Development and Independent Validation of a Prognostic Gene Expression Signature Based on RB1, PTEN, and TP53 in Metastatic Hormone-sensitive Prostate Cancer Patients.

BACKGROUND: Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC). OBJECTIVE: To study the clinical implications of TSG mRNA expression in mHSPC patients. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective biomarker study in mHSPC patients. TSGlow status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSGwt for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis. RESULTS AND LIMITATIONS: A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSGlow (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSGlow was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSGlow patients, while a significant benefit was observed for ADT + D in the TSGwt group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART. CONCLUSIONS: TSGlow expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted. PATIENT SUMMARY: The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.

Prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitor treatment

Purpose We evaluated the prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitors (ICIs) treatment. Methods We conducted a multicenter retrospective study of patients with advanced/metastatic urothelial carcinoma treated with ICIs in four Spanish institutions. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) v.5.0 guidelines. The primary endpoint was overall survival (OS). Other endpoints were overall response rate (ORR) and progression-free survival (PFS). irAEs were evaluated as a time-dependent covariate to avoid immortal time bias. Results A total of 114 patients were treated with ICIs between May 2013 and May 2019, 105 (92%) of whom received ICIs as monotherapy. irAEs of any grade were experienced in 56 (49%) patients and 21 (18%) patients had grade ≥ 3 toxicity. The most frequent irAEs were gastrointestinal and dermatological toxicities, reported in 25 (22%) and 20 (17%) patients, respectively. Patients with grade 1–2 irAEs had significantly longer OS compared to those without grade 1–2 irAEs (median 18.2 vs. 8.7 months, HR = 0.61 [95% CI 0.39–0.95], p = 0.03). No association with efficacy was observed for patients with grade ≥ 3 irAEs. No difference in PFS was observed after adjusting for the immortal time bias. ORR was higher in patients who developed irAEs (48% vs 17%, p < 0.001). Conclusions Our findings suggest that development of irAEs was associated with higher ORR, and patients who developed grade 1–2 irAEs had longer OS. Prospective studies are necessary to confirm our findings (AU)

Curcumin as a hepatoprotective agent against chemotherapy-induced liver injury.

Despite significant advances in cancer therapeutics, chemotherapy remains the cornerstone of treatment for many tumors. Importantly, however, chemotherapy-induced toxicity, including hepatotoxicity, can lead to the interruption or discontinuation of potentially effective therapy. In recent years, special attention has been paid to the search for complementary therapies to mitigate chemotherapy-induced toxicity. Although there is currently a lack of specific interventions to mitigate or prevent hepatotoxicity in chemotherapy-treated patients, the polyphenol compound curcumin has emerged as a potential strategy to overcome this adverse effect. Here we review, firstly, the molecular and physiological mechanisms and major risk factors of chemotherapy-induced hepatotoxicity. We then present an overview of how curcumin has the potential to mitigate hepatotoxicity by targeting specific molecular mechanisms. Hepatotoxicity is a well-described side effect of cytotoxic drugs that can limit their clinical application. Inflammation and oxidative stress are the most common mechanisms involved in hepatotoxicity. Several studies have shown that curcumin could prevent and/or palliate chemotherapy-induced liver injury, mainly due to its anti-inflammatory, antioxidant, antifibrotic and hypolipidemic properties. Further clinical investigation using bioavailable curcumin formulations is warranted to demonstrate its efficacy as an hepatoprotective agent in cancer patients.

Prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitor treatment.

PURPOSE: We evaluated the prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitors (ICIs) treatment. METHODS: We conducted a multicenter retrospective study of patients with advanced/metastatic urothelial carcinoma treated with ICIs in four Spanish institutions. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) v.5.0 guidelines. The primary endpoint was overall survival (OS). Other endpoints were overall response rate (ORR) and progression-free survival (PFS). irAEs were evaluated as a time-dependent covariate to avoid immortal time bias. RESULTS: A total of 114 patients were treated with ICIs between May 2013 and May 2019, 105 (92%) of whom received ICIs as monotherapy. irAEs of any grade were experienced in 56 (49%) patients and 21 (18%) patients had grade ≥ 3 toxicity. The most frequent irAEs were gastrointestinal and dermatological toxicities, reported in 25 (22%) and 20 (17%) patients, respectively. Patients with grade 1-2 irAEs had significantly longer OS compared to those without grade 1-2 irAEs (median 18.2 vs. 8.7 months, HR = 0.61 [95% CI 0.39-0.95], p = 0.03). No association with efficacy was observed for patients with grade ≥ 3 irAEs. No difference in PFS was observed after adjusting for the immortal time bias. ORR was higher in patients who developed irAEs (48% vs 17%, p < 0.001). CONCLUSIONS: Our findings suggest that development of irAEs was associated with higher ORR, and patients who developed grade 1-2 irAEs had longer OS. Prospective studies are necessary to confirm our findings.

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

(1) Background: 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.

Nomogram based on baseline clinicopathological characteristics for predicting bladder cancer-specific survival to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

PURPOSE: To develop a risk score based on a prognostic model and a nomogram integrating baseline clinicopathological variables to predict bladder cancer-specific survival (BCSS) to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) patients. METHODS: We retrospectively identified a consecutive sample of 247 MIBC patients treated with cisplatin-based NAC-plus-cystectomy in two Spanish hospitals between 2000 and 2019. Age at MIBC diagnosis, sex, histology, lymphovascular invasion, previous non-MIBC, hydronephrosis, and clinical TNM were included in the initial Cox regression model. A risk score was computed based on the final prognostic model and a nomogram was used to estimate BCSS at 2 and 5 years. RESULTS: Median age was 66 years; 89% were males; 83% had pure urothelial carcinoma; 16.2% had previous non-MIBC. Clinical stage was T2N0, T3-4aN0, and Tx-4N + in 24%, 57%, and 19% of patients, respectively. Complete pathological response was seen in 29.4% and downstaging to non-MIBC (ypT1, ypTa, ypTis) in 12.5% of patients. Overall 5-year BCSS was 59%. Four prognostic factors were identified: variant histology, previous non-MIBC, female sex and hydronephrosis. By adding the points attributed to each of these factors, we categorized patients in three groups: low-risk (0 points); intermediate-risk (1-9 points); high-risk (≥ 10 points). Five-year BCSS was 72%, 53%, and 15%, respectively (p < 0.0001). CONCLUSION: We developed a nomogram and risk score based on four baseline clinicopathological characteristics to predict BCSS to NAC-plus-cystectomy in MIBC patients. If validated in prospective studies, this nomogram can be useful for selecting patients likely to benefit from NAC.

Phase 2 Randomized Study of Radiation Therapy and 3-Year Androgen Deprivation With or Without Concurrent Weekly Docetaxel in High-Risk Localized Prostate Cancer Patients.

PURPOSE: Docetaxel improves survival in patients with metastatic prostate cancer. This randomized phase 2 trial aimed to assess the activity of weekly docetaxel with radiation therapy (RT) plus androgen deprivation in patients with high-risk localized prostate cancer. The study examined the benefit of 9 weekly docetaxel administrations to RT plus 3 years of luteinizing hormone-releasing hormone analogues. METHODS AND MATERIALS: A total of 132 patients were recruited for the study. Patients' characteristics included T3-T4 stage (81.1%), Gleason score ≥8 (77.3%), prostate-specific antigen level >20 ng/mL (28.9%), and pN+ (18.2%). All patients included in the trial received either the standard-of-care control arm with luteinizing hormone-releasing hormone analogues plus RT (arm A) or the experimental arm (RT + 9 weekly cycles of docetaxel + 3 years of androgen deprivation therapy, arm B). The primary objective was to achieve a high percentage of patients who were free of biochemical recurrence within 5 years of randomization. Secondary endpoints included biochemical recurrence-free survival (BRFS), progression-free survival (PFS), overall survival (OS), clinical response rate, biochemical response rate, and toxicity. RESULTS: No difference between the arms of the study was found in biochemical recurrence (93.4% at 60 months for arm A vs 85.3% for arm B; P = .3297). PFS at 60 months was 93.4% and 83.7% in arms A and B, respectively (P = .2532). Five-year survival was 93.3% (95% confidence interval, 83.1-97.45) in arm A versus 93.6% (83.8-97.55) in arm B; median PFS and OS have not been reached. Prostate-specific antigen level ≤0.2 ng/mL at 3 months after the end of treatment was seen in 81.25% of patients in arm A compared with 90.48% of patients in arm B (P = .2028). BRFS was not significantly different between treatment arms. Diarrhea was the main nonhematologic toxicity. Long-term follow-up has not yet been enough to meet median PFS and OS. CONCLUSIONS: Concurrent weekly docetaxel can be administered safely with standard doses of RT without a significant increase in the toxicity profile. No statistically significant differences for 5-year BRFS, PFS, and OS have been observed when docetaxel was added to conventional treatment.