Genomic Profiling and Molecular Characterisation of Metastatic Urothelial Carcinoma.

The clinical management of metastatic urothelial carcinoma (mUC) is undergoing a major paradigm shift; the integration of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) into the mUC therapeutic strategy has succeeded in improving platinum-based chemotherapy outcomes. Given the expanding therapeutic armamentarium, it is crucial to identify efficacy-predictive biomarkers that can guide an individual patient's therapeutic strategy. We reviewed the literature data on mUC genomic alterations of clinical interest, discussing their prognostic and predictive role. In particular, we explored the role of the fibroblast growth factor receptor (FGFR) family, epidermal growth factor receptor 2 (HER2), mechanistic target of rapamycin (mTOR) axis, DNA repair genes, and microsatellite instability. Currently, based on the available clinical data, FGFR inhibitors and HER2-directed ADCs are effective therapeutic options for later lines of biomarker-driven mUC. However, emerging genomic data highlight the opportunity for earlier use and/or combination with other drugs of both FGFR inhibitors and HER2-directed ADCs and also reveal additional potential drug targets that could change mUC management.

Concomitant Immunotherapy and Metastasis-Directed Radiotherapy in Upper Tract Urothelial Carcinoma: A Biomarker-Driven, Original, Case-Based Proof-of-Concept Study.

Metastatic upper tract urothelial carcinoma (mUTUC) has a poor prognosis. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in patients with metastatic urothelial carcinoma. However, data supporting the use of ICIs in patients with mUTUC are limited. A promising synergy between ICI and concomitant radiotherapy (RT) has been reported in patients with mUTUC. Our research involved a case-based investigation and emphasized the successful integration of different specialists' skills. Observed after partial urethrectomy procedures for muscle-invasive upper tract urothelial carcinoma (UTUC), the radiological detection of lung metastases prompted us to implement cisplatin-based first-line chemotherapy and molecular characterization in the treatment process. We uncovered alterations in the ERBB2 and FGFR3 genes and mismatch repair deficiency at a molecular level. First-line chemotherapy treatment led to a stable disease, and the patient was started on maintenance immunotherapy with Avelumab. Subsequently, an increase in the size of the lung nodules was described, and the patient received radiotherapy for three lung lesions in combination with immunotherapy. After 3 months, a restaging CT scan reported a complete response, which is still ongoing. We discuss the mechanisms driving RT/ICI synergy and the molecular profile of mUTUC as factors that should be considered in therapeutic strategy planning. Molecular insight enhances the originality of our study, providing a nuanced understanding of the genetic landscape of mUTUC and paving the way for targeted therapeutic strategies. The therapeutic armamentarium expansion encourages the design of a multimodal and personalized approach for each mUTUC patient, taking into account tumor heterogeneity and molecular profiling.

Genomic Profiling and Molecular Characterization of Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) treatment has undergone three major paradigm shifts in recent years, first with the introduction of molecular targeted therapies, then with immune checkpoint inhibitors, and, more recently, with immune-based combinations. However, to date, molecular predictors of response to targeted agents have not been identified for ccRCC. The WHO 2022 classification of renal neoplasms introduced the molecularly defined RCC class, which is a first step in the direction of a better molecular profiling of RCC. We reviewed the literature data on known genomic alterations of clinical interest in ccRCC, discussing their prognostic and predictive role. In particular, we explored the role of VHL, mTOR, chromatin modulators, DNA repair genes, cyclin-dependent kinases, and tumor mutation burden. RCC is a tumor whose pivotal genomic alterations have pleiotropic effects, and the interplay of these effects determines the tumor phenotype and its clinical behavior. Therefore, it is difficult to find a single genomic predictive factor, but it is more likely to identify a signature of gene alterations that could impact prognosis and response to specific treatment. To accomplish this task, the interpolation of large amounts of clinical and genomic data is needed. Nevertheless, genomic profiling has the potential to change real-world clinical practice settings.

Multimodal Management of Colorectal Liver Metastases: State of the Art.

Liver is the most common site of colorectal cancer (CRC) metastases. Treatment of CRC liver metastases (CRLM) includes different strategies, prevalently based on the clinical and oncological intent. Valid approaches in liver-limited or liver-prevalent disease include surgery, percutaneous ablative procedures (radiofrequency ablation, microwave ablation), intra-arterial perfusional techniques (chemo-embolization, radio-embolization) as well as stereotactic radiotherapy. Systemic treatments, including chemotherapy, immunotherapy and other biological agents, are the only options for patients with no chance of locoregional approaches. The use of chemotherapy in other settings, such as neoadjuvant, adjuvant or conversion therapy of CRLM, is commonly accepted in the clinical practice, although data from several clinical trials have been mostly inconclusive. The optimal integration of all these strategies, when applicable and clinically indicated, should be ever considered in patients affected by CRLM based on clinical evidence and multidisciplinary experience. Here we revised in detail all the possible therapeutic approaches of CRLM focusing on the current evidences, the studies still in progress and the often contradictory data.