Targeted therapies in Collecting Duct Carcinoma: something new from next generation sequencing?

Abstract

Background: Collecting duct carcinoma (CDC) of Bellini is a rare, aggressive form of primary renal tumor occurring in less than 1% of all renal cell carcinoma (RCC). More than two third of patients with CDC exhibit locoregional or systemic symptoms on presentation but currently no equivocal indication exists for surgical and medical treatment of metastatic disease. Medical therapeutic approach is actually based on chemotherapy regimens; we previously published data on promising activity of target agents in this orphan disease highlighting that modern therapy may improve outcomes. Material and methods: Sixteen patients with advanced CDC, referring to our Center, were treated from December 2004 up today. All patients were relapsed after nephrectomy, median age was 58 years and they were treated with targeted therapies until progressive disease or unacceptable toxicity. In this subset of patients Ion Torrent next generation sequencing technology ("Hot-spot Cancer Panel") was used to obtain molecular data. The aim of the study is to evaluate the activity of targeted therapies in metastatic CDC and to collect molecular data in order to identify predictive biomarker for the development of evidence-based treatment strategies. Results: Nine patients (57%) were treated with sunitinib in first line, two (12%) with temsirolimus, three (19%) with sorafenib, 2 (12%) with pazopanib. Eight patients (50%) were treated with 2 or more therapeutic lines. Four patients, two treated with sunitinib, two with soarfenib and one with temsirolimus obtained a satisfying response (disease control lasting 4-33 months). Median overall survival was 5 months and safety data were consistent with the literature. Next generation sequencing was successfully performed in two samples until today, other results are not available currently. Rare gene mutations were found: FBXW7 in one case, JAK 3and KRAS in the other case. FBXW7 encodes for a member of the F-box protein family which function in phosphorylation-dependent ubiquitination while JAK3 encodes for an intracellular tyrosine kinase involved in cytokine signaling related to T cell development and proliferation. Conclusion: CDC has a poor prognosis compared to non-CDC renal cell carcinoma; new targeted agents may represent an alternative therapeutic strategy . The identification of predictive biomarkers is a priority for a better knowledge of the disease natural history and for the development of specific treatment for this pathology.