Abstract P3-08-20: Clinical next-generation sequencing analysis in ER-positive HER2-negative metastatic breast cancer patients: Mutation frequency & clinical correlations

Abstract

Abstract Background: Clinical next-generation sequencing (NGS) has opened new perspectives on genome-driven therapy for metastatic breast cancer (MBC) through the identification of recurrent driver mutations. However, therapeutic relevance of the detection of these mutations with a potential impact on disease outcome and treatment resistance remains unclear. Patients and Methods: A monocentric retrospective study was performed to investigate mutation frequency and disease outcome in 86 metastatic breast cancers patients treated in UZ-Leuven and tested for the presence of mutations in representative formalin-fixed, paraffin-embedded tumor tissue using a routine diagnostic panel of 26 cancer genes (TruSight Tumor 26, Illumina, mean coverage 500X). It mainly concerned metastatic lesions (96.5%). Out of 86 patients, 63 had hormone receptor (HR) positive/ HER2-negative disease; 8 were HER2-positive and 15 triple negative as determined by immunohistochemistry (IHC)/Fluurescence in situ hybridization (FISH). The 63 ER-positive/ HER2-negative cases were selected for further investigation. Single-nucleotide variants and insertions/deletions were reported. Results: Overall, mutations (> 5% allelic frequency) were found in 60.3% of the cases. As expected, mutations in PIK3CA and TP53 were being most frequently encountered (35% and 19% respectively); variants in AKT1, KRAS and PTEN were less common (5%, 3% and 2% respectively). Focusing on ER-positive/HER2-negative cases, 13 out of 63 had a single PIK3CA mutation, 6 had a single TP53 mutation and 21 cases had more than 1 mutation. In 23 out of 63 cases, no potentially actionable mutation could be identified using the 26 cancer gene panel. Interestingly, we found a clinically relevant and statistically significant difference in median progression-free survival between patients harboring a TP53 mutation only (19,8 months (m), range 12.1 – 27.4) and those harboring a PIK3CA mutation only (84m, range 7.4 – 215.1) or patients without any detected mutation (45,3m, range 5.8 – 225.8). Similarly, overall survival was significantly worse for TP53 mutated cases compared with patients with a PIK3CA or no mutation at all. Finally, a brief comparison of MBC-therapies used in these different subgroups showed the interesting finding that none of 7 PIK3CA-mutated tumors treated with fulvestrant monotherapy showed treatment response. Conclusion: This small retrospective analysis showed that clinical sequencing using a small targeted NGS panel reveals mutations in 60.3% of MBC patients, with 40% being targetable. Besides predictive implications, detection of these mutations could also have major prognostic implications on distant metastasis free survival and overall survival. Citation Format: Goyens J, Punie K, Wildiers H, Smeets A, Vander Borght S, Floris G, Vergote I, Van Nieuwenhuysen E, Han S, Nevelsteen I, Neven P, Vanden Bempt I. Clinical next-generation sequencing analysis in ER-positive HER2-negative metastatic breast cancer patients: Mutation frequency & clinical correlations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-20.