Induction ofPIK3CAalterations during neoadjuvant letrozole may improve outcome in postmenopausal breast cancer patients

Abstract

Purpose Estrogen receptor positive (ER+) breast cancer constitutes almost 85% of all breast cancer patients and are a genetically highly heterogenic group. Data on the association of somatic alterations to outcome and prognosis are however sparse. In this neoadjuvant endocrine phase II trial including postmenopausal breast cancer patients with ER+, HER2 normal breast cancer, we investigated the rate of pathogenic mutations before and after treatment as well as the association with treatment response and survival. Methods Pretreatment and posttreatment tumour samples from 109 patients treated with neoadjuvant letrozole were collected and analysed with Next Generation Sequencing utilizing a panel of 12 genes (ALK, BRAF, EGFR, ERBB2,ERBB3,ESR1,KIT,KRAS,NRAS,PDGFRA,PIK3CA, andRAF1). Residual disease was assessed by a modified Miller Payne scale and the Residual Cancer Burden index. Survival data were collected prospectively. Results Among the 109 patients, 52 had at least one pathogenic mutation in the pretreatment sample and 60 in the posttreatment sample. The most frequently mutated gene wasPIK3CA, followed byEGFRandKRAS.Twelve different pathogenicPIK3CAmutations were identified, primarily in exon 20 and exon 9. An alteredPIK3CAmutation profile from the pre- to the posttreatment specimen was significantly associated to improved pathological outcome. Overall and Disease-Free Survival benefits inPIK3CAmutated patients was observed. Conclusion Considerable heterogeneity was identified both among patients and between pre- and posttreatment samples.PIK3CAhas the potential to be a predictive biomarker. To further assess the implications of a treatment related alteredPIK3CAmutation profile, more data are needed.