Metastatic colorectal cancer is colorectal adenocarcinoma that has disseminated beyond the bowel wall and regional nodes, most commonly to the liver and then lung, peritoneum, and other distant sites. The metastatic phenotype reflects cooperation between APC/WNT dysregulation, KRAS and BRAF pathway activation, epithelial plasticity, stromal remodeling, angiogenesis, and adaptation to the hepatic seed-and-soil niche.
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name: Metastatic Colorectal Cancer
creation_date: '2026-03-28T21:10:00Z'
updated_date: '2026-05-10T07:01:32Z'
description: >-
Metastatic colorectal cancer is colorectal adenocarcinoma that has disseminated
beyond the bowel wall and regional nodes, most commonly to the liver and then lung,
peritoneum, and other distant sites. The metastatic phenotype reflects cooperation
between APC/WNT dysregulation, KRAS and BRAF pathway activation, epithelial plasticity,
stromal remodeling, angiogenesis, and adaptation to the hepatic seed-and-soil niche.
categories:
- Gastrointestinal Cancer
- Metastatic Cancer
- Solid Tumor
parents:
- colorectal cancer
disease_term:
preferred_term: metastatic colorectal cancer
term:
id: MONDO:0005575
label: colorectal cancer
mappings:
mondo_mappings:
- term:
id: MONDO:0005575
label: colorectal cancer
mapping_predicate: skos:closeMatch
mapping_source: MONDO
mapping_justification: Closest MONDO parent term available for metastatic colorectal cancer.
prevalence:
- population: New colorectal cancer diagnoses
percentage: 20
notes: About one in five patients has metastatic disease at presentation.
evidence:
- reference: PMID:33591350
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Of new colorectal cancer diagnoses, 20% of patients have metastatic disease at presentation and another 25% who present with localized disease will later develop metastases.
explanation: This gives an evidence-backed estimate of metastatic CRC at diagnosis.
- population: Metastatic colorectal cancer
percentage: 20
notes: Fewer than 20% of patients with metastatic CRC survive beyond 5 years from diagnosis.
evidence:
- reference: PMID:33591350
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Among people diagnosed with metastatic colorectal cancer, approximately 70% to 75% of patients survive beyond 1 year, 30% to 35% beyond 3 years, and fewer than 20% beyond 5 years from diagnosis.
explanation: This provides a clinically relevant long-term survival benchmark for metastatic CRC.
pathophysiology:
- name: WNT and RAS Pathway Cooperation
description: >-
Metastatic colorectal cancer typically evolves on a background of APC/WNT pathway
dysregulation, with KRAS and BRAF alterations shaping invasion, therapy response,
and
liver metastatic fitness. These pathways reinforce proliferative signaling and
resistance to anoikis during dissemination.
evidence:
- reference: PMID:25632202
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: KRAS and BRAF mutations are associated with inferior survival, independent of MSI status, in Japanese patients with curatively resected CRC.
explanation: This supports the clinical importance of KRAS and BRAF signaling even after accounting for MSI status.
biological_processes:
- preferred_term: Wnt signaling pathway
modifier: INCREASED
term:
id: GO:0016055
label: Wnt signaling pathway
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
- name: Liver Tropism and Hepatic Colonization
description: >-
The liver is the dominant first metastatic site because colorectal venous drainage
enters the portal circulation and because hepatic stromal, endothelial, and immune
niches support tumor cell arrest and outgrowth.
evidence:
- reference: PMID:29201802
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The liver is the first location of metastatic disease; due to that the main mechanism of dissemination is through the portal system.
explanation: This supports the dominant hepatic tropism of metastatic colorectal cancer.
biological_processes:
- preferred_term: cell migration
modifier: INCREASED
term:
id: GO:0016477
label: cell migration
- name: EMT-Linked Invasive Dissemination
description: >-
Metastatic colorectal cancer cells detach from the primary epithelium, invade
through vascular and stromal barriers, and colonize the liver through a stepwise
dissemination program consistent with EMT-linked invasive plasticity.
evidence:
- reference: PMID:29201802
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: Metastasis of the liver from colorectal cancer represents the final stage of a multistep biological process.
explanation: This supports a sequential detachment, invasion, and colonization program in metastatic CRC that is consistent with EMT-linked dissemination.
biological_processes:
- preferred_term: epithelial to mesenchymal transition
modifier: INCREASED
term:
id: GO:0001837
label: epithelial to mesenchymal transition
- preferred_term: positive regulation of cell migration
modifier: INCREASED
term:
id: GO:0030335
label: positive regulation of cell migration
- name: Anoikis Escape
description: >-
A subset of metastatic colorectal cancers survives matrix detachment during transit,
allowing circulating or portal-disseminating cells to persist long enough to seed
the liver and other distant niches.
evidence:
- reference: PMID:41027285
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: MM tumors exhibited suppressed ferroptosis and activation of the TGF-β signaling pathway, while SM tumors displayed inhibited anoikis and activation of the WNT signaling pathway, accompanied by activated angiogenesis.
explanation: This directly supports inhibition of anoikis as a distinct metastatic program in colorectal cancer liver metastasis.
- name: Angiogenic Remodeling
description: >-
Metastatic colorectal cancer promotes angiogenic remodeling at secondary sites
to
sustain micrometastatic survival, vascular adaptation, and outgrowth in the hepatic
microenvironment.
evidence:
- reference: PMID:41027285
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: MM tumors exhibited suppressed ferroptosis and activation of the TGF-β signaling pathway, while SM tumors displayed inhibited anoikis and activation of the WNT signaling pathway, accompanied by activated angiogenesis.
explanation: This directly supports activated angiogenesis as a distinct metastatic CRC program.
biological_processes:
- preferred_term: angiogenesis
modifier: INCREASED
term:
id: GO:0001525
label: angiogenesis
- name: Seed-and-Soil Microenvironment Support
description: >-
Metastatic outgrowth depends on reciprocal signaling between tumor cells and stromal
populations such as cancer-associated fibroblasts, which help create a permissive
hepatic microenvironment and immunosuppressive niche.
evidence:
- reference: PMID:40530415
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Within the "seed and soil" paradigm, disrupting both tumor cells and their supportive microenvironment is essential to suppress disease progression.
explanation: This explicitly frames colorectal liver metastasis in seed-and-soil terms.
biological_processes:
- preferred_term: negative regulation of immune response
modifier: INCREASED
term:
id: GO:0050777
label: negative regulation of immune response
phenotypes:
- category: Gastrointestinal
name: Abdominal pain
frequency: FREQUENT
description: Abdominal pain reflects primary tumor burden, liver metastases, bowel obstruction, or peritoneal spread.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
- category: Constitutional
name: Weight loss
frequency: VERY_FREQUENT
description: Metastatic colorectal cancer commonly causes catabolic weight loss.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
- category: Constitutional
name: Fatigue
frequency: VERY_FREQUENT
description: Fatigue arises from chronic inflammation, anemia, treatment toxicity, and extensive disease.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- category: Hepatic
name: Jaundice
frequency: OCCASIONAL
description: Jaundice may appear with bulky liver metastases or biliary obstruction.
phenotype_term:
preferred_term: Jaundice
term:
id: HP:0000952
label: Jaundice
genetic:
- name: APC
association: Somatic loss of function
notes: APC inactivation is the canonical initiator of WNT pathway activation in colorectal carcinogenesis and metastatic progression.
- name: KRAS
association: Somatic activating mutation
notes: KRAS mutations promote metastatic fitness, EGFR resistance, and inferior survival.
- name: BRAF
association: Somatic activating mutation
notes: BRAF, especially V600E, is linked to aggressive metastatic behavior and poor prognosis.
- name: Mismatch repair deficiency / MSI-high state
association: Hypermutator phenotype
notes: MSI-high tumors have distinct immune biology and may respond better to checkpoint blockade despite advanced disease.
environmental:
- name: Obesity
notes: Obesity increases colorectal cancer risk and can reinforce inflammatory programs linked to metastatic progression.
- name: Alcohol exposure
notes: Alcohol contributes to colorectal cancer risk and often coexists with metabolic and inflammatory exposures.
notes: >-
Metastatic colorectal cancer is biologically heterogeneous, but liver colonization,
KRAS/BRAF-driven signaling, WNT pathway activation, and stromal cooperation are
recurring
mechanistic themes. MSI-high disease represents a distinct immune-responsive metastatic
subset.
treatments:
- name: Encorafenib Plus Binimetinib and Cetuximab for BRAF V600E Disease
description: Encorafenib, binimetinib, and cetuximab provide a targeted regimen for BRAF V600E-mutant metastatic colorectal cancer, pairing BRAF and MEK inhibition with EGFR blockade to suppress MAPK feedback signaling.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: encorafenib
term:
id: NCIT:C98283
label: Encorafenib
- preferred_term: binimetinib
term:
id: CHEBI:145371
label: binimetinib
- preferred_term: cetuximab
term:
id: NCIT:C1723
label: Cetuximab
evidence:
- reference: DOI:10.1200/jco.22.01693
reference_title: 'ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated <i>BRAF</i><sup>V600E</sup>-Mutant Metastatic Colorectal Cancer'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The positive BEACON colorectal cancer (CRC) safety lead-in,
evaluating encorafenib + cetuximab + binimetinib in previously treated
patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the
design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier:
NCT03693170 ).
explanation: The phase II ANCHOR CRC study directly evaluates this BRAF/MEK/EGFR targeted combination in BRAF V600E-mutant metastatic CRC.
- name: Cetuximab for RAS Wild-Type Disease Stratified by APC Mutation Status
description: Cetuximab combined with chemotherapy for RAS wild-type metastatic CRC shows improved outcomes in APC-mutant tumors. APC mutation status serves as a predictive biomarker, with APC-mutant tumors achieving higher response rates and longer overall survival compared to APC wild-type tumors, suggesting that Wnt pathway dysregulation influences EGFR inhibitor sensitivity.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: cetuximab
term:
id: NCIT:C1723
label: Cetuximab
evidence:
- reference: PMID:42199488
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: partial response was achieved in 64 patients with APC-mutated tumors (85%) and 17 patients with APC wild type tumors (59%). There was a significant difference in the objective response rate (ORR) between patients with APC mutation and wild type (p-value of 0.003).
explanation: This clinical study demonstrates APC mutation status as a predictive biomarker for cetuximab response in RAS wild-type disease, with significantly higher objective response rates in APC-mutant patients.
- reference: PMID:42199488
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The median OS was not reached (95% CI, 31.5-NA) in patients with the APC mutation, whereas it was 37.3 months (95% CI, 23.4-NA) in those with APC-wild type tumors (p = 0.024).
explanation: APC-mutant patients treated with cetuximab-containing chemotherapy show significantly longer median overall survival compared to APC wild-type patients.
references:
- reference: DOI:10.1001/jamanetworkopen.2024.52661
title: Circulating Tumor DNA Testing in Curatively Resected Colorectal Cancer and Salvage Resection
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Circulating Tumor DNA Testing in Curatively Resected Colorectal Cancer and Salvage Resection
supporting_text: ImportanceSerial circulating tumor DNA (ctDNA) has emerged as a routine surveillance strategy for patients with resected colorectal cancer, but how serial ctDNA monitoring is associated with potential curative outcomes has not been formally assessed.ObjectiveTo examine whether there is a benefit of adding serial ctDNA assays to standard-of-care imaging surveillance for potential curative outcomes in patients with resected colorectal cancer.Design, Setting, and ParticipantsIn this single-center (City of Hope Comprehensive Cancer Center, Duarte, California), retrospective, case cohort study, patients with stage II to IV colorectal cancer underwent curative resection and were monitored with serial ctDNA assay and National Cancer Center Network (NCCN)–guided imaging surveillance from September 20, 2019, to April 3, 2024.
evidence:
- reference: DOI:10.1001/jamanetworkopen.2024.52661
reference_title: Circulating Tumor DNA Testing in Curatively Resected Colorectal Cancer and Salvage Resection
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ImportanceSerial circulating tumor DNA (ctDNA) has emerged as a routine surveillance strategy for patients with resected colorectal cancer, but how serial ctDNA monitoring is associated with potential curative outcomes has not been formally assessed.ObjectiveTo examine whether there is a benefit of adding serial ctDNA assays to standard-of-care imaging surveillance for potential curative outcomes in patients with resected colorectal cancer.Design, Setting, and ParticipantsIn this single-center (City of Hope Comprehensive Cancer Center, Duarte, California), retrospective, case cohort study, patients with stage II to IV colorectal cancer underwent curative resection and were monitored with serial ctDNA assay and National Cancer Center Network (NCCN)–guided imaging surveillance from September 20, 2019, to April 3, 2024.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.1007/s12094-023-03309-z
title: Real-world study on microsatellite instability and mismatch repair deficiency testing patterns among patients with metastatic colorectal cancer in Spain
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 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).
supporting_text: 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).
evidence:
- reference: DOI:10.1007/s12094-023-03309-z
reference_title: Real-world study on microsatellite instability and mismatch repair deficiency testing patterns among patients with metastatic colorectal cancer in Spain
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 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).
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.1038/s41591-023-02696-8
title: 'Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial'
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis.
supporting_text: KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis.
evidence:
- reference: DOI:10.1038/s41591-023-02696-8
reference_title: 'Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.1038/s41591-024-03254-6
title: ctDNA-based molecular residual disease and survival in resectable colorectal cancer
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: ctDNA-based molecular residual disease and survival in resectable colorectal cancer
supporting_text: ctDNA-based molecular residual disease and survival in resectable colorectal cancer
- reference: DOI:10.1038/s41598-024-54972-3
title: 'Survival outcome and prognostic factors for early-onset and late-onset metastatic colorectal cancer: a population based study from SEER database'
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Colorectal cancer is the third most common cancer worldwide and there has been a concerning increase in the incidence rate of colorectal cancer among individuals under the age of 50.
supporting_text: Colorectal cancer is the third most common cancer worldwide and there has been a concerning increase in the incidence rate of colorectal cancer among individuals under the age of 50.
evidence:
- reference: DOI:10.1038/s41598-024-54972-3
reference_title: 'Survival outcome and prognostic factors for early-onset and late-onset metastatic colorectal cancer: a population based study from SEER database'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Colorectal cancer is the third most common cancer worldwide and there has been a concerning increase in the incidence rate of colorectal cancer among individuals under the age of 50.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.1158/1078-0432.ccr-23-3660
title: Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment.
supporting_text: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment.
evidence:
- reference: DOI:10.1158/1078-0432.ccr-23-3660
reference_title: Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.1200/jco.22.01693
title: 'ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated <i>BRAF</i><sup>V600E</sup>-Mutant Metastatic Colorectal Cancer'
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated <i>BRAF</i><sup>V600E</sup>-Mutant Metastatic Colorectal Cancer'
supporting_text: 'The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170 ).'
evidence:
- reference: DOI:10.1200/jco.22.01693
reference_title: 'ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated <i>BRAF</i><sup>V600E</sup>-Mutant Metastatic Colorectal Cancer'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170 ).'
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.1200/po.23.00127
title: Tumor-Informed Circulating Tumor DNA for Minimal Residual Disease Detection in the Management of Colorectal Cancer
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Recurrence after curative-intent treatment occurs in 20%-50% of patients with stage II-IV colorectal cancer (CRC), underscoring the need for early detection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA).
supporting_text: Recurrence after curative-intent treatment occurs in 20%-50% of patients with stage II-IV colorectal cancer (CRC), underscoring the need for early detection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA).
evidence:
- reference: DOI:10.1200/po.23.00127
reference_title: Tumor-Informed Circulating Tumor DNA for Minimal Residual Disease Detection in the Management of Colorectal Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Recurrence after curative-intent treatment occurs in 20%-50% of patients with stage II-IV colorectal cancer (CRC), underscoring the need for early detection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA).
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.3390/cancers16112004
title: 'Survival Analysis of Metastatic Early-Onset Colorectal Cancer Compared to Metastatic Average-Onset Colorectal Cancer: A SEER Database Analysis'
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Early-onset colorectal cancer (EO-CRC) is defined as colorectal cancer diagnosed before the age of 50 years, and its incidence has been increasing over the last decade, now accounting for 10% of all new CRC diagnoses.
supporting_text: Early-onset colorectal cancer (EO-CRC) is defined as colorectal cancer diagnosed before the age of 50 years, and its incidence has been increasing over the last decade, now accounting for 10% of all new CRC diagnoses.
evidence:
- reference: DOI:10.3390/cancers16112004
reference_title: 'Survival Analysis of Metastatic Early-Onset Colorectal Cancer Compared to Metastatic Average-Onset Colorectal Cancer: A SEER Database Analysis'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Early-onset colorectal cancer (EO-CRC) is defined as colorectal cancer diagnosed before the age of 50 years, and its incidence has been increasing over the last decade, now accounting for 10% of all new CRC diagnoses.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.3390/cancers16162796
title: 'Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review'
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide.
supporting_text: Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide.
evidence:
- reference: DOI:10.3390/cancers16162796
reference_title: 'Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.3390/cancers16223870
title: 'Precision Medicine for Metastatic Colorectal Cancer: Where Do We Stand?'
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Metastatic colorectal cancer is a leading cause of cancer-related death across the world.
supporting_text: Metastatic colorectal cancer is a leading cause of cancer-related death across the world.
evidence:
- reference: DOI:10.3390/cancers16223870
reference_title: 'Precision Medicine for Metastatic Colorectal Cancer: Where Do We Stand?'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Metastatic colorectal cancer is a leading cause of cancer-related death across the world.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.3390/cancers16233928
title: 'Prognostic and Predictive Determinants of Colorectal Cancer: A Comprehensive Review'
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Colorectal cancer (CRC) remains a significant global health burden, necessitating a thorough understanding of prognostic and predictive factors to enhance patient outcomes.
supporting_text: Colorectal cancer (CRC) remains a significant global health burden, necessitating a thorough understanding of prognostic and predictive factors to enhance patient outcomes.
evidence:
- reference: DOI:10.3390/cancers16233928
reference_title: 'Prognostic and Predictive Determinants of Colorectal Cancer: A Comprehensive Review'
supports: SUPPORT
evidence_source: OTHER
snippet: Colorectal cancer (CRC) remains a significant global health burden, necessitating a thorough understanding of prognostic and predictive factors to enhance patient outcomes.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.3390/medsci12030047
title: Survival Analysis, Clinical Characteristics, and Predictors of Cerebral Metastases in Patients with Colorectal Cancer
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Colorectal cancer (CRC) is the third most common cancer globally and a leading cause of cancer-related deaths.
supporting_text: Colorectal cancer (CRC) is the third most common cancer globally and a leading cause of cancer-related deaths.
evidence:
- reference: DOI:10.3390/medsci12030047
reference_title: Survival Analysis, Clinical Characteristics, and Predictors of Cerebral Metastases in Patients with Colorectal Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Colorectal cancer (CRC) is the third most common cancer globally and a leading cause of cancer-related deaths.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
- reference: DOI:10.6004/jnccn.2024.0029
title: Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology
found_in:
- Metastatic_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States.
supporting_text: Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States.
evidence:
- reference: DOI:10.6004/jnccn.2024.0029
reference_title: Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States.
explanation: Deep research cited this publication as relevant literature for Metastatic Colorectal Cancer.
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).
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).
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).
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).
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).
(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).
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).
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.
No CTD/TOXNET/WHO/CDC exposure-specific evidence was retrieved in this run; this section remains incomplete.
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).
(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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
No animal-model or comparative pathology evidence was retrieved in this run; these sections are incomplete.
The following table synthesizes the key biomarker subgroups, testing definitions, guideline-positioned therapies, and recent efficacy numbers (2023–2024 prioritized):
| 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.
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
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(benson2024coloncancerversion media afa7e635): 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.
(underwood2024precisionmedicinefor pages 2-4): Patrick W. Underwood and Timothy M. Pawlik. Precision medicine for metastatic colorectal cancer: where do we stand? Cancers, 16:3870, Nov 2024. URL: https://doi.org/10.3390/cancers16223870, doi:10.3390/cancers16223870. This article has 12 citations.
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(jeriyabar2024survivalanalysisclinical pages 1-2): Antoine Jeri-Yabar, Liliana Vittini-Hernandez, Jerry K. Benites-Meza, and Sebastian Prado-Nuñez. Survival analysis, clinical characteristics, and predictors of cerebral metastases in patients with colorectal cancer. Medical Sciences, 12:47, Sep 2024. URL: https://doi.org/10.3390/medsci12030047, doi:10.3390/medsci12030047. This article has 4 citations.
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(cotan2024prognosticandpredictive pages 10-11): 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.
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(emiloju2024tumorinformedcirculatingtumor pages 1-2): Oluwadunni E. Emiloju, Michael Storandt, Tyler Zemla, Nguyen Tran, Krishan Jethwa, Amit Mahipal, Jessica Mitchell, Cornelius Thiels, Kellie Mathis, Robert McWilliams, Joleen Hubbard, Frank Sinicrope, Qian Shi, and Zhaohui Jin. Tumor-informed circulating tumor dna for minimal residual disease detection in the management of colorectal cancer. JCO Precision Oncology, Feb 2024. URL: https://doi.org/10.1200/po.23.00127, doi:10.1200/po.23.00127. This article has 12 citations and is from a peer-reviewed journal.
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(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.
(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.