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Phosphatidylinositol 3-kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy
Sherri Z Millis1, Denis L Jardim2, Lee Albacker1
1Foundation Medicine, Cambridge, Massachusetts.
Background:
The phosphatidylinositol 3-kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co-alterations serving as potential resistance/attenuation mechanisms.
Methods:
Consecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment-certified laboratory using comprehensive genomic profiling performed by next-generation sequencing (315 genes). The co-alterations evaluated included the Erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto-oncogene tyrosine kinase (MET), and mitogen-activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR).
Results:
Alterations in any of 18 PI3K-pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co-occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019). The co-occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers.
Conclusions:
Comprehensive genomic profiling reveals altered PI3K-related genes in 44% of solid malignancies, including rare disease and histology types. The frequency of alterations and the co-occurrence of resistance pathways vary by tumor type, directly affecting opportunities for targeted therapy.
Insights
The phosphatidylinositol 3-kinase (PI3K) pathway is altered in 44% of solid tumors, with common alterations in PIK3CA, PTEN, and STK11. Co-occurring alterations in resistance pathways vary by tumor type, impacting targeted therapy options.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- The phosphatidylinositol 3-kinase (PI3K) pathway is frequently dysregulated in various cancers.
- Understanding PI3K pathway alterations and co-alterations is crucial for identifying therapeutic strategies.
Purpose of the Study:
- To describe the landscape of PI3K pathway alterations in a large cohort of solid tumors.
- To identify co-alterations that may confer resistance or attenuate PI3K pathway signaling.
Main Methods:
- Comprehensive genomic profiling using next-generation sequencing on 60,991 solid tumor samples.
- Analysis of alterations in 18 PI3K-pathway associated genes and co-alterations in ERBB2, ERBB3, ERBB4, RAS, MET, MAP2K, TP53, ESR1, and AR genes.
Main Results:
- PI3K pathway alterations were found in 44% of tumors, with PIK3CA, PTEN, and STK11 being the most frequently altered genes.
- Uterine, cervical, anal, and breast cancers showed high frequencies of PI3K alterations.
- Specific tumor types exhibited significant co-occurrence of PI3K pathway alterations with MAPK pathway genes (e.g., colorectal, mesothelioma, anal, head and neck cancers) and with ESR1/AR alterations (e.g., bladder, colorectal, uterine, prostate cancers).
Conclusions:
- Comprehensive genomic profiling reveals frequent PI3K-related gene alterations across diverse solid malignancies.
- The frequency and co-occurrence patterns of these alterations vary significantly by tumor type and histology, influencing targeted therapy selection.
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