Management of bacillus Calmette-Guerin (BCG) refractory superficial bladder cancer: results with intravesical BCG and Interferon combination therapy

BCG is the most efficacious intravesical treatment for superficial bladder cancer. However, 30%-40% of tumors are refractory. BCG failure is an indication for cystectomy but several salvage intravesical (IVe) strategies have been proposed. Early results with reduced dose BCG in combination with IFN-a in patients are currently the most promising. We have adopted this approach and now report our preliminary results. This is the first report of this salvage therapy from Canada, the birthplace of IVe BCG therapy for superficial bladder cancer. The "O'Donnell protocol" of reduced dose IVe BCG plus IFN-a was followed in 12 patients with BCG refractory superficial transitional cell carcinoma. A retrospective review of the efficacy and toxicity of the treatment was conducted. One year from induction therapy with salvage BCG/IFN-a, 6 of the 12 (50%) of patients were tumor free. Of the six recurrences, 3(50%) did not respond to the IVe therapy and had residual/recurrent tumor at the first follow-up visit. Risk factors for treatment failure were identified. The combinative therapy was well tolerated with minimal toxicity compared to previous full dose BCG. Our 12 month data with reduced dose IVe BCG plus IFN-a salvage therapy for BCG refractory superficial TCC confirm previous reports of >50% complete response rates. We need longer follow up in a larger patient population to determine the durability of this promising therapy in patients who would otherwise undergo radical cystectomy

Clinical and Genomic Factors Associated with Greater Tumor Mutational Burden in Prostate Cancer

Tumor mutational burden (TMB) is a biomarker that predicts response to immune checkpoint inhibitor therapy. We currently lack a comprehensive understanding of how genomic and clinical factors correlate with TMB. We used a clinicogenomic database to assess independent predictors of TMB levels. The study included 2740 prostate cancer specimens from prostate gland (51.6%), lymph nodes (14.6%), and bone (10.4%). Androgen deprivation therapy use beyond 24 mo was weakly associated with high TMB (fold-change estimate [FCE] 1.14, 95% confidence interval [CI] 1.03–1.26; p = 0.009). In comparison to the prostate gland, metastases in the bladder (FCE 1.20, 95% CI 1.02–1.42; p = 0.029), liver (FCE 1.26, 95% CI 1.10–1.43; p < 0.001), and other locations (FCE 1.26, 95% CI 1.11–1.43; p < 0.001) were associated with high TMB. Microsatellite instability high (FCE 8.46, 95% CI 6.42–11.15; p < 0.001) and intermediate (FCE 1.77, 95% CI 1.46–2.14; p < 0.001) status were associated with greater TMB. Altered genes associated with greater TMB included MLH1 (FCE 1.81; p = 0.004), MSH2 (FCE 1.87; p < 0.001), MSH6 (FCE 1.92; p < 0.001), BRCA2 (FCE 1.69; p < 0.001), CDK12 (FCE 1.40; p < 0.001), MRE11 (FCE 2.28; p = 0.016), and PALB2 (FCE 2.08; p < 0.001). Our study demonstrates that TMB is relatively stable over lines of therapies and can be used to guide treatment at diagnosis or in later lines for patients with metastatic prostate cancer. Patient summary: The number of genetic mutations in a tumor (tumor mutational burden, TMB) may help in predicting a patient’s response to immunotherapy in advanced prostate cancer. We evaluated clinical and genetic factors that may affect TMB. We found that metastases in the bladder and liver are more likely to have high TMB than the primary tumor. Some individual genes are associated with high TMB. No prior treatment type was strongly associated with TMB, suggesting that TMB can be used to guide treatment at any time point.These data were presented at the American Society of Clinical Oncology 2023 Genitourinary Cancers Symposium

Multi-institutional analysis of clinical and imaging risk factors for detecting clinically significant prostate cancer in men with PI-RADS 3 lesions

Background Most Prostate Imaging-Reporting and Data System (PI-RADS) 3 lesions do not contain clinically significant prostate cancer (CSPCa; grade group >= 2). This study was aimed at identifying clinical and magnetic resonance imaging (MRI)-derived risk fac- tors that predict CSPCa in men with PI-RADS 3 lesions. Methods This study analyzed the detection of CSPCa in men who underwent MRI-targeted biopsy for PI-RADS 3 lesions. Multivariable logistic regression models with goodness-of-fit testing were used to identify variables associated with CSPCa. Receiver operating curves and decision curve analyses were used to estimate the clinical utility of a predictive model. Results Of the 1784 men reviewed, 1537 were included in the training cohort, and 247 were included in the validation cohort. The 309 men with CSPCa (17.3%) were older, had a higher prostate-specific antigen (PSA) density, and had a greater likelihood of an anteriorly located lesion than men without CSPCa (p < .01). Multivariable analysis revealed that PSA density (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.05-1.85; p < .01), age (OR, 1.05; 95% CI, 1.02-1.07; p < .01), and a biopsy-naive status (OR, 1.83; 95% CI, 1.38-2.44) were independently associated with CSPCa. A prior negative biopsy was negatively associated (OR, 0.35; 95% CI, 0.24-0.50; p < .01). The application of the model to the validation cohort resulted in an area under the curve of 0.78. A predicted risk threshold of 12% could have prevented 25% of biopsies while detecting almost 95% of CSPCas with a sensitivity of 94% and a specificity of 34%. Conclusions For PI-RADS 3 lesions, an elevated PSA density, older age, and a biopsy-naive status were associated with CSPCa, whereas a prior negative biopsy was negatively associated. A predictive model could prevent PI-RADS 3 biopsies while missing few CSPCas. Lay summary Among men with an equivocal lesion (Prostate Imaging-Reporting and Data System 3) on multiparametric magnetic resonance imaging (mpMRI), those who are older, those who have a higher prostate-specific antigen density, and those who have never had a biopsy before are at higher risk for having clinically significant prostate cancer (CSPCa) on subsequent biopsy. However, men with at least one negative biopsy have a lower risk of CSPCa. A new predictive model can greatly reduce the need to biopsy equivocal lesions noted on mpMRI while missing only a few cases of CSPCa

Prostatic Ductal Adenocarcinoma Controlled for Tumor Grade, Stage, and Margin Status Does Not Independently Influence the Likelihood of Biochemical Recurrence in Localized Prostate Cancer After Radical Prostatectomy

Context.— Prostatic ductal adenocarcinoma (PDA) has historically been considered to be an aggressive subtype of prostate cancer. Objective.— To investigate if PDA is independently associated with worse biochemical recurrence (BCR)–free survival after radical prostatectomy. Design.— A review of 1584 radical prostatectomies was performed to grade, stage, and assess margin status in each tumor nodule. Radical prostatectomies with localized PDA (ie, those lacking metastasis) in the tumor nodule with the highest grade and stage and worst margin status were matched with prostatic acinar adenocarcinoma according to grade, stage, and margin status. The effect of PDA on BCR was assessed by multivariable Cox regression and Kaplan-Meier analyses. Results.— Prostatic ductal adenocarcinoma was present in 171 cases. We excluded 24 cases because of lymph node metastasis (n = 13), PDA not in the highest-grade tumor nodule (n = 9), and positive surgical margin in a lower-grade tumor nodule (n = 2). The remaining 147 cases included 26 Grade Group (GG) 2, 44 GG3, 6 GG4, and 71 GG5 cancers. Seventy-six cases had extraprostatic extension, 33 had seminal vesicle invasion, and 65 had positive margins. Follow-up was available for 113 PDA and 109 prostatic acinar adenocarcinoma cases. Prostate-specific antigen density (odds ratio, 3.7; P = .001), cancer grade (odds ratio, 3.3–4.3; P = .02), positive surgical margin (odds ratio, 1.7; P = .02), and tumor volume (odds ratio, 1.3; P = .02) were associated with BCR in multivariable analysis. Prostatic ductal adenocarcinoma, its percentage, intraductal carcinoma, and cribriform Gleason pattern 4 were not significant independent predictors of BCR. Conclusions.— Advanced locoregional stage, higher tumor grade, and positive surgical margin status rather than the mere presence of PDA are more predictive of worse BCR-free survival outcomes following radical prostatectomy in men with a component of PDA