Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel

Metastatic prostate cancer; Chemotherapy; Hormonal therapyCáncer de próstata metastásico; Quimioterapia; Terapia hormonalCàncer de pròstata metastàtic; Quimioteràpia; Teràpia hormonalBackground: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3-0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4-0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2-0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1-3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1-2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2-2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2-1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1-3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX

Results from the INMUNOSUN-SOGUG trial: a prospective phase II study of sunitinib as a second-line therapy in patients with metastatic renal cell carcinoma after immune checkpoint-based combination therapy

Immune checkpoint inhibitors; Metastatic renal carcinoma; Second-line treatmentInhibidors del punt de control immunitari; Carcinoma renal metastàtic; Tractament de segona líniaInhibidores del punto de control inmunitario; Carcinoma renal metastásico; Tratamiento de segunda líneaBackground: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies. Patients and methods: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate. Results: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib. Conclusion: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.This work was supported by Pfizer, S.L.U. (Madrid, Spain). Pfizer, S.L.U. provided an unrestricted research grant with drug funding and drug supply to conduct the study (no grant number)

Prognostic Gene Expression-Based Signature in Clear-Cell Renal Cell Carcinoma

The inaccuracy of the current prognostic algorithms and the potential changes in the therapeutic management of localized ccRCC demands the development of an improved prognostic model for these patients. To this end, we analyzed whole-transcriptome profiling of 26 tissue samples from progressive and non-progressive ccRCCs using Illumina Hi-seq 4000. Differentially expressed genes (DEG) were intersected with the RNA-sequencing data from the TCGA. The overlapping genes were used for further analysis. A total of 132 genes were found to be prognosis-related genes. LASSO regression enabled the development of the best prognostic six-gene panel. Cox regression analyses were performed to identify independent clinical prognostic parameters to construct a combined nomogram which includes the expression of CERCAM, MIA2, HS6ST2, ONECUT2, SOX12, TMEM132A, pT stage, tumor size and ISUP grade. A risk score generated using this model effectively stratified patients at higher risk of disease progression (HR 10.79; p < 0.001) and cancer-specific death (HR 19.27; p < 0.001). It correlated with the clinicopathological variables, enabling us to discriminate a subset of patients at higher risk of progression within the Stage, Size, Grade and Necrosis score (SSIGN) risk groups, pT and ISUP grade. In summary, a gene expression-based prognostic signature was successfully developed providing a more precise assessment of the individual risk of progression

Biomarcadors i resistència a la quimioteràpia en càncer de pròstata

[cat] El càncer de pròstata es la segona causa de mort per càncer en els homes. Tot i que la majoria de pacients amb càncer de pròstata metastàtic responen al tractament de deprivació androgènica, tots ells acabaran desenvolupant càncer de pròstata resistent a la castració. En l’any 2004, la combinació de docetaxel i prednisona va esdevenir un nou estàndard de tractament en el càncer de pròstata resistent a la castració. Posteriorment, dos agents hormonals, abiraterona i enzalutamida, i un nou quimioteràpic, cabazitaxel, han estat aprovats per al tractament del càncer de pròstata resistent a la castració. No obstant, totes aquestes teràpies no son curatives i es necessària la identificació de biomarcadors predictius de resposta, i conèixer els mecanismes de resistència a aquests tractaments. Els objectius d’aquesta tesis són desxifrar nous mecanismes de resistència a docetaxel, i identificar nous biomarcadors predictius de resposta a aquest i també pronòstics. A través de l’anàlisi d’expressió gènica de línies cel·lulars resistents a docetaxel, així com de mostres de càncer de pròstata localitzat d’alt risc de pacients tractats amb docetaxel de forma neoadjuvant, hem identificat que el procés de transició epitel·li-mesènquima intervé en la resistència a docetaxel. D’altre banda, la inhibició de ZEB1 mitjançant siRNAs reverteix la resistència a docetaxel i provoca la infraexpressió de marcadors mesenquimals. A més a més, es va identificar un subgrup de cèl·lules positives per a ZEB1 i CD44, que eren intrínsicament resistent a la quimioteràpia, i en mostres clíniques aquests marcadors es van correlacionar amb un comportament clínic més agressiu. Per un altre banda, la detecció del gen de fusió TMPRSS2-ERG a la sang es correlaciona amb una baixa taxa de respostes per PSA a docetaxel, així com amb una supervivència lliure de progressió per PSA i clínic/radiològica més curta en els pacients afectes de càncer de pròstata resistent a la castració tractats amb docetaxel. Finalment, mitjançant un anàlisi d’expressió gènica en mostres de la capa mononuclear de sang perifèrica es van identificar un total de 282 gens diferencialment expressats entre mostres amb més de 5 cèl·lules circulants tumorals i menys de 5. D’aquests resultats es va derivar un model consistent en dos gens, SELENBP1 i MMP9, que permet identificar una població amb una pitjor supervivència global.[eng] Prostate cancer (PC) is the second leading cause of death from cancer in men. Although most patients with metastatic prostate cancer respond to androgen deprivation therapy, virtually all of them eventually develop castration-resistant prostate cancer (CRPC). In 2004, the combination of docetaxel and prednisone was established as the new standard of care for patients with CRPC. More recently, two hormonal agents, abiraterone and enzalutamide, and a new taxane, cabazitaxel, have been approved for the treatment of CRPC. However, current therapies are not curative and research is needed to identify predictors of benefit and mechanisms of resistance for each agent. We aim to identify novel mechanisms of resistance to docetaxel and predictive and prognostic biomarkers in PC. Using cell lines resistant to docetaxel and also clinical samples of high risk localized PC treated with neoadjuvant docetaxel; we discovered that the epithelial-to-mesenchymal transition process mediates docetaxel resistance. The inhibition of this process by ZEB1 siRNA transfection reverted docetaxel resistance and reduced the mesenchymal biomarkers. Moreover, a subset of cells positive for ZEB1 and CD44 are intrinsically resistant to this chemotherapy, and in clinical samples, these biomarkers correlated with aggressive clinical behavior. Additionally, the detection of the fusion gene TMPRSS2-ERG in the blood is correlated with a lower PSA response rate, a shorter PSA progression-free survival and clinical/radiological progression-free survival to docetaxel in CPRC patients. Finally, a global gene expression analysis in peripheral blood mononuclear cells allowed us to identify the differential expression of 282 genes between samples with ≥5 circulating tumor cells (CTCs) vs <5 CTCs. Using a two-gene model, we identified a subset of metastatic CRPC with poor overall survival