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New research · Pathology
Virchows Archiv : an international journal of pathology · 1w
Cohort studyVirchows Archiv : an international journal of pathology · 2026

HER2 overexpression/amplification in colorectal cancer: spatial intratumoral heterogeneity as a key determinant of detection discordance and therapy response.

Xiaoding Liu, Si Su, Xuqing Shi … Zhiyong Liang
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PathologyCohort study

Within-block HER2 heterogeneity accounted for most test disagreements in colorectal cancer

HER2 overexpression/amplification in colorectal cancer: spatial intratumoral heterogeneity as a key determinant of detection discordance and therapy response.

Xiaoding Liu … Zhiyong Liang
Virchows Archiv : an international journal of pathology · 2026
Background

HER2-targeted therapy is increasingly used in colorectal cancer (colorectal cancer).

Methods

Two consecutive retrospective cohorts from Peking Union Medical College Hospital (2018-2024) were analyzed.

n = 1,343
Results
82%
Share of disagreeing cases showing uneven HER2 staining within one tumor block
n = 1,343
More results

In the IHC cohort (n = 3,585), spatial HER2 expression heterogeneity was comprehensively assessed.

HER2 amplification was detected in 2.53% (34/1,343) of tumors and defined a distinct molecular subset characterized by fewer RAS/KRAS mutations and more frequent CDK12 and TP53 alterations.

More results

Concordance between next-generation sequencing and IHC was higher when applying ToGA criteria (κ = 0.85) compared to the HERACLES criteria, particularly in cases with high-level amplifications (gene copy number ≥ 10).

This heterogeneity represents a key determinant of inter-method discordance and may influence response to HER2-targeted therapy.

“
Conclusion

These findings support integrating spatial assessment into HER2 testing algorithms and warrant prospective validation of its predictive value.

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