Comprehensive molecular and phenotypic profiling of end-stage IV cancer identifies treatable targets and improves survival in individual patients

Abstract

Background: Comprehensive profiling of patients’ tumor tissue in cases with end-stage IV cancer was conducted to identify mutations, proteins and activated cancer pathways potentially eligible for targeted therapies. Data evaluation included test results, clinical data, clinical trials and longitudinal follow-up data. Methods: Tissue collection and processing was conducted under highly standardized and controlled conditions to preserve the expression profile in tissue as it appears in the human body. Samples that passed the quality control (tumor content ≥ 50%) were analyzed using the following techniques: immunohistochemistry (IHC), next-generation sequencing (NGS) and simple western charge-based assays (NanoPro 1000 system). Expression of the major receptor proteins and phosphorylation of the signaling proteins ERK1/2, MEK1/2 and AKT of the MAP kinase pathway and the PI3K/AKT/mTOR-pathway were measured to infer targets on the (phospho-) proteomic level. On the genomic level DNA sequencing of “hotspot” regions covering 50 oncogenes and tumor suppressor genes was conducted using the Ion AmpliSeqTM Cancer Hotspot Panel v2. Results: Analyses of 82 patients were performed and 27 patients met the determined evaluation criteria. These patients were divided into two groups. In one group (n = 13) targets for available therapeutics could be identified and patients were treated accordingly. In the other group (n = 14) targets could not be found or were not regarded as useful by the oncologist. These patients were treated with conventional, palliative therapies. The 6-month follow-up revealed a better outcome when patients were treated according to an identified target. 46% of patients responded to targeted treatment. 15% of patients had a complete remission (CR), 8% had a stable disease (SD) and another 23% had a partial remission (PR). 38% progressed under targeted therapy and 15% died. In contrast, only 21% responded under conventional, palliative therapy by showing a stable disease, 64% of patients progressed (PD) and 14% died. No complete or partial remission was observed in patients treated by conventional approaches. Conclusions: A comprehensive molecular and phenotypic tumor characterization can identify in individual patients, suffering from highly advanced cancer, targeted therapies that impact cancer growth and lead in single cases even to a complete remission. Legal entity responsible for the study: IndivuTest GmbH Funding: IndivuTest GmbH Disclosure (FOR ALL LISTED AUTHORS): A. Samsen, S.Schneider, S. Von Der Heyde, W. Saeger, B. Grebenstein and Hartmut Juhl are employees of IndivuTest GmbH. The authors declare no other competing financial interests. The study was conducted in Hamburg, Germany, and reviewed and approved by the competent ethics review committee of the Medical Association of Hamburg, Germany under reference number PV5035. Prior to this study, all patients gave their written informed consent.