Comprehensive genetic profiling and molecularly guided treatment for patients with primary CNS tumors

Abstract

Despite major advances in molecular profiling and classification of primary brain tumors, personalized treatment remains limited for most patients. Here, we explored the feasibility of individual molecular profiling and the efficacy of biomarker-guided therapy for adult patients with primary brain cancers in the real-world setting within the molecular tumor board Freiburg, Germany. We analyzed genetic profiles, personalized treatment recommendations, and clinical outcomes of 102 patients with 21 brain tumor types. Alterations in the cell cycle, BRAF, and mTOR pathways most frequently led to personalized treatment recommendations. Molecularly informed therapies were recommended in 71% and implemented in 32% of patients with completed molecular diagnostics. The disease control rate following targeted treatment was 50% and the overall response rate was 30%, with a progression-free survival 2/1 ratio of at least 1.3 in 31% of patients. This study highlights the efficacy of molecularly guided treatment and the need for biomarker-stratified trials in brain cancers.

Fig. 1. Workflow and distribution of entities in the MTB-FR primary CNS tumor cohort.

a Schematic overview of the MTB-FR workflow and numbers of primary CNS tumor patients assessed during this workflow. LFU, Loss to follow-up. b Distribution of brain cancer entities based on CNS-WHO grades defined by the WHO 2021 classification (n = 102). wt wildtype, mut mutated, codel co-deleted.

Fig. 2. Tumor sequencing results.

Case-level mutational profiles of 87 primary brain tumors genotyped by WES or targeted next-generation sequencing using capture panels. Each column represents a tumor sample, each row represents a gene. Genes with at least four recurrent mutations in the cohort are shown. The map was manually clustered to highlight mutation co-occurrence. The percentage of patients carrying an alteration in each gene is shown as a bar graph on the right. Sequencing method, diagnosis as well as CNS-WHO grades are depicted as a color code in the first three rows. Bold gene names indicate genetic alterations resulting in treatment recommendations. WES Whole exome sequencing, wt wildtype, mut mutated, codel co-deleted, PLNTY polymorphous low-grade neuroepithelial tumor of the young.

Fig. 3. MTB-FR treatment recommendations.

a Case-level profile of MTB-FR therapy recommendations for 62 patients. Each column represents one case. Each row represents one recommendation. The recommended agent is stated for each row along with the respective NCT evidence levels. The map was manually clustered based on the cancer entity and recommended treatment. The percentage of recommendations is shown as a bar graph on the right. Implemented recommendations are shown in dark red rectangles, recommended treatment that was not implemented is shown in light red rectangles. Diagnosis and CNS-WHO grades are color-coded in the first rows. Wt wildtype, mut mutated, codel co-deleted, PLNTY polymorphous low-grade neuroepithelial tumor of the young, TZM Temozolomide. b Recommendations are assigned to 9 biological processes. The proportion of these recommendations to the total number of recommendations is shown as a bar plot. The bars are subdivided and colored according to the proportion of recommendations assigned to each CNS-WHO grade. HRD, homologous recombination deficiency. c Proportion of recommendations for combination therapies (either 1 targeted agent plus chemotherapy [light green] or 2 targeted agents [darker green]) and monotherapies (either one targeted agent [darkest green] or checkpoint inhibitor treatment [black]). d Proportion of recommendations based on NCT evidence levels (Methods). e Pie chart demonstrating the proportion of mutation types in the PTEN gene. f Sankey plot visualizing the result of immunohistological (IHC) PTEN analysis in tumors with PTEN mutations, demonstrating cases in which PTEN expression is retained (dark blue) by IHC and those in which PTEN is lost (dark green). IHC, Immunohistochemistry. NA not assessed. g Representative image of immunohistochemical slides showing (A) preserved PTEN expression and (B) loss of PTEN expression.

Fig. 4. Response to implemented treatment.

a Modified swimmer plot showing a patient-based treatment course and follow-up period. Time is given in days. The tumor entity is shown as a rectangle in a color code provided in the legend within the figure panel. The colored dot for each case represents the best response. Dark blue bars indicate the time of treatment with recommended therapy. Light blue bars indicate time without recommended treatment. Gray bars indicate discontinuation of the recommended treatment. Patients with a black triangle at the end of the bar are still being followed up. Patients with a black bar have died. MRIs during disease progression are shown with a triangle. The color is chosen according to the remission status as stated in the legend within the figure panel. Black triangles above the bars indicate the dose reduction of the recommended therapy. One patient was lost to follow-up immediately after starting treatment. No follow-up data is available for this patient. LFU loss to follow-up, wt wildtype, mut mutated, codel co-deleted, PD progressive disease, SD stable disease, PR partial remission. b Disease control rate (DCR) and overall response rate (ORR) achieved by recommended therapies among different CNS-WHO Grades. c DCR and ORR achieved by recommended therapies among different NCT evidence levels (m1 vs. m2/3).