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ERBB2/HER2 Alterations in ctDNA and Metachronous Tissues of Patients with Metastatic Urothelial Cancer
Gillian Vandekerkhove1,2, Andrew J Murtha1, David C Müller1,3
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Purpose:
HER2 targeting is increasingly relevant in metastatic urothelial cancer (mUC) because of emerging antibody-drug conjugates, in which assessment of tumor HER2/ERBB2 status could aid interpretation of ongoing trials. We evaluated whether precise ERBB2 genotype can be determined from mUC ctDNA and the relationship with tissue status.
Experimental Design:
ERBB2 genotype was determined through targeted sequencing of longitudinal samples from 226 patients with mUC. Heterogeneity was evaluated across ctDNA and metachronous tumor tissue ERBB2 genotype and compared with HER2 IHC.
Results:
Activating ERBB2 mutation and/or amplification was identified in 16% and 29% of patients by ctDNA and tissue sequencing, respectively. Alternatively, 55% of tissue samples were HER2 IHC positive. Agreement between HER2 IHC and ERBB2 genotype (by either ctDNA or tissue) was 64%, in contrast to 87% between patient-matched ctDNA and tissue genotypes. Across serial samples, genotype and IHC revealed marked heterogeneity in ERBB2 status. Factors linked with heterogeneity included ERBB2 amplifications on extrachromosomal DNA, detected through whole-genome sequencing of ctDNA and FISH, and subclonal ERBB2 mutations, which were evident in half of ctDNA and one-third of tissue samples.
Conclusions:
We report a combined analysis of HER2 IHC and ERBB2 genotype in mUC ctDNA and archival tissue, revealing high spatiotemporal heterogeneity. Our data suggest that sole reliance on DNA- or protein-based HER2 assessment is insufficient to capture nuanced genomic indicators of HER2 pathway reliance and support a role for ctDNA alongside existing methods for characterizing HER2/ERBB2 status during biomarker development in mUC.
Insights
Assessing HER2/ERBB2 status in metastatic urothelial cancer (mUC) using both ctDNA and tissue reveals significant heterogeneity. Relying on single methods is insufficient for understanding HER2 pathway reliance in mUC.
Area of Science:
- Oncology
- Genetics
- Biomarker Discovery
Background:
- HER2/ERBB2 targeting is crucial in metastatic urothelial cancer (mUC) due to emerging antibody-drug conjugates.
- Accurate assessment of tumor HER2/ERBB2 status is vital for interpreting clinical trial results.
Purpose of the Study:
- To determine if ERBB2 genotype can be precisely identified from circulating tumor DNA (ctDNA) in mUC.
- To investigate the relationship between ctDNA-derived ERBB2 genotype and tumor tissue status.
- To evaluate the spatiotemporal heterogeneity of HER2/ERBB2 status in mUC.
Main Methods:
- Targeted sequencing of longitudinal samples from 226 mUC patients to determine ERBB2 genotype.
- Evaluation of heterogeneity across ctDNA and tumor tissue ERBB2 genotypes.
- Comparison of ctDNA and tissue ERBB2 genotypes with HER2 immunohistochemistry (IHC).
- Whole-genome sequencing and FISH analysis for specific heterogeneity factors.
Main Results:
- Activating ERBB2 mutations/amplifications were found in 16% of patients via ctDNA and 29% via tissue sequencing.
- HER2 IHC positivity was observed in 55% of tissue samples.
- Agreement between HER2 IHC and ERBB2 genotype was 64%, while ctDNA and tissue genotype agreement was 87%.
- Significant spatiotemporal heterogeneity in ERBB2 status was observed across serial samples.
Conclusions:
- Combined analysis of HER2 IHC and ERBB2 genotype in mUC ctDNA and tissue reveals high heterogeneity.
- Sole reliance on DNA- or protein-based HER2 assessment is insufficient to capture HER2 pathway reliance.
- ctDNA plays a complementary role alongside existing methods for characterizing HER2/ERBB2 status in mUC biomarker development.
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