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Published on: August 2, 2024
Association between HER2 expression, genomic characteristics, and tumor immune microenvironment dynamics in
Julia Salinaro1,2, Payton De La Cruz1, Shriya Perati2
1Program in Women's Oncology, Women and Infants Hospital, Providence, RI, United States.
Background:
Despite the rapid clinical approval of the HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd) for patients with HER2-expressing epithelial ovarian cancer (EOC), preclinical mechanistic studies are lacking.The goal of this investigation was to determine the genomic and immunogenic characteristics associated with HER2 expressing EOC in order to better understand the mechanism of treatment response and what subset of patients will benefit most from single agent and combinatorial HER2-directed treatment regimens.
Methods:
130 EOC patients were retrospectively identified from our institution's internal clinical genomic database. Selected genomic characteristics were stratified by gastric HER2 score and distributions were analyzed by Fisher's exact test. A subset of 34 EOC tumors were internally HER2 stained and fluorescent immunohistochemistry analysis of PD-L1, CD4, and CD8 was performed. EOC cell lines were treated with T-DXd and PD-L1 and VEGFA levels were assessed via quantitative PCR. VEGF expression following combinatorial T-DXd and bevacizumab treatment was determined via western blot.
Results:
Non-significant differences were detected in HRD, CCNE1 amplification, and ARID1A status between HER2 high (n=29) and low (n=101) tumors in an EOC and high grade serous ovarian cancer (HGSOC) sub-cohort (n=98). Although not statistically significant, patients with HER2 high tumors had lower levels of FOLR1 positivity and higher levels of PD-L1 positivity in both EOC and HGSOC cohorts. Intratumoral PD-L1 expression and CD4+ T cell levels were significantly higher (p<0.05) in HER2 high tumors. Finally, T-DXd substantially downregulated PD-L1 and VEGFA expression, and bevacizumab and T-DXd synergistically reduced VEGF expression.
Conclusions:
HER2 high EOC tumors are more likely to be FOLR1 negative and PD-L1 positive, and treatment with T-DXd downregulates PDL-1 and VEGFA expression. These findings support further examination to determine if immunotherapy and anti-angiogenic treatments synergize with T-DXd in EOC.
Insights
HER2-high epithelial ovarian cancer (EOC) tumors show increased PD-L1 expression and respond to trastuzumab deruxtecan (T-DXd) by downregulating PD-L1 and VEGFA. This suggests potential synergy with immunotherapy and anti-angiogenic agents in EOC treatment.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Trastuzumab deruxtecan (T-DXd) is approved for HER2-expressing epithelial ovarian cancer (EOC).
- Preclinical data on T-DXd mechanisms in EOC are limited.
- Understanding genomic and immunogenic features of HER2-expressing EOC is crucial for optimizing treatment.
Purpose of the Study:
- To investigate the genomic and immunogenic characteristics of HER2-expressing EOC.
- To elucidate the mechanism of T-DXd response in EOC.
- To identify patient subsets benefiting from HER2-directed therapies.
Main Methods:
- Retrospective analysis of 130 EOC patients' genomic data.
- HER2 staining and immunohistochemistry for PD-L1, CD4, and CD8 on 34 EOC tumors.
- In vitro assessment of T-DXd effects on PD-L1 and VEGFA in EOC cell lines.
- Evaluation of T-DXd and bevacizumab combination effects on VEGF.
Main Results:
- HER2-high EOC tumors showed trends towards lower FOLR1 and higher PD-L1 positivity.
- Significantly higher intratumoral PD-L1 and CD4+ T cell levels were observed in HER2-high tumors.
- T-DXd treatment downregulated PD-L1 and VEGFA expression.
- Combined T-DXd and bevacizumab synergistically reduced VEGF expression.
Conclusions:
- HER2-high EOC tumors are characterized by PD-L1 positivity and reduced FOLR1 expression.
- T-DXd treatment modulates key immune and angiogenic markers (PD-L1, VEGFA).
- Findings support further investigation into combining T-DXd with immunotherapy and anti-angiogenic agents in EOC.
