Phosphatidylinositol 3‐kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy opportunities

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.

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