What is the significance of HER2 (Human Epidermal growth factor Receptor 2) neu status in colorectal adenocarcinoma (colorectal cancer) metastasis?

HER2 Status in Metastatic Colorectal Adenocarcinoma

HER2 testing is recommended in RAS wild-type metastatic colorectal cancer patients to identify candidates for HER2-targeted therapy, as approximately 3-5% of these patients harbor HER2 amplification and may benefit from anti-HER2 blockade. 1

Clinical Significance and Testing Recommendations

When to Test

• HER2 amplification testing should be performed specifically in RAS wild-type (KRAS/NRAS wild-type) metastatic colorectal cancer patients 1
• Testing can be done at initial diagnosis alongside other molecular markers, though anti-HER2 therapy is typically reserved for second-line and beyond 1
• The Chinese Society of Clinical Oncology recommends HER2 testing in patients who have failed standard treatment 1

Prevalence and Patient Selection

• HER2 positivity occurs in approximately 1.6-3.4% of all colorectal cancers, but enriches to 3-5% in the RAS wild-type population 2, 3
• HER2-positive colorectal cancers are predominantly left-sided and have intestinal-type histology 1
• HER2 positivity significantly correlates with higher UICC stages, lymph node metastases, and more advanced disease 2

Testing Methodology

Diagnostic Approach

Initial testing should use immunohistochemistry (IHC), with fluorescence in situ hybridization (FISH) for confirmation of equivocal cases 1

HER2 Positivity Criteria (Colorectal-Specific)

The criteria differ from breast and gastric cancer scoring systems 1:

• IHC 3+: Strong membranous staining (basolateral or complete membrane) in >50% of tumor cells 1
• IHC 2+: Requires FISH confirmation
  • FISH positive: HER2/CEP17 ratio >2.0 in >50% of tumor cells 1
• IHC 0 or 1+: HER2 negative

Critical caveat: Unlike breast cancer where >30% staining suffices, colorectal cancer requires >50% of tumor cells to show strong staining for HER2 positivity 1

Spatial and Temporal Heterogeneity

Testing Site Considerations

• There is significant discordance (14-21%) in HER2 status between primary tumors and metastatic sites 4, 5
• When feasible, test both primary and metastatic lesions, particularly if treatment decisions hinge on HER2 status 4, 5
• Among multiple liver metastases from the same patient, HER2 status can vary in 21% of cases 5
• No significant difference exists between synchronous and metachronous metastases regarding HER2 heterogeneity 5

Practical Implications

Given the 19% discrepancy rate between primary and metastatic sites, consider retesting metastatic tissue if anti-HER2 therapy is being contemplated, especially if the primary tumor was HER2 negative 5

Prognostic Significance

• HER2-positive colorectal cancers demonstrate a tendency toward poorer overall survival, though not always reaching statistical significance 2
• HER2 positivity correlates with more aggressive disease features including higher T-category and nodal involvement 2
• In sigmoideal and rectal carcinomas specifically, HER2 positivity associates with higher T-category and UICC stages 2

Relationship with Other Biomarkers

RAS Status

• HER2 testing is specifically recommended in RAS wild-type patients, as this population is most likely to benefit from HER2-targeted therapy 1
• However, HER2 amplification can coexist with KRAS mutations in 5.3-17% of cases 6, 4
• No significant correlation exists between HER2 expression and KRAS mutation status 4

Other Concurrent Alterations

• PIK3CA mutations can coexist with HER2 amplification in approximately 33% of HER2-positive cases 6
• Testing for PIK3CA and HER2 activating mutations (as opposed to amplification) is not recommended outside clinical trials 1

Emerging Technologies

Circulating Tumor DNA (ctDNA)

• HER2 copy number variation can be detected in plasma ctDNA with a concordance rate of approximately 67% compared to tissue testing 3
• ctDNA may serve as a noninvasive alternative for HER2 status determination and monitoring treatment response 3
• Changes in HER2 copy number in ctDNA correlate with imaging-based tumor response 3

Next-Generation Sequencing

• NGS-based assays can simultaneously detect HER2 amplification and other genomic alterations 6
• Only high-level HER2 copy number gains (typically >8-fold) correspond to HER2 positivity by current diagnostic criteria 6
• Low-level copy number gains (2.74-3.04 fold) do not meet criteria for HER2 positivity and should not guide anti-HER2 therapy decisions 6

Key Clinical Pitfalls

1. Do not use breast cancer HER2 scoring criteria - colorectal cancer requires modified criteria with higher thresholds 1
2. Avoid testing only the primary tumor - spatial heterogeneity necessitates consideration of metastatic site testing 4, 5
3. Do not equate low-level copy number gains with actionable HER2 positivity - only high-level amplification predicts benefit from anti-HER2 therapy 6
4. Remember that HER2 testing primarily guides therapy after progression on standard treatments, not first-line decisions 1

1, 2, 3, 6, 4, 5