PO.CL12.01 · 临床研究

子宫内膜癌MMR亚型间肿瘤微环境的异质性：来自ENGOT-EN6-NSGO/GOG-3031/RUBY试验的分析

Heterogeneity in tumor microenvironment across MMR subtypes of endometrial cancer: Analysis from the ENGOT-EN6-NSGO/GOG-3031/RUBY trial

编号 3881 展板 14 时间 4/20 02:00–05:00 区域 Section 46 主讲 Lucy Gilbert

分会场 Molecular Classification and Tumor Biology in Cancer

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作者与单位 Authors & Affiliations

Lucy Gilbert¹, Annika Auranen², Mitchell I. Edelson³, Mikalai Pishchyk⁴, Joseph Buscema⁵, Tamar Safra⁶, Nicole S. Nevadunsky⁷, Christine Gennigens⁸, Kari Ring⁹, Line Bjørge¹⁰, Bhavana Pothuri¹¹, Helen D. Eshed¹², Iwona Podzielinski¹³, Noelle G. Cloven¹⁴, Tashanna K. Myers¹⁵, Kathryn P. Pennington¹⁶, Claire Rooney¹⁷, Rumen Kostadinov¹⁸, Robert W. Holloway¹⁹, Trine Nøttrup²⁰

¹Division of Gynecologic Oncology, Research Institute, McGill University Health Centre, Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada,²Tays Cancer Centre and FICAN Mid, Tampere University and Tampere University Hospital, Tampere, Finland,³Hanjani Institute for Gynecologic Oncology, Jefferson Abington Hospital, Willow Grove, PA,⁴Grodno Regional Clinical Hospital, Grodno, Belarus,⁵Gynecologic Oncology, Tucson Medical Center Health Cancer Center – Wilmot, Tucson, AZ,⁶Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel,⁷Department of Obstetrics, Gynecology, and Women’s Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY,⁸Department of Medical Oncology, CHU of Liège; and Belgium and Luxembourg Gynaecological Oncology Group (BGOG), Leuven, Belgium,⁹University of Virginia Health System, Charlottesville, VA,¹⁰Haukeland University Hospital and University of Bergen, Bergen, Norway,¹¹Departments of Obstetrics/Gynecology and Medicine, Division of Gynecologic Oncology, Laura & Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA and GOG Foundation, Philadelphia, PA,¹²Texas Oncology, Austin, TX,¹³Department of Gynecologic Oncology, Parkview Health, Fort Wayne, IN,¹⁴Texas Oncology, Fort Worth, TX,¹⁵Baystate Medical Center, Springfield, MA,¹⁶Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Fred Hutchinson Cancer Center, University of Washington School of Medicine, Seattle, WA,¹⁷GSK, Cambridge, United Kingdom,¹⁸GSK, Upper Providence, PA,¹⁹AdventHealth Cancer Institute, Orlando, FL,²⁰Department of Oncology, Copenhagen University Hospital - Rigshospitalet; and Nordic Society of Gynecologic Oncology (NSGO), Copenhagen, Denmark

摘要 Abstract

中文摘要

背景：在RUBY第1部分（NCT03981796）中，dostarlimab + 卡铂-紫杉醇（D+CP）较单用CP显著改善了原发晚期或复发性子宫内膜癌（EC）患者的PFS和OS。虽然MMR缺陷（dMMR）是临床应答的预测生物标志物，但在MMR完整（MMRp）亚组中也观察到获益。需要对这些肿瘤的潜在生物学和异质性有更多认识，以阐明对D+CP应答的潜在驱动因素。方法：对RUBY第1部分的400份肿瘤样本进行RNA测序（RNASeq）和全外显子组测序。根据研究入组所用的检测方法将肿瘤分类为dMMR或MMRp。分析了与浸润细胞类型或致癌过程相关的基因组改变和RNAseq特征。结果：肿瘤转录谱的无监督聚类揭示了两个不同的组织学亚型相关聚类。dMMR肿瘤主要位于子宫内膜样聚类中；MMRp肿瘤分布于两个聚类。基因特征分析显示，dMMR亚组中高免疫细胞特征评分的肿瘤显著富集（见表）；然而，也观察到与部分MMRp肿瘤存在相当程度的重叠，后者表现出相似的高特征评分。相反，与肿瘤衰老和干扰素刺激基因相关的特征在MMRp亚组中富集。基因组分析揭示了TP53、PTEN、PIK3CA和ARID1A的频繁改变，dMMR肿瘤中若干基因（如JAK1和RNF43）的突变率更高，并伴有更高的肿瘤突变负荷。结论：这些结果凸显了EC的分子和转录组异质性，为探索MMR状态之外的肿瘤特征对EC中dostarlimab+CP应答的影响提供了假设。这些生物标志物与结局之间关联的探索正在进行中。表：MMR亚组间的基因特征特征 P值（Wilcoxon）特征评分较高者 dMMR/MSI-H中位数 MMRp/MSS中位数肿瘤衰老_Combes <0.001 MMRp/MSS −0.66 0.27 Th1细胞_Danaher <0.001 dMMR/MSI-H 0.26 −0.28 NK细胞_Bagaev <0.001 dMMR/MSI-H 0.38 −0.22 细胞毒性细胞_Danaher <0.001 dMMR/MSI-H 0.30 −0.31 T细胞_Bagaev <0.001 dMMR/MSI-H 0.20 −0.22 髓系干扰素刺激基因_Combes <0.001 MMRp/MSS −0.61 0.17 缩写：dMMR，错配修复缺陷；MSI-H，微卫星高度不稳定；MSS，微卫星稳定；NK，自然杀伤；MMRp，错配修复完整；Th1，1型辅助性T细胞

查看英文原文 English abstract

Background: In RUBY Part 1 (NCT03981796), dostarlimab + carboplatin-paclitaxel (D+CP) significantly improved PFS and OS vs CP alone in pts with primary advanced or recurrent endometrial cancer (EC). Although MMR deficiency (dMMR) is a predictive biomarker for clinical response, benefit is also observed in the MMR proficient (MMRp) subgroup. Additional insights into the underlying biology and heterogeneity of these tumors are needed to inform potential drivers of response to D+CP. Methods: RNA sequencing (RNASeq) and whole exome sequencing were performed on 400 tumor samples from RUBY Part 1. Tumors were categorized as dMMR or MMRp per the testing method used for study enrollment. Genomic alterations and RNAseq signatures associated with infiltrating cell types or oncogenic processes were analyzed. Results: Unsupervised clustering of tumor transcriptional profiles revealed two distinct histological subtype-associated clusters. dMMR tumors were predominantly in the endometrioid cluster; MMRp tumors were distributed across both clusters. Gene signature analysis revealed significant enrichment for tumors with high immune cell signature scores in the dMMR subgroup (Table); however, considerable overlap was observed with a subset of MMRp tumors demonstrating similarly high signature scores. Conversely, signatures associated with tumor senescence and interferon-stimulated genes were enriched in the MMRp subgroup. Genomic analysis revealed frequent alterations in TP53 , PTEN , PIK3CA, and ARID1A , with higher mutation rates of several genes (eg, JAK1 and RNF43 ) observed in dMMR tumors, concomitant with higher tumor mutational burden. Conclusions: These results highlight the molecular and transcriptomic heterogeneity of EC, providing hypotheses to explore the impact of tumor characteristics beyond MMR status on response to dostarlimab+CP in EC. Exploration of the association between these biomarkers and outcomes is ongoing. Table: Gene signatures across MMR subgroups Signature P value (Wilcoxon) Signature score higher in Median dMMR/MSI-H Median MMRp/MSS Tumor senescence_Combes <0.001 MMRp/MSS −0.66 0.27 Th1 cells_Danaher <0.001 dMMR/MSI-H 0.26 −0.28 NK cells_Bagaev <0.001 dMMR/MSI-H 0.38 −0.22 Cytotoxic cells_Danaher <0.001 dMMR/MSI-H 0.30 −0.31 T cells_Bagaev <0.001 dMMR/MSI-H 0.20 −0.22 Myeloid interferon-stimulated genes_Combes <0.001 MMRp/MSS −0.61 0.17 Abbreviations: dMMR, mismatch repair deficient; MSI-H, microsatellite instability-high; MSS, microsatellite-stable; NK, natural killer; MMRp, mismatch repair proficient; Th1, T helper type 1

利益披露 Disclosure

L. Gilbert, Alkermes, Ascendis Pharma, AstraZeneca, Daiichi Sankyo, Espersas, ImmunoGen, IMV Technologies, K-Group Beta/Zentalis Pharmaceuticals, Mersana Therapeutics, ). MSK Pharmalogistic, Novocure, OncoQuest Pharmaceuticals, Pfizer, Roche, Shattuck Labs, Sutro Biopharma, Tesaro/GSK, and Seagen/Pfizer ). Repare Therapeutics Other, consulting fees. GSK ), Travel, Other, consulting fees, honoraria, and participation in advisory board meetings. MSD ), Travel, Other, consulting fees and and participation in advisory board meetings. GOG Foundation ), Travel. Zentalis Pharmaceuticals Travel. CanariaBio Other, participation in advisory board meetings. Corcept Therapeutics ), Other, participation in advisory board meetings. Eisai Other, participation in advisory board meetings. ImmunoGen/AbbVie Other, participation in advisory board meetings. Kora Healthcare Other, participation in advisory board meetings. A. Auranen, GSK Travel. NSGO-CTU g., Board of Directors, non-salaried role). M. I. Edelson, GSK and AbbVie Travel. Intuitive Surgical ). MSD Other, spouse was a salaried employee with stock options at MSD (through August 2022). Pfizer Other, spouse is a current employee at Pfizer. M. Pishchyk, None. J. Buscema, GSK Other, payment for participation on an advisory board. T. Safra, None.. N. S. Nevadunsky, None. C. Gennigens, AstraZeneca ), Travel, Other, honoraria and participation on a data safety monitoring or advisory board. Deciphera ). GSK ), Travel, Other, consulting fees and participation on a data safety monitoring or advisory board. Bristol Myers Squibb Other, honoraria and participation on a data safety monitoring or advisory board. Ipsen Travel, Other, honoraria, consulting fees, and participation on a data safety monitoring or advisory board. MSD Travel, Other, honoraria, consulting fees, and participation on a data safety monitoring or advisory board. Pfizer Travel, Other, honoraria. PharmaMar Travel, Other, honoraria. Eisai Other, participation on a data safety monitoring or advisory board. Genmab Other, participation on a data safety monitoring or advisory board. pharma& Other, participation on a data safety monitoring or advisory board. K. Ring, None. L. Bjørge, GSK Other, consulting fees for a European advisory board and honoraria. MSD Other, honoraria. Onkologisk Forum Other, leader (2018-2022). NSGO Other, president (2021-2024). NSGO-CTU foundation Other, leader (2021-2024). ESMO Other, faculty member for the Gynaecological Cancers group. B. Pothuri, Acrivon Therapeutics, Agenus, Alkermes, AstraZeneca, Celgene/Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo, DualityBio, Eisai, I-Mab Biopharma, ImmunoGen/AbbVie, Imunon, Incyte ). Karyopharm Therapeutics, LOXO Oncology/Lilly, Mersana Therapeutics, MSD, NRG Oncology, Onconova, Therapeutics/Traws Pharma, Pfizer, Roche/Genentech, Seagen/Pfizer, Sutro Biopharma, Takeda, Tesaro/GSK ). Toray Industries, VBL Therapeutics, and Xencor ). AstraZeneca, BeiGene, BioNTech, DualityBio, Eisai, GOG Foundation, I-Mab Biopharma, ImmunoGen/AbbVie, Imunon, Imvax, Incyte, InxMed, Karyopharm Therapeutics, LOXO Oncology/Lilly, Mersana Therapeutics Other, consulting/advisory board fees. Natera, Nuvation Bio, Onconova Therapeutics/Traws Pharma, OnCusp Therapeutics, R Pharm, Regeneron, Seagen/Pfizer, Sutro Biopharma, and Tesaro/GSK Other, consulting/advisory board fees. H. D. Eshed, ImmunoGen Other, honorarium for participation in a speakers’ bureau. I. Podzielinski, None. N. G. Cloven, AbbVie, Genmab, GSK, ImmunoGen/AbbVie, Kartos Therapeutics, Novita Pharmaceuticals, and Zentalis Pharmaceuticals Other, advisory board fees. T. K. Myers, ImmunoGen/AbbVie Other, honoraria for lectures. K. P. Pennington, None. C. Rooney, GSK Employment, Other, Holds financial equities. AstraZeneca Employment, Other, former employee and holds financial equities. R. Kostadinov, GSK Employment, Other, holds financial equities. R. W. Holloway, AstraZeneca, Clovis Oncology, Eisai, and Merck Other, honoraria. Genelux Other, consulting fees. GSK Other, consulting fees and honoraria. T. Nøttrup, AstraZeneca Other, honoraria and data safety monitoring board or advisory board. MSD Other, honoraria and data safety monitoring board or advisory board. GSK Travel, honoraria. NSGO g., Board of Directors, non-salaried role), unpaid leadership role (president).

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