Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profiled via whole-exome and transcriptome sequencing. META-PRISM tumors, particularly prostate, bladder, and pancreatic types, displayed the most transformed genomes compared with primary untreated tumors. Standard-of-care resistance biomarkers were identified only in lung and colon cancers—9.6% of META-PRISM tumors, indicating that too few resistance mechanisms have received clinical validation. In contrast, we verified the enrichment of multiple investigational and hypothetical resistance mechanisms in treated compared with nontreated patients, thereby confirming their putative role in treatment resistance. Additionally, we demonstrated that molecular markers improve 6-month survival prediction, particularly in patients with advanced breast cancer. Our analysis establishes the utility of the META-PRISM cohort for investigating resistance mechanisms and performing predictive analyses in cancer. Significance: This study highlights the paucity of standard-of-care markers that explain treatment resistance and the promise of investigational and hypothetical markers awaiting further validation. It also demonstrates the utility of molecular profiling in advanced-stage cancers, particularly breast cancer, to improve the survival prediction and assess eligibility to phase I clinical trials. This article is highlighted in the In This Issue feature, p. 1027

Growing evidence highlights the pivotal role of the gut microbiota in cancer development, progression, response to therapy, and survivorship. Diet plays a central role in shaping gut microbiota composition, influencing the immune system and overall host health. Plant-based diets and the Mediterranean diet promote health-associated microbial communities that increase the production of several metabolic-end products, including short-chain fatty acids that support mucosal barrier integrity, anti-inflammatory effects, and modulation of the immunity of the host. Conversely, Western dietary patterns promote cancer progression and negatively impact the response to standard treatments. Furthermore, gut microbiota influences the effectiveness of cancer therapies, including chemotherapy, radiotherapy and, mainly, immunotherapy. Modulating microbial species, their metabolites, or their activities in the cancer microenvironment through dietary interventions, common or engineered probiotics, prebiotics, postbiotics, antibiotics or fecal microbial transplant are emerging as promising strategies for cancer prevention and tailored management in survivorship. In this review, we explore the intricate interplay between diet, gut microbiota, and cancer, focusing on how specific microbial communities’ impact therapeutic outcomes, and the challenges in the modulation of the microbiota environment through several interventions, including diet. This emerging paradigm paves the way for integrating nutrition and microbiota-targeted strategies as innovative tools in the context of precision medicine.

Introduction: Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC. Materials and Methods: This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry–liquid chromatography method. Results: We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups. Conclusion: In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC. Implications for Practice: Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context.

The treatment landscape of metastatic renal cell carcinoma (mRCC), a chemotherapy-resistant disease, has dramatically changed in the last decade after the introduction of small molecule inhibitors targeting the vascular endothelial growth factor receptor and mammalian target of rapamycin kinases. The CheckMate 025 phase III trial in second line mRCC also introduced immunotherapy with immune-checkpoint inhibitors as an option in the management of mRCC. Both small molecules and immunotherapy are used as single agents and they are associated with different toxicities. Recent data demonstrated that the combination of 2 immunotherapies, nivolumab and ipilimumab, is more effective than tyrosine kinase inhibitors (TKI) monotherapy as first line treatment in intermediate and poor risk mRCC. Furthermore, combination of immunotherapies and TKI has been tested in several trials to evaluate if the combo with agents presenting a different mechanism of action is more effective than monotherapy with TKI. During the past several years, combined therapy of cytokines doublets or cytokines and bevacizumab doublets demonstrated little improvement in clinical outcomes and a relevant toxicity profile. Conversely, the combination of new agents has been recently shown to improve survival in patients with metastatic disease, thus changing the treatment landscape of mRCC. This comprehensive review aims at summarizing the recent advances in the treatment of mRCC.

Pleural mesothelioma is a rare disease with a dismal prognosis and few therapeutic options. Until recently the median overall survival for a pleural mesothelioma patient was up to 2 years, with few exceptional cases of patients achieving a longer survival. Here, we report the clinical case of a patient whose survival spanned over 10 years. The patient underwent several systemic treatments, including three different chemotherapy lines (cisplatin‐pemetrexed, vinorelbine and platinum rechallenge) and two immunotherapy regimens using immune checkpoint inhibitors (anti CTLA‐4 tremelimumab and anti PD‐1 nivolumab). At the time this report was written, the patient was off‐treatment, asymptomatic and with a stable radiological disease. Our case demonstrates that a prolonged survival with a preserved quality of life may be reached in selected patients through the exploitation of the available treatments in an expertise setting.