Department of Urology, Upstate Medical University, 750 East Adams St., Syracuse, NY, 13210, USA.
University of Washington and Fred Hutchinson Cancer Center, Seattle, WA, USA.
Target Oncol. 2024 Nov;19(6):981-990. doi: 10.1007/s11523-024-01100-w. Epub 2024 Oct 5.
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.
To evaluate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in CAPC.
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).
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.
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.
在乳腺癌中，携带两个或更多 PIK3CA 短变异（SV）（“多命中”）突变的肿瘤与抗 PIK3CA 靶向治疗的改善结果相关。在临床上晚期前列腺癌（CAPC）中，多命中 PIK3CA 改变的情况和临床意义仍不清楚。
评估 CAPC 中单命中和多命中 PIK3CA 基因组改变的基因组图谱。
使用 Foundation Medicine FoundationCore 数据库鉴定了 19978 例接受杂交捕获全基因组分析的 CAPC 肿瘤，以评估所有类别的基因组改变（GA）并确定肿瘤突变负担（TMB）、微卫星不稳定性（MSI）、基因组起源、单碱基替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）确定。
18741 例（93.8%）肿瘤为 PIK3CA 野生型（WT），1155 例（5.8%）为单 PIK3CA SV，82 例（0.4%）为多命中 PIK3CA SV。与 PIK3CA WT CAPC 相比，单命中（6.6 比 3.8；p < 0.0001）和多命中（12.8 比 3.8；p < 0.0001）肿瘤的每个肿瘤更具驱动 GA，并且更高的 MMR 突变特征、MSI 高状态和 TMB 水平的发生率与 PIK3CA WT 相比（p < 0.0001）。GA 中的其他差异包括多命中时 BRCA2 中的 GA 频率高于 WT（18.3%比 8.5%；p = 0.0191），多命中时 ATM 中的 GA 频率高于 WT（13.4%比 5.6%；p = 0.02）和单命中时 PTEN 中的 GA 频率高于 WT（40.2%比 30.1%；p < 0.0001）。同源重组缺陷特征在 PIK3CA WT 中比单命中（11.2%比 7.6%；p = 0.0002）更高。三组之间的 PD-L1 表达无显著差异。
在 CAPC 中鉴定出多命中 PIK3CA GA 突出了一种潜在的独特表型，这可能与抗 PIK3CA 靶向治疗和检查点抑制的反应相关，支持相关临床试验设计。
