PIK3CA Mutation is Associated With Increased Local Failure in Lung Stereotactic Body Radiation Therapy

Abstract

Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway has been associated with radioresistance. It is unclear whether such mutations also confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT). Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT. We retrospectively reviewed 168 patients who underwent SBRT to primary or metastatic lung lesions from 2007-2015 for whom molecular testing data was available for EGFR, AKT, and PIK3CA genes. For tumors of lung origin (n = 156), molecular testing data was included from the lung tumor. For metastatic tumors to the lung (n = 12), molecular testing data from either a primary or metastatic tumor site was used. Association between clinical factors, including molecular mutation status, and LF was evaluated with Cox regression analysis. The Kaplan-Meier method was used to assess differences in LF rates based on PIK3CA mutation status. The most common histology was adenocarcinoma (92%) among all tumors. Six patients (4%) had PIK3CA mutation, 36 patients (21%) had EGFR mutation, and one patient (0.6%) had AKT mutation. Median lesion size was 2.0 cm (range, 0.6–5.6 cm), median dose was 48 Gy (range 30–70 Gy), and median number of fractions was 4 (range, 3–10). Median follow-up was 21 months (range, 0.2–70 months). LF was observed for 16 patients (10%). On univariate analysis, PIK3CA mutation presence was associated with LF (HR 11.0 [95% CI 2.3-52.6], P = 0.003), while tumor histology (adenocarcinoma vs. other), tumor size (≤2 cm vs. >2 cm), primary tumor site (lung vs. other), BED (<100 Gy versus ≥100 Gy) and EGFR mutation presence were not. At one year, probability of LF in lesions with PIK3CA mutations was 25.0% vs. 3.1% in lesions without mutations (P < 0.001). Lesions with PIK3CA mutations were associated with a decreased time to LF (mean 17.4 months [95% CI 11.1-12.8 months]) compared to those without PIK3CA mutation (mean 61.3 months [95% CI 57.0-65.7 months]). Although the number of patients affected was small, PIK3CA mutation was significantly associated with a much higher risk of LF in patients undergoing lung SBRT. This association has not previously been reported for lung SBRT and indicates the need for further validation and study.