Intra-patient and inter-metastasis heterogeneity of HER2-low status in metastatic breast cancer
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Published on: December 5, 2017
Tatjana Geukens1, Maxim De Schepper2, François Richard3
1Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium; Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
Introduction:
Anti-HER2 antibody-drug conjugates (ADCs) have shown important efficacy in HER2-low metastatic breast cancer (mBC). Criteria for receiving ADCs are based on a single assay on the primary tumour or a small metastatic biopsy. We assessed the intra-patient inter-metastasis heterogeneity of HER2-low status in HER2-negative mBC.
Patients And Methods:
We included samples of 10 patients (7 ER-positive and 3 ER-negative) donated in the context of our post-mortem tissue donation program UPTIDER. Excisional post-mortem biopsies of 257 metastases and 8 breast tumours underwent central HER2 immunohistochemistry (IHC), alongside 41 pre-mortem primary or metastatic samples. They were classified as HER2-zero, HER2-low (HER2-1+ or HER2-2+, in situ hybridisation [ISH] negative) or HER2-positive (HER2-3+ or HER2-2+, ISH-positive) following ASCO/CAP guidelines 2018. HER2-zero was further subdivided into HER2-undetected (no staining) and HER2-ultralow (faint staining in ≤10% of tumour cells).
Results:
Median post-mortem interval was 2.5 h. In 8/10 patients, HER2-low and HER2-zero metastases co-existed, with the proportion of HER2-low lesions ranging from 5% to 89%. A total of 32% of metastases currently classified as HER2-zero were HER2-ultralow. Intra-organ inter-metastasis heterogeneity of HER2-scores was observed in the liver in 3/6 patients. Patients with primary ER-positive disease had a higher proportion of HER2-low metastases as compared to ER-negative disease (46% versus 8%, respectively). At the metastasis level, higher percentages of ER-expressing cells were observed in HER2-low or -ultralow as compared to HER2-undetected metastases.
Conclusions:
Important intra-patient inter-metastasis heterogeneity of HER2-low status exists. This questions the validity of HER2-low in its current form as a theranostic marker.
Insights
Intra-patient heterogeneity in HER2-low status among metastases is significant in metastatic breast cancer (mBC). This finding challenges the current use of HER2-low as a reliable theranostic marker for antibody-drug conjugates (ADCs).
Area of Science:
- Oncology
- Translational Research
- Cancer Biomarkers
Background:
- Anti-HER2 antibody-drug conjugates (ADCs) demonstrate efficacy in HER2-low metastatic breast cancer (mBC).
- Current ADC eligibility relies on HER2 status determined by single assays on primary tumors or limited biopsies.
- Significant heterogeneity in HER2 expression across metastases could impact treatment selection.
Purpose of the Study:
- To assess the intra-patient inter-metastasis heterogeneity of HER2-low status in HER2-negative metastatic breast cancer.
- To evaluate the implications of this heterogeneity for the theranostic utility of HER2-low status.
Main Methods:
- Post-mortem biopsies from 10 patients with metastatic breast cancer were analyzed.
- 257 metastases and 8 primary tumors underwent central HER2 immunohistochemistry (IHC) and in situ hybridization (ISH).
- HER2 status was classified according to ASCO/CAP guidelines, with HER2-zero further subdivided into HER2-undetected and HER2-ultralow.
Main Results:
- HER2-low and HER2-zero metastases co-existed in 80% of patients, with HER2-low proportions varying widely (5-89%).
- 32% of metastases classified as HER2-zero were found to be HER2-ultralow.
- Intra-organ heterogeneity of HER2 scores was observed in the liver; ER-positive primary disease correlated with a higher proportion of HER2-low metastases.
Conclusions:
- Substantial intra-patient inter-metastasis heterogeneity of HER2-low status exists in metastatic breast cancer.
- This heterogeneity raises concerns about the current validity of HER2-low status as a theranostic marker for ADCs.
- Further investigation is needed to refine HER2 assessment strategies for optimal patient selection for HER2-targeted therapies.
