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Single-Hit and Multi-hit PIK3CA Short Variant Genomic Alterations in Clinically Advanced Prostate Cancer: A Genomic
Michael F Basin1, Carla M Miguel1, Joseph M Jacob1
1Department of Urology, Upstate Medical University, 750 East Adams St., Syracuse, NY, 13210, USA.
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.
Insights
Multi-hit PIK3CA alterations in advanced prostate cancer are linked to more driver genomic alterations and may predict response to targeted therapies. This finding supports new clinical trial designs for PIK3CA-targeted treatments.
Area of Science:
- Oncology
- Genomics
- Cancer Therapeutics
Background:
- Multi-hit PIK3CA mutations correlate with better outcomes in breast cancer patients treated with anti-PIK3CA therapies.
- The genomic profile and clinical relevance of multi-hit PIK3CA alterations in advanced prostate cancer are not well understood.
Purpose of the Study:
- To investigate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in clinically advanced prostate cancer (CAPC).
Main Methods:
- Utilized the FoundationCore database to analyze comprehensive genomic profiling data from 19,978 CAPC tumors.
- Assessed all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), and homologous recombination deficiency (HRD) signatures.
- Determined PD-L1 expression via immunohistochemistry (IHC).
Main Results:
- Multi-hit PIK3CA alterations were found in 0.4% of CAPC tumors, while single-hit alterations were present in 5.8%.
- Both single-hit and multi-hit PIK3CA alterations were associated with more driver GAs, higher TMB, and increased prevalence of MMR mutational signatures and MSI-high status compared to PIK3CA wild-type tumors.
- Specific co-occurring GAs included BRCA2 and ATM in multi-hit PIK3CA cases, and PTEN in single-hit cases. HRD signatures were higher in PIK3CA wild-type tumors.
Conclusions:
- The presence of multi-hit PIK3CA genomic alterations in CAPC suggests a distinct tumor phenotype.
- This phenotype may indicate sensitivity to anti-PIK3CA targeted therapies and checkpoint inhibitors.
- Findings support the design of clinical trials investigating these targeted therapies in CAPC.
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