Abstract
In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer. Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor >1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer-specific survival were examined using Kaplan-Meier or competing risk methodology. PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer-specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004). This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase-targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized.
Highlights
IntroductionSomatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes
In breast cancer, somatic mutations in the PIK3CA gene are common
A smaller subset of 192 cases underwent Sanger resequencing for all PIK3CA exons, but this method was inferior for mutation detection on the FFPEderived DNA
Summary
Somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. In this analysis of 590 patients with primary invasive breast cancers with a median follow-up of 12.8 years, we define the positive prognostic significance for PIK3CA mutations. PIK3CA mutations are associated with favorable clinicopathologic features: lower tumor grade, hormone receptor–positive status, HER2 negativity, older age at diagnosis, lower tumor stage, and lymph node negativity. When the entire coding region is analyzed, additional missense mutations occur in up to 18% of breast cancers [19, 20] In cellbased assays, these rare mutations confer a gain of function as measured by lipid kinase activity, constitutive activation of Akt, and cellular transformation, with a range of oncogenic potency [4]. The frequency of PIK3CA mutation supports the significance of PI3Ks in breast cancer biology
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