210P - Therapeutic implications of phosphoproteomics in molecular cancer diagnostics

Background

Precision oncology approaches employing genomics-guided targeted therapies for individual patients have provided significant survival benefits in several cancer types. However, varying response rates in solid malignancies, many patients without actionable genomic lesions, and increasing evidence that non-genomic mechanisms may play an important role in tumors indicate that genomics alone is often insufficient to inform and guide the clinical care of patients. Since most targeted anti-cancer drugs inhibit the activity of protein kinases, measuring the tumor phosphoproteome as a direct readout of oncogenic pathway activity is poised to enhance molecular stratification.

Methods

We established a clinical (phospho)proteomic workflow for integration into the molecular tumor board (MTB) workflow of the Germany-wide INFORM (for children with relapsed cancers) and MASTER (for young adults with refractory cancers and patients with rare tumors) registry studies and profiled > 1200 tumor tissue specimen from patients enrolled in the DKFZ/NCT/DKTK MASTER study or the INFORM registry trial.

Results

We show for the first time that comprehensive (phospho)proteome profiling is feasible and informative in a real-world prospective precision oncology setting. Discussion of (phospho)proteomic data of > 600 prospective patients in weekly MTB meetings revealed that adding a (phospho)proteomic layer can supply critical information for personalized therapies that is not discernable from genomic and transcriptomic data. In an independent value evaluation (329 target recommendations in 104 patients), the phosphoproteome layer was decisive in 22% of all recommended targets. Based on anecdotal cases with available clinical follow-up, we provide evidence that (phospho)proteome profiling carries important diagnostic value by detecting actionable tumor-driving kinase signaling in patients without actionable genomic lesions or by functionalizing genomic variants of unknown significance.

Conclusions

Measuring the tumor phosphoproteome as a direct readout of oncogenic pathway activity is feasible and adds complementary, therapy-relevant information in a real-world prospective precision oncology setting.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Chair of proteomics and bioanalytics, TUM.

Funding

EU, DKTK, chordoma foundation.

Disclosure

P. Horak: Non-Financial Interests, Personal, Advisory Role: Platomics; Financial Interests, Personal, Ownership Interest: Platomics; Financial Interests, Personal, Other, Honoraria: Roche, Trillium GmbH. S. Kreutzfeldt: Non-Financial Interests, Personal, Advisory Role: Roche. S.M. Pfister: Non-Financial Interests, Institutional, Advisory Role: BioSkryb; Non-Financial Interests, Personal, Ownership Interest, Cofounder/stakeholder: Heidelberg Epignostix GmbH; Financial Interests, Institutional, Research Funding: Lilly, Roche, Charles River, BayerHealth Care, Amgen, Sanofi, AstraZeneca, Servier. S. Fröhling: Non-Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Funding, Honoraria, Travel, Accommodations, Expenses: PharmaMar, Amgen; Financial Interests, Personal and Institutional, Funding, Honoraria, Travel, Accommodations, Expenses, Research Funding: Roche, Lilly; Financial Interests, Institutional, Research Funding: AstraZeneca, Pfizer. B. Kuster: Financial Interests, Personal, Ownership Interest, co-founder and shareholder, no operational role: MSAID, OmniScouts. All other authors have declared no conflicts of interest.