Multi-omic based molecular profiling of advanced cancer identifies treatable targets and improves survival in individual patients.

Alexandra Samsen,Cay-Uwe Von Seydewitz,Carsten Bokemeyer,Kerstin A David,Bianca Grebenstein,Carsten Zornig,Friedrich Overkamp,Wiebke Hollburg,Eike Von Leitner,Silvia Von Der Heyde,Wolfgang Saeger,Peter Layer,Sandra Schneider,Max Graap,Alexander Stein,Hartmut Juhl,Ludger Heflik,Axel Stang,Bernd Flath

doi:10.18632/oncotarget.26198

Abstract

A proof-of-concept study was conducted to assess whether patients with advanced stage IV cancer for whom predominantly no standard therapy was available could benefit from comprehensive molecular profiling of their tumor tissue to provide targeted therapy. Tumor samples of 83 patients were collected under highly standardized conditions and analyzed using immunohistochemistry, next-generation sequencing and phosphoprotein profiling. Expression and phosphorylation of key oncogenic pathways were measured to identify targets at the (phospho-) proteomic level. At genomic level, 50 oncogenes and tumor suppressor genes were analyzed. Based on molecular profiling, targeted therapies were decided by the attending oncologist. Accordingly, 28 patients who met the defined criteria fell in two equal-sized groups. One group received targeted therapies while the other did not. Following six months of treatment, disease control was achieved by 49% of patients receiving targeted therapy (complete remission, 14%; partial remission, 21%; stable disease, 14%; disease progression, 36%; death, 14%) and 21% of patients receiving non-targeted therapy (stable disease, 21%; disease progression, 64%; death, 14%). Individual patients experienced dramatic responses to a therapy which otherwise would not have been applied. This approach clarifies the value of multi-omic molecular profiling for cancer diagnostics.

Highlights

Given estimates that over 800 cancer treatments are currently in clinical development [1], molecular profiling of tumors will likely become increasingly important to enable appropriate treatment decisions to be made
Follow-up data were available for 66/83 (80%) patients; 38/66 patients (58%) were excluded from the evaluation, due to the fact that the majority of these patients (32/38 [84%]) died prior to the first follow-up interval, two tumor samples were not collected under high-quality standardized conditions, two patients received therapy based on oncological experience and not due to the outcome of molecular profiling, and follow-up data had been collected at only one interval for two patients (Figure 2)
The distribution of the tumor types of the evaluable patients was: colorectal cancer (25%), cancer of unknown primary (CUP) (14%), single rare tumor types (14%), gastric cancer (11%), cholangiocarcinoma (7%), pancreatic cancer (7%), triple-negative breast cancer (TNBC) (7%), breast cancer (4%), esophageal carcinoma (4%), non-small cell lung carcinoma (NSCLC) (4%) and renal cell carcinoma (4%) (Table 1)

Summary

Introduction

Given estimates that over 800 cancer treatments are currently in clinical development [1], molecular profiling of tumors will likely become increasingly important to enable appropriate treatment decisions to be made. A more holistic view may be achieved by considering the genomic as well as the (phospho-) proteomic level. Such comprehensive molecular analysis and subsequent matching to related therapies has previously been associated with improved outcomes for some patients with metastatic cancer [8, 9]. Such diagnostic approaches depend on standardized tissue collection with short ischemia time (

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