Transitioning the Molecular Tumor Board from Proof of Concept to Clinical Routine: A German Single-Center Analysis

Abstract

Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.

Keywords: cancer genetics; cancer immunotherapy; cancer molecular biology; cancer progression; combination therapies; molecular profiling; molecular tumor board; personalized cancer medicine; precision oncology; targeted therapies.

Figure 1

Results of sequencing: (A) The bar plot depicts the number of sequence variants detected in tumor DNA using the 48-gene panel for 221 patients. Colors indicate non-targetable COSMIC- (grey) and non-targetable hotspot mutations (blue). Actionable variants are shown in green (drug-sensitizing) and red (drug-resistance) based on the OncoKB classification. (B) The heatmap depicts the 50 most frequently mutated somatic genes of the 104 patients analyzed by whole-exome sequencing (WES). The colors indicate tumor entities, type of mutation, tumor mutational burden and BRCAness-score (= AC3−signature). Only mutations with a variant allele frequency greater than 10% and a minor allele frequency less than 0.1% were considered. (C) The bar diagram depicts all mutations that were annotated as targetable by the OncoKB classification. The colors indicate tumor entities. (D) The heatmap depicts copy number variations of the most frequently affected oncogenes. The colors indicate tumor entities and the total copy number per oncogene. Gene copy number gains that were annotated as targetable by the OncoKB algorithm are depicted in red.

Figure 2

Flow diagram of patients discussed at the MTB. Responses were determined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.; (a–d) represent various drug categories as indicated. PR = Partial remission. SD = Stable disease. PD = Progressive disease. ICB = Immune checkpoint blockade. TT = Targeted therapy. TKI = Tyrosine kinase inhibitor. SM = Small molecule. AB = Antibody. ICB + X = Combination of immune checkpoint blockade with another drug. Ch + AB = Combination of chemotherapy with an antibody. FU = Follow-up. NE = Not evaluable.