BRAF V600E-Mutant Colorectal Cancer

1. Disease Information

1.1 Overview (what is the disease?)

BRAF V600E–mutant colorectal cancer denotes colorectal cancer characterized by an activating missense substitution in BRAF (valine→glutamic acid at codon 600), which constitutively activates MAPK signaling and defines a clinically distinct subgroup with poor prognosis in metastatic disease. (morris2020improvementsinclinical pages 1-5)

A clear trial-level description from BEACON CRC highlights the clinical context and biological rationale: - “Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis …” and “Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.” (kopetz2019encorafenibbinimetiniband pages 1-2)

1.2 Key identifiers (OMIM/Orphanet/ICD/MeSH/MONDO)

• MONDO / MeSH / ICD-10 / ICD-11 / OMIM / Orphanet: not found in retrieved sources (in practice, coded as CRC with biomarker annotation rather than a unique ICD code). (morris2020improvementsinclinical pages 1-5)

1.3 Common synonyms / alternative names

• “BRAFV600E-mutant metastatic colorectal cancer (mCRC)” (kopetz2019encorafenibbinimetiniband pages 1-2)
• “BRAFV600E-mutated colorectal cancer” (cutsem2023anchorcrcresults pages 1-2)
• “BRAF V600E mutated mCRC” (eriksen2022aphaseii pages 1-2)

1.4 Patient-level vs aggregated resources

Most evidence is aggregated from trials and cohorts. Real-world cohorts explicitly use EHR extraction (e.g., clinicopathologic data extracted from electronic records). (zurloh2023impactofencorafenib pages 1-2)

2. Etiology

2.1 Disease causal factors

• Genetic/mechanistic: Somatic activating BRAF p.V600E is the defining causal driver alteration; BRAF is a serine/threonine kinase in the EGFR–RAS–RAF–MEK–ERK (MAPK) cascade. (morris2020improvementsinclinical pages 1-5, potocki2023clinicalcharacterizationof pages 1-2)
• Pathway association: BRAF-mutant CRC is strongly linked to the serrated neoplasia pathway and to epigenetic phenotypes including CIMP and often MSI/dMMR in sporadic cases. (guerrero2023brafinhibitorsin pages 1-2, effendiys2024biomarkersasa pages 3-6)

2.2 Risk factors

2.2.1 Genetic risk factors

• Subtype context: Sporadic MSI tumors show marked enrichment for BRAF mutations (review-level): “observed in 60% of MSI tumors vs 5–10% of MSS tumors,” and “about 20% of patients with mutated BRAF V600E concurrently exhibit microsatellite instability.” (guerrero2023brafinhibitorsin pages 1-2)

2.2.2 Environmental / lifestyle risk factors (molecular-subtype specific)

A 2024 Mendelian randomization analysis provides subtype-specific causal evidence linking adiposity to BRAF-mutated/CIMP-high pathways: - Per 1-SD (5.1 kg/m²) higher BMI, risk increased for: - Jass type 1 (MSI-high, CIMP-high, BRAF-mutated, KRAS-wildtype): OR 2.14 (95% CI 1.46–3.13) - Jass type 2 (non–MSI-high, CIMP-high, BRAF-mutated, KRAS-wildtype): OR 2.20 (95% CI 1.26–3.86) (papadimitriou2024bodysizeand pages 1-2)

High-fat diet is repeatedly framed as a CRC risk context in preclinical literature, including in BRAF-driven mouse-model work (see Section 13 and 15). (theofanous2024exploringtheprotective pages 69-72, theofanous2024exploringtheprotective pages 1-5)

2.3 Protective factors

Evidence directly specific to BRAF V600E CRC prevention in humans is limited in retrieved sources. The retrieved evidence includes preclinical and limited human biomarker signals for dietary compounds: - In APCMIN/+ mice on high-fat diet, resveratrol reduced “intestinal adenoma number and tumour burden by ~40% and ~57%” at low dose in one study summarized in the thesis review table. (theofanous2024exploringtheprotective pages 69-72) - In a small human CRC/metastasis context referenced by the same thesis, resveratrol interventions were associated with biomarker changes such as “cleaved caspase 3 … 39%” in hepatic metastases and a “5% reduction in Ki67 proliferation” (short-term, small n). (theofanous2024exploringtheprotective pages 69-72)

2.4 Gene–environment interactions

A BRAF V600E-driven mouse model in the resveratrol/HFD work showed genotype-dependent response to dietary fat exposure (interaction leading to rapid weight loss and early culling before polyp development), indicating that BRAF-driven physiology may modulate diet response in vivo. (theofanous2024exploringtheprotective pages 69-72)

3. Phenotypes

3.1 Clinicopathologic phenotype (common patterns)

A large 2023 nationwide advanced CRC cohort (n=7,604) found BRAF V600E is enriched in multiple clinicopathologic settings: - Female sex (OR 2.009) - Right/proximal colon primary (OR 8.356) - High-grade tumors (OR 4.061) - Mucinous histology (OR 3.430) and partially mucinous (OR 2.718) - Signet cell features (OR 1.544) - Mixed adeno-neuroendocrine cancers (MANEC; OR 9.211) - Vascular and perineural invasion (potocki2023clinicalcharacterizationof pages 4-5)

In real-world clinical description, BRAF V600E mCRC is also described as more often right-sided, more common in female patients, and associated with MSI-high features. (zurloh2023impactofencorafenib pages 1-2)

3.2 Symptom/sign phenotype

Symptoms generally reflect colorectal cancer and metastatic spread; the retrieved corpus did not provide quantitative symptom frequencies specific to BRAF V600E subtype.

3.3 Suggested HPO terms (examples)

Because the retrieved evidence emphasizes pathology and metastatic patterns more than symptom inventories, HPO suggestions are necessarily generic for CRC/mCRC: - Abdominal pain (HP:0002027) - Hematochezia (HP:0001892) - Weight loss (HP:0001824) - Anemia (HP:0001903) - Metastatic neoplasm (HP:0003002)

(Phenotype frequency data not available in retrieved sources.)

3.4 Quality-of-life impact

A review notes BRAF V600E CRC is linked to worse HRQoL compared with BRAF-wildtype CRC, but quantitative QoL instrument values were not available in retrieved excerpts. (morris2020improvementsinclinical pages 1-5)

4. Genetic/Molecular Information

4.1 Causal genes

• BRAF (B-RAF proto-oncogene, serine/threonine kinase) is the defining driver gene in this subtype. (morris2020improvementsinclinical pages 1-5, potocki2023clinicalcharacterizationof pages 1-2)

4.2 Pathogenic variants

• BRAF p.Val600Glu (V600E): activating substitution at residue 600, constitutive MAPK pathway activation. (morris2020improvementsinclinical pages 1-5)

Somatic vs germline: In CRC, BRAF V600E is typically treated as a somatic tumor driver; it is also used clinically to help exclude Lynch syndrome when MSI-H is present (see Diagnostics). (effendiys2024biomarkersasa pages 3-6, iliepetrov2024…ofcolorectal pages 7-9)

4.3 Modifier/co-alterations and resistance alterations

The 2024 BEACON CRC multi-omics biomarker analysis identified acquired resistance alterations: - “RAS, MAP2K1 and MET alterations were most commonly acquired” on encorafenib+cetuximab±binimetinib. (kopetz2024molecularprofilingof pages 1-2) - “baseline TP53 mutation was associated with acquired MET amplification.” (kopetz2024molecularprofilingof pages 1-2)

4.4 Epigenetics

BRAF-mutant CRC is linked to CIMP biology (hypermethylation phenotype), often aligned with serrated pathway development. (guerrero2023brafinhibitorsin pages 1-2, effendiys2024biomarkersasa pages 3-6)

5. Environmental Information

5.1 Environmental/lifestyle factors

• Obesity/body size: causal MR support for higher BMI increasing risk of BRAF-mutated/CIMP-high pathway CRC subtypes (see Etiology). (papadimitriou2024bodysizeand pages 1-2)
• Dietary fat/high-fat diet: discussed as CRC risk context and experimentally interrogated in BRAF-driven mouse models. (theofanous2024exploringtheprotective pages 69-72, theofanous2024exploringtheprotective pages 1-5)

5.2 Infectious agents

No infectious agents specific to BRAF V600E CRC were identified in retrieved sources.

6. Mechanism / Pathophysiology

6.1 Core pathway: EGFR–RAS–RAF–MEK–ERK (MAPK)

BRAF V600E acts downstream of EGFR and RAS to drive MAPK signaling, increasing proliferation and reducing apoptosis. (morris2020improvementsinclinical pages 1-5)

6.2 Why BRAF inhibitor monotherapy fails in CRC (EGFR feedback)

The dominant mechanistic concept guiding therapy is EGFR-mediated MAPK pathway reactivation after BRAF inhibition: - BEACON CRC (NEJM): “Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.” (kopetz2019encorafenibbinimetiniband pages 1-2) - BEACON updated analysis (JCO): “BRAF inhibition results in a rapid release of feedback-suppressed epidermal growth-factor receptor (EGFR)–mediated MAPK signaling, leading to a rebound in MAPK activation and continued cell proliferation.” (tabernero2021encorafenibpluscetuximab pages 1-2)

Causal chain (simplified): 1) BRAF V600E → constitutive ERK signaling → malignant growth (morris2020improvementsinclinical pages 1-5) 2) BRAF inhibitor alone ↓ ERK transiently → releases feedback suppression → EGFR activation → RAS signaling → RAF dimerization/reactivation → restored ERK signaling → resistance (tabernero2021encorafenibpluscetuximab pages 1-2, morris2020improvementsinclinical pages 11-14) 3) Combine BRAF + EGFR (±MEK) inhibition → deeper pathway suppression and improved outcomes (kopetz2019encorafenibbinimetiniband pages 1-2, tabernero2021encorafenibpluscetuximab pages 1-2)

6.3 MSI/dMMR and immunobiology

BRAF mutations are enriched in sporadic MSI tumors and ~20% of BRAF V600E mCRC may be MSI, a key determinant of checkpoint inhibitor sensitivity. (guerrero2023brafinhibitorsin pages 1-2, effendiys2024biomarkersasa pages 3-6)

6.4 Suggested ontology terms

GO Biological Process (suggestions): - MAPK cascade (GO:0000165) - ERK1 and ERK2 cascade (GO:0070371) - Regulation of cell proliferation (GO:0042127) - Negative regulation of apoptotic process (GO:0043066) - Epithelial cell proliferation (GO:0050673)

CL Cell Ontology (suggestions): - Colonic epithelial cell / intestinal epithelial cell (CL:0000584 may map to enterocyte; general epithelial cell CL:0000066) - Colonic stem cell (broadly: intestinal stem cell) - Tumor-associated macrophage (for microenvironment studies; not directly evidenced in retrieved BRAF-specific excerpts)

UBERON (suggestions): - Colon (UBERON:0001155) - Large intestine (UBERON:0000059)

7. Anatomical Structures Affected

7.1 Organ/tissue level

• Primary: colon/colorectum (UBERON:0001155 / UBERON:0000059) (general CRC context)
• Metastatic patterns may include peritoneal, bone, and brain involvement (review-level), though frequencies were not in retrieved excerpts. (morris2020improvementsinclinical pages 1-5)

7.2 Cell/subcellular

• Primary cell population: colonic epithelial tumor cells
• Key signaling compartment: cytoplasmic kinase signaling and nuclear transcriptional outputs downstream of ERK

8. Temporal Development

8.1 Onset

CRC is generally adult-onset. Early-onset CRC shows lower prevalence of BRAF mutations overall than late-onset CRC (not BRAF V600E-specific prevalence): OR 0.63 (0.51–0.78). (lawler2024thehistologicaland pages 1-2)

8.2 Progression

BRAF V600E mCRC is described as rapidly progressive with poor outcomes on historical standard therapies. (kopetz2019encorafenibbinimetiniband pages 1-2, morris2020improvementsinclinical pages 1-5)

9. Inheritance and Population

9.1 Epidemiology

• Prevalence of BRAF V600E in advanced CRC: 6.77% in a nationwide cohort of 7,604 advanced CRC patients tested in one laboratory (Oct 2017–Dec 2019). (potocki2023clinicalcharacterizationof pages 1-2)
• Trial/review estimates: ~10–15% in metastatic CRC. (cutsem2023anchorcrcresults pages 1-2)

9.2 Inheritance

This is predominantly a somatic tumor genotype rather than a Mendelian inherited disease entity in standard oncology usage.

9.3 Demographics

• Enrichment in female patients and right-sided primaries is strongly supported by the 2023 nationwide cohort (ORs above). (potocki2023clinicalcharacterizationof pages 4-5)

10. Diagnostics

10.1 Core biomarker tests and workflows

A practical, widely used workflow in metastatic CRC includes: extended RAS testing (KRAS/NRAS), BRAF testing, and MSI/MMR status assessment. (effendiys2024biomarkersasa pages 3-6, NCT05217446 chunk 1)

Assay modalities supported in retrieved sources: - MMR/MSI: Immunohistochemistry (IHC) for MMR proteins and PCR for MSI are explicitly discussed as standard approaches in a 2024 biomarker overview. (effendiys2024biomarkersasa pages 3-6) - BRAF testing: typically performed on tumor tissue; can be done alongside RAS. (effendiys2024biomarkersasa pages 3-6) - NGS panels: highlighted for comprehensive detection including atypical/non-V600 BRAF variants. (iliepetrov2024…ofcolorectal pages 7-9)

10.2 Lynch syndrome exclusion / differential

• BRAF V600E in MSI-H CRC is commonly used to help exclude Lynch syndrome in sporadic MSI-H disease in diagnostic algorithms (review-level and diagnostic discussion). (effendiys2024biomarkersasa pages 3-6, iliepetrov2024…ofcolorectal pages 7-9)

10.3 Liquid biopsy / ctDNA implementation

Clinical trial registrations and protocols show ctDNA is being used both for enrollment and for resistance-guided retreatment decisions: - NCT05217446 allows BRAF confirmation from “tumor tissue or blood” (implying ctDNA accepted) with mandatory local MSI-H/dMMR confirmation and known RAS status. (NCT05217446 chunk 1) - NCT06578559 (BRICKET) requires ctDNA at entry showing no KRAS/NRAS/MAP2K1 mutations and no MET amplification before encorafenib+cetuximab rechallenge. (NCT06578559 chunk 1)

11. Outcome / Prognosis

11.1 Natural history / poor prognosis

BEACON CRC provides a trial-level summary of poor prognosis after initial therapy failure: - “median overall survival of 4 to 6 months after failure of initial therapy” in BRAF V600E mCRC (historical context). (kopetz2019encorafenibbinimetiniband pages 1-2)

11.2 Survival statistics from recent cohorts

• Real-world cohort (Germany, 2023; n=51): median OS 17.6 months overall; targeted therapy in later lines associated with OS 25.1 months in those receiving a BRAF inhibitor. (zurloh2023impactofencorafenib pages 1-2)
• Multi-center real-world propensity-matched study (2024; n=125): median OS 14.9 months; triplet chemotherapy+bevacizumab OS 17.4 vs 13.4 months pre-PSM and 17.4 vs 10.4 months post-PSM. (wei2024clinicopathologicfeaturesand pages 10-10)

11.3 Prognostic factors

In a 2024 multi-center study, poor differentiation and liver metastases were negative independent prognostic factors for OS in BRAF V600E mCRC. (wei2024clinicopathologicfeaturesand pages 10-10)

12. Treatment

12.1 Targeted therapy standard of care: Encorafenib + cetuximab (post–first line)

BEACON CRC established BRAF+EGFR targeted therapy as standard after prior therapy.

Phase III BEACON CRC (interim analysis; NEJM 2019): - Mechanistic abstract quote: “Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.” (kopetz2019encorafenibbinimetiniband pages 1-2) - Outcomes: - Triplet (encorafenib+binimetinib+cetuximab): median OS 9.0 vs control 5.4 months (HR 0.52) - Confirmed ORR 26% vs 2% - Grade ≥3 AEs: 58% (triplet), 50% (doublet), 61% (control) (kopetz2019encorafenibbinimetiniband pages 1-2)

Updated BEACON CRC analysis (JCO 2021): - OS: 9.3 months (triplet) and 9.3 months (doublet) vs 5.9 months (control) - ORR: 26.8% (triplet), 19.5% (doublet), 1.8% (control) - Grade ≥3 AEs: 65.8% (triplet), 57.4% (doublet), 64.2% (control) (tabernero2021encorafenibpluscetuximab pages 1-2)

These outcomes are also supported visually by the BEACON updated OS Kaplan–Meier and response table (tabernero2021encorafenibpluscetuximab media 2b387ba4, tabernero2021encorafenibpluscetuximab media 9dac50ff).

MAXO suggestions: - EGFR inhibitor therapy (cetuximab) - BRAF inhibitor therapy (encorafenib) - MEK inhibitor therapy (binimetinib)

12.2 First-line targeted therapy strategies (emerging/2023–2025)

ANCHOR CRC phase II (JCO 2023; first-line triplet, single-arm): - cORR 47.4% (95% CI 37.0–57.9) - median PFS 5.8 months - median OS 18.3 months (cutsem2023anchorcrcresults pages 1-2)

BREAKWATER phase III (Nature Medicine 2025; first interim, first-line EC+mFOLFOX6): - ORR 60.9% vs SOC 40.0% - OS HR 0.47 (interim) - Serious AEs 37.7% vs 34.6% (kopetz2025encorafenibcetuximaband pages 1-2)

12.3 Safety lead-in evidence (BEACON)

BEACON safety lead-in (JCO 2019): - ORR 48%; median PFS 8.0 months; median OS 15.3 months (cutsem2019binimetinibencorafeniband pages 1-2) - DLTs included serous retinopathy, decreased LVEF, infusion reactions; common grade 3–4 AEs included fatigue (13%), anemia (10%), ↑CPK (10%), ↑AST (10%), UTI (10%). (cutsem2019binimetinibencorafeniband pages 1-2)

12.4 Immunotherapy

The retrieved evidence emphasizes that MSI-H/dMMR status is a key selection biomarker for PD-1 blockade in metastatic CRC, including in BRAF-mutant disease. (eriksen2022aphaseii pages 1-2)

A key real-world implementation example is an ongoing/registered trial: - NCT05217446 compares encorafenib+cetuximab+pembrolizumab vs pembrolizumab alone in untreated MSI-H/dMMR, BRAF V600E mCRC, permitting BRAF confirmation by tissue or blood. (NCT05217446 chunk 1)

12.5 Resistance and sequencing

The 2024 BEACON translational analysis supports surveillance of resistance mechanisms and suggests biologically plausible targets (RAS/MAP2K1/MET) for next-line strategies. (kopetz2024molecularprofilingof pages 1-2)

A direct implementation of resistance-informed strategy is the ctDNA-guided rechallenge trial NCT06578559 excluding ctDNA-detectable RAS/MAP2K1/MET alterations at retreatment entry. (NCT06578559 chunk 1)

13. Prevention

13.1 Primary prevention

BRAF V600E is a tumor genotype rather than a preventable infectious etiology. However, CRC primary prevention strategies likely apply and are supported by subtype-specific evidence that obesity is causally linked to BRAF-mutated/CIMP-high pathways (targeting BMI reduction as a plausible primary prevention lever). (papadimitriou2024bodysizeand pages 1-2)

13.2 Secondary prevention (screening/early detection)

CRC screening strategies (colonoscopy, stool-based tests) are not detailed in the retrieved excerpts, but MSI/MMR and BRAF testing are emphasized once CRC is diagnosed, particularly for Lynch syndrome triage and systemic therapy selection. (effendiys2024biomarkersasa pages 3-6, iliepetrov2024…ofcolorectal pages 7-9)

13.3 Tertiary prevention

In metastatic disease, tertiary prevention focuses on preventing progression/complications via effective systemic therapy and molecularly guided sequencing (e.g., BEACON regimen, ctDNA monitoring trials). (tabernero2021encorafenibpluscetuximab pages 1-2, NCT06578559 chunk 1)

14. Other Species / Natural Disease

No naturally occurring non-human species disease analogs specific to BRAF V600E CRC were identified in the retrieved sources.

15. Model Organisms and Experimental Systems

15.1 Mouse models (BRAF-driven CRC and diet interactions)

A 2024 BRAF V600E-driven CRC mouse-model study/thesis explored high-fat diet effects and resveratrol modulation, including multi-omics phenotyping (microbiome, metabolomics, cytokines) and intestinal lipid biology. (theofanous2024exploringtheprotective pages 1-5)

Quantitative preclinical “prevention-like” effects summarized in that thesis include resveratrol reducing adenoma number/tumor burden in APCMIN/+ mice on high-fat diet by ~40% and ~57% at a low dose in one study table. (theofanous2024exploringtheprotective pages 69-72)

15.2 Patient-derived organoids (PDOs) and living biobanks

Organoids are emphasized as clinically relevant models for CRC heterogeneity and treatment response: - Ex vivo organoid review (Cancers 2024) notes organoids preserve tumor heterogeneity and explicitly mentions “models with high microsatellite instability associated with BRAF V600E mutations,” and positions living biobanks for personalized treatment testing. (randalldemllo2024exvivointestinal pages 4-6) - EGFR-targeting review (IJMS 2024) describes organoids as reflecting “genetic heterogeneity” and being used to study resistance to anti-EGFR therapies in personalized medicine contexts. (tardito2024epidermalgrowthfactor pages 1-2)

15.3 PDX models for drug response (EGFR therapy)

A 2024 Nature Communications study underscores PDX value for studying cetuximab sensitivity: - PDXs are “tumour fragments engrafted into mice” and retain “structural complexity, heterogeneity, and stromal interactions” better than in vitro models; 231 CRC PDXs were profiled and screened for cetuximab response to train a predictive multi-omics model. (perron2024integrativeensemblemodelling pages 1-2)

15.4 Model limitations (expert synthesis from authoritative reviews)

• Organoids lack full tumor microenvironment and pharmacokinetics/ADME; PDX provides in vivo context but is lower throughput and costly. (randalldemllo2024exvivointestinal pages 4-6)

Current applications and real-world implementations (2023–2024 emphasis)

1) Routine molecular profiling in metastatic CRC including RAS/BRAF and MSI/MMR to guide therapy selection and exclude ineffective anti-EGFR monotherapy in inappropriate genotypes. (effendiys2024biomarkersasa pages 3-6, NCT05217446 chunk 1) 2) Approved targeted standard after prior therapy: encorafenib + cetuximab (BEACON-established). (tabernero2021encorafenibpluscetuximab pages 1-2) 3) First-line intensification and targeted combinations in clinical trials (ANCHOR CRC; BREAKWATER). (cutsem2023anchorcrcresults pages 1-2, kopetz2025encorafenibcetuximaband pages 1-2) 4) ctDNA integration for resistance-guided rechallenge (BRICKET, NCT06578559). (NCT06578559 chunk 1) 5) Organoid and PDX platforms for drug-response prediction and resistance studies, supporting precision medicine pipelines. (randalldemllo2024exvivointestinal pages 4-6, perron2024integrativeensemblemodelling pages 1-2, tardito2024epidermalgrowthfactor pages 1-2)

Relevant statistics and data highlights

• Prevalence of BRAF V600E in advanced CRC: 6.77% in 7,604-patient cohort (2023 report). (potocki2023clinicalcharacterizationof pages 1-2)
• Clinicopathologic enrichment: OR 8.356 for right-sided primaries; OR 4.061 high grade; OR 3.430 mucinous; OR 9.211 MANEC/neuroendocrine component. (potocki2023clinicalcharacterizationof pages 4-5)
• BEACON updated OS and ORR: OS 9.3 vs 5.9 months; ORR 19.5% (doublet) and 26.8% (triplet) vs 1.8% control. (tabernero2021encorafenibpluscetuximab pages 1-2)
• BMI causal association with BRAF-mutated/CIMP-high subtypes: OR ~2.1–2.2 per 1-SD higher BMI. (papadimitriou2024bodysizeand pages 1-2)

Synthesis tables and visual evidence

The table below consolidates identifiers, epidemiology/phenotype, and core clinical trial outcomes.

Table: This table compiles disease metadata, clinicopathologic characteristics, and the most clinically relevant treatment studies for BRAF V600E–mutant colorectal cancer. It is designed to support rapid knowledge-base population with cited prevalence, phenotype, biomarker, and outcome data.

BEACON updated Kaplan–Meier OS curves and tumor response table are available as visual evidence. (tabernero2021encorafenibpluscetuximab media 2b387ba4, tabernero2021encorafenibpluscetuximab media 9dac50ff)

Limitations / gaps in retrieved sources

• Formal ontology identifiers (MONDO, MeSH, ICD-10/11 mapping specific to BRAF V600E subtype) were not found in the retrieved corpus.
• Quantitative symptom frequencies, QoL instrument scores, and detailed CRC screening guideline text were not present in retrieved excerpts.
• Species-wide “natural disease” analogs and veterinary disease parallels were not identified.

Primary-source URLs (examples)

• BEACON CRC (NEJM 2019; published Oct 2019): https://doi.org/10.1056/NEJMoa1908075 (kopetz2019encorafenibbinimetiniband pages 1-2)
• BEACON updated (JCO 2021; published Feb 2021): https://doi.org/10.1200/JCO.20.02088 (tabernero2021encorafenibpluscetuximab pages 1-2)
• ANCHOR CRC (JCO 2023; published May 2023): https://doi.org/10.1200/JCO.22.01693 (cutsem2023anchorcrcresults pages 1-2)
• BEACON multi-omics profiling (Nature Medicine 2024; published Sep 2024): https://doi.org/10.1038/s41591-024-03235-9 (kopetz2024molecularprofilingof pages 1-2)
• Body size MR (eBioMedicine 2024; published Mar 2024): https://doi.org/10.1016/j.ebiom.2024.105010 (papadimitriou2024bodysizeand pages 1-2)
• ctDNA-guided rechallenge trial registry (posted 2024): https://clinicaltrials.gov/study/NCT06578559 (NCT06578559 chunk 1)

References

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2. (kopetz2024molecularprofilingof pages 1-2): Scott Kopetz, Danielle A. Murphy, Jie Pu, Fortunato Ciardiello, Jayesh Desai, Eric Van Cutsem, Harpreet Singh Wasan, Takayuki Yoshino, Hedieh Saffari, Xiaosong Zhang, Phineas Hamilton, Tao Xie, Rona Yaeger, and Josep Tabernero. Molecular profiling of braf-v600e-mutant metastatic colorectal cancer in the phase 3 beacon crc trial. Nature Medicine, 30:3261-3271, Sep 2024. URL: https://doi.org/10.1038/s41591-024-03235-9, doi:10.1038/s41591-024-03235-9. This article has 77 citations and is from a highest quality peer-reviewed journal.

3. (NCT06578559 chunk 1): Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients BRAF V600E Mutated mCRC. Gruppo Oncologico del Nord-Ovest. 2024. ClinicalTrials.gov Identifier: NCT06578559

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