No checkmate in metastatic setting: Navigating real world patients applying personalized therapy based on extensive tumor profiling.
Authors: Schaffrin-Nabe Doerthe Dr. , Tannapfel Andrea , Dr. Josten-Nabe Anke , Dr. Schuster Stefan , Dr. Reismann David , Dr. Melchior Felix , Dr. Patil Darshana , Dr. Grünwald Robert , Schaffrin Merle , Voigtmann Rudolf 
Published: June 2023

e15015

Background: Today the toolbox of predictive and prognostic biomarkers to adapt cancer treatment is already equipped with valuable tests and medications, but application in real world patients is still hampered. The focus on DNA alterations reveals targets only in 40-60% of the patients, and afterwards successful application thereof is on a different page. Extensive tumor profiling (ETP) could represent a tool to improve treatment efficacy detecting more actionable characteristics to combine eligible therapies. Methods: Over the course of 4 years we treated 37 patients with aggressive metastastic solid tumors based on 50 ETPs, namely exacta (Genetics, Expression profiling, IHC, Immunocytochemistry, Pharmacogenomics and Chemosensitivity). After failure of guideline therapies, ETP was performed using tissue or if not available blood analysis. With ETP we are not restricted to genetics, so finding therapeutic promising targets in 99% of the patients e.g. KRASpG12D: MEK inhibition/Hydroxychloroquin as autophagy inhibitor; KRASpG12C: Sotorasib/MEK inhibition; ERBB2pV697L: Margetuximab/Gemcitabine, STK11 and elevated gene expression profiling of mTOR, VEGFA: Everolimus, Becvacizumab, 5-FU. In accordance with Winther/Resilient trial we used patients as their own control. Results: In 26% of the patients we observed a doubling of the progression free survival (PFS2) after ETP in comparison to last therapy (PFS1). The median ratio PFS2/PFS1 was 1.41 (SD = 0.96) and in 48% of ETPs we observed a PFS > 6 months. In 70% of the ETPs we achieved a ratio of ≥1 at least. In the univariate analyses of the ratio, we found a lower ratio for a higher number of oncogenes (p = 0.04) and the presence of a p53 mutation (p = 0.013). The multivariate analyses of the ratio revealed the influence of several parameters (R² = 78.9%): a higher ratio was associated with lower ECOG status and lower grading. The presence of p53 mutations significantly decreased the ratio (p = 0,009). Number of previous therapies and presence of visceral metastases decreased the ratio, while isolated bone metastases increased the ratio. Also a higher number of targeted oncogenes raised the ratio. Focusing on patients with a ratio ≥2, 2.8 oncogenes were detected per ETP and in 61% of the tests the oncogenes were targeted. In patients with a ratio < 1, 4.3 oncogenes were detected and 46% were targeted. p53 mutations were a relevant prognostic marker, in patients with a ratio ≥2 in 15% of the ETPs we discovered a mutation, in the subgroup with a ratio < 1 in 66%. Therefore p53 itself might represent a future therapeutic target. Conclusions: ETP offers a chance for a majority of late stage patients often characterized by visceral crisis to prolong PFS with acceptable ECOG status. ETP is a milestone as cancer itself is a complex disease with the need for complex solutions.