Background Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25–50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments–certified laboratory. Outcome measurements and statistical analysis The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Results and limitations Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p = 0.024) and validation (p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p < 0.001; 87% sensitivity, 100% specificity) and better overall survival (p = 0.007). This test remained predictive for pathologic response in the validation set (p = 0.033), with a trend towards better overall survival (p = 0.055). These results require further validation in additional sample sets. Conclusions: Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Patient summary Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

Purpose We conducted a systematic review and pooled analysis of small renal masses under active surveillance to identify progression risk and characteristics associated with metastases. Materials and Methods A MEDLINE search was performed to identify all clinical series reporting surveillance of localized renal masses. For studies reporting individual level data, clinical and radiographic characteristics of tumors without progression were compared to those progressing to metastases. Results 18 series (880 patients, 936 masses) met screening criteria from which 18 patients progressing to metastasis were identified (mean 40.2 months). Six studies (259 patients, 284 masses) provided individual level data for pooled analysis. With a mean follow up of 33.5±22.6 months, mean initial tumor diameter was 2.3±1.3 cm and mean linear growth rate was 0.31±0.38 cm/year. 65 masses (23%) exhibited zero net growth under surveillance; of which none progressed to metastasis. Pooled analysis revealed increased age (75.1±9.1 vs. 66.6±12.3 years, p=0.03), initial tumor diameter (4.1±2.1 vs. 2.3±1.3 cm, p<0.0001), initial estimated tumor volume (66.3±100.0 vs. 15.1±60.3 cm3, p<0.0001), linear growth rate (0.8±0.65 vs. 0.3±0.4 cm/yr, p=0.0001), and volumetric growth rate (27.1±24.9 vs. 6.2±27.5 cm3/yr, p<0.0001) in the progression cohort. Conclusions A substantial proportion of small renal masses remain radiographically static following an initial period of active surveillance. Progression to metastases occurs in a small percentage of patients and is generally a late event. These results indicate that in patients with competing health risks, radiographic surveillance may be an acceptable initial approach with delayed intervention reserved for those exhibiting significant linear or volumetric growth.

Purpose Given the limited sensitivity and specificity of prostate-specific antigen (PSA), its widespread use as a screening tool has raised concerns for the overdiagnosis of low-risk and the underdiagnosis of high-grade prostate cancer. To improve early-detection biopsy decisions, the National Cancer Institute conducted a prospective validation trial to assess the diagnostic performance of the prostate cancer antigen 3 (PCA3) urinary assay for the detection of prostate cancer among men screened with PSA. Patients and Methods In all, 859 men (mean age, 62 years) from 11 centers scheduled for a diagnostic prostate biopsy between December 2009 and June 2011 were enrolled. The primary outcomes were to assess whether PCA3 could improve the positive predictive value (PPV) for an initial biopsy (at a score > 60) and the negative predictive value (NPV) for a repeat biopsy (at a score < 20). Results For the detection of any cancer, PPV was 80% (95% CI, 72% to 86%) in the initial biopsy group, and NPV was 88% (95% CI, 81% to 93%) in the repeat biopsy group. The addition of PCA3 to individual risk estimation models (which included age, race/ethnicity, prior biopsy, PSA, and digital rectal examination) improved the stratification of cancer and of high-grade cancer. Conclusion These data independently support the role of PCA3 in reducing the burden of prostate biopsies among men undergoing a repeat prostate biopsy. For biopsy-naive patients, a high PCA3 score (> 60) significantly increases the probability that an initial prostate biopsy will identify cancer.