PO.CL01.01 · 临床研究

线粒体自噬相关基因表达与CALGB（Alliance）/SWOG 80405入组的转移性结直肠癌患者临床结局的相关性

Correlation of mitophagy related genes expression and clinical outcome in metastatic colorectal cancer patients enrolled in CALGB (Alliance)/SWOG 80405

编号 1011 展板 5 时间 4/19 02:00–05:00 区域 Section 40 主讲 Shivani Soni, PhD

分会场 Biomarkers Predictive of Therapeutic Benefit 1

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作者与单位 Authors & Affiliations

Shivani Soni¹, Yan Yang², Michela Bartolini¹, Pooja Mittal³, Fang-Shu Ou⁴, Lesly Torres-Gonzalez⁵, Unnati Hemant Shah⁵, Jae Ho Lo¹, Steve Soto Trujillo¹, Yitzhar Goretsky⁵, Wu Zhang⁵, Alan P. Venook⁶, Sandra Algaze¹, Joshua Millstein⁷, Heinz-Josef Lenz⁵

¹Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, CA,²Population and Public Health, USC Norris Comprehensive Cancer Center, Los Angeles, CA,³Keck School of Medicine of USC, Los Angeles, CA,⁴Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN,⁵USC Norris Comprehensive Cancer Center, Los Angeles, CA,⁶University of California, San Francisco, CA,⁷Population and Public Health Sciences, USC Norris Comprehensive Cancer Center, Los Angeles, CA

摘要 Abstract

中文摘要

背景。线粒体自噬在清除功能失调的线粒体以维持细胞稳态方面发挥关键作用，但也被认为参与了癌症的肿瘤发生。此前，我们表明线粒体自噬通路基因的遗传变异对接受贝伐珠单抗（bevacizumab）为基础化疗的转移性CRC（mCRC）患者（pts）具有预测价值。在本研究中，我们分析了与PINK1/Parkin和BNIP3/NIX/FUNDC1线粒体自噬通路相关基因的肿瘤表达谱与大型III期随机临床试验CALGB SWOG 80405临床结局之间的相关性。方法。我们分析了433例接受一线化疗联合靶向药物贝伐珠单抗（Bev，n=226）或西妥昔单抗（Cet，n=207）的mCRC患者。从FFPE样本中分离的肿瘤RNA使用HiSeq 2500平台（Illumina）测序。根据线粒体自噬相关基因（BNIP3、BNIP3L、PINK1、PRKN）的表达水平，将患者分为高、中、低三分位组，比较各组的中位总生存期（mOS）和中位无进展生存期（mPFS）。使用多变量Cox比例风险模型计算似然比检验、风险比（HRs）和95%置信区间（CIs），并校正年龄、性别、ECOG体能状态、肿瘤位置、转移部位数量、KRAS状态、共识分子亚型和治疗组。结果：总体而言，经多重检验校正后，BNIP3L对PFS和OS均显示出显著的预后价值（错误发现率[FDR]<0.05）。与中或高表达水平相比，BNIP3L低表达的肿瘤显示出更长的PFS和OS（mPFS 14.8 vs. 10.0 vs. 9.2个月，HR 1.16，95% CI 1.04-1.29，p=0.0182；mOS：37.4 vs. 30.2 vs. 24.4个月，HR 1.22，95% CI 1.09-1.38，p=0.0036），且独立于治疗。在接受Cet治疗的患者中，高PRKN表达与改善的PFS和OS相关（mPFS：8.9 vs. 10.3 vs. 14.6个月，HR 0.79；95% CI 0.69-0.91，p=7.3e-05；mOS：21.2 vs. 27.7 vs. 41.1个月，HR 0.87；95% CI 0.75-1.01，p=0.00084），而低PINK1表达与更长的OS显著相关（mOS：24.9 vs. 30.9 vs. 39.2个月，HR 1.23；95% CI 1.04-1.46，p=0.013）。在接受Bev治疗的患者中，未观察到PRKN或PINK1的显著关联。BNIP3表达分析未发现显著结果。结论。由于线粒体自噬具有肿瘤内在（线粒体生物能量学）和微环境（与免疫成分相互作用）效应，它是CRC生物学中的关键参与者。我们的研究强调了BNIP3L的预后价值以及PINK1和PRKN的预测潜力，提示一种使用线粒体靶向药物和靶向药物（如Cet）的潜在联合治疗方法，这值得进一步研究。资助：Genentech；Clinicaltrials.gov标识符：NCT00265850

查看英文原文 English abstract

Background. Mitophagy plays a crucial role in removing dysfunctional mitochondria to maintain cellular homeostasis but also has been implicated in cancer tumorigenesis. Previously, we showed that genetic variation in mitophagy pathway genes holds a predictive value in metastatic CRC (mCRC) patients (pts) treated with bevacizumab-based chemotherapy. In this study, we analyzed the correlation between tumor expression profiles of genes associated with PINK1/Parkin and BNIP3/NIX/FUNDC1 mitophagy pathways with clinical outcome in a large phase III randomized clinical trial CALGB SWOG 80405. Method. We analyzed 433 pts with mCRC treated with first-line chemotherapy in combination with the targeted agents bevacizumab (Bev, n = 226) or cetuximab (Cet, n = 207). Tumor RNA isolated from FFPE samples was sequenced using the HiSeq 2500 platform (Illumina). Median Overall survival (mOS) and median progression-free survival (mPFS) were compared across pts groups divided into high, medium, and low tertiles based on mitophagy-related gene ( BNIP3 , BNIP3L , PINK1 , PRKN ) expression levels. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using multivariable Cox proportional hazards models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, Consensus Molecular Subtypes, and treatment arm. Results: Overall, BNIP3L demonstrated significant prognostic value for both PFS and OS after adjustment for multiple testing (false discovery rate [FDR] < 0.05). Tumors with low BNIP3L expression showed longer PFS and OS compared to those with medium or high expression levels (mPFS 14.8 vs. 10.0 vs. 9.2 months, HR 1.16, 95% CI 1.04 - 1.29 p = 0.0182; mOS: 37.4 vs. 30.2 vs. 24.4 months, HR 1.22, 95% CI 1.09 - 1.38, p = 0.0036), independent of treatment. In pts treated with Cet, high PRKN expression was associated with improved PFS and OS (mPFS: 8.9 vs. 10.3 vs. 14.6 months, HR 0.79; 95% CI 0.69 - 0.91, p = 7.3e-05; mOS: 21.2 vs. 27.7 vs. 41.1 months, HR 0.87; 95% CI 0.75 - 1.01, p = 0.00084), whereas low PINK1 expression was significantly associated with longer OS (mOS: 24.9 vs. 30.9 vs. 39.2 months, HR 1.23; 95% CI 1.04 -1.46, p = 0.013). No significant associations were observed in Bev-treated patients for PRKN or PINK1 . No significant results were found for BNIP3 expression analysis. Conclusion. Mitophagy is a crucial player in CRC biology due to its tumor-intrinsic (mitochondrial bioenergetics) and microenvironment (interacts with immune components) effects. Our study highlights the prognostic value of BNIP3L and predictive potential of PINK1 and PRKN , suggesting a potential combinatorial therapeutic approach using mitochondrial targeting drugs and targeted agents e.g Cet, which warrants further investigation. Support: Genentech; Clinicaltrials.gov Identifier: NCT00265850

利益披露 Disclosure

S. Soni, None.. Y. Yang, None.. M. Bartolini, None.. F. Ou, None.. J. H. Lo, None.. S. S. Trujillo, None.. Y. Goretsky, None.. A. P. Venook, None.. S. Algaze, None.. J. Millstein, None.

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