Etiology (causal factors, risk/protective factors, GxE)

Direct etiologic and exposure‑based risk/protective factor evidence was not retrieved in this run (e.g., obesity, diet, alcohol, smoking, IBD, aspirin, microbiome). This section should be supplemented from large epidemiologic resources and preventive guidelines (USPSTF, WHO, GBD), as requested in the template.

Genetic contributions relevant to CRC (and thus to mCRC development): A precision medicine review notes that germline pathogenic variants occur in ~6–10% of CRC patients, with Lynch syndrome genes (MLH1/MSH2/MSH6/PMS2) most common; NCCN recommends genetic testing when personal/family history suggests hereditary risk (underwood2024precisionmedicinefor pages 2-4).

3. Phenotypes (clinical presentation, QoL; HPO mapping)

3.1 Key phenotypic concepts in mCRC

The clinically dominant phenotype is distant organ metastasis, most commonly to the liver and lung, with rarer sites (brain, bone) contributing to morbidity and worse survival (jeriyabar2024survivalanalysisof pages 4-6, jeriyabar2024survivalanalysisclinical pages 1-2).

3.2 Metastatic patterns and frequencies (SEER)

A SEER analysis of 23,278 patients with metastatic CRC (2010–2020) found that 93.32% had a solitary metastatic site; liver-only metastasis was ~70% (70.06% early-onset; 69.97% average-onset), while lung-only metastasis was ~17–19% and brain-only metastasis ~0.56–1.03% (jeriyabar2024survivalanalysisof pages 4-6). A separate SEER analysis (2010–2021) reported brain metastasis at diagnosis in 0.92% (228/24,703) of mCRC patients (jeriyabar2024survivalanalysisclinical pages 1-2).

3.3 Survival-linked phenotype severity (brain metastasis)

Patients with brain metastases at diagnosis had median overall survival 6 months vs 21 months in those without brain metastasis in the SEER cohort (jeriyabar2024survivalanalysisclinical pages 1-2).

3.4 Suggested HPO terms (examples)

(These are suggested mappings for knowledge-base structuring; specific term IDs should be verified against HPO.) - Hepatic metastases: “Metastatic neoplasm of the liver” (HPO mapping candidate) (jeriyabar2024survivalanalysisof pages 4-6) - Pulmonary metastases: “Pulmonary metastases” (candidate) (jeriyabar2024survivalanalysisof pages 4-6) - Brain metastases: “Brain metastasis” (candidate) (jeriyabar2024survivalanalysisclinical pages 1-2) - Elevated carcinoembryonic antigen (CEA): “Increased circulating carcinoembryonic antigen level” (candidate; discussed as prognostic in SEER modeling and ctDNA comparisons) (ren2024survivaloutcomeand pages 6-8, parikh2024minimalresidualdisease pages 1-2)

Quality-of-life (QoL) measurement details were limited in retrieved evidence; however, ANCHOR CRC reported patient-reported symptom improvement ≥30% across cycles using Patient Global Impression of Changes in BRAF V600E mCRC treated with targeted triplet therapy (cutsem2023anchorcrcresults pages 1-2).

4. Genetic / Molecular Information (drivers, variants, biomarkers)

4.1 Core molecular profiling recommended in mCRC (NCCN v3.2024)

NCCN Colon Cancer v3.2024 recommends baseline molecular testing in metastatic CRC that explicitly includes KRAS/NRAS, BRAF, HER2 amplification, and MSI/MMR status (if not previously done), and it prefers NGS panels because they also detect rare actionable alterations such as NTRK and RET fusions; testing may use tissue or blood (liquid) biopsy (benson2024coloncancerversion pages 2-3).

4.2 Key somatic drivers and actionable alterations (with prevalence where available)

4.3 Biomarker definitions and testing criteria (examples)

4.4 OpenTargets disease–target associations (useful for knowledge graphs)

OpenTargets lists high-scoring associations for metastatic colorectal cancer including VEGF pathway targets (e.g., KDR/FLT1/FLT4/TEK) and BRAF/RET (OpenTargets Search: metastatic colorectal cancer). These associations are not treatment recommendations per se, but can support structured knowledge-base linking of mCRC to canonical therapeutic targets.

5. Environmental Information

No CTD/TOXNET/WHO/CDC exposure-specific evidence was retrieved in this run; this section remains incomplete.

6. Mechanism / Pathophysiology

6.1 Key pathway-level mechanisms directly supported by retrieved evidence

6.2 Immune biology: MSI-H/dMMR as an immunotherapy-responsive state

dMMR/MSI-H tumors show strong sensitivity to immune checkpoint inhibition, establishing MSI/MMR as a mechanistic and predictive biomarker for therapy selection (garciacarbonero2024realworldstudyon pages 1-2, ashouri2024exploringpredictiveand pages 8-9).

6.3 Suggested GO biological process terms (candidates)

(IDs should be verified during ontology curation.) - EGFR signaling pathway; MAPK cascade; negative regulation of EGFR signaling (adaptive feedback); DNA mismatch repair; adaptive immune response; T cell activation.

6.4 Suggested Cell Ontology (CL) cell types (candidates)

  • Tumor-infiltrating T lymphocytes (for ICI mechanisms); colorectal epithelial tumor cells; cancer-associated fibroblasts (not directly evidenced here; include only after adding mechanistic primary sources).

7. Anatomical Structures Affected (UBERON mapping candidates)

Based on SEER distributions and mCRC clinical phenotype: - Primary sites: colon (UBERON: colon), rectum (UBERON: rectum) (implicit in all mCRC sources). - Most common metastatic sites: liver (UBERON: liver), lung (UBERON: lung) (jeriyabar2024survivalanalysisof pages 4-6). - Less common but high-impact metastatic sites: brain (UBERON: brain) (jeriyabar2024survivalanalysisclinical pages 1-2); bone metastases discussed as prognostic in SEER hazard models (ren2024survivaloutcomeand pages 5-6).

8. Temporal Development (onset, progression)

8.1 Age distribution and “early-onset” metastatic CRC

In SEER (2010–2020), 17.79% of metastatic CRC cases were classified as early-onset (<50 years), and early-onset cases had improved median OS compared with average-onset cases (30 vs 18 months) (jeriyabar2024survivalanalysisof pages 1-2).

8.2 Molecular residual disease (MRD) as a temporal progression marker

ctDNA-based MRD can precede radiologic recurrence. In CIRCULATE-Japan GALAXY, ctDNA positivity preceded radiologic recurrence by a median 5.9 months (nakamura2024ctdnabasedmolecularresidual pages 1-2).

9. Inheritance and Population (epidemiology)

9.1 Survival statistics (SEER)

9.2 Metastatic site prevalence

  • Liver-only metastasis ~70%; lung-only ~16.76% (early-onset) vs 19.33% (average-onset); brain-only 0.56% vs 1.03% in the SEER 2010–2020 metastatic CRC cohort (jeriyabar2024survivalanalysisof pages 4-6).

9.3 Germline contribution

A precision medicine review reports germline mutations in ~6–10% of CRC patients (Lynch genes most common), relevant for family risk and cascade testing (underwood2024precisionmedicinefor pages 2-4).

10. Diagnostics

10.1 Guideline-positioned molecular diagnostics (NCCN v3.2024)

NCCN recommends baseline metastatic molecular profiling including KRAS/NRAS, BRAF, HER2 amplification, and MSI/MMR, with preference for NGS panels to capture rare fusions (e.g., NTRK, RET) and to support biomarker-directed therapy selection; testing may be tissue- or blood-based (benson2024coloncancerversion pages 2-3).

10.2 Liquid biopsy / ctDNA (recent developments and real-world implementation)

ctDNA is increasingly implemented for MRD/risk stratification and surveillance, but evidence shows mixed clinical utility in routine practice.

Key recent quantitative results: - Oligometastatic/metastatic CRC after curative-intent procedures: plasma-only multiomic MRD assay: postprocedure ctDNA at 3 weeks was associated with shorter RFS (HR 5.27) and OS (HR 12.83) (Clinical Cancer Research, May 2024) (parikh2024minimalresidualdisease pages 1-2). - Large prospective observational evidence (CIRCULATE-Japan GALAXY, Nature Medicine Sep 2024): MRD positivity associated with inferior DFS (HR 11.99) and OS (HR 9.68); ctDNA positivity preceded radiologic recurrence by median 5.9 months; ctDNA-negative had very low recurrence (e.g., 5.27% in a surveillance analysis subset) (nakamura2024ctdnabasedmolecularresidual pages 1-2). - Real-world adoption and limitations (Mayo Clinic): 84% of ctDNA assays did not change management; guidelines had not endorsed routine ctDNA surveillance and further data are needed (JCO Precision Oncology, Feb 2024) (emiloju2024tumorinformedcirculatingtumor pages 1-2). - Incremental benefit of adding serial ctDNA to NCCN-guided imaging surveillance: only 1.6% of patients achieved curative surgical intervention attributable to ctDNA surveillance in one cohort (JAMA Network Open, Dec 2024) (ji2024circulatingtumordna pages 1-2).

Abstract quote examples (ctDNA): - Nature Medicine (Sep 2024) states ctDNA MRD detection is associated with recurrence and survival: “ctDNA positivity during the MRD window… inferior disease-free survival (DFS; hazard ratio (HR): 11.99…) and overall survival (OS; HR: 9.68…)” (nakamura2024ctdnabasedmolecularresidual pages 1-2). - JAMA Network Open (Dec 2024) summary: adding serial ctDNA assays “led to curative surgical intervention in 1.6% of patients” (ji2024circulatingtumordna pages 1-2).

11. Outcome / Prognosis

11.1 Prognostic drivers (molecular and clinical)

12. Treatment (current standard, 2023–2024 advances, real-world implementation)

12.1 NCCN 2024: biomarker-driven treatment paradigm

NCCN Colon Cancer v3.2024 highlights that treatment selection in metastatic disease is driven by the mutational profile, and provides explicit biomarker-linked therapy pathways (benson2024coloncancerversion pages 2-3, benson2024coloncancerversion media afa7e635).

A representative NCCN systemic therapy decision figure (including “biomarker-directed” regimens and lines of therapy) is shown here: - NCCN Figure (cropped): biomarker-directed second-line and later options (BRAF V600E, HER2, KRAS G12C, NTRK, RET; also incorporates MMR/MSI and POLE/POLD1) (benson2024coloncancerversion media afa7e635).

12.2 Immunotherapy for MSI-H/dMMR mCRC

A Spanish real-world paper reiterates guideline consensus that all mCRC should be tested for MSI/dMMR and summarizes pivotal trial efficacy: - KEYNOTE-177: PFS benefit (16.5 vs 8.2 months) in untreated MSI-H/dMMR mCRC (garciacarbonero2024realworldstudyon pages 1-2). - CheckMate-142: ORR 31% nivolumab monotherapy and 69% nivolumab+ipilimumab (garciacarbonero2024realworldstudyon pages 1-2).

Real-world implementation gap: In Spain (May 2020–May 2021), testing reached 84% overall, but only 29% of dMMR/MSI-H tumors received first-line immunotherapy (garciacarbonero2024realworldstudyon pages 1-2).

Abstract quote example (testing policy): “Clinical practice guidelines recommend that all patients with metastatic colorectal cancer (mCRC) should be tested for mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H).” (Clinical & Translational Oncology, Aug 2024) (garciacarbonero2024realworldstudyon pages 1-2).

12.3 KRAS G12C: KRAS inhibitor + EGFR antibody combinations (major 2024 development)

Abstract quote example: “Divarasib plus cetuximab… was well tolerated with an encouraging overall response rate of 62.5% in patients with KRAS G12C-positive colorectal cancer.” (desai2024divarasibpluscetuximab pages 1-2).

12.4 BRAF V600E targeted therapy

12.5 HER2-amplified mCRC targeted therapy

NCCN lists multiple anti-HER2 regimens (including T‑DXd and trastuzumab-based combinations), with reported ORRs such as 45.3% (T‑DXd in DESTINY‑CRC01) and 38.1% (trastuzumab+tucatinib in MOUNTAINEER) in guideline excerpts (benson2024coloncancerversion pages 15-16).

12.6 Suggested MAXO terms (examples; IDs should be verified)

  • Immune checkpoint inhibitor therapy; monoclonal antibody therapy; small molecule kinase inhibitor therapy; combination antineoplastic therapy; tumor biomarker testing; circulating tumor DNA testing; metastasectomy; stereotactic radiotherapy.

12.7 Experimental / ongoing trials (from ClinicalTrials.gov retrieval)

Examples of active or completed mCRC biomarker-linked studies retrieved include: - KRAS G12C adagrasib (KRYSTAL-1): NCT03785249 (desai2024divarasibpluscetuximab pages 1-2) - Tucatinib + trastuzumab: NCT03043313 (trial record retrieved; biomarker context in NCCN/biomarker review) (benson2024coloncancerversion pages 15-16).

13. Prevention

Prevention/screening-specific evidence (USPSTF/WHO/CDC) was not retrieved in this run; this section is incomplete. Nevertheless, ctDNA and biomarker reviews emphasize that CRC has “a slow progression providing a wide treatment window” and that screening can prevent CRC and reduce mortality, contextualizing the prevention opportunity even though mCRC is an advanced endpoint (emiloju2024tumorinformedcirculatingtumor pages 1-2).

14. Other Species / Natural Disease; 15. Model Organisms

No animal-model or comparative pathology evidence was retrieved in this run; these sections are incomplete.

High-value structured summary (biomarker-directed therapy)

The following table synthesizes the key biomarker subgroups, testing definitions, guideline-positioned therapies, and recent efficacy numbers (2023–2024 prioritized):

Table (click to expand)
Biomarker / subgroup Approx. prevalence in mCRC Recommended testing method / definition Key approved / standard therapies Key efficacy outcomes with numbers (trial/source) Notes
dMMR / MSI-H ~15% CRC overall; ~4% stage IV; Spanish real-world mCRC cohort: 6% dMMR/MSI among tested patients (14/244) Universal metastatic testing recommended; assess MMR/MSI if not previously done. MSI/MMR testing used to predict benefit from immune checkpoint inhibitors; also relevant for Lynch syndrome workup. Methods in practice include IHC/PCR in the Spanish cohort (garciacarbonero2024realworldstudyon pages 1-2, benson2024coloncancerversion pages 2-3, ashouri2024exploringpredictiveand pages 8-9) Pembrolizumab; nivolumab ± ipilimumab; NCCN also links checkpoint inhibitors to dMMR/MSI-H or POLE/POLD1-mutant disease (Jun 2024 NCCN, https://doi.org/10.6004/jnccn.2024.0029) (garciacarbonero2024realworldstudyon pages 1-2, benson2024coloncancerversion pages 10-11) KEYNOTE-177: 1L pembrolizumab vs chemotherapy, median PFS 16.5 vs 8.2 mo, HR 0.60, p=0.0002; OS trend HR 0.74, median OS not reached vs 36.7 mo with crossover up to 60% (Garcia-Carbonero, Aug 2024, https://doi.org/10.1007/s12094-023-03309-z). CheckMate-142: ORR 31% with nivolumab alone and 69% with nivolumab+ipilimumab in reported data; Ashouri review also cites 24-mo PFS 74% and 24-mo OS 79% with nivolumab+ipilimumab and CheckMate-8HW PFS NR vs 5.9 mo, HR 0.21 (garciacarbonero2024realworldstudyon pages 1-2, ashouri2024exploringpredictiveand pages 8-9) First-line immunotherapy standard for MSI-H/dMMR mCRC. Real-world implementation gap persists: only 29% of dMMR/MSI-H tumors received first-line immunotherapy in the Spanish cohort despite 84% overall testing (garciacarbonero2024realworldstudyon pages 1-2)
RAS wild-type (KRAS/NRAS WT), especially left-sided tumors RAS mutations ~50–55% of CRC, so WT is the complementary subgroup NCCN: KRAS/NRAS genotyping for all mCRC; use tumor tissue (primary or metastasis). Anti-EGFR therapy should not be used in tumors with KRAS or NRAS mutation (Jun 2024 NCCN, https://doi.org/10.6004/jnccn.2024.0029) (benson2024coloncancerversion pages 2-3, benson2024coloncancerversion pages 10-11) Cetuximab or panitumumab with chemotherapy (e.g., FOLFOX; also CAPEOX combinations listed by NCCN for selected settings) (benson2024coloncancerversion pages 10-11) PRIME: panitumumab+FOLFOX improved PFS HR 0.72 (95% CI 0.58–0.90; P=0.004) and OS HR 0.77 (95% CI 0.64–0.94; P=0.009) in KRAS/NRAS WT. PARADIGM: median OS 37.9 vs 34.3 mo (panitumumab vs bevacizumab) in left-sided RAS WT and 36.2 vs 31.3 mo overall RAS WT. CALGB/SWOG 80405: OS 29.0 vs 30.0 mo (cetuximab vs bevacizumab) (NCCN Jun 2024, https://doi.org/10.6004/jnccn.2024.0029) (benson2024coloncancerversion pages 10-11) Benefit is strongest in molecularly selected WT disease; acquired resistance after anti-EGFR therapy is common, with secondary RAS alterations reported in ~50% within 12 months in review data (ashouri2024exploringpredictiveand pages 2-5, benson2024coloncancerversion pages 2-3)
KRAS-mutant (all) ~50–55% CRC; common KRAS variants: G12D 36%, G12V 21.8%, G13D 18.8% RAS testing by tumor genotyping; NCCN prefers NGS panels because they can also detect rarer actionable events (e.g., NTRK, RET). KRAS/NRAS-mutant tumors should not receive cetuximab/panitumumab, except EGFR antibody can be paired with a KRAS G12C inhibitor in non-first-line KRAS G12C disease (benson2024coloncancerversion pages 2-3) No anti-EGFR monotherapy/standard EGFR combination in routine KRAS-mutant disease; enroll in biomarker-directed strategies if KRAS G12C (below) (benson2024coloncancerversion pages 2-3, cotan2024prognosticandpredictive pages 10-11) KRAS-mutant mCRC has worse outcomes in review data: OS 20.9 vs 16.9 mo for WT vs mutant in HORIZON II; KRAS G12C especially poor prognosis with OS 4.3 vs 23.3 mo in cited review summary (Ashouri, Aug 2024, https://doi.org/10.3390/cancers16162796) (ashouri2024exploringpredictiveand pages 2-5) Main clinical role is negative selection against anti-EGFR therapy, except the KRAS G12C-specific EGFR co-blockade setting (benson2024coloncancerversion pages 2-3)
KRAS G12C-mutant ~3–4% of CRC; NCCN excerpt estimates KRAS G12C is ~17% of KRAS-mutant cases Detect by tumor genotyping/NGS; NCCN notes tissue or blood may be used for molecular profiling, with NGS preferred for broad detection (Jun 2024 NCCN, https://doi.org/10.6004/jnccn.2024.0029) (benson2024coloncancerversion pages 2-3, benson2024coloncancerversion pages 15-16) Adagrasib + cetuximab; sotorasib + panitumumab; emerging divarasib + cetuximab (trial) (benson2024coloncancerversion pages 2-3, benson2024coloncancerversion pages 15-16, desai2024divarasibpluscetuximab pages 1-2) KRYSTAL-1: adagrasib monotherapy ORR 19%, DCR 86%, median PFS 5.6 mo, median OS 19.8 mo; adagrasib + cetuximab ORR 46%, DCR 100%, median PFS 6.9 mo, median OS 13.4 mo in one review summary; NCCN updated pooled data cite ORR 34.0%, DCR 85.1%, median PFS 6.9 mo, median OS 15.9 mo (Jun 2024 NCCN, https://doi.org/10.6004/jnccn.2024.0029) (cotan2024prognosticandpredictive pages 10-11, benson2024coloncancerversion pages 15-16). CodeBreaK-300 early data: sotorasib+panitumumab PFS 5.6 mo (960 mg) vs SOC 2.2 mo (ashouri2024exploringpredictiveand pages 2-5). Divarasib + cetuximab phase 1b: ORR 62.5% (95% CI 40.6–81.2), median DOR 6.9 mo, median PFS 8.1 mo in KRAS G12C inhibitor–naive patients (Nature Medicine, Dec 2024, https://doi.org/10.1038/s41591-023-02696-8) (desai2024divarasibpluscetuximab pages 1-2) EGFR-mediated adaptive feedback is a major resistance mechanism, explaining why EGFR co-blockade outperforms KRAS G12C inhibitor monotherapy (desai2024divarasibpluscetuximab pages 1-2, cotan2024prognosticandpredictive pages 10-11)
BRAF V600E-mutant ~8–12% mCRC; broader reports cite 10–15% Test for BRAF mutation as part of baseline metastatic profiling; BRAFV600E is a poor-prognosis biomarker (benson2024coloncancerversion pages 2-3, ashouri2024exploringpredictiveand pages 6-8) Encorafenib + cetuximab (preferred targeted doublet in previously treated disease); triplet encorafenib + binimetinib + cetuximab has similar OS but more toxicity; first-line triplet under study/selected situations (benson2024coloncancerversion pages 15-16, cutsem2023anchorcrcresults pages 1-2) BEACON: control vs encorafenib+cetuximab vs triplet showed OS 5.9 vs 9.3 vs 9.3 mo and PFS 1.5 vs 4.3 vs 4.5 mo; NCCN cites confirmed ORR 1.8% vs 19.5% vs 26.8% (Jun 2024 NCCN, https://doi.org/10.6004/jnccn.2024.0029; Ashouri Aug 2024 https://doi.org/10.3390/cancers16162796) (ashouri2024exploringpredictiveand pages 6-8, benson2024coloncancerversion pages 15-16). ANCHOR CRC first-line triplet in BRAFV600E mCRC: ORR 47.4% (95% CI 37.0–57.9), median PFS 5.8 mo, median OS 18.3 mo (JCO, May 2023, https://doi.org/10.1200/jco.22.01693) (cutsem2023anchorcrcresults pages 1-2) BRAFV600E is associated with proximal location, aggressive biology, unfavorable metastatic pattern, and reduced OS; anti-EGFR alone is insufficient because BRAF blockade triggers EGFR feedback activation (cutsem2023anchorcrcresults pages 1-2, ashouri2024exploringpredictiveand pages 6-8, cotan2024prognosticandpredictive pages 10-11)
HER2-amplified / overexpressed (usually RAS/BRAF WT) ~2–6% mCRC; other review estimate 3–5% NCCN recommends HER2 testing for all mCRC. Methods: IHC, FISH, or NGS. IHC 3+ = positive overexpression; IHC 2+ = equivocal and should prompt FISH; FISH ratio ≥2 confirms amplification (ashouri2024exploringpredictiveand pages 6-8, ashouri2024exploringpredictiveand pages 8-9, benson2024coloncancerversion pages 15-16) Fam-trastuzumab deruxtecan-nxki (T-DXd); trastuzumab + pertuzumab; trastuzumab + lapatinib; trastuzumab + tucatinib (NCCN Jun 2024, https://doi.org/10.6004/jnccn.2024.0029) (benson2024coloncancerversion pages 15-16) DESTINY-CRC01 (T-DXd): ORR 45.3%, median PFS 6.9 mo, median OS not reached at reported cut; ILD/pneumonitis in 8 patients with 3 deaths. MyPathway (trastuzumab+pertuzumab): ORR 32%. HERACLES (trastuzumab+lapatinib): ORR 30%, DCR 59%, median PFS 5.3 mo, median OS 11.5 mo. MOUNTAINEER (trastuzumab+tucatinib): confirmed ORR 38.1% (NCCN Jun 2024, https://doi.org/10.6004/jnccn.2024.0029; reviews 2024) (cotan2024prognosticandpredictive pages 13-15, ashouri2024exploringpredictiveand pages 8-9, benson2024coloncancerversion pages 15-16) Enriched in left-sided and RAS/BRAF WT tumors; may mediate anti-EGFR resistance. Responses are lower in KRAS-mutant disease in post hoc analyses (cotan2024prognosticandpredictive pages 13-15, ashouri2024exploringpredictiveand pages 8-9)
NTRK fusion-positive ~0.7% Broad NGS is preferred because rare actionable fusions may be missed by single-gene testing; NCCN biomarker-directed therapy figure includes NTRK gene fusions (benson2024coloncancerversion pages 2-3, underwood2024precisionmedicinefor pages 2-4, benson2024coloncancerversion media afa7e635) Larotrectinib; entrectinib (Underwood review also references repotrectinib) (underwood2024precisionmedicinefor pages 2-4) No trial efficacy numbers were present in the gathered evidence excerpts used here; therapy assignment is supported by biomarker-directed NCCN/precision oncology summaries (underwood2024precisionmedicinefor pages 2-4, benson2024coloncancerversion media afa7e635) Rare but actionable; typically identified through broad NGS rather than stepwise hotspot testing (benson2024coloncancerversion pages 2-3, benson2024coloncancerversion media afa7e635)
RET fusion-positive ~0.2% Broad NGS preferred for rare fusion detection; NCCN biomarker-directed therapy figure includes RET gene fusions (benson2024coloncancerversion pages 2-3, underwood2024precisionmedicinefor pages 2-4, benson2024coloncancerversion media afa7e635) Selpercatinib (underwood2024precisionmedicinefor pages 2-4, benson2024coloncancerversion media afa7e635) No numeric CRC-specific efficacy outcomes were provided in the gathered excerpts used here (underwood2024precisionmedicinefor pages 2-4, benson2024coloncancerversion media afa7e635) Very rare, but clinically actionable when found; reinforces value of comprehensive molecular profiling in mCRC (benson2024coloncancerversion pages 2-3, underwood2024precisionmedicinefor pages 2-4)
POLE / POLD1-mutant (hypermutated subgroup) Not quantified in gathered excerpts Mentioned by NCCN alongside dMMR/MSI-H as a subgroup for checkpoint inhibitor consideration; usually identified by comprehensive tumor sequencing (benson2024coloncancerversion pages 10-11) Checkpoint inhibitor immunotherapy (NCCN linkage in metastatic algorithm; Jun 2024, https://doi.org/10.6004/jnccn.2024.0029) (benson2024coloncancerversion pages 10-11) No separate efficacy figures for POLE/POLD1-mutant mCRC were available in the gathered evidence excerpts (benson2024coloncancerversion pages 10-11) Clinically important as an additional hypermutated/immunotherapy-sensitive subset beyond MSI-H/dMMR (benson2024coloncancerversion pages 10-11)

Table: This table summarizes biomarker-defined treatment subgroups in metastatic colorectal cancer using gathered 2023-2024 evidence and NCCN v3.2024 excerpts. It highlights recommended testing, standard targeted/immunotherapy options, and key efficacy numbers to support rapid clinical and research reference.

Key statistics and “latest research” highlights (2023–2024)

  1. NCCN 2024 endorses broad baseline molecular profiling for metastatic CRC (KRAS/NRAS, BRAF, HER2, MSI/MMR; NGS preferred to capture NTRK/RET) and maps these biomarkers to therapy selection (benson2024coloncancerversion pages 2-3, benson2024coloncancerversion media afa7e635).
  2. KRAS G12C dual blockade is a major 2024 advance: divarasib+cetuximab ORR 62.5% and median PFS 8.1 months in KRAS G12C inhibitor–naïve CRC (Nature Medicine Dec 2024) (desai2024divarasibpluscetuximab pages 1-2).
  3. ctDNA MRD is increasingly validated as a strong prognostic tool (Nature Medicine Sep 2024: DFS HR 11.99, OS HR 9.68, median lead time 5.9 months), but real-world studies show limited immediate management impact and unclear outcome benefit from routine surveillance (nakamura2024ctdnabasedmolecularresidual pages 1-2, ji2024circulatingtumordna pages 1-2, emiloju2024tumorinformedcirculatingtumor pages 1-2).
  4. Population prognosis (SEER): early-onset metastatic CRC median OS 30 months vs 18 months for average-onset; liver-only metastasis ~70% (jeriyabar2024survivalanalysisof pages 1-2, jeriyabar2024survivalanalysisof pages 4-6).

URLs and publication dates (selected, high-authority sources used)

Limitations of this report (due to tool-accessible evidence in this run)

Several requested template sections remain incomplete because primary sources for etiology/risk factors, prevention/screening guidelines, detailed phenotype/QoL instruments, microbiome/environmental contributors, and model organism data were not retrieved via the current searches. The molecular diagnostics, treatment, ctDNA/MRD, and population prognosis components are well-supported by 2023–2024 guideline/trial/registry evidence in this run (benson2024coloncancerversion pages 2-3, desai2024divarasibpluscetuximab pages 1-2, nakamura2024ctdnabasedmolecularresidual pages 1-2, jeriyabar2024survivalanalysisof pages 1-2).

References

  1. (OpenTargets Search: metastatic colorectal cancer): Open Targets Query (metastatic colorectal cancer, 48 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (garciacarbonero2024realworldstudyon pages 1-2): Rocio Garcia-Carbonero, Beatriz González Astorga, Rosario Vidal Tocino, Débora Contreras Toledo, Carles Pericay, Ana Fernández Montes, Esther Falcó, Marta González Cordero, Juan José Reina Zoilo, Vicente Alonso, Nuria Rodríguez Salas, Mireia Gil-Raga, Cristina Santos, David Páez, Beatriz Anton-Pascual, Fernando Aguilar, and Pilar Morales. Real-world study on microsatellite instability and mismatch repair deficiency testing patterns among patients with metastatic colorectal cancer in spain. Clinical & Translational Oncology, 26:864-871, Aug 2024. URL: https://doi.org/10.1007/s12094-023-03309-z, doi:10.1007/s12094-023-03309-z. This article has 7 citations and is from a peer-reviewed journal.

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  22. (benson2024coloncancerversion pages 10-11): Al B. Benson, A. Venook, Mohamed Adam, George J. Chang, Yi-Jen Chen, K. K. Ciombor, Stacey A Cohen, Harry S. Cooper, Dustin Deming, Ignacio Garrido-Laguna, Jean L Grem, Paul Haste, J. R. Hecht, Sarah Hoffe, S. Hunt, H. Hussan, K. Johung, Nora Joseph, Natalie N. Kirilcuk, S. Krishnamurthi, Midhun Malla, Jennifer K Maratt, W. Messersmith, J. Meyerhardt, E. D. Miller, M. Mulcahy, Steven J. Nurkin, M. Overman, Aparna Parikh, Hitendra Patel, Katrina Pedersen, Leonard Saltz, Charles Schneider, David Shibata, Benjamin Shogan, J. Skibber, Constantinos T Sofocleous, Anna Tavakkoli, Christopher G. Willett, Christina Wu, Lisa A. Gurski, Jenna Snedeker, and Frankie Jones. Colon cancer, version 3.2024, nccn clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network : JNCCN, Jun 2024. URL: https://doi.org/10.6004/jnccn.2024.0029, doi:10.6004/jnccn.2024.0029. This article has 450 citations.

  23. (cotan2024prognosticandpredictive pages 13-15): Horia T. Cotan, Radu A. Emilescu, Cristian I. Iaciu, Cristina M. Orlov-Slavu, Mihaela C. Olaru, Ana M. Popa, Mariana Jinga, Cornelia Nitipir, Oliver Daniel Schreiner, and Romeo Cristian Ciobanu. Prognostic and predictive determinants of colorectal cancer: a comprehensive review. Cancers, 16:3928, Nov 2024. URL: https://doi.org/10.3390/cancers16233928, doi:10.3390/cancers16233928. This article has 19 citations.