Abstract P2-02-05: Persistence of PIK3CA mutations detection in cell free tumor DNA as surrogate markers for hormonosensibility in patients with hormone receptor-positive breast cancer. The miRho clinical study

Abstract

Abstract Background: HT resistance occurs in nearly all patients with mBC. The identification of early predictive biomarkers of HT failure could help tailoring monitoring or an early change in HT. Circulating biomarkers would allow, a global evaluation of all the metastatic sites without the need of invasive biopsies. Mutation in the phosphatidylinositol 3 phosphate kinase gene (PIK3CA) is one of the most frequent events in ER+ BC and has been involved in HT resistance. We evaluated the early predictive value of cell free DNA (cfDNA) PIK3CA detection in a population of first line HT BC patients. Material and methods: 39 patients treated for an ER+/HER2- metastatic BC by first line HT in 2 French Comprehensive Cancer Centers were prospectively included in a dedicated clinical trial (NCT01612871) between June 2012 and January 2014. Serial blood sampling was performed before the initiation of HT (T0), 4 weeks (T1), 3 months (T3), 6 months (T6) and at tumor progression. Patients were followed until progression or end of the study (2 years follow-up). cfDNA was isolated from plasma using the QiaAmp circulating nucleic acid isolation kit (Qiagen). Mutation detection was performed using droplet digital PCR on a QX100TM system (Bio-Rad). The assay targeted wild type PIK3CA and mutations p.E542K, p.E545K in exon 9 and p.H1047R in exon 20. Target concentration was calculated as copies/reaction and cfDNA concentrations were reported as number of copies/mL of plasma. To assess the limit of detection of the three assays, isogenic reference DNA with known mutant allele frequency was used (Horizon Diagnostics). Based on confidence interval for Poisson parameter, a sample was considered positive if the average mutant copies detected was 4 copies and above per reaction. Results: Median age of the population was 63 (range 40-86). HT was as follow: letrozole 32, tamoxifen 5, anastrozole 1 and exemestane 1 patients, respectively. Most patients (28, 71.8%) presented with non-measurable disease, precluding a relevant evaluation of predictive factors for response. Progression-free survival (PFS) was used instead as primary endpoint. Serum samples results were available for 37 and 35 patients at T0 and T1 respectively. PIK3CA mutations were present in 10 (27.8%) and 5 (14.3%) cases at T0 and T1 respectively. While presence of a cfDNA PIK3CA mutation in the T0 sample was not associated with PFS, the persistence of a detectable circulating mutation at T1 was highly significant of a worse PFS (40% vs. 76.7% at 1 year; p=0.0053). Conclusions: In this dedicated clinical trial, 4-weeks persistence of cfDNA PIK3CA mutation appears highly correlated with PFS. Early identification of this mutated population could allow the evaluation of therapies targeting the PI3K/AKT/mTOR pathway in a selected population affected with an unfavorable prognosis. Dedicated studies and ancillary studies of such targeted therapies are warranted. Citation Format: Jacot W, Dalenc F, Lopez-Crapez E, Chaltiel L, Durigova A, Gros N, Lacaze J-L, Pouderoux S, Gladieff L, Romieu G, Roché H, Filleron T, Lamy P-J. Persistence of PIK3CA mutations detection in cell free tumor DNA as surrogate markers for hormonosensibility in patients with hormone receptor-positive breast cancer. The miRho clinical study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-05.