Proteomic profiles of peritoneal fluid-derived small extracellular vesicles correlate with patient outcome in ovarian cancer.

Cancer-derived small extracellular vesicles (sEVs) are capable of modifying the tumor microenvironment and promoting tumor progression. Ovarian cancer (OvCa) is a lethal malignancy that preferentially spreads through the abdominal cavity. Thus, the secretion of such vesicles into the peritoneal fluid could be a determinant factor in the dissemination and behavior of this disease. We designed a prospective observational study to assess the impact of peritoneal fluid-derived sEVs (PFD-sEVs) in OvCa clinical outcome. For this purpose, 2 patient cohorts were enrolled: patients with OvCa who underwent a diagnostic or cytoreductive surgery and nononcological patients, who underwent abdominal surgery for benign gynecological conditions and acted as the control group. Systematic extraction of PFD-sEVs from surgical samples enabled us to observe significant quantitative and qualitative differences associated with cancer diagnosis, disease stage, and platinum chemosensitivity. Proteomic profiling of PFD-sEVs led to the identification of molecular pathways and proteins of interest and to the biological validation of S100A4 and STX5. In addition, unsupervised analysis of PFD-sEV proteomic profiles in high-grade serous ovarian carcinomas (HGSOCs) revealed 2 clusters with different outcomes in terms of overall survival. In conclusion, comprehensive characterization of PFD-sEV content provided a prognostic value with potential implications in HGSOC clinical management.

MEK inhibitor sensitivity in BRAF fusion-driven prostate cancer

Purpose The identification of subpopulations harboring druggable targets has become a major step forward in the subclassification of solid tumors into small groups suitable for specific therapies. BRAF fusions represent a paradigm of uncommon and targetable oncogenic events and have been widely correlated to the development of specific malignancies. However, they are only present in a limited frequency across most common tumor types. At this regard, we performed a genomic screening aimed to identifying rare variants associated to advanced prostate cancer development. Methods Tumoral tissue genomic screening of 41 patients developing advanced prostate cancer was performed at our center as part of the GETHI XX study. The project, sponsored by the Spanish Collaborative Group in Rare Cancers (GETHI), aims to analyze the molecular background of rare tumors and to discover unfrequent molecular variants in common tumors. Results Here we present the clinical outcome and an in-deep molecular analysis performed in a case harboring a SND1-BRAF fusion gene. The identification of such rearrangement in a patient refractory to standard therapies led to the administration of trametinib (MEK inhibitor). Despite unsensitive to standard therapies, the patient achieved a dramatic response to trametinib. A comprehensive study of the tumor demonstrated this event to be a trunk alteration with higher expression of MEK in areas of tumor invasion. Conclusions Our study describes the patient-driven discovery of the first BRAF fusion-driven prostate cancer effectively treated with trametinib. Consequently, MAPK pathway activation could define a new subtype of prostate cancer susceptible to a tailored management. (AU)

MEK inhibitor sensitivity in BRAF fusion-driven prostate cancer.

PURPOSE: The identification of subpopulations harboring druggable targets has become a major step forward in the subclassification of solid tumors into small groups suitable for specific therapies. BRAF fusions represent a paradigm of uncommon and targetable oncogenic events and have been widely correlated to the development of specific malignancies. However, they are only present in a limited frequency across most common tumor types. At this regard, we performed a genomic screening aimed to identifying rare variants associated to advanced prostate cancer development. METHODS: Tumoral tissue genomic screening of 41 patients developing advanced prostate cancer was performed at our center as part of the GETHI XX study. The project, sponsored by the Spanish Collaborative Group in Rare Cancers (GETHI), aims to analyze the molecular background of rare tumors and to discover unfrequent molecular variants in common tumors. RESULTS: Here we present the clinical outcome and an in-deep molecular analysis performed in a case harboring a SND1-BRAF fusion gene. The identification of such rearrangement in a patient refractory to standard therapies led to the administration of trametinib (MEK inhibitor). Despite unsensitive to standard therapies, the patient achieved a dramatic response to trametinib. A comprehensive study of the tumor demonstrated this event to be a trunk alteration with higher expression of MEK in areas of tumor invasion. CONCLUSIONS: Our study describes the patient-driven discovery of the first BRAF fusion-driven prostate cancer effectively treated with trametinib. Consequently, MAPK pathway activation could define a new subtype of prostate cancer susceptible to a tailored management.

Prognostic Value and Clinical Significance of FGFR Genomic Alterations (GAs) in Metastatic Urothelial Cancer Patients.

Fibroblast growth factor receptor (FGFR) genomic alterations (GAs) represent an actionable target, key to the pathogenesis of some urothelial cancers (UCs). Though FGFR GAs are common in noninvasive UC, little is known about their role in the metastatic(m) setting and response to therapy. This study aimed to assess the impact of FGFR alterations on sensitivity to systemic treatments and survival and to validate Bajorin's and Bellmunt's prognostic scores in mUC patients according to their FGFR status. We retrospectively analyzed data from 98 patients with tumor-sequenced UC who received treatment between January 2010 and December 2020. Up to 77 developed metastatic disease and were deemed the study population. Twenty-six showed FGFR GAs. A trend toward a better response to cisplatin and checkpoint inhibitors was suggested favoring FGFR GA tumors. FGFR GA patients who received an FGFR inhibitor as first-line had poorer responses compared with other options (20% vs. 68.4%, p = 0.0065). Median PFS was 6 vs. 5 months in the FGFR GA vs. FGFR WT cohort (p = 0.71). Median OS was significantly worse in the FGFR GA vs. FGFR WT cohort (16.2 vs. 31.9 months, p = 0.045). Multivariate analyses deemed FGFR GAs as a factor independently associated with the outcome (HR 2.59 (95% CI 1.21-5.55)). Bajorin's model correctly predicted clinical outcomes in the whole study population but not in FGFR GA cases. FGFR GAs are a relevant biomarker in mUC that could condition the response to systemic therapy. New prognostic models, including this molecular determination, should be designed and validated.

[The role of corticoids in the management of advanced prostate cancer.] / Corticoides en el manejo del cáncer de próstata avanzado.

Prostate cancer is the most frequent malignant tumor in males in developed countries and represents the second cause of cancer death. Over the last years, the number of treatments available for patients with advanced prostate cancer has improved significantly, achieving better disease control and notably better overall survival (1). Corticosteroids have been extensively used in the treatment of castration resistant prostate cancer due to their palliative benefits on symptoms secondary to their potent anti-inflammatory activity and their demonstrated antitumor activity. At present time, we have a wide therapeutic arsenal for patients with metastatic prostate cancer and concomitant medication with corticosteroids may counteract adverse events of the main validated therapies. Nevertheless, long term exposition to corticosteroid treatment required by prostate cancer patients may have negative implications in terms of development of potential adverse events and, in certain cases, even facilitating disease progression.

Corticoides en el manejo del cáncer de próstata avanzado / The role of corticoids in the management of advanced prostate cancer

El cáncer de próstata es el tumor maligno más frecuente en el varón en países desarrollados y constituye la segunda causa de muerte por cáncer. En los últimos años, el número de tratamientos disponibles para pacientes con cáncer de próstata avanzado ha aumentado significativamente, consiguiendo mejor control de la enfermedad y una mejoría notable de la supervivencia global (1).Los corticosteroides han sido ampliamente utilizados en el tratamiento del cáncer de próstata resistente a castración por sus beneficios paliativos de síntomas debido a su potente actividad anti-inflamatoria y por su actividad antitumoral demostrada. En el momento actual disponemos de un amplio arsenal terapéutico para los pacientes con carcinoma de próstata metastásico y la medicación concomitante con corticoides puede contrarrestar los efectos adversos de las principales terapias validadas. Sin embargo, la exposición a largo plazo al tratamiento corticoideo que precisan los pacientes con cáncer de próstata avanzado puede tener implicaciones negativas en cuanto al desarrollo de potenciales efectos adversos e incluso en algunos casos facilitando la progresión de la enfermedad

Prostate cancer is the most frequent malignant tumor in males in developed countries and represents the second cause of cancer death. Over the last years, the number of treatments available for patients with advanced prostate cancer has improved significantly, achieving better disease control and notably better overall survival (1). Corticosteroids have been extensively used in the treatment of castration resistant prostate cancer due to their palliative benefits on symptoms secondary to their potent anti-inflammatory activity and their demonstrated antitumor activity. At present time, we have a wide therapeu adretic arsenal for patients with metastatic prostate cancer and concomitant medication with corticosteroids may counteract adverse events of the main validated therapies. Nevertheless, long term exposition to corticosteroid treatment required by prostate cancer patients may have negative implications in terms of development of potential adverse events and, in certain cases, even facilitating disease progression