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.

中文翻译：

---

妊娠滋养细胞肿瘤的分子谱分析：确定治疗靶点

客观的

高风险或复发性妊娠滋养细胞肿瘤 (GTN) 的治疗是一种高毒性的多药化疗。对于进行性或复发性 GTN 患者，检查点抑制剂已显示出抗肿瘤活性；然而，确定 GTN 的新疗法仍然是一个未满足的需求。因此，我们试图描述 GTN 的分子结构，以确定潜在的治疗靶点。

方法

GTN 样本采用分子下一代测序 (NGS) 或全外显子组测序(WES) 和蛋白质免疫组织化学 (IHC) 分析相结合的方式进行分析。 GTN 样本包括完全性葡萄胎、绒毛膜癌、上皮样滋养细胞肿瘤 (ETT) 和胎盘部位滋养细胞肿瘤 (PSTT)。

结果

我们分析了 30 例 GTN，其中包括 15 例绒毛膜癌、7 例 ETT、5 例 PSTT、1 例侵袭性葡萄胎和 2 例混合组织学。中位年龄为 41.5 岁。 GTN 样本被发现为 PD-L1 阳性 (92.3%)、肿瘤突变负荷 (TMB) 低 (92.8%) 和微卫星稳定 (MSS) (100%)。 46% 的绒毛膜癌样本含有基因组改变，包括TP53 (33%) 和同源重组修复(HRR) (13%) 基因。 40% 的 ETT 病例中存在 RTK-RAS 通路信号传导的改变。

结论

该真实世界数据库中以及先前文献中报道的 PD-L1 阳性率很高，支持继续开展评估免疫疗法治疗 GTN 的临床试验。确定的其他潜在靶向治疗包括分别基于TP53、HRR 基因和 RTK-RAS 途径的分子改变的 Wee1、PARP 和 MEK 抑制剂。