Single-Hit and Multi-hit PIK3CA Short Variant Genomic Alterations in Clinically Advanced Prostate Cancer: A Genomic Landscape Study.

IF 4.4 3区医学 Q2 ONCOLOGY

Targeted Oncology Pub Date : 2024-10-05 DOI:10.1007/s11523-024-01100-w

Michael F Basin, Carla M Miguel, Joseph M Jacob, Hanan Goldberg, Petros Grivas, Philippe E Spiess, Andrea Necchi, Ashish M Kamat, Dean C Pavlick, Richard S P Huang, Douglas I Lin, Natalie Danziger, Ethan S Sokol, Smruthy Sivakumar, Ryon Graf, Liang Cheng, Neil Vasan, Jeffrey Ross, Alina Basnet, Gennady Bratslavsky

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引用次数: 0

Abstract

Background: Tumors harboring two or more PIK3CA short variant (SV) ("multi-hit") mutations have been linked to improved outcomes with anti-PIK3CA-targeted therapies in breast cancer. The landscape and clinical implications of multi-hit PIK3CA alterations in clinically advanced prostate cancer (CAPC) remains elusive.

Objective: To evaluate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in CAPC.

Patients and methods: The Foundation Medicine FoundationCore database was used to identify 19,978 CAPC tumors that underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA) and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, single-base substitution mutational signatures, and homologous recombination deficiency signature (HRDsig). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3).

Results: 18,741 (93.8%) tumors were PIK3CA wild type (WT), 1155 (5.8%) featured single PIK3CA SV, and 82 (0.4%) featured multi-hit PIK3CA SVs. Single-hit (6.6 versus 3.8; p < 0.0001) and multi-hit (12.8 versus 3.8; p < 0.0001) featured more driver GA per tumor than PIK3CA WT CAPC, as well as higher prevalence of MMR mutational signature, MSI high status, and TMB levels versus PIK3CA WT (p < 0.0001). Other differences in GA included higher frequencies of GA in BRCA2 in multi-hit versus WT (18.3% versus 8.5%; p = 0.0191), ATM in multi-hit versus WT (13.4% versus 5.6%; p = 0.02) and PTEN in single-hit versus WT (40.2% versus 30.1%; p < 0.0001). Homologous recombination deficiency signatures were higher in PIK3CA WT versus single-hit (11.2% versus 7.6%; p = 0.0002). There were no significant differences in PD-L1 expression among the three groups.

Conclusions: Identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique phenotype that may be associated with response to anti-PIK3CA targeted therapy and checkpoint inhibition, supporting relevant clinical trial designs.

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临床晚期前列腺癌中单个和多个 PIK3CA 短变异基因组畸变：基因组图谱研究

背景：携带两个或两个以上PIK3CA短变体（SV）（"多命中"）突变的肿瘤与乳腺癌抗PIK3CA靶向疗法的疗效改善有关。临床晚期前列腺癌（CAPC）中多位PIK3CA变异的情况和临床意义仍不清楚：目的：评估CAPC中单个和多个PIK3CA基因组改变的情况：使用Foundation Medicine FoundationCore数据库鉴定了19,978例CAPC肿瘤，对这些肿瘤进行了基于混合捕获的全面基因组图谱分析，以评估所有类别的基因组改变（GA），并确定肿瘤突变负荷（TMB）、微卫星不稳定性（MSI）、基因组祖先、单碱基置换突变特征和同源重组缺陷特征（HRDsig）。肿瘤细胞 PD-L1 表达通过 IHC（Dako 22C3）检测：18741例（93.8%）肿瘤为PIK3CA野生型（WT），1155例（5.8%）为单PIK3CA SV，82例（0.4%）为多PIK3CA SV。与 PIK3CA WT CAPC 相比，单发（6.6 对 3.8；P＜0.0001）和多发（12.8 对 3.8；P＜0.0001）的每个肿瘤具有更多的驱动基因 GA，以及更高的 MMR 突变特征、MSI 高状态和 TMB 水平（P＜0.0001）。GA方面的其他差异包括：BRCA2多重突变与WT相比（18.3%对8.5%；p = 0.0191）、ATM多重突变与WT相比（13.4%对5.6%；p = 0.02）以及PTEN单次突变与WT相比（40.2%对30.1%；p < 0.0001），GA频率更高。PIK3CA WT 与单一基因突变相比，同源重组缺陷特征更高（11.2% 对 7.6%；p = 0.0002）。三组患者的PD-L1表达无明显差异：结论：CAPC中PIK3CA多靶点GA的鉴定突显了一种潜在的独特表型，这种表型可能与抗PIK3CA靶向治疗和检查点抑制的反应相关，支持相关的临床试验设计。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Targeted Oncology 医学-肿瘤学

CiteScore

8.40

自引率

3.70%

发文量

审稿时长

>12 weeks

期刊介绍： Targeted Oncology addresses physicians and scientists committed to oncology and cancer research by providing a programme of articles on molecularly targeted pharmacotherapy in oncology. The journal includes: Original Research Articles on all aspects of molecularly targeted agents for the treatment of cancer, including immune checkpoint inhibitors and related approaches. Comprehensive narrative Review Articles and shorter Leading Articles discussing relevant clinically established as well as emerging agents and pathways. Current Opinion articles that place interesting areas in perspective. Therapy in Practice articles that provide a guide to the optimum management of a condition and highlight practical, clinically relevant considerations and recommendations. Systematic Reviews that use explicit, systematic methods as outlined by the PRISMA statement. Adis Drug Reviews of the properties and place in therapy of both newer and established targeted drugs in oncology.