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Molecular profiling of gestational trophoblastic neoplasia: Identifying therapeutic targets
Leah McNally1, Sharon Wu2, Kurt Hodges2
1Duke University, Durham, NC, USA.
Objective:
The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets.
Methods:
GTN samples were analyzed using a combination of molecular - next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses. GTN samples encompassed complete moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT).
Results:
We analyzed 30 cases of GTN including 15 choriocarcinoma, 7 ETT, 5 PSTT, 1 invasive mole and 2 mixed histologies. The median age was 41.5. GTN samples were found to be PD-L1 positive (92.3%), tumor mutational burden (TMB) low (92.8%), and microsatellite stable (MSS) (100%). Forty-six percent of choriocarcinoma specimens contained a genomic alteration including TP53 (33%) and homologous recombination repair (HRR) (13%) genes. Alterations in RTK-RAS pathway signaling was present in 40% of ETT cases.
Conclusions:
The high rate of PD-L1 positivity in this real-world database and reported in prior literature support continued clinical trial development evaluating immunotherapy for treatment of GTN. Other potential targeted treatments identified include Wee1, PARP and MEK inhibitors based on molecular alterations in TP53, HRR genes, and RTK-RAS pathways respectively.
Insights
This study reveals high PD-L1 positivity in gestational trophoblastic neoplasia (GTN), supporting immunotherapy trials. Molecular analysis identified potential targets like TP53, HRR, and RTK-RAS pathways for novel GTN therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- High-risk or recurrent gestational trophoblastic neoplasia (GTN) treatment involves toxic chemotherapy.
- Checkpoint inhibitors show promise, but novel therapies for GTN are needed.
- Understanding GTN's molecular profile is crucial for identifying new therapeutic targets.
Purpose of the Study:
- To characterize the molecular landscape of gestational trophoblastic neoplasia (GTN).
- To identify potential therapeutic targets for GTN based on molecular alterations.
Main Methods:
- Analyzed 30 GTN samples (choriocarcinoma, ETT, PSTT, etc.) using next-generation sequencing (NGS)/whole exome sequencing (WES) and immunohistochemistry (IHC).
Main Results:
- GTN samples showed high PD-L1 positivity (92.3%), low tumor mutational burden (TMB) (92.8%), and were microsatellite stable (MSS) (100%).
- Genomic alterations found in 46% of choriocarcinoma, including TP53 (33%) and homologous recombination repair (HRR) genes (13%).
- RTK-RAS pathway alterations present in 40% of epithelioid trophoblastic tumors (ETT).
Conclusions:
- High PD-L1 positivity supports further clinical trials for GTN immunotherapy.
- Identified potential targeted treatments: Wee1, PARP, and MEK inhibitors for TP53, HRR, and RTK-RAS alterations, respectively.
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