Background Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients. Methods Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used. Results KRAS -mutated cohort included 58 patients, and overall 73 treatments ( N = 39 chemotherapy and N = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0–61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1–25.0, p = 0.0016). Increased MAFA (T1–T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2–3.8, p = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2–8.4, p = 0.0168). Conclusions Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.

Background: Epithelial ovarian cancer is the most lethal gynecological cancer and the high mortality is due to the frequent presentation at advanced stage, and to primary or acquired resistance to platinum-based therapy. Methods: We developed three new models of ovarian cancer patient-derived xenografts (ovarian PDXs) resistant to cisplatin (cDDP) after multiple in vivo drug treatments. By different and complementary approaches based on integrated metabolomics (both targeted and untargeted mass spectrometry-based techniques), gene expression, and functional assays (Seahorse technology) we analyzed and compared the tumor metabolic profile in each sensitive and their corresponding cDDP-resistant PDXs. Results: We found that cDDP-sensitive and -resistant PDXs have a different metabolic asset. In particular, we found, through metabolomic and gene expression approaches, that glycolysis, tricarboxylic acid cycle and urea cycle pathways were deregulated in resistant versus sensitive PDXs. In addition, we observed that oxygen consumption rate and mitochondrial respiration were higher in resistant PDXs than in sensitive PDXs under acute stress conditions. An increased oxidative phosphorylation in cDDP-resistant sublines led us to hypothesize that its interference could be of therapeutic value. Indeed, in vivo treatment of metformin and cDDP was able to partially reverse platinum resistance. Conclusions: Our data strongly reinforce the idea that the development of acquired cDDP resistance in ovarian cancer can bring about a rewiring of tumor metabolism, and that this might be exploited therapeutically.

Purpose: Preclinical studies show that antiangiogenic therapy exacerbates tumor glycolysis and activates liver kinase B1/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. We investigated whether certain metabolism-related in situ biomarkers could predict benefit to regorafenib in the phase II randomized REGOMA trial.Patients and Methods: IHC and digital pathology analysis were used to investigate the expression in glioblastoma (GBM) sections of monocarboxylate transporter 1 and 4 (MCT1 and MCT4), associated with OXPHOS and glycolysis, respectively, phosphorylated AMPK (pAMPK), and phosphorylated acetyl-CoA carboxylase (pACC), a canonical target of AMPK activity. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression-free survival (PFS) in patients with relapsed GBM treated either with regorafenib or lomustine.Results: Between November 2015 and February 2017, 119 patients were enrolled (n ¼ 59 regorafenib and n ¼ 60 lomustine) and stratified for surgery at recurrence, and baseline characteristics were balanced. Biomarker analysis was performed in 84 patients (71%), including 42 patients of the regorafenib arm and 42 patients of the lomustine arm. Among all markers analyzed, only pACC showed predictive value in terms of OS. In fact, median OS was 9.3 months [95% confidence interval (CI), 5.6-13.2] for regorafenib and 5.5 months (95% CI, 4.2-6.6) for lomustine for pACC-positive patients, HR, 0.37 (95% CI, 0.20-0.70); log rank P ¼ 0.0013; test for interaction ¼ 0.0453. No statistically significant difference was demonstrated for PFS according to pACC status.Conclusions: We found that AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed GBM.