PI3K Pathway Aberrations May Reveal Targeted Therapy Opportunities
Combination therapies targeting both mutations in the PI3K pathway and HER2 or hormone receptor overexpression should be evaluated.
Alterations in the phosphatidylinositol-3-kinase (PI3K) signaling pathway occurred more frequently in the presence of hormone receptor overexpression and in HER2-positive malignancies in a variety of cancer types, a study published in JAMA Oncology has shown.1
Mutations in the PI3K pathway drive carcinogenesis. Because simultaneously occurring mutations in hormone receptors and/or HER2 may play a role in the mechanism of response and resistance to treatment, researchers analyzed 19,784 tumors samples from more than 40 cancer types sent from clinicians in 60 countries. Tumor samples were molecularly profiled using next generation sequencing, immunohistochemical analysis, and fluorescent or chromogenic in situ hybridization.
Results showed that 38% of patients overall had a mutation in 1 or more PI3K pathway components, most commonly PTEN loss in 30%, followed by mutations in PIK3CA in 13%, PTEN in 6%, or AKT1 in 1%.
Researchers found that 70% of patients with endometrial cancer and greater than 50% of patients with anal, breast, cervical, colorectal, hepatocellular, and prostate cancer had aberrations in at least 1 PI3K pathway gene and/or gene product.
Frequently observed aberrations included PTEN loss in: 57% of patients with hepatocellular carcinoma, 48% of patients with colorectal cancer, 36% of those with gastric cancer, 52% of those with prostate cancer, and 49% of patients with endometrial cancer. PIK3CA mutations were present in 37%, 31%, 29%, and 27% of endometrial, breast, cervical, and anal tumor samples, respectively.
Mutations in PIK3CA, PTEN, and AKT1 occurred more often in the present of hormone receptor overexpression, as well as in HER2-positive tumors versus HER2-negative tumors, though researchers observed the opposite pattern for PTEN mutation or PTEN loss.
The findings suggest that combination therapies targeting both mutations in the PI3K pathway and HER2 or hormone receptor overexpression should be evaluated across cancer types.
1. Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid tumors. JAMA Oncol. 2016 Jul 7. doi: 10.1001/jamaoncol.2016.0891 [Epub ahead of print]