Molecular profiling of gestational trophoblastic neoplasia: Identifying therapeutic targets.

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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leah McNally: None. Sharon Wu: employee of Caris Life Sciences. Kurt Hodges: employee of Caris Life Sciences. Matt Oberley: employee of Caris Life Sciences. John J Wallbillich: None. Nathaniel L Jones: None. Thomas J Herzog: Scientific Advisory Boards &/or Honorarium: Aadi Bioscience, Astra Zeneca, Caris, Clovis, Eisai, Epsilogen, Genentech, GSK, J&J, Merck, Mersana, Novocure, Seattle Genetics. Premal H Thaker: Grants to institution from: Merck and GSK. Scientific Advisory Boards: AstraZeneca, GlaxoSmithKline, Immunon, Immunogen, SeaGen, Novocure, Mersana, Verastem, Zentalis. Angeles Alvarez Secord: Duke receives Clinical trial grant funding from AbbVie, Aravive, AstraZeneca, Clovis, Eisai, Ellipses Pharma, GSK, I-MAB Biopharma, Immunogen, Merck, Oncoquest, Roche/Genentech, Seagen, Inc., Theradex, VBL, Zentalis, and the National Cancer Trial Network. Advisory Boards (uncompensated) for AstraZeneca, Clovis, Gilead, GSK, Immunogen, Imvax, Merck, Mersana, Natera, Onconova, Oncoquest. Participation on Steering Committees (uncompensated): Aravive (AxXelerate); Roche/Genentech (AtTEND trial); VBL (OVAL trial); and Oncoquest (GOG-3035/FLORA-5). SGO Board of Directors, GOG Foundation Board of Directors, AAOGF Board of Trustees. Marilyn Huang: University of Miami received clinical grant funding fromMerck, Jansen; Scientific advisory board: Clovis, Seattle Genetics, Eisai, Immunogen, VB111, Tesaro/GSK, Voluntis/Aptar Digital Health.
(Published by Elsevier Inc.)