HER2-positive colorectal cancer is a molecularly defined subtype characterized by ERBB2 (HER2) amplification or overexpression, occurring in approximately 3-5% of metastatic colorectal cancers. HER2 amplification is enriched in RAS/BRAF wild-type tumors and represents an emerging actionable target. Unlike breast and gastric cancer, HER2-positive CRC responds modestly to single-agent HER2-targeted therapy, but combination approaches with HER2-directed agents and anti-EGFR therapy or dual HER2 blockade have shown promising activity. HER2 amplification may also be a mechanism of acquired resistance to anti-EGFR therapy.
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name: HER2-Positive Colorectal Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
HER2-positive colorectal cancer is a molecularly defined subtype characterized by
ERBB2
(HER2) amplification or overexpression, occurring in approximately 3-5% of metastatic
colorectal cancers. HER2 amplification is enriched in RAS/BRAF wild-type tumors
and
represents an emerging actionable target. Unlike breast and gastric cancer, HER2-positive
CRC responds modestly to single-agent HER2-targeted therapy, but combination approaches
with HER2-directed agents and anti-EGFR therapy or dual HER2 blockade have shown
promising
activity. HER2 amplification may also be a mechanism of acquired resistance to anti-EGFR
therapy.
categories:
- Gastrointestinal Cancer
- Colorectal Cancer
- Molecularly Defined Cancer
parents:
- colorectal adenocarcinoma
pathophysiology:
- name: ERBB2 (HER2) Amplification and Overexpression
description: >-
ERBB2 gene amplification leads to overexpression of the HER2 receptor tyrosine
kinase
on the cell surface. Amplified HER2 forms homodimers and heterodimers with other
ERBB
family members (particularly HER3), leading to ligand-independent receptor activation
and downstream signaling.
evidence:
- reference: PMID:41361014
reference_title: "Survival outcomes of ERBB2-amplified metastatic colorectal cancer treated with first-line chemotherapy."
supports: PARTIAL
snippet: Among 5545 patients, 144 (3.1%) had ERBB2 amp+ mCRC.
explanation: This abstract quantifies ERBB2-amplified metastatic colorectal cancer, supporting the existence of this molecular subgroup.
cell_types:
- preferred_term: colon epithelial cell
term:
id: CL:0011108
label: colon epithelial cell
biological_processes:
- preferred_term: ERBB2 signaling pathway
modifier: INCREASED
term:
id: GO:0038128
label: ERBB2 signaling pathway
downstream:
- target: MAPK Pathway Activation
description: HER2 signaling activates RAS-RAF-MEK-ERK cascade
- target: PI3K-AKT Pathway Activation
description: HER2 signaling activates PI3K-AKT-mTOR cascade through HER3
- name: MAPK Pathway Activation
description: >-
HER2 receptor activation leads to recruitment of adaptor proteins (GRB2/SOS) that
activate RAS, initiating the MAPK signaling cascade. This drives cell proliferation
and survival. The MAPK pathway is a major effector of HER2 oncogenic signaling
in
colorectal cancer.
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
downstream:
- target: Enhanced Cell Proliferation
description: MAPK signaling drives cell cycle progression
- name: PI3K-AKT Pathway Activation
description: >-
HER2 heterodimerization with HER3 is particularly potent at activating PI3K signaling
because HER3 contains multiple PI3K binding sites. This leads to AKT activation,
promoting cell survival and resistance to apoptosis. PI3K pathway activation may
contribute to resistance to HER2-targeted therapy.
biological_processes:
- preferred_term: phosphatidylinositol 3-kinase signaling
modifier: INCREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
- name: Enhanced Cell Proliferation
description: >-
Combined MAPK and PI3K pathway activation drives enhanced cell proliferation through
cyclin D1 induction and cell cycle progression. This leads to uncontrolled tumor
growth dependent on HER2 signaling.
locations:
- preferred_term: colon
term:
id: UBERON:0001155
label: colon
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
histopathology:
- name: Adenocarcinoma
finding_term:
preferred_term: Adenocarcinoma
term:
id: NCIT:C2852
label: Adenocarcinoma
frequency: VERY_FREQUENT
description: Adenocarcinoma is the most common pathologic subtype of colon cancer.
evidence:
- reference: PMID:35613396
reference_title: "[Adenosquamous carcinoma of the colon: a case report and review of the literature]."
supports: PARTIAL
snippet: "Adenocarcinoma is the most common pathologic subtype of colon cancer"
explanation: Abstract reports adenocarcinoma as the most common pathologic subtype of colon cancer.
phenotypes:
- category: Gastrointestinal
name: Colon Cancer
frequency: VERY_FREQUENT
diagnostic: true
description: >-
HER2-positive colorectal cancer presents as a primary colonic or rectal malignancy.
Left-sided (distal) tumors may be enriched in HER2-amplified cases.
phenotype_term:
preferred_term: Colon cancer
term:
id: HP:0003003
label: Colon cancer
- category: Gastrointestinal
name: Abdominal Pain
frequency: FREQUENT
description: >-
Abdominal discomfort from tumor mass effect or bowel obstruction.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
- category: Gastrointestinal
name: Hematochezia
frequency: FREQUENT
description: >-
Rectal bleeding from tumor ulceration, particularly with left-sided tumors.
phenotype_term:
preferred_term: Hematochezia
term:
id: HP:0002573
label: Hematochezia
- category: Hematologic
name: Anemia
frequency: FREQUENT
description: >-
Iron deficiency anemia from chronic blood loss.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
- category: Constitutional
name: Weight Loss
frequency: OCCASIONAL
description: >-
Unintentional weight loss with advanced disease.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
biochemical:
- name: HER2 Immunohistochemistry
notes: >-
IHC scoring uses the same criteria as gastric cancer (modified from breast cancer):
0/1+ negative, 2+ equivocal requiring FISH confirmation, 3+ positive. Colorectal-specific
scoring criteria have been proposed (HERACLES criteria) with stricter requirements.
- name: HER2 FISH/ISH
notes: >-
Fluorescence in situ hybridization or other in situ hybridization methods detect
ERBB2
gene amplification. HER2/CEP17 ratio greater than 2.0 or HER2 copy number greater
than 6
indicates amplification. Required for IHC 2+ cases.
- name: Next-Generation Sequencing
notes: >-
NGS can detect ERBB2 amplification through copy number analysis and may identify
activating ERBB2 mutations as alternative mechanisms of HER2 pathway activation.
genetic:
- name: ERBB2 (HER2)
association: Somatic Amplification
notes: >-
ERBB2 amplification occurs in 3-5% of metastatic CRC, enriched in RAS/BRAF wild-type
tumors where it may represent 5-14%. Amplification is the primary mechanism, though
activating mutations also occur rarely. Copy number correlates with response to
HER2-targeted therapy.
- name: ERBB2 Activating Mutations
association: Somatic Activating Mutation
notes: >-
Activating mutations in ERBB2 (e.g., S310F, L755S, V777L) occur in approximately
2%
of CRC and may respond to HER2-targeted therapies. These are distinct from amplification
and can co-occur with RAS mutations.
- name: RAS/BRAF Wild-Type
association: Enrichment Context
notes: >-
HER2 amplification is strongly associated with RAS wild-type status and is typically
mutually exclusive with BRAF V600E. This makes HER2-positive CRC a distinct molecular
subgroup within RAS/BRAF wild-type tumors.
treatments:
- name: Trastuzumab plus Lapatinib
description: >-
Dual HER2 blockade with trastuzumab (anti-HER2 antibody) and lapatinib (HER1/HER2
TKI).
HERACLES trial demonstrated 30% objective response rate in chemotherapy-refractory,
HER2-positive, RAS wild-type metastatic CRC.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: trastuzumab
term:
id: CHEBI:231601
label: trastuzumab
- name: Trastuzumab plus Pertuzumab
description: >-
Dual HER2 antibody blockade with trastuzumab and pertuzumab, which block different
HER2 epitopes and prevent HER2/HER3 heterodimerization. MyPathway basket trial
showed
activity in HER2-amplified CRC.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: trastuzumab
term:
id: CHEBI:231601
label: trastuzumab
- name: Trastuzumab Deruxtecan (T-DXd)
description: >-
Antibody-drug conjugate consisting of anti-HER2 antibody linked to topoisomerase
I
inhibitor payload. DESTINY-CRC01 showed promising activity in HER2-positive metastatic
CRC with strong IHC 3+ expression.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: trastuzumab deruxtecan
term:
id: NCIT:C128799
label: Trastuzumab Deruxtecan
- name: Tucatinib plus Trastuzumab
description: >-
Combination of HER2-selective TKI tucatinib with trastuzumab. MOUNTAINEER trial
demonstrated significant activity in HER2-positive metastatic CRC, leading to
FDA
accelerated approval.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: trastuzumab
term:
id: CHEBI:231601
label: trastuzumab
- name: Surgical Resection
description: >-
Surgery for localized disease or selected metastatic cases. HER2 status does not
change standard surgical approaches but informs systemic therapy decisions.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
disease_term:
preferred_term: HER2-positive colorectal cancer
term:
id: MONDO:0005575
label: colorectal cancer
classifications:
icdo_morphology:
classification_value: Adenocarcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1007/s00432-022-04230-8
title: 'HER2 overexpression/amplification status in colorectal cancer: a comparison between immunohistochemistry and fluorescence in situ hybridization using five different immunohistochemical scoring criteria'
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'HER2 overexpression/amplification status in colorectal cancer: a comparison between immunohistochemistry and fluorescence in situ hybridization using five different immunohistochemical scoring criteria'
supporting_text: Although HER2 has gradually become an important therapeutic target for colorectal cancer (CRC), a unified and standard HER2 scoring system was still not established in CRC, and the debatable results of immunohistochemistry and fluorescence in situ hybridization (FISH) in CRC requires further exploration.
evidence:
- reference: DOI:10.1007/s00432-022-04230-8
reference_title: 'HER2 overexpression/amplification status in colorectal cancer: a comparison between immunohistochemistry and fluorescence in situ hybridization using five different immunohistochemical scoring criteria'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Although HER2 has gradually become an important therapeutic target for colorectal cancer (CRC), a unified and standard HER2 scoring system was still not established in CRC, and the debatable results of immunohistochemistry and fluorescence in situ hybridization (FISH) in CRC requires further exploration.
explanation: Deep research cited this publication as relevant literature for HER2 Positive Colorectal Cancer.
- reference: DOI:10.1038/s41467-023-38032-4
title: Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer
supporting_text: DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published.
evidence:
- reference: DOI:10.1038/s41467-023-38032-4
reference_title: Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published.
explanation: Deep research cited this publication as relevant literature for HER2 Positive Colorectal Cancer.
- reference: DOI:10.1038/s41467-024-53223-3
title: 'HER2-related biomarkers predict clinical outcomes with trastuzumab deruxtecan treatment in patients with HER2-expressing metastatic colorectal cancer: biomarker analyses of DESTINY-CRC01'
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'HER2-related biomarkers predict clinical outcomes with trastuzumab deruxtecan treatment in patients with HER2-expressing metastatic colorectal cancer: biomarker analyses of DESTINY-CRC01'
supporting_text: 'HER2-related biomarkers predict clinical outcomes with trastuzumab deruxtecan treatment in patients with HER2-expressing metastatic colorectal cancer: biomarker analyses of DESTINY-CRC01'
- reference: DOI:10.1038/s41598-024-62096-x
title: RAS/RAF mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established.
supporting_text: HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established.
evidence:
- reference: DOI:10.1038/s41598-024-62096-x
reference_title: RAS/RAF mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established.
explanation: Deep research cited this publication as relevant literature for HER2 Positive Colorectal Cancer.
- reference: DOI:10.1093/jncics/pkad082
title: Systematic literature review and meta-analysis of HER2 amplification, overexpression, and positivity in colorectal cancer
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Colorectal cancer (CRC) is the second most common cause of cancer death globally.
supporting_text: Colorectal cancer (CRC) is the second most common cause of cancer death globally.
evidence:
- reference: DOI:10.1093/jncics/pkad082
reference_title: Systematic literature review and meta-analysis of HER2 amplification, overexpression, and positivity in colorectal cancer
supports: SUPPORT
evidence_source: OTHER
snippet: Colorectal cancer (CRC) is the second most common cause of cancer death globally.
explanation: Deep research cited this publication as relevant literature for HER2 Positive Colorectal Cancer.
- reference: DOI:10.1158/1078-0432.ccr-23-2581
title: <i>RAS/RAF</i> Comutation and <i>ERBB2</i> Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments.'
supporting_text: 'ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments.'
evidence:
- reference: DOI:10.1158/1078-0432.ccr-23-2581
reference_title: <i>RAS/RAF</i> Comutation and <i>ERBB2</i> Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments.'
explanation: Deep research cited this publication as relevant literature for HER2 Positive Colorectal Cancer.
- reference: DOI:10.32604/or.2024.047309
title: 'Genomic profiling of colorectal cancer in large-scale Chinese patients: amplification and somatic mutations in ERBB2'
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: 'Genomic profiling of colorectal cancer in large-scale Chinese patients: amplification and somatic mutations in ERBB2'
supporting_text: 'Genomic profiling of colorectal cancer in large-scale Chinese patients: amplification and somatic mutations in ERBB2'
- reference: DOI:10.3390/cancers16162854
title: Resistance to Anti-HER2 Therapies in Gastrointestinal Malignancies
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation.
supporting_text: Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation.
evidence:
- reference: DOI:10.3390/cancers16162854
reference_title: Resistance to Anti-HER2 Therapies in Gastrointestinal Malignancies
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation.
explanation: Deep research cited this publication as relevant literature for HER2 Positive Colorectal Cancer.
- reference: DOI:10.3390/cancers16183145
title: Prognostic and Predictive Roles of HER2 Status in Non-Breast and Non-Gastroesophageal Carcinomas
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: The oncogene ERBB2, also known as HER2 or c-ERB2, is located on chromosome 17 (q12).
supporting_text: The oncogene ERBB2, also known as HER2 or c-ERB2, is located on chromosome 17 (q12).
evidence:
- reference: DOI:10.3390/cancers16183145
reference_title: Prognostic and Predictive Roles of HER2 Status in Non-Breast and Non-Gastroesophageal Carcinomas
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The oncogene ERBB2, also known as HER2 or c-ERB2, is located on chromosome 17 (q12).
explanation: Deep research cited this publication as relevant literature for HER2 Positive Colorectal Cancer.
- reference: DOI:10.6004/jnccn.2023.7022
title: 'Real-World Treatment Patterns in Patients With HER2-Amplified Metastatic Colorectal Cancer: A Clinical-Genomic Database Study'
found_in:
- HER2_Positive_Colorectal_Cancer-deep-research-falcon.md
findings:
- statement: HER2 amplification (HER2+) occurs in approximately 3% of patients with metastatic colorectal cancer (mCRC).
supporting_text: HER2 amplification (HER2+) occurs in approximately 3% of patients with metastatic colorectal cancer (mCRC).
evidence:
- reference: DOI:10.6004/jnccn.2023.7022
reference_title: 'Real-World Treatment Patterns in Patients With HER2-Amplified Metastatic Colorectal Cancer: A Clinical-Genomic Database Study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: HER2 amplification (HER2+) occurs in approximately 3% of patients with metastatic colorectal cancer (mCRC).
explanation: Deep research cited this publication as relevant literature for HER2 Positive Colorectal Cancer.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on HER2-Positive Colorectal Cancer covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
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For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
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Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
HER2-positive colorectal cancer refers to CRCs with ERBB2 (HER2) amplification and/or HER2 protein overexpression that may act as an oncogenic driver and therapeutic target. In CRC, HER2 positivity is clinically used to select patients for HER2-directed therapy, particularly in metastatic CRC (mCRC) and often in the context of RAS wild-type disease. (singh2024systematicliteraturereview pages 1-2, singh2024rasrafcomutationand pages 2-4)
Information summarized here is primarily from: - Aggregated disease-level resources (systematic review/meta-analysis) (singh2024systematicliteraturereview pages 1-2, singh2024systematicliteraturereview pages 4-7) - Human clinical trials and cohorts (DESTINY-CRC01; large molecular cohorts; real-world clinico-genomic database) (yoshino2023finalresultsof pages 1-2, lee2024rasrafmutationsand pages 1-2, strickler2023realworldtreatmentpatterns pages 1-2) - Preclinical models (isogenic cell lines and murine xenografts exploring co-mutations and drug sensitivity) (singh2024rasrafcomutationand pages 2-4, singh2024rasrafcomutationand pages 14-16)
Subtype-specific lifestyle/environmental risk factors (beyond general CRC risk factors) were not identified in the retrieved evidence.
No HER2-subtype-specific gene–environment interaction evidence was identified in the retrieved sources.
The retrieved evidence primarily characterizes HER2-positive CRC by molecular profile, anatomic enrichment, and treatment response, rather than distinct presenting symptoms.
Subtype-associated patterns supported by evidence: - Primary site enrichment: HER2 amplification is enriched in left-sided colon and rectum (e.g., ~95% of HER2-amplified cases in left colon/rectum in a 992-patient primary CRC cohort). (lee2024rasrafmutationsand pages 1-2) - Microsatellite status: HER2-amplified CRCs are predominantly microsatellite-stable (MSS) (e.g., 41/41 HER2-amplified cases MSS in a 992-patient cohort). (lee2024rasrafmutationsand pages 1-2, lee2024rasrafmutationsand pages 5-6)
General CRC phenotypes (not subtype-specific in retrieved sources): bleeding, anemia, bowel habit change, abdominal pain, obstruction, weight loss, fatigue.
(These HPO terms are offered as knowledge-base placeholders; the retrieved HER2+ CRC sources did not quantify symptom frequencies.)
Trial operational definition (DESTINY-CRC01): - HER2-positive mCRC defined as IHC 3+ or IHC 2+/ISH+ (cohort A). (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 3-4)
CRC-specific HERACLES diagnostic criteria (IHC/FISH): - HERACLES positivity includes: 1) IHC 3+ in ≥50% CRC cells; 2) IHC 3+ in 10–50% plus FISH HER2/CEP17 ≥2.0 in ≥50% cells; 3) >50% IHC 2+ plus FISH HER2/CEP17 ≥2.0. (sun2023her2overexpressionamplificationstatus pages 2-4)
Common FISH positivity thresholds used in CRC scoring studies: - HER2/CEP17 ratio ≥2.0 or average HER2 copy number ≥6.0. (sun2023her2overexpressionamplificationstatus pages 1-2, sun2023her2overexpressionamplificationstatus pages 4-6)
Meta-analysis definition of HER2+ CRC (integrating IHC/ISH/NGS): - HER2+ defined as (1) IHC 3+, (2) IHC 2+ and ISH+, or (3) NGS positive. (singh2024systematicliteraturereview pages 1-2)
A 2024 systematic review/meta-analysis restricted to FDA-approved assays estimated: - Overall HER2+ rate: 4.1% (95% CI 3.4–5.0; n=17,589). (singh2024systematicliteraturereview pages 1-2) - RAS WT enrichment: 6.1% (95% CI 5.4–6.9) in RAS WT vs 1.1% in RAS-mutant CRC (P<0.0001). (singh2024systematicliteraturereview pages 1-2) - Sidedness enrichment: pooled 5.8% in left-sided vs 2.7% in right-sided CRC. (singh2024systematicliteraturereview pages 4-7) - MSS enrichment: MSS comprised ~98.8–100% of HER2+ cases in small included studies; MSI-H showed low HER2 rates. (singh2024systematicliteraturereview pages 7-8)
Large cohort confirmation (primary CRC): - HER2 amplification prevalence: 4.1% (41/992); distribution: right 1.0%, left 5.1%, rectum 4.8%, and all 41 amplified were MSS. (lee2024rasrafmutationsand pages 1-2)
HER2-amplified primary CRC cohort (n=41 HER2-amplified of 992): - KRAS activating mutations: 24.4% (10/41); TP53 alterations: 82.9% (34/41); APC: 51.2% (21/41); PIK3CA: 17.1% (7/41); NRAS/BRAF: 0% in amplified cases. (lee2024rasrafmutationsand pages 2-3)
Large Chinese sequencing cohort (n=2454): - ERBB2 amplification: 3.46% (85/2454); ERBB2 mutations: 2.24% (55/2454). (liu2024genomicprofilingof pages 1-2) - MSI-H relationship differs by alteration type: 32.7% of ERBB2-mutant CRCs were MSI-H, while no ERBB2-amplified cases were MSI-H. (liu2024genomicprofilingof pages 1-2) - Co-alteration pattern differs: ERBB2 SNV cases had higher KRAS/PIK3CA co-alterations (KRAS 45.8%, PIK3CA 31.2%) than ERBB2 amplification cases (KRAS 14.1%, PIK3CA 7.7%); TP53 co-occurred more with amplification (92.3%) than mutation (58.3%). (liu2024genomicprofilingof pages 1-2)
RAS/RAF co-alteration as a resistance-relevant subtype: - In ERBB2-amplified CRC, ~20% harbor oncogenic RAS/RAF co-alterations, associated with lower-level ERBB2 amplification, increased intratumoral heterogeneity, and interlesional discordance, with implications for reduced response to trastuzumab-based combinations. (singh2024rasrafcomutationand pages 2-4)
No HER2-subtype-specific environmental exposures, infectious triggers, or protective factors were identified in the retrieved sources.
1) ERBB2 amplification increases HER2 receptor abundance and signaling competence (driver event defining the subtype). (singh2024rasrafcomutationand pages 2-4) 2) HER2 signaling can activate downstream proliferative pathways (e.g., MAPK/PI3K signaling); in CRC this is clinically relevant because HER2 amplification is linked to resistance to EGFR-directed therapy even in RAS WT tumors. (singh2024rasrafcomutationand pages 2-4) 3) Therapeutic blockade using HER2-directed antibodies, TKIs, and ADCs can produce objective responses in biomarker-defined HER2-positive mCRC. (yoshino2023finalresultsof pages 1-2, mo2024resistancetoantiher2 pages 5-6)
A key 2024 analysis proposes that RAS/RAF co-alterations define a distinct ERBB2-amplified CRC subgroup characterized by: - Lower ERBB2 copy number, more intratumoral heterogeneity, and interlesional discordance, and - Resistance to trastuzumab-based combinations (e.g., trastuzumab/tucatinib), while retaining sensitivity to trastuzumab deruxtecan in preclinical and some clinical contexts. (singh2024rasrafcomutationand pages 14-16, singh2024rasrafcomutationand pages 2-4)
GO Biological Process (suggested): - ERBB2 signaling: “ERBB2 signaling pathway” (GO term exists; exact ID not retrieved here) - Receptor tyrosine kinase signaling: “transmembrane receptor protein tyrosine kinase signaling pathway”
Cell types (CL; suggested): - Colonic epithelial cell / colorectal adenocarcinoma cell (CL IDs not retrieved in the evidence run)
HER2 amplification is enriched in left colon and rectum (primary tumor localization), suggesting preferential anatomic distribution within the large intestine. (lee2024rasrafmutationsand pages 1-2, singh2024systematicliteraturereview pages 4-7)
Suggested UBERON terms (placeholders): - Colon: UBERON:0001155 - Rectum: UBERON:0001052
HER2 positivity describes a molecular subtype rather than a unique age-of-onset category. The key time-course information in retrieved sources concerns advanced/metastatic disease and response in later treatment lines.
HER2-directed therapy evidence is largely in previously treated metastatic CRC, including trials after ≥2 prior regimens. (yoshino2023finalresultsof pages 1-2)
Best supported contemporary estimate (FDA-assay restricted meta-analysis): - HER2+ CRC prevalence ~4.1% overall, enriched to ~6.1% in RAS WT CRC. (singh2024systematicliteraturereview pages 1-2)
HER2-positive CRC is predominantly driven by somatic alterations (amplification and/or somatic mutation); germline inheritance patterns are not a defining feature in the retrieved sources.
Practical workflow reflected in evidence: - IHC as screening; IHC 2+ is equivocal and generally requires reflex ISH/FISH confirmation; FISH positivity can be defined by HER2/CEP17 ≥2.0 and/or copy number thresholds (e.g., ≥6). (sun2023her2overexpressionamplificationstatus pages 4-6, quaquarini2024prognosticandpredictive pages 4-5)
Scoring system variability and harmonization challenge: - A CRC cohort study compared multiple IHC criteria and concluded that the IRS-p approach may be more sensitive/specific versus other systems when benchmarked to FISH; discordance can occur due to heterogeneity and chromosome 17 copy-number changes. (sun2023her2overexpressionamplificationstatus pages 1-2, sun2023her2overexpressionamplificationstatus pages 10-12)
NGS may define ERBB2 copy-number amplification and co-alterations relevant for predicting response/resistance (e.g., RAS/RAF co-alterations; ERBB2 SNV vs amplification differences; PRESSING-HER2 concept referenced in evidence base). (singh2024rasrafcomutationand pages 2-4, liu2024genomicprofilingof pages 1-2)
A large real-world dataset used blood-based Guardant360 to identify ERBB2 amplification in mCRC and link results to treatment claims and outcomes, demonstrating real-world implementation of ctDNA-guided subtype identification. (strickler2023realworldtreatmentpatterns pages 1-2)
In HER2-positive cohort A of DESTINY-CRC01 (IHC3+ or IHC2+/ISH+), median outcomes were: - PFS 6.9 months, OS 15.5 months, with objective responses confined to HER2-positive (cohort A). (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 4-6)
A survival curve and cohort response table are shown in the DESTINY-CRC01 figure/table crops retrieved (PFS/OS curves and response table). (yoshino2023finalresultsof media ab04ee1c, yoshino2023finalresultsof media 2afcc8a6)
A. Tucatinib + trastuzumab (HER2+ mCRC; trial-defined) - Clinical efficacy benchmarks frequently cited in 2024–2025 literature include ORR ~38% and median PFS ~8 months for trastuzumab+tucatinib, with median OS ~24 months (from trial reporting summarized in recent sources). (mo2024resistancetoantiher2 pages 5-6, singh2024rasrafcomutationand pages 2-4)
ClinicalTrials.gov implementation metadata (MOUNTAINEER; NCT03043313): - Phase 2, open-label; status COMPLETED; enrollment 117; primary endpoint confirmed ORR by BICR RECIST 1.1; secondary endpoints include DoR/PFS/OS and safety. Dates: start 2017-06-23, primary completion 2022-03-28, study completion 2023-11-02; results first posted 2023-04-18; last update posted 2024-11-26. URL: https://clinicaltrials.gov/study/NCT03043313 (NCT03043313 chunk 1)
B. Trastuzumab deruxtecan (T-DXd; ADC) (DESTINY-CRC01, NCT03384940) - DESTINY-CRC01 (Nature Communications, publication date June 2023, URL https://doi.org/10.1038/s41467-023-38032-4) enrolled 86 patients into IHC/ISH-defined cohorts and showed responses confined to the HER2-positive cohort. (yoshino2023finalresultsof pages 1-2)
Key outcomes (DESTINY-CRC01): - Cohort A definition: IHC 3+ or IHC 2+/ISH+ (n=53). (yoshino2023finalresultsof pages 1-2) - ORR 45.3% (24/53; 95% CI 31.6–59.6). (yoshino2023finalresultsof pages 3-4) - Median PFS 6.9 months; median OS 15.5 months; median DoR 7.0 months. (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 4-6) - No responses in HER2-low cohorts (IHC2+/ISH− or IHC1+). (yoshino2023finalresultsof pages 1-2)
Safety (DESTINY-CRC01): - Adjudicated drug-related ILD/pneumonitis: 9.3% (8/86) including 3 grade 5 (3.5%); median time to onset reported as 66.5 days (range 7–165). (yoshino2023finalresultsof pages 3-4) - Grade ≥3 TEAEs: 65.1% overall; drug-related grade ≥3 TEAEs 48.8%. (yoshino2023finalresultsof pages 4-6, yoshino2023finalresultsof pages 8-9)
The ILD/pneumonitis adjudication table crop and key efficacy table/curves were retrieved as images (Table/figure crops). (yoshino2023finalresultsof media ab04ee1c, yoshino2023finalresultsof media 821b3066)
C. Trastuzumab deruxtecan dose-finding in CRC (DESTINY-CRC02; NCT04744831) ClinicalTrials.gov metadata (URL: https://clinicaltrials.gov/study/NCT04744831): - Phase 2; multicenter randomized; two dose arms 5.4 mg/kg vs 6.4 mg/kg Q3W; population IHC3+ or IHC2+/ISH+ advanced/metastatic CRC; enrollment 122; primary endpoint ORR by BICR; secondary endpoints include PFS/OS and safety. Dates: start 2021-03-05, primary completion 2022-11-01, study completion 2024-12-04; results first posted 2024-01-02. (NCT04744831 chunk 1)
A GuardantINFORM (Guardant360 + claims) study (JNCCN, Aug 2023, URL https://doi.org/10.6004/jnccn.2023.7022) evaluated 142 patients with ERBB2-amplified mCRC and showed: - Regimens after HER2 confirmation were heterogeneous; most common were anti-VEGF±chemo (31.0%) and HER2-directed therapy+chemo (28.9%). (strickler2023realworldtreatmentpatterns pages 3-4) - Adoption increased over time: HER2-directed therapy used in 22.8% pre-2018 vs 36.5% post-2018, but many patients still did not receive HER2-directed therapy. (strickler2023realworldtreatmentpatterns pages 4-6, strickler2023realworldtreatmentpatterns pages 1-2) - Median real-world time to next treatment (rwTTNT): 8.4 months overall, 11.0 months for HER2-directed therapy vs 7.2 months for non–HER2-directed therapies (descriptive). (strickler2023realworldtreatmentpatterns pages 1-2)
No HER2-subtype-specific prevention strategies were identified. Prevention and screening remain those for CRC broadly (e.g., population CRC screening), but this was not addressed in the retrieved HER2+ subtype sources.
No evidence retrieved.
A 2024 study integrating clinical cohorts with experimental systems used: - Isogenic CRC cell lines and murine xenograft models to show that RAS/RAF co-alterations in ERBB2-amplified CRC are associated with resistance to trastuzumab-based combinations (e.g., trastuzumab/tucatinib) but retained sensitivity to trastuzumab deruxtecan, and to link these effects to copy-number level and heterogeneity. (singh2024rasrafcomutationand pages 14-16, singh2024rasrafcomutationand pages 2-4)
The following table consolidates prevalence/enrichment, co-mutations, trial outcomes, and real-world adoption:
| Domain | Finding | Quantitative detail | Notes/definition | Citations |
|---|---|---|---|---|
| Prevalence | Overall HER2-positive CRC | 4.1% (95% CI 3.4–5.0) | Meta-analysis definition: IHC 3+ or IHC 2+/ISH+ or NGS+ | (singh2024systematicliteraturereview pages 1-2, singh2024systematicliteraturereview pages 4-7) |
| Prevalence | HER2-positive in RAS wild-type CRC | 6.1% (95% CI 5.4–6.9) | Higher than RAS-mutant CRC | (singh2024systematicliteraturereview pages 1-2, singh2024systematicliteraturereview pages 4-7) |
| Prevalence | HER2-positive in RAS-mutant CRC | 1.1% (95% CI 0.3–4.4) | Significantly lower than RAS WT | (singh2024systematicliteraturereview pages 1-2, singh2024systematicliteraturereview pages 4-7) |
| Enrichment | Left-sided vs right-sided CRC | 5.8% vs 2.7% | Left-sided enrichment in pooled analysis | (singh2024systematicliteraturereview pages 4-7) |
| Enrichment | Rectal-only HER2-positive estimate | 4.7% (95% CI 2.8–8.0) | Rectal primaries also enriched | (singh2024systematicliteraturereview pages 7-8, singh2024systematicliteraturereview pages 4-7) |
| Enrichment | MSS vs MSI-H | MSS: 98.8%–100% of HER2+ cases in small studies; MSI-H: 0%–1.2% | Strong enrichment in microsatellite-stable tumors | (singh2024systematicliteraturereview pages 7-8) |
| Cohort study | HER2 amplification in primary CRC | 4.1% (41/992) | Large primary CRC cohort | (lee2024rasrafmutationsand pages 1-2, lee2024rasrafmutationsand pages 5-6) |
| Cohort study | Site distribution of HER2 amplification | Right colon 1.0%; left colon 5.1%; rectum 4.8% | ~95% of amplified tumors in left colon + rectum | (lee2024rasrafmutationsand pages 1-2) |
| Cohort study | MSI in HER2-amplified tumors | 0% MSI-H; 100% MSS | In 41/41 HER2-amplified CRCs | (lee2024rasrafmutationsand pages 1-2, lee2024rasrafmutationsand pages 5-6, lee2024rasrafmutationsand pages 2-3) |
| Molecular co-alteration | KRAS in HER2-amplified cohort | 24.4% (10/41) | HER2-amplified primary CRC cohort | (lee2024rasrafmutationsand pages 2-3, lee2024rasrafmutationsand pages 1-2) |
| Molecular co-alteration | TP53 in HER2-amplified cohort | 82.9% (34/41) | Frequent co-alteration | (lee2024rasrafmutationsand pages 2-3, lee2024rasrafmutationsand pages 1-2) |
| Molecular co-alteration | APC in HER2-amplified cohort | 51.2% (21/41) | HER2-amplified primary CRC cohort | (lee2024rasrafmutationsand pages 2-3) |
| Molecular co-alteration | PIK3CA in HER2-amplified cohort | 17.1% (7/41) | HER2-amplified primary CRC cohort | (lee2024rasrafmutationsand pages 2-3) |
| Molecular co-alteration | NRAS/BRAF in HER2-amplified cohort | 0% NRAS; 0% BRAF | In the 41-case HER2-amplified cohort | (lee2024rasrafmutationsand pages 2-3, lee2024rasrafmutationsand pages 7-9) |
| Molecular co-alteration | RAS/RAF co-alterations among ERBB2-amplified CRC | ~20% | Associated with lower ERBB2 copy number and greater heterogeneity | (singh2024rasrafcomutationand pages 2-4) |
| Large genomic cohort | ERBB2 amplification rate | 3.46% (85/2454) | Chinese CRC cohort | (liu2024genomicprofilingof pages 1-2, liu2024genomicprofilingof pages 2-3) |
| Large genomic cohort | ERBB2 mutation rate | 2.24% (55/2454) | Chinese CRC cohort | (liu2024genomicprofilingof pages 1-2, liu2024genomicprofilingof pages 2-3) |
| Large genomic cohort | MSI-H by ERBB2 alteration type | 32.7% of ERBB2-mutant cases; 0% of ERBB2-amplified cases | Distinct biology of mutation vs amplification | (liu2024genomicprofilingof pages 1-2, liu2024genomicprofilingof pages 2-3) |
| Large genomic cohort | KRAS/PIK3CA in ERBB2 SNV vs amplification | KRAS 45.8% vs 14.1%; PIK3CA 31.2% vs 7.7% | ERBB2-mutant tumors more often co-altered with KRAS/PIK3CA than amplified tumors | (liu2024genomicprofilingof pages 1-2) |
| Large genomic cohort | TP53 in ERBB2 amplification vs mutation | 92.3% vs 58.3% | TP53 especially enriched with ERBB2 amplification | (liu2024genomicprofilingof pages 1-2) |
| Testing/diagnosis | FISH positivity threshold | HER2/CEP17 ratio ≥2.0 or average HER2 copy number ≥6.0 | Used in CRC scoring comparison study | (sun2023her2overexpressionamplificationstatus pages 1-2, sun2023her2overexpressionamplificationstatus pages 4-6) |
| Testing/diagnosis | HER2 amplification rate by FISH in 664-case cohort | 7.08% (47/664) | Large unselected Chinese CRC cohort | (sun2023her2overexpressionamplificationstatus pages 1-2, sun2023her2overexpressionamplificationstatus pages 4-6) |
| DESTINY-CRC01 definition | Cohort A | HER2-positive: IHC 3+ or IHC 2+/ISH+ (n=53) | T-DXd 6.4 mg/kg q3w | (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 3-4, siena2024her2relatedbiomarkerspredict pages 1-2) |
| DESTINY-CRC01 definition | Cohort B | IHC 2+/ISH− (n=15) | HER2-low/nonamplified comparator cohort | (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 3-4, siena2024her2relatedbiomarkerspredict pages 1-2) |
| DESTINY-CRC01 definition | Cohort C | IHC 1+ (n=18) | HER2-low comparator cohort | (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 3-4, siena2024her2relatedbiomarkerspredict pages 1-2) |
| T-DXd efficacy | ORR in Cohort A | 45.3% (24/53; 95% CI 31.6–59.6) | No responses in cohorts B or C | (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 3-4) |
| T-DXd efficacy | ORR by baseline HER2 subgroup | IHC 3+: 57.5%; IHC 2+/ISH+: 7.7% | Higher activity in IHC 3+ disease | (yoshino2023finalresultsof pages 4-6, yoshino2023finalresultsof pages 8-9) |
| T-DXd efficacy | Disease control rate | 83.0% in Cohort A | Cohort B 60.0%; Cohort C 22.2% | (yoshino2023finalresultsof pages 3-4) |
| T-DXd efficacy | Median PFS | 6.9 months | Cohort A; B 2.1 months; C 1.4 months | (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 4-6, yoshino2023finalresultsof pages 8-9) |
| T-DXd efficacy | Median OS | 15.5 months | Cohort A | (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 4-6, yoshino2023finalresultsof pages 9-10) |
| T-DXd efficacy | Median duration of response | 7.0 months | Cohort A | (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 3-4) |
| T-DXd safety | Grade ≥3 TEAEs | 65.1% overall | Drug-related grade ≥3 TEAEs 48.8% | (yoshino2023finalresultsof pages 4-6, yoshino2023finalresultsof pages 8-9) |
| T-DXd safety | Drug-related ILD/pneumonitis | 9.3% (8/86) | 4 grade 2, 1 grade 3, 3 grade 5 | (yoshino2023finalresultsof pages 1-2, yoshino2023finalresultsof pages 3-4, yoshino2023finalresultsof pages 9-10) |
| T-DXd safety | Fatal drug-related ILD | 3.5% (3/86) | Three grade 5 cases | (yoshino2023finalresultsof pages 3-4, yoshino2023finalresultsof pages 9-10) |
| T-DXd safety | Most common grade ≥3 AEs | Decreased neutrophil count; anemia | Most frequently reported grade ≥3 TEAEs | (yoshino2023finalresultsof pages 1-2) |
| Real-world practice | Cohort size | 142 HER2-amplified mCRC patients | GuardantINFORM/claims database | (strickler2023realworldtreatmentpatterns pages 3-4, strickler2023realworldtreatmentpatterns pages 1-2) |
| Real-world practice | Most common regimen before 2018 | Anti-VEGF ± chemotherapy: 31.6% (n=25) | After HER2 confirmation | (strickler2023realworldtreatmentpatterns pages 3-4, strickler2023realworldtreatmentpatterns pages 1-2) |
| Real-world practice | HER2-directed therapy use after 2018 | 36.5% (n=23) | Became most common regimen post-2018 | (strickler2023realworldtreatmentpatterns pages 3-4, strickler2023realworldtreatmentpatterns pages 1-2) |
| Real-world practice | HER2-therapy uptake over time | 22.8% pre-2018 vs 36.5% post-2018 | Increased but still underused | (strickler2023realworldtreatmentpatterns pages 4-6) |
| Real-world practice | Median rwTTNT overall | 8.4 months (95% CI 6.5–10.0) | Across entire cohort | (strickler2023realworldtreatmentpatterns pages 3-4, strickler2023realworldtreatmentpatterns pages 1-2) |
| Real-world practice | Median rwTTNT by treatment type | HER2-directed 11.0 months vs non-HER2 7.2 months | Descriptive comparison | (strickler2023realworldtreatmentpatterns pages 3-4, strickler2023realworldtreatmentpatterns pages 1-2) |
| Real-world practice | Median rwTTNT in RAS WT subgroup | HER2-directed 11.6 months vs non-HER2 8.1 months | Suggests benefit in molecularly selected patients | (strickler2023realworldtreatmentpatterns pages 3-4) |
Table: This table summarizes the most decision-relevant quantitative findings for HER2-positive colorectal cancer across epidemiology, molecular co-alterations, trastuzumab deruxtecan trial outcomes, and real-world treatment adoption. It is designed as a compact reference for disease knowledge base curation.
References
(singh2024systematicliteraturereview pages 1-2): Harshabad Singh, Ashley Kang, Lisa Bloudek, Ling-I Hsu, Maria Corinna Palanca-Wessels, Michael Stecher, Muriel Siadak, and Kimmie Ng. Systematic literature review and meta-analysis of her2 amplification, overexpression, and positivity in colorectal cancer. JNCI Cancer Spectrum, Oct 2024. URL: https://doi.org/10.1093/jncics/pkad082, doi:10.1093/jncics/pkad082. This article has 16 citations and is from a peer-reviewed journal.
(sun2023her2overexpressionamplificationstatus pages 2-4): Qi Sun, Qi Li, Fuping Gao, Hongyan Wu, Yao Fu, Jun Yang, Xiangshan Fan, Xiaobin Cui, and Xiaohong Pu. Her2 overexpression/amplification status in colorectal cancer: a comparison between immunohistochemistry and fluorescence in situ hybridization using five different immunohistochemical scoring criteria. Journal of Cancer Research and Clinical Oncology, 149:579-592, Aug 2023. URL: https://doi.org/10.1007/s00432-022-04230-8, doi:10.1007/s00432-022-04230-8. This article has 8 citations and is from a peer-reviewed journal.
(singh2024rasrafcomutationand pages 2-4): Harshabad Singh, Pranshu Sahgal, Kevin Kapner, Steven M. Corsello, Hersh Gupta, Rahul Gujrathi, Yvonne Y. Li, Andrew D. Cherniack, Raquelle El Alam, Joseph Kerfoot, Elizabeth Andrews, Annette Lee, Chetan Nambiar, Alison M. Hannigan, Joshua Remland, Lauren Brais, Meghan E. Leahy, Douglas A. Rubinson, Benjamin L. Schlechter, Matthew Meyerson, Yanan Kuang, Cloud P. Paweletz, Jessica K. Lee, Julia C.F. Quintanilha, Andrew J. Aguirre, Kimberly J. Perez, Brandon M. Huffman, Humberto Rossi, Thomas A. Abrams, Sheheryar Kabraji, Livio Trusolino, Andrea Bertotti, Ewa T. Sicinska, Aparna R. Parikh, Brian M. Wolpin, Alexa B. Schrock, Marios Giannakis, Kimmie Ng, Jeffrey A. Meyerhardt, Jason L. Hornick, Nilay S. Sethi, and James M. Cleary. ras/raf comutation and erbb2 copy number modulates her2 heterogeneity and responsiveness to her2-directed therapy in colorectal cancer. Clinical Cancer Research, 30:1669-1684, Feb 2024. URL: https://doi.org/10.1158/1078-0432.ccr-23-2581, doi:10.1158/1078-0432.ccr-23-2581. This article has 14 citations and is from a highest quality peer-reviewed journal.
(strickler2023realworldtreatmentpatterns pages 1-2): John H. Strickler, Ling-I Hsu, Phoebe Wright, Michael Stecher, Muriel F. Siadak, Maria Corinna Palanca-Wessels, Junhua Yu, Nicole Zhang, Carin R. Espenschied, Kathryn Lang, and Tanios S. Bekaii-Saab. Real-world treatment patterns in patients with her2-amplified metastatic colorectal cancer: a clinical-genomic database study. Journal of the National Comprehensive Cancer Network : JNCCN, 21 8:805-812.e1, Aug 2023. URL: https://doi.org/10.6004/jnccn.2023.7022, doi:10.6004/jnccn.2023.7022. This article has 7 citations.
(yoshino2023finalresultsof pages 1-2): Takayuki Yoshino, Maria Di Bartolomeo, Kanwal Raghav, Toshiki Masuishi, Fotios Loupakis, Hisato Kawakami, Kensei Yamaguchi, Tomohiro Nishina, Zev Wainberg, Elena Elez, Javier Rodriguez, Marwan Fakih, Fortunato Ciardiello, Kapil Saxena, Kojiro Kobayashi, Emarjola Bako, Yasuyuki Okuda, Gerold Meinhardt, Axel Grothey, Salvatore Siena, and Maria Di Bartolomeo. Final results of destiny-crc01 investigating trastuzumab deruxtecan in patients with her2-expressing metastatic colorectal cancer. Nature Communications, Jun 2023. URL: https://doi.org/10.1038/s41467-023-38032-4, doi:10.1038/s41467-023-38032-4. This article has 152 citations and is from a highest quality peer-reviewed journal.
(singh2024systematicliteraturereview pages 4-7): Harshabad Singh, Ashley Kang, Lisa Bloudek, Ling-I Hsu, Maria Corinna Palanca-Wessels, Michael Stecher, Muriel Siadak, and Kimmie Ng. Systematic literature review and meta-analysis of her2 amplification, overexpression, and positivity in colorectal cancer. JNCI Cancer Spectrum, Oct 2024. URL: https://doi.org/10.1093/jncics/pkad082, doi:10.1093/jncics/pkad082. This article has 16 citations and is from a peer-reviewed journal.
(lee2024rasrafmutationsand pages 1-2): Sun Mi Lee and Hyunjoo Oh. Ras/raf mutations and microsatellite instability status in primary colorectal cancers according to her2 amplification. Scientific Reports, May 2024. URL: https://doi.org/10.1038/s41598-024-62096-x, doi:10.1038/s41598-024-62096-x. This article has 10 citations and is from a peer-reviewed journal.
(singh2024rasrafcomutationand pages 14-16): Harshabad Singh, Pranshu Sahgal, Kevin Kapner, Steven M. Corsello, Hersh Gupta, Rahul Gujrathi, Yvonne Y. Li, Andrew D. Cherniack, Raquelle El Alam, Joseph Kerfoot, Elizabeth Andrews, Annette Lee, Chetan Nambiar, Alison M. Hannigan, Joshua Remland, Lauren Brais, Meghan E. Leahy, Douglas A. Rubinson, Benjamin L. Schlechter, Matthew Meyerson, Yanan Kuang, Cloud P. Paweletz, Jessica K. Lee, Julia C.F. Quintanilha, Andrew J. Aguirre, Kimberly J. Perez, Brandon M. Huffman, Humberto Rossi, Thomas A. Abrams, Sheheryar Kabraji, Livio Trusolino, Andrea Bertotti, Ewa T. Sicinska, Aparna R. Parikh, Brian M. Wolpin, Alexa B. Schrock, Marios Giannakis, Kimmie Ng, Jeffrey A. Meyerhardt, Jason L. Hornick, Nilay S. Sethi, and James M. Cleary. ras/raf comutation and erbb2 copy number modulates her2 heterogeneity and responsiveness to her2-directed therapy in colorectal cancer. Clinical Cancer Research, 30:1669-1684, Feb 2024. URL: https://doi.org/10.1158/1078-0432.ccr-23-2581, doi:10.1158/1078-0432.ccr-23-2581. This article has 14 citations and is from a highest quality peer-reviewed journal.
(lee2024rasrafmutationsand pages 5-6): Sun Mi Lee and Hyunjoo Oh. Ras/raf mutations and microsatellite instability status in primary colorectal cancers according to her2 amplification. Scientific Reports, May 2024. URL: https://doi.org/10.1038/s41598-024-62096-x, doi:10.1038/s41598-024-62096-x. This article has 10 citations and is from a peer-reviewed journal.
(yoshino2023finalresultsof pages 3-4): Takayuki Yoshino, Maria Di Bartolomeo, Kanwal Raghav, Toshiki Masuishi, Fotios Loupakis, Hisato Kawakami, Kensei Yamaguchi, Tomohiro Nishina, Zev Wainberg, Elena Elez, Javier Rodriguez, Marwan Fakih, Fortunato Ciardiello, Kapil Saxena, Kojiro Kobayashi, Emarjola Bako, Yasuyuki Okuda, Gerold Meinhardt, Axel Grothey, Salvatore Siena, and Maria Di Bartolomeo. Final results of destiny-crc01 investigating trastuzumab deruxtecan in patients with her2-expressing metastatic colorectal cancer. Nature Communications, Jun 2023. URL: https://doi.org/10.1038/s41467-023-38032-4, doi:10.1038/s41467-023-38032-4. This article has 152 citations and is from a highest quality peer-reviewed journal.
(sun2023her2overexpressionamplificationstatus pages 1-2): Qi Sun, Qi Li, Fuping Gao, Hongyan Wu, Yao Fu, Jun Yang, Xiangshan Fan, Xiaobin Cui, and Xiaohong Pu. Her2 overexpression/amplification status in colorectal cancer: a comparison between immunohistochemistry and fluorescence in situ hybridization using five different immunohistochemical scoring criteria. Journal of Cancer Research and Clinical Oncology, 149:579-592, Aug 2023. URL: https://doi.org/10.1007/s00432-022-04230-8, doi:10.1007/s00432-022-04230-8. This article has 8 citations and is from a peer-reviewed journal.
(sun2023her2overexpressionamplificationstatus pages 4-6): Qi Sun, Qi Li, Fuping Gao, Hongyan Wu, Yao Fu, Jun Yang, Xiangshan Fan, Xiaobin Cui, and Xiaohong Pu. Her2 overexpression/amplification status in colorectal cancer: a comparison between immunohistochemistry and fluorescence in situ hybridization using five different immunohistochemical scoring criteria. Journal of Cancer Research and Clinical Oncology, 149:579-592, Aug 2023. URL: https://doi.org/10.1007/s00432-022-04230-8, doi:10.1007/s00432-022-04230-8. This article has 8 citations and is from a peer-reviewed journal.
(singh2024systematicliteraturereview pages 7-8): Harshabad Singh, Ashley Kang, Lisa Bloudek, Ling-I Hsu, Maria Corinna Palanca-Wessels, Michael Stecher, Muriel Siadak, and Kimmie Ng. Systematic literature review and meta-analysis of her2 amplification, overexpression, and positivity in colorectal cancer. JNCI Cancer Spectrum, Oct 2024. URL: https://doi.org/10.1093/jncics/pkad082, doi:10.1093/jncics/pkad082. This article has 16 citations and is from a peer-reviewed journal.
(lee2024rasrafmutationsand pages 2-3): Sun Mi Lee and Hyunjoo Oh. Ras/raf mutations and microsatellite instability status in primary colorectal cancers according to her2 amplification. Scientific Reports, May 2024. URL: https://doi.org/10.1038/s41598-024-62096-x, doi:10.1038/s41598-024-62096-x. This article has 10 citations and is from a peer-reviewed journal.
(liu2024genomicprofilingof pages 1-2): YUZHI LIU, EVELYNE BISCHOF, ZHIQIN CHEN, JIAHUAN ZHOU, BEI ZHANG, DING ZHANG, YONG GAO, and MING QUAN. Genomic profiling of colorectal cancer in large-scale chinese patients: amplification and somatic mutations in erbb2. Oncology Research, 32:1429-1438, Aug 2024. URL: https://doi.org/10.32604/or.2024.047309, doi:10.32604/or.2024.047309. This article has 1 citations and is from a peer-reviewed journal.
(mo2024resistancetoantiher2 pages 5-6): Christiana Mo, Michelle Sterpi, Hyein Jeon, and Fernand Bteich. Resistance to anti-her2 therapies in gastrointestinal malignancies. Cancers, 16:2854, Aug 2024. URL: https://doi.org/10.3390/cancers16162854, doi:10.3390/cancers16162854. This article has 6 citations.
(quaquarini2024prognosticandpredictive pages 4-5): Erica Quaquarini, Federica Grillo, Lorenzo Gervaso, Giovanni Arpa, Nicola Fazio, Alessandro Vanoli, and Paola Parente. Prognostic and predictive roles of her2 status in non-breast and non-gastroesophageal carcinomas. Cancers, 16:3145, Sep 2024. URL: https://doi.org/10.3390/cancers16183145, doi:10.3390/cancers16183145. This article has 10 citations.
(sun2023her2overexpressionamplificationstatus pages 10-12): Qi Sun, Qi Li, Fuping Gao, Hongyan Wu, Yao Fu, Jun Yang, Xiangshan Fan, Xiaobin Cui, and Xiaohong Pu. Her2 overexpression/amplification status in colorectal cancer: a comparison between immunohistochemistry and fluorescence in situ hybridization using five different immunohistochemical scoring criteria. Journal of Cancer Research and Clinical Oncology, 149:579-592, Aug 2023. URL: https://doi.org/10.1007/s00432-022-04230-8, doi:10.1007/s00432-022-04230-8. This article has 8 citations and is from a peer-reviewed journal.
(yoshino2023finalresultsof pages 4-6): Takayuki Yoshino, Maria Di Bartolomeo, Kanwal Raghav, Toshiki Masuishi, Fotios Loupakis, Hisato Kawakami, Kensei Yamaguchi, Tomohiro Nishina, Zev Wainberg, Elena Elez, Javier Rodriguez, Marwan Fakih, Fortunato Ciardiello, Kapil Saxena, Kojiro Kobayashi, Emarjola Bako, Yasuyuki Okuda, Gerold Meinhardt, Axel Grothey, Salvatore Siena, and Maria Di Bartolomeo. Final results of destiny-crc01 investigating trastuzumab deruxtecan in patients with her2-expressing metastatic colorectal cancer. Nature Communications, Jun 2023. URL: https://doi.org/10.1038/s41467-023-38032-4, doi:10.1038/s41467-023-38032-4. This article has 152 citations and is from a highest quality peer-reviewed journal.
(yoshino2023finalresultsof media ab04ee1c): Takayuki Yoshino, Maria Di Bartolomeo, Kanwal Raghav, Toshiki Masuishi, Fotios Loupakis, Hisato Kawakami, Kensei Yamaguchi, Tomohiro Nishina, Zev Wainberg, Elena Elez, Javier Rodriguez, Marwan Fakih, Fortunato Ciardiello, Kapil Saxena, Kojiro Kobayashi, Emarjola Bako, Yasuyuki Okuda, Gerold Meinhardt, Axel Grothey, Salvatore Siena, and Maria Di Bartolomeo. Final results of destiny-crc01 investigating trastuzumab deruxtecan in patients with her2-expressing metastatic colorectal cancer. Nature Communications, Jun 2023. URL: https://doi.org/10.1038/s41467-023-38032-4, doi:10.1038/s41467-023-38032-4. This article has 152 citations and is from a highest quality peer-reviewed journal.
(yoshino2023finalresultsof media 2afcc8a6): Takayuki Yoshino, Maria Di Bartolomeo, Kanwal Raghav, Toshiki Masuishi, Fotios Loupakis, Hisato Kawakami, Kensei Yamaguchi, Tomohiro Nishina, Zev Wainberg, Elena Elez, Javier Rodriguez, Marwan Fakih, Fortunato Ciardiello, Kapil Saxena, Kojiro Kobayashi, Emarjola Bako, Yasuyuki Okuda, Gerold Meinhardt, Axel Grothey, Salvatore Siena, and Maria Di Bartolomeo. Final results of destiny-crc01 investigating trastuzumab deruxtecan in patients with her2-expressing metastatic colorectal cancer. Nature Communications, Jun 2023. URL: https://doi.org/10.1038/s41467-023-38032-4, doi:10.1038/s41467-023-38032-4. This article has 152 citations and is from a highest quality peer-reviewed journal.
(NCT03043313 chunk 1): Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer. Seagen Inc.. 2017. ClinicalTrials.gov Identifier: NCT03043313
(yoshino2023finalresultsof pages 8-9): Takayuki Yoshino, Maria Di Bartolomeo, Kanwal Raghav, Toshiki Masuishi, Fotios Loupakis, Hisato Kawakami, Kensei Yamaguchi, Tomohiro Nishina, Zev Wainberg, Elena Elez, Javier Rodriguez, Marwan Fakih, Fortunato Ciardiello, Kapil Saxena, Kojiro Kobayashi, Emarjola Bako, Yasuyuki Okuda, Gerold Meinhardt, Axel Grothey, Salvatore Siena, and Maria Di Bartolomeo. Final results of destiny-crc01 investigating trastuzumab deruxtecan in patients with her2-expressing metastatic colorectal cancer. Nature Communications, Jun 2023. URL: https://doi.org/10.1038/s41467-023-38032-4, doi:10.1038/s41467-023-38032-4. This article has 152 citations and is from a highest quality peer-reviewed journal.
(yoshino2023finalresultsof media 821b3066): Takayuki Yoshino, Maria Di Bartolomeo, Kanwal Raghav, Toshiki Masuishi, Fotios Loupakis, Hisato Kawakami, Kensei Yamaguchi, Tomohiro Nishina, Zev Wainberg, Elena Elez, Javier Rodriguez, Marwan Fakih, Fortunato Ciardiello, Kapil Saxena, Kojiro Kobayashi, Emarjola Bako, Yasuyuki Okuda, Gerold Meinhardt, Axel Grothey, Salvatore Siena, and Maria Di Bartolomeo. Final results of destiny-crc01 investigating trastuzumab deruxtecan in patients with her2-expressing metastatic colorectal cancer. Nature Communications, Jun 2023. URL: https://doi.org/10.1038/s41467-023-38032-4, doi:10.1038/s41467-023-38032-4. This article has 152 citations and is from a highest quality peer-reviewed journal.
(NCT04744831 chunk 1): Trastuzumab Deruxtecan in Participants With HER2-overexpressing Advanced or Metastatic Colorectal Cancer. Daiichi Sankyo. 2021. ClinicalTrials.gov Identifier: NCT04744831
(strickler2023realworldtreatmentpatterns pages 3-4): John H. Strickler, Ling-I Hsu, Phoebe Wright, Michael Stecher, Muriel F. Siadak, Maria Corinna Palanca-Wessels, Junhua Yu, Nicole Zhang, Carin R. Espenschied, Kathryn Lang, and Tanios S. Bekaii-Saab. Real-world treatment patterns in patients with her2-amplified metastatic colorectal cancer: a clinical-genomic database study. Journal of the National Comprehensive Cancer Network : JNCCN, 21 8:805-812.e1, Aug 2023. URL: https://doi.org/10.6004/jnccn.2023.7022, doi:10.6004/jnccn.2023.7022. This article has 7 citations.
(strickler2023realworldtreatmentpatterns pages 4-6): John H. Strickler, Ling-I Hsu, Phoebe Wright, Michael Stecher, Muriel F. Siadak, Maria Corinna Palanca-Wessels, Junhua Yu, Nicole Zhang, Carin R. Espenschied, Kathryn Lang, and Tanios S. Bekaii-Saab. Real-world treatment patterns in patients with her2-amplified metastatic colorectal cancer: a clinical-genomic database study. Journal of the National Comprehensive Cancer Network : JNCCN, 21 8:805-812.e1, Aug 2023. URL: https://doi.org/10.6004/jnccn.2023.7022, doi:10.6004/jnccn.2023.7022. This article has 7 citations.
(lee2024rasrafmutationsand pages 7-9): Sun Mi Lee and Hyunjoo Oh. Ras/raf mutations and microsatellite instability status in primary colorectal cancers according to her2 amplification. Scientific Reports, May 2024. URL: https://doi.org/10.1038/s41598-024-62096-x, doi:10.1038/s41598-024-62096-x. This article has 10 citations and is from a peer-reviewed journal.
(liu2024genomicprofilingof pages 2-3): YUZHI LIU, EVELYNE BISCHOF, ZHIQIN CHEN, JIAHUAN ZHOU, BEI ZHANG, DING ZHANG, YONG GAO, and MING QUAN. Genomic profiling of colorectal cancer in large-scale chinese patients: amplification and somatic mutations in erbb2. Oncology Research, 32:1429-1438, Aug 2024. URL: https://doi.org/10.32604/or.2024.047309, doi:10.32604/or.2024.047309. This article has 1 citations and is from a peer-reviewed journal.
(siena2024her2relatedbiomarkerspredict pages 1-2): Salvatore Siena, Kanwal Raghav, Toshiki Masuishi, Kensei Yamaguchi, Tomohiro Nishina, Elena Elez, Javier Rodriguez, Ian Chau, Maria Di Bartolomeo, Hisato Kawakami, Fumitaka Suto, Makito Koga, Koichiro Inaki, Yusuke Kuwahara, Issey Takehara, Daniel Barrios, Kojiro Kobayashi, Axel Grothey, and Takayuki Yoshino. Her2-related biomarkers predict clinical outcomes with trastuzumab deruxtecan treatment in patients with her2-expressing metastatic colorectal cancer: biomarker analyses of destiny-crc01. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-53223-3, doi:10.1038/s41467-024-53223-3. This article has 27 citations and is from a highest quality peer-reviewed journal.
(yoshino2023finalresultsof pages 9-10): Takayuki Yoshino, Maria Di Bartolomeo, Kanwal Raghav, Toshiki Masuishi, Fotios Loupakis, Hisato Kawakami, Kensei Yamaguchi, Tomohiro Nishina, Zev Wainberg, Elena Elez, Javier Rodriguez, Marwan Fakih, Fortunato Ciardiello, Kapil Saxena, Kojiro Kobayashi, Emarjola Bako, Yasuyuki Okuda, Gerold Meinhardt, Axel Grothey, Salvatore Siena, and Maria Di Bartolomeo. Final results of destiny-crc01 investigating trastuzumab deruxtecan in patients with her2-expressing metastatic colorectal cancer. Nature Communications, Jun 2023. URL: https://doi.org/10.1038/s41467-023-38032-4, doi:10.1038/s41467-023-38032-4. This article has 152 citations and is from a highest quality peer-reviewed journal.