Immune checkpoint blockade in renal cell carcinoma.

Immune checkpoint blockade (ICB) is the foundation of current first-line therapies in patients with metastatic renal cell carcinoma (mRCC) with the potential for eliciting long-lasting remissions. With the expanding arsenal of ICB-based therapies, biomarkers of response are urgently needed to guide optimal therapeutic selection. We review the data behind ICB therapy in RCC, emerging biomarkers of response, and the evolving role of surgery in patients with mRCC.

Clinicopathologic features associated with survival after cytoreductive nephrectomy for nonclear cell renal cell carcinoma.

OBJECTIVES: To report the overall survival (OS) outcomes of patients with nonclear cell renal cell carcinoma (nccRCC) treated at our institution with a cytoreductive nephrectomy (CN) and better understand the clinical and pathological characteristics of the patients that respond best. MATERIAL AND METHODS: We queried our prospectively maintained database for patients who underwent CN for nccRCC between 1989 and 2018. Histology was reviewed by an expert genitourinary pathologist, and nccRCC tumors were subdivided into papillary, unclassified, chromophobe, and other histology. Baseline clinicopathology, treatments, and survival outcomes were recorded. Preoperative hematological parameters including the neutrophil-to-lymphocyte ratio (NLR) were analyzed. Significant univariate predictors of OS were tested in a multivariate model. RESULTS: There were 100 nccRCC patients treated with CN. Median age was 61 years (IQR: 48-69) and 65% were male. There were 79 patient deaths with a median OS of 13.7 months (10.8-27.2). Estimated 2- and 5-year survival was 40.1% and 12.2%, respectively. Median follow-up of survivors was 13 months (IQR: 3-30). On multivariate analysis, increasing NLR (hazard ratio [HR] 1.27; 95% confidence interval [CI] 1.14-1.40, P < 0.001) and sarcomatoid features (HR 2.18; 95% CI 1.19-3.97, P = 0.014) conferred worse OS and the presence of papillary features were a favorable prognostic feature (HR 0.37; 95% CI 0.21-0.65, P < 0.001). CONCLUSIONS: OS outcomes in patients with nccRCC who underwent a CN are consistently modest throughout the study period. Patients with papillary features and a lower preoperative NLR may be better candidates for a CN.

Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations.

INTRODUCTION: Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. METHODS: We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas (n = 110), University of Tokyo (n = 37), The International Cancer Genome Consortium (n = 31), and from our own institutional prospective database (n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations. RESULTS: In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033. CONCLUSIONS: We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed.

Prospective Evaluation of Unprocessed Core Needle Biopsy DNA and RNA Yield from Lung, Liver, and Kidney Tumors: Implications for Cancer Genomics.

CONTEXT: Targeted needle biopsies are increasingly performed for the genetic characterization of cancer. While the nucleic acid content of core needle biopsies after standard pathology processing (i.e., formalin fixation and paraffin embedding (FFPE)) has been previously reported, little is known about the potential yield for molecular analysis at the time of biopsy sample acquisition. OBJECTIVES: Our objective was to improve the understanding of DNA and RNA yields from commonly used core needle biopsy techniques prior to sample processing. METHODS: We performed 552 ex vivo 18 and 20G core biopsies in the lungs, liver, and kidneys. DNA and RNA were extracted from fresh-frozen core samples and quantified for statistical comparisons based on needle gauge, biopsy site, and tissue type. RESULTS: Median tumor DNA yields from all 18G and 20G samples were 5880 ng and 2710 ng, respectively. Median tumor RNA yields from all 18G and 20G samples were 1100 ng and 230 ng, respectively. A wide range of DNA and RNA quantities (1060-13,390 ng and 370-6280 ng, respectively) were acquired. Median DNA and RNA yields from 18G needles were significantly greater than those from 20G needles across all organs (p < 0.001). CONCLUSIONS: Core needle biopsy techniques for cancer diagnostics yield a broad range of DNA and RNA for molecular pathology, though quantities are greater than what has been reported for FFPE processed material. Since non-formalin-fixed DNA is advantageous for molecular studies, workflows that optimize core needle biopsy yield for molecular characterization should be explored.