Whole exome sequencing of rare aggressive breast cancer histologies.

Little is known about mutational landscape of rare breast cancer (BC) subtypes. The aim of the study was to apply next generation sequencing to three different subtypes of rare BCs in order to identify new genes related to cancer progression. We performed whole exome and targeted sequencing of 29 micropapillary, 23 metaplastic, and 27 pleomorphic lobular BCs. Micropapillary BCs exhibit a profile comparable to common BCs: PIK3CA, TP53, GATA3, and MAP2K4 were the most frequently mutated genes. Metaplastic BCs presented a high frequency of TP53 (78 %) and PIK3CA (48 %) mutations and were recurrently mutated on KDM6A (13 %), a gene involved in histone demethylation. Pleomorphic lobular carcinoma exhibited high mutation rate of PIK3CA (30 %), TP53 (22 %), and CDH1 (41 %) and also presented mutations in PYGM, a gene involved in glycogen metabolism, in 8 out of 27 samples (30 %). Further analyses of publicly available datasets showed that PYGM is dramatically underexpressed in common cancers as compared to normal tissues and that low expression in tumors is correlated with poor relapse-free survival. Immunohistochemical staining on formalin-fixed paraffin-embedded tissues available in our cohort of patients confirmed higher PYGM expression in normal breast tissue compared to equivalent tumoral zone. Next generation sequencing methods applied on rare cancer subtypes can serve as a useful tool in order to uncover new potential therapeutic targets. Sequencing of pleomorphic lobular carcinoma identified a high rate of alterations in PYGM. These findings emphasize the role of glycogen metabolism in cancer progression.

Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation.

BACKGROUND: MET and AXL dysregulation is reported as a bypass mechanism driving tumour progression in non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This non-comparative phase I study investigated the combination of gefitinib with S49076, a MET/AXL inhibitor, in advanced EGFR TKI-resistant NSCLC patients with MET and/or AXL dysregulation. METHODS: Patients received S49076 at escalating doses of 500 or 600 mg with a fixed dose of 250 mg gefitinib orally once daily in continuous 28day cycles. MET and AXL dysregulation and EGFR/T790M mutation status were centrally assessed in tumour biopsies at screening. Tumour response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). EGFR TKI resistance mechanisms were analysed by next-generation sequencing. The clonal evolution of tumours was monitored with the analysis of circulating tumour DNA. RESULTS: Of 92 pre-screened patients, 22 met the molecular inclusion criteria and 14 were included. The recommended dose was 600 mg daily S49076. Best overall responses were 2 partial responses (1 patient with MET dysregulation only, 1 MET and AXL co-dysregulation) and 8 patients with stable disease. Other potential concomitant mechanisms of resistance to EGFR TKI were identified in more than half of the included patients. CONCLUSIONS: S49076 plus gefitinib demonstrated a good tolerability with limited anti-tumour activity. Due to the low number of eligible patients, no tendency in term of activity appeared in any specific molecular subset and the data did not allow for identification of AXL overexpression as an oncogenic driver.