PO.CL12.02 · 临床研究

高LGR5表达的肺鳞状细胞癌的临床、基因组和治疗结局：一项来自LC-SCRUM-Asia数据库的研究

Clinical, genomic, and therapeutic outcomes of lung squamous cell carcinoma with high LGR5 expression : A study from the LC-SCRUM-Asia database

编号 7919 展板 24 时间 4/22 09:00–12:00 区域 Section 48 主讲 Yu Tanaka, MD;PhD

分会场 Translational Biomarkers and Emerging Molecular Approaches

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作者与单位 Authors & Affiliations

Yu Tanaka¹, Shuji Murakami², Kazumi Nishino³, Motoko Tachihara⁴, Ichiro Nakachi⁵, Mayu Kawakami⁶, Satoshi Hara⁷, hitomi Aono⁸, Shoichi Kuyama⁹, Gaku Yamamoto¹, Eri Sugiyama¹, Tetsuya Sakai¹, Hiroki Izumi¹, Shigeki Umemura¹, HIBIKI UDAGAWA¹, Yoshitaka Zenke¹, Shingo Matsumoto¹, Kiyotaka Yoh¹, Koichi Goto¹

¹National Cancer Center Hospital East, Chiba, Japan,²Kanagawa Cancer Center, Kanagawa, Japan,³Osaka International Cancer Institute, Osaka, Japan,⁴Kobe University Hospital, Hyogo, Japan,⁵Research Scholar, Dept. of Medicine, University of Colorado Denver, Aurora, CO,⁶Saiseikai Imabari Hospital, Ehime, Japan,⁷Itami City Hospital, Osaka, Japan,⁸Tokyo Metropolitan Police Hospital, Tokyo, Japan,⁹National Hospital Organization Iwakuni Clinical Center, Yamaguchi, Japan

摘要 Abstract

中文摘要

引言：Petosemtamab是一种靶向LGR5（富含亮氨酸重复的G蛋白偶联受体5）和EGFR的双特异性抗体，正在进行临床开发。Wnt驱动的LGR5是一种干细胞相关标志物，通过阻止溶酶体降解来稳定EGFR，从而促进癌细胞存活。然而，其在肺鳞状细胞癌（LUSC）中的作用仍不清楚。本研究评估了LGR5表达对LUSC临床特征、基因组改变和治疗结局的影响。方法：使用LC-SCRUM-Asia临床-基因组数据库，通过AMOY Master Panel评估LGR5、EGFR及其他基因的mRNA水平。高LGR5定义为高于中位数。在高LGR5组和低LGR5组之间比较临床、基因组特征和治疗结局。结果：在2021年6月至2022年2月期间，对233例LUSC患者评估了LGR5表达。LGR5表达中位数为0.02 FPKM（范围：0.00-5.44），EGFR表达中位数为12.09 FPKM（范围：0.07-572.49）。LGR5与EGFR表达之间未观察到相关性（Pearson r = -0.0387，P = 0.687）。临床特征，包括年龄、性别、吸烟史、ECOG-PS和临床分期，在高LGR5组和低LGR5组之间无显著差异。驱动基因改变的患病率（KRAS突变：6对3，EGFR突变：2对4，MET ex14跳跃：2对4，ALK融合：3对1）也未显示显著差异（P = 0.816）。在103例接受一线ICI（联合或不联合化疗）的患者中，高LGR5组的中位PFS为8.0个月，低LGR5组为5.6个月（HR = 0.91，95% CI：0.58-1.44，P = 0.570）。在90例接受一线铂类化疗的患者中，高LGR5组的中位PFS为5.5个月，低LGR5组为4.3个月（HR = 0.99，95% CI：0.52-1.91，P = 0.985）。作为干细胞功能关键调控因子的Wnt（P加权Log2FC = 0.753）、Hedgehog（P加权Log2FC = 0.877）和Notch（P加权Log2FC = 0.564）通路在高LGR5组中显著上调（所有P < 0.05）。结论：高LGR5表达并未界定LUSC在临床或基因组上截然不同的亚组；然而，它与一种以Wnt、Hedgehog和Notch通路上调为特征的转录干性激活表型相关。这些发现提示LGR5高表达的LUSC代表一种生物学上截然不同的亚型，可能为未来LGR5×EGFR靶向治疗的开发提供参考。

查看英文原文 English abstract

Introduction: Petosemtamab, a bispecific antibody targeting LGR5 (Leucine-rich repeat-containing G-protein coupled receptor 5) and EGFR, is under clinical development. Wnt-driven LGR5, a stem cell-associated marker, stabilizes EGFR by preventing lysosomal degradation, thereby promoting cancer cell survival. However, its role in lung squamous cell carcinoma (LUSC) remains unclear. This study evaluates the impact of LGR5 expression on clinical characteristics, genomic alterations, and therapeutic outcomes in LUSC. Methods: Using the LC-SCRUM-Asia clinico-genomic database, mRNA levels of LGR5 , EGFR , and other genes were assessed via the AMOY Master Panel. High LGR5 was defined as above the median. Clinical, genomic characteristics, and treatment outcomes were compared between high and low LGR5 groups. Results: LGR5 expression was evaluated in 233 LUSC patients between June 2021 and February 2022. The median LGR5 expression was 0.02 FPKM (range: 0.00-5.44), and the median EGFR expression was 12.09 FPKM (range: 0.07-572.49). No correlation was observed between LGR5 and EGFR expression (Pearson r = -0.0387, P = 0.687). Clinical characteristics, including age, sex, smoking history, ECOG-PS, and clinical stage, did not differ significantly between high and low LGR5 groups. The prevalence of driver gene alterations ( KRAS mutation: 6 vs. 3, EGFR mutation: 2 vs. 4, MET ex14 skipping: 2 vs. 4, ALK fusion: 3 vs. 1) also showed no significant differences ( P = 0.816). Among 103 patients receiving first-line ICI with or without chemotherapy, the median PFS was 8.0 months in the high LGR5 group and 5.6 months in the low LGR5 group (HR = 0.91, 95% CI: 0.58-1.44, P = 0.570). In 90 patients treated with first-line platinum-based chemotherapy, the median PFS was 5.5 months in the high LGR5 group and 4.3 months in the low LGR5 group (HR = 0.99, 95% CI: 0.52-1.91, P = 0.985). Wnt ( P -weighted Log2FC = 0.753), Hedgehog ( P -weighted Log2FC = 0.877), and Notch ( P -weighted Log2FC = 0.564) pathways, key regulators of stem cell function, were significantly upregulated in the high LGR5 group (all P < 0.05). Conclusion: High LGR5 expression does not define a clinically or genomically distinct subgroup of LUSC; however, it is associated with a transcriptionally stemness-activated phenotype characterized by upregulation of Wnt, Hedgehog, and Notch pathways. These findings suggest that LGR5-high LUSC represents a biologically distinct subtype that may inform future development of LGR5×EGFR-targeted therapies.

利益披露 Disclosure

Y. Tanaka, CHUGAI PHARMACEUTICAL CO., LTD. ). MSD ). Eli Lilly and Company ). AstraZeneca ). Taiho ). S. Murakami, None. K. Nishino, ONO ). TAIHO ). MSD ). AbbVie ). Daiichi-Sankyo ). Amgen ). Eisai ). Sanofir ). Janssen ). Novartis ). Pfizer ). Eli Lilly ). Merck Biopharma ). Takeda ). AstraZeneca ). Merus NV ). Gilead ). Chugai ). Bayer ). M. Tachihara, AstraZeneca ). Chugai Pharmaceutical ). Eli Lilly Japan Co Ltd ). Ono Pharmaceutical Co Ltd ). Bristol-Myers Squibb Co Ltd ). Chugai Pharmaceutical Co Ltd ). MSD KK ). Novartis pharmaceuticals K.K ). Takeda Pharmaceutical Co., Ltd. ). Taiho Pharmaceutical Co., Ltd. ). Nippon Boehringer Ingelheim Co.,Ltd. ). Daiichi Sankyo ). Pfizer Japan Inc. ). Janssen Pharmaceutical K.K. ). M. Kawakami, None.. S. Hara, None.. H. Aono, None.. S. Kuyama, None. G. Yamamoto, Astra Zeneca Independent Contractor. E. Sugiyama, None. T. Sakai, Amgen ). GSK ). Daiichi-Sankyo ). NEC ). H. Izumi, Amgen ). Eisai Co., Ltd. ). Takeda ). Bristol‑Myers Squibb Japan ). Chugai ). AstraZeneca K.K. ). Ono Pharmaceutical Co., Ltd. ). MSD ). Merck ). S. Umemura, Taiho Pharmaceutical ). Lilly ). MSD ). H. Udagawa, Takeda Pharmaceutical Co., Ltd ). Nippon Boehringer Ingelheim Co., Ltd ). Amgen K.K. ). Taiho Pharmaceutical Co., Ltd. ). MSD K.K ). DAIICHI SANKYO COMPANY, LIMITED ). CHUGAI PHARMACEUTICAL CO., LTD ). Y. Zenke, AstraZeneca ). Daiichi-Sankyo ). Amgen ). GSK, Roche ). MSD ). Merck ). S. Matsumoto, Merck KGaA Independent Contractor. Chugai Pharmaceutical Co., Ltd. Independent Contractor. MSD ). K. Yoh, AbbVie ). Amgen ). ArriVent Biopharma ). AstraZeneca ). Boehringer Ingelheim ). Chugai ). Daiichi-Sankyo ). Lilly ). MSD ). Taiho ). Takeda ). K. Goto, Merus NV ). Astellas Pharma ). AstraZeneca K.K. ). Nippon Boehringer Ingelheim ). Bristol-Myers Squibb K.K. ). Chugai ). Daiichi-Sankyo ). Eisai, Janssen. ). Kyowa Kirin ). Merck Biopharma ). MBL ). MSD K.K. ). Novartis ). ONO ). Pfizer R&D Japan ). Sumitomo Pharma ). Taiho ). Eli Lilly Japan ). Bayer Yakuhin ). Takeda. ).

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