Cell-free (cf)DNA analysis identifies PIK3CA/AKT1 mutations associated with greater PFS improvement from the addition of ipatasertib (IPAT) to paclitaxel (P) in triple-negative breast cancer (TNBC)

Abstract

Background: The oral Akt inhibitor IPAT is being evaluated in cancers with a high prevalence of PI3K/Akt pathway activation. In the placebo‐controlled randomised phase II LOTUS trial (NCT02162719), adding IPAT to P as first‐line therapy for metastatic TNBC improved PFS in unselected patients (stratified hazard ratio [HR] 0.60 [90% CI 0.40‐0.91]), with a more pronounced effect in patients with PIK3CA/AKT1/ PTEN‐altered tumours [Dent, ASCO 2017]. cfDNA sequencing was performed to assess the utility of blood samples for detecting tumour mutations in TNBC. Methods: Pre‐treatment plasma and tumour samples were evaluated for genetic alterations using Foundation Medicine's FoundationACT and FoundationOne next‐generation sequencing assays, respectively. Samples from 88 patients were evaluable by cfDNA, 72 of whom also had evaluable tumour samples (52 primary tumour). To test the prognostic effect of cfDNA mutational burden, patients were classified as having high or low variant allele fraction (VAF) in cfDNA using the median as a cutoff. Results: In 81 patients (92%), at least one mutation was detectable by cfDNA sequencing. Concordance with tissue sequencing was 75%. High VAF was associated with shorter PFS than low VAF in both the IPAT +P arm (HR 2.39 [90% CI 1.19‐4.70]) and the placebo + P arm (HR 2.68 [90% CI 1.46‐5.11]). High VAF was also associated with the presence of>1 metastatic site but not tumour volume per RECIST v1.1. In 22 patients (25%), an activating PIK3CA (n=16) or AKT1 (n=6) mutation was detected in cfDNA; concordance with tissue sequencing was 100%. PFS improvement with the addition of IPAT to P was more pronounced in patients with detectable PIK3CA/AKT1 mutations (HR 0.15 [90% CI 0.03‐0.50]) than in those without a detectable mutation (HR 0.82 [90% CI 0.50‐1.31]). Conclusions: These results highlight the potential role of cfDNA in evaluating patient prognosis as well as identifying genetic markers associated with improved treatment outcomes. Furthermore, they support the occurrence of PIK3CA and AKT1 mutations as early genetic events present in primary tissue samples that are maintained during metastasis.