Analytical and clinical validation of Ion Torrent™ Oncomine™ Dx Express Test for identifying PIK3CA/AKT1/PTEN-altered tumors in patients with hormone receptor-positive advanced breast cancer for treatment with capivasertib

This study reports on analytical and clinical validation of the highly automated Ion Torrent™ Oncomine™ Dx Express Test (ODxET) for detecting PIK3CA / AKT1 / PTEN -altered tumors in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer that may benefit from treatment with capivasertib plus fulvestrant. Analytical validation studies were completed using commercially sourced breast cancer tissue specimens to establish the ODxET assay detection capability (limit of detection, limit of blank), precision (repeatability, reproducibility), and effect of endogenous interfering substances for detecting PIK3CA / AKT1 / PTEN alterations. Clinical validation was performed using 429 residual breast cancer tissue samples from the Phase 3 CAPItello-291 trial and progression-free survival (PFS) was analyzed for patients with PIK3CA / AKT1 / PTEN -altered tumors, as detected by ODxET, and compared to efficacy outcomes from the CAPItello-291 study. Comparison of assay agreement between ODxET and FoundationOne®CDx (F1CDx) gave an overall, positive and negative percent agreement of 89.2%, 82.0%, and 96.6%, respectively. The 18% false negative rate observed with ODxET was largely attributable to limited detection of complex PTEN variants. PFS benefit was observed with capivasertib plus fulvestrant versus placebo plus fulvestrant in patients with PIK3CA / AKT1 / PTEN -altered tumors detected by ODxET ( n =162; hazard ratio 0.55, 95% confidence interval [CI]: 0.38–0.78). This is similar to the observed PFS benefit in the population with PIK3CA / AKT1 / PTEN -altered tumors identified by F1CDx in the CAPItello-291 trial (hazard ratio 0.49, 95% CI: 0.38–0.64). This study demonstrates the clinical utility of ODxET to identify patients with PIK3CA / AKT1 / PTEN -altered tumors that may benefit from treatment with capivasertib plus fulvestrant.