Response assessment using [68 Ga]Ga-PSMA ligand PET in patients undergoing systemic therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: To assess which parameters of [68 Ga]Ga-PSMA-11 positron emission tomography (PSMA-PET) predict response to systemic therapies in metastatic (m) castration-resistant prostate cancer (CRPC). In addition, to investigate which of these factors are associated with overall survival (OS). METHODS: We retrospectively assessed the following PSMA-PET parameters in 43 patients before and after systemic therapies for mCRPC: PSMA total tumor volume (TTV), mean standardized uptake value (SUVmean), SUVmax, and SUVpeak. prostate-specific antigen (PSA) levels and PSMA-PET/CT(magnetic resonance imaging [MRI]) imaging were both performed within 8 weeks before and 6 weeks after systemic therapy. PSMA-PET and CT (MRI) images were reviewed according to the modified PET Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results were compared to PSA response. Univariable survival analyses were performed. RESULTS: Overall, 43 patients undergoing 67 systemic therapies were included (9 patients radium-223, 12 cabazitaxel, 22 docetaxel, 6 abiraterone, and 18 enzalutamide). Median serum PSA level before any therapy was 11.3 ng/mL (interquartile range [IQR] = 3.3, 30.1). Delta (d) PSA after systemic therapies was -41%, dTTV 10.5%, dSUVmean -7.5%, dSUVmax -13.3%, dSUVpeak -12%, and dRECIST -13.3%. Overall, 31 patients had dPSA response (46.3%), 12 stable disease (17.9%), and 24 progressive disease (35.8%). All observed PET parameters, as well as the RECIST evaluation, were significantly associated with PSA response (dTTV P = .003, dSUVmean P = .003, dSUVmax P = .011, dSUVpeak P < 0001, dRECIST P = .012), while RECIST assessment was applicable in 37 out of 67 patients (55.2%). Within a median follow-up of 33 months (IQR = 26, 38), 10 patients (23.3%) died of PC. On univariable survival analyses, neither the investigated PET parameters nor PSA level or RECIST criteria were associated with OS. CONCLUSION: PSMA-PET provides reliable parameters for prediction of response to systemic therapies for mCRPC. These parameters, if confirmed, could enhance RECIST criteria, specifically concerning its limitations for sclerotic bone lesions.

Obesity is associated with biochemical recurrence after radical prostatectomy: A multi-institutional extended validation study.

BACKGROUND: There are no clear data regarding the association between body mass index (BMI) and outcomes after radical prostatectomy (RP). This study aimed to investigate the association between BMI and biochemical recurrence (BCR) after RP in a large international contemporary cohort of patients with prostate cancer. METHODS: We retrospectively analyzed data from 6,519 patients who underwent RP at 5 institutions. BMI was analyzed as both a continuous and categorical variable (<25kg/m2, 25-29.9kg/m2 [overweight], and≥30kg/m2 [obese]). The associations of continuous and categorical BMI with BCR were evaluated using univariable and multivariable Cox models, and prognostic accuracy was assessed using Harrell׳s C-index. RESULTS: The median BMI was 28kg/m2 (interquartile range: 24-32kg/m2); 2,155 patients (33.1%) had a BMI = 25 to 29.9kg/m2 and 2,462 patients (37.7%) had a BMI≥30kg/m². Overweight and obese status were associated with extracapsular extension (P = 0.001) and seminal vesicle invasion (P = 0.005). The median follow-up was 28 months, and the estimated 5-year BCR-free survival rates for patients with a BMI<25kg/m2, 25 to 29.9kg/m2, and≥30kg/m² were 92%, 86%, and 79%, respectively (P<0.001). Multivariable analyses (adjusted for preoperative prostate-specific antigen levels, biopsy Gleason score, and clinical stage) revealed that obesity was associated with the risk of extracapsular extension (P<0.001), seminal vesicle invasion (P<0.001), and BCR (hazard ratio: 1.37, P<0.001). BMI and obesity remained associated with BCR after adjusting for postoperative characteristics. Addition of BMI slightly increased the discrimination of the multivariable clinical prognostic model (from 79.9%-80.9%). CONCLUSIONS: Overweight and obese status was associated with adverse pathological features and BCR after RP. However, the addition of BMI did not significantly improve the prognostic accuracy of a model that was based on established predictors.

The Neutrophil-to-lymphocyte Ratio as a Prognostic Factor for Patients with Urothelial Carcinoma of the Bladder Following Radical Cystectomy: Validation and Meta-analysis.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) as a marker of systemic inflammatory response has been proposed as a prognostic factor for patients with urothelial carcinoma of the bladder (UCB) following radical cystectomy (RC). OBJECTIVE: To validate NLR as a prognostic biomarker and to perform a pooled meta-analysis. DESIGN, SETTING, AND PARTICIPANTS: The NLR was assessed in 4061 patients within 30 days before RC. A systematic review of the literature was undertaken using electronic databases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations with overall survival (OS) and cancer-specific survival (CSS) were evaluated using Cox models. Hazard ratios (HRs) were pooled in a meta-analysis using random-effects modeling. RESULTS AND LIMITATIONS: A high NLR (≥2.7) was associated with advanced pathological tumor stages (p<0.001), lymph node involvement (p<0.001), lymphovascular invasion (p=0.008), and positive soft0tissue surgical margins (p=0.001). In multivariate analyses, a high NLR was independently associated with both OS (HR 1.11, 95% confidence interval [CI] 1.01-1.22; p=0.029) and cancer-specific survival (CSS) (HR 1.21, 95% CI 1.07-1.37, p=0.003). The discrimination of the multivariate models increased by 0.2% on inclusion of NLR. Five studies were included in the meta-analysis. The HR for NLR greater than the cutoff was 1.46 (95% CI 1.01-1.92) for OS and 1.51 (95% CI 1.17-1.85) for CSS. Limitations include the retrospective study design and the lack of standardized follow-up. CONCLUSION: In patients with UCB treated with RC, a high preoperative NLR is associated with more advanced tumor stage, lymph node metastasis, and worse prognosis. The NLR may be a readily available and useful biomarker for preoperative prognostic stratification. PATIENT SUMMARY: We investigated the neutrophil-to-lymphocyte ratio (NLR) as a prognostic marker in patients with bladder cancer treated with radical cystectomy. We found that a high NLR is associated with worse oncologic outcomes, suggesting it could play a role in risk stratification.

Immunotherapies for bladder cancer: a new hope.

PURPOSE OF REVIEW: We review recent data on immunotherapies for bladder cancer and discuss strategies to maximize the antitumor effect of immunotherapy in solid tumors. RECENT FINDINGS: Anti-programmed death ligand 1 has shown promise in advanced bladder cancer. Clinical trials of immune checkpoint inhibitors as monotherapy or in combination are underway. Here we review strategies for enhancing antitumor immunity using immunomodulating agents or combination treatments that may increase tumor response. SUMMARY: Combining immune checkpoint inhibitors with other treatment modalities may lead to the development of new treatment strategies in advanced bladder cancer; however, identifying predictive biomarkers is essential for appropriate patient selection.

Integrative analysis of prostate cancer aggressiveness.

BACKGROUND: Clinical management of prostate cancer (PC) is still highly demanding on the identification of robust biomarkers which will allow a more precise prediction of disease progression. METHODS: We profiled both mRNA expression and DNA copy number alterations (CNAs) from laser capture microdissected cells from 31 PC patients and 17 patients with benign prostatic hyperplasia using Affymetrix GeneChip® technology. PC patients were subdivided into an aggressive (Gleason Score 8 or higher, and/or T3/T4 and/or N+/M+) and non-aggressive (all others) form of PC. Furthermore, we correlated the two datasets, as genes whose varied expression is due to a chromosomal alteration, may suggest a causal implication of these genes in the disease. All statistical analyses were performed in R version 2.15.0 and Bioconductor version 1.8.1., respectively. RESULTS: We confirmed several common altered chromosomal regions as well as recently discovered loci such as deletions on chromosomes 3p14.1-3p13 and 13q13.3-13q14.11 supporting a possible role for RYBP, RGC32, and ELF1 in tumor suppression. Integrative analysis of expression and CN data combined with data retrieved from online databases propose PTP4A3 and ELF1 as possible factors for tumor progression. CONCLUSIONS: Copy number data analysis revealed some significant differences between aggressive and non-aggressive tumors, while gene expression data alone could not define an aggressive group of patients. The assessment of CNA may have diagnostic and prognostic value in PC.

Rechallenge with mTOR inhibitors in metastatic renal cell carcinoma patients who progressed on previous mTOR inhibitor therapy.

OBJECTIVE: To determine if mammalian target of rapamycin (mTOR) inhibitor (everolimus or temsirolimus) rechallenge in the third- or fourth-line setting after sequential use of a vascular endothelial growth factor receptor (VEGF)-targeted agent and an mTOR inhibitor is a feasible and effective treatment strategy in patients with metastatic renal cell carcinoma (mRCC). METHODS: Patients who received a VEGF-targeted agent, an mTOR inhibitor and rechallenge with a second mTOR inhibitor at 2 institutions (Hôpital Européen Georges-Pompidou and Vienna Medical School) between 30 March 2001 and 15 September 2011 were included. Analyses of radiographic images were performed according to the Response Evaluation Criteria in Solid Tumors, version 1.0, to determine the objective response rate and treatment duration (TD). RESULTS: Twelve patients met the inclusion criteria. Following 1 or 2 VEGF receptor-tyrosine kinase inhibitors, 7 patients firstly received everolimus and 5 patients received temsirolimus. Irrespective of treatment sequence, 6 of 12 patients (50%) responded to everolimus and 4 of 12 patients (33%) responded to temsirolimus; 3 patients (25%) did not respond to either. Median TDs (95% confidence interval) for everolimus → temsirolimus and temsirolimus → everolimus sequences were 10.3 months (8.8-19.2 months) and 5.8 months (2.9-19.3 months), respectively. CONCLUSIONS: Despite the limited number of patients, this highlights the feasibility of utilizing mTOR rechallenge as an integral part of sequential treatment strategies in mRCC.

MNS16A tandem repeat minisatellite of human telomerase gene and prostate cancer susceptibility.

Telomere dysfunction is an early event in the development of prostate cancer and telomerase (TERT) activity is detectable in the majority of prostate cancers. Genetic variation in TERT and its regulatory elements may influence prostate carcinogenesis. MNS16A, a functional polymorphic tandem repeat minisatellite of TERT, has been studied in several malignancies. We determined MNS16A genotypes in an Austrian case-control study for the first time in the context of prostate cancer, comprising 1165 prostate cancer cases and 674 benign prostate hyperplasia controls with PCR. In addition to the five reported variable number of tandem repeats (VNTRs), we identified VNTR-212, a rare variant, for the first time in a European population. Multiple logistic regression analysis revealed no differences in genotype distribution between cases and controls. However, in stratified analysis, MNS16A VNTR-274 (OR = 0.25, 95% CI = 0.06-0.79, P = 0.016) and genotype 274/302 (OR = 0.13, 95% CI = 0.01-0.58, P = 0.005) were associated with a significantly decreased risk of prostate cancer in the age group >70 years. Our finding of a MNS16A genotype conferring a protective effect against prostate cancer in older men suggests a potential role of this polymorphism in prostate cancer susceptibility but demands to be validated in further studies.

Common genetic polymorphisms of AURKA and prostate cancer risk.

PURPOSE: AURKA is a centrosome-associated serine/threonine kinase involved in mitotic chromosomal segregation. The AURKA gene is located on chromosome 20q13, also known as HPC20 prostate cancer susceptibility locus. Therefore, we investigated in this Caucasian case-control study two single nucleotide polymorphisms (SNPs) of the AURKA gene, rs8173 located in the 3'-untranslated region (G1891C) and rs2273535 in exon 5 (Phe31Ile), and their association with prostate cancer risk. METHODS: DNA was extracted from peripheral blood of 824 prostate cancer patients and 1,081 control patients with benign prostatic hyperplasia (BPH). Genotypes were determined using 5'-nuclease TaqMan assays. Multiple logistic regressions were performed to calculate odds ratios (OR) and confidence intervals (CI) and to adjust for confounders. RESULTS: The odds ratios calculated relative to the wild-type were for the homozygous polymorphic genotypes 1.11 (95% CI = 0.70-1.76) for rs8173 and 1.32 (95% CI = 0.76-2.31) for rs2273535, respectively. Stratified analyses according to Gleason score showed also no statistically significant association for the investigated polymorphisms and prostate cancer risk. CONCLUSIONS: The two investigated SNPs in AURKA were not found to be associated with prostate cancer risk. Other common SNPs of AURKA should be investigated in further studies because of its location on a prostate cancer susceptibility locus.