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

期刊论文
出版模式：

开放获取
发表日期：

2024年10月5日

查看全文

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

摘要

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.