Simpa Samuel Salami

The tumor immune microenvironment (TIME) shows significant heterogeneity in primary clear cell renal cell carcinoma (ccRCC). As TIME heterogeneity between primary and paired metastatic tumors of ccRCC is less understood, we characterized and compared the TIME of primary ccRCC with paired asynchronous metastases. We analyzed patients who developed ccRCC recurrence post radical nephrectomy and had both primary and metastatic treatment-naïve tissue available. Capture whole-transcriptome sequencing was performed on formalin-fixed paraffin-embedded (FFPE) specimens using the Illumina platform. Differential gene expression (DGE) analysis and gene set enrichment analysis (GSE) was performed using R packages limma and fgsea respectively. TIME deconvolution was quantified using CIBERSORT, an in-silico flow cytometry tool. In aggregate, 42 tumor samples from 19 patients (19 primary tumors with 23 matched metastases) were analyzed. Metastatic sites included lung (n = 6), bone (n = 6), adrenal (n = 4), liver (n = 2), lymph node (n = 2), and soft tissue (n = 3). In unsupervised hierarchical clustering, primary tumors clustered together and not with their matched metastatic tumor. Of the immune cells assayed, primary tumors displayed greater Tregs than their matched (and unmatched) metastases (p < 0.001). Among metastatic sites, bone had high levels of EMT activity compared to their matched primary tumors and lung metastatic tumors were enriched in E2F targets. We demonstrate differences in pathway enrichment and immune cell populations in primary ccRCC and their matched metastases, including a higher infiltration of immunosuppressive T regulatory cells in the tumor immune microenvironment of primary ccRCC. Metastatic tumors not only differed from their paired primary tumors but also differed in gene expression, gene set enrichment, and immune cell composition between metastatic tissue sites.

Prostate cancer is characterized by multifocality, inter- and intra-patient tumour heterogeneity, and differences in risk of progression to metastatic disease, castration resistance and lethality, which can make prognosis challenging. Consequently, sampling methods that provide accurate insight into disease phenotype to facilitate risk-stratification of patients are crucial. The variable biology of prostate cancer seems to be recapitulated in the phenotypic heterogeneity of circulating tumour cells (CTCs). CTC sampling offers a liquid biopsy method to achieve minimally invasive longitudinal sampling for disease monitoring. CTC analysis has also offered a crucial insight into aggressive phenotypes, disease metastasis and treatment response, particularly in clinical trials. The clinical use of CTC count for prognosis in advanced prostate cancer has been approved by the FDA, but is not routinely used clinically, as these cells are technically challenging to isolate and analyse. However, methodological advances continue to improve CTC enrichment and profiling. Understanding the clinical utility of CTCs and future innovations is crucial to incorporating CTCs into the clinical management of prostate cancer.

Background and Objective: The tumor immune microenvironment (TIME) shows significant heterogeneity in primary clear cell renal cell carcinoma (ccRCC). As TIME heterogeneity between primary and paired metastatic tumors of ccRCC is less understood, we characterize and compare the TIME of primary ccRCC with paired asynchronous metastases. Methods We analyzed patients who developed ccRCC recurrence post radical nephrectomy and had both primary and metastatic treatment-naïve tissue available. Capture whole-transcriptome sequencing was performed on formalin-fixed paraffin-embedded (FFPE) specimens using the Illumina platform. Differential gene expression (DGE) analysis and gene set enrichment analysis (GSE) was performed using R packages limma and fgsea respectively. TIME deconvolution was quantified using CIBERSORT, an in-silico flow cytometry tool. Key Findings and Limitations: In aggregate, 42 tumor samples from 19 patients (19 primary tumors with 23 matched metastases) were analyzed. Metastatic sites included lung (n = 6), bone (n = 6), adrenal (n = 4), liver (n = 2), lymph node (n = 2), and soft tissue (n = 3). In unsupervised hierarchical clustering, primary tumors clustered together and not with their matched metastatic tumor. Of the immune cells assayed, primary tumors displayed greater Tregs than their matched (and unmatched) metastases (p < 0.001). Among metastatic sites, bone had high levels of EMT activity compared to their matched primary tumors and lung metastatic tumors were enriched in E2F targets. Conclusions and Clinical Implications: We demonstrate differences in pathway enrichment and immune cell populations in primary ccRCC and their matched metastases, including a higher infiltration of immunosuppressive T regulatory cells in the tumor immune microenvironment of primary renal ccRCC. Metastatic tumors not only differed from their paired primary tumors but also differed in gene expression, gene set enrichment, and immune cell composition between metastatic tissue sites.

PURPOSE: We previously developed and validated a 15-gene prognostic signature (15G score) in localized clear cell renal cell carcinoma (ccRCC). Given its ability to differentiate aggressive and indolent disease, we sought to apply the 15G score to patients with metastatic ccRCC to evaluate its prognostic performance in this setting. METHODS: We analyzed 2,121 patients from four major metastatic ccRCC trial data sets: IMmotion 151 ( IMM151 ), IMmotion 150 ( IMM150 ), Javelin Renal 101 ( JR101 ), and Checkmate 009, 010, and 025 ( CM009/010/025 ) and assessed six treatment groups: atezolizumab plus bevacizumab, sunitinib, atezolizumab, avelumab plus axitinib, nivolumab, and everolimus. We classified patients into 15G score high or low using RNA-sequencing and a previously derived threshold. We tested the association of 15G score high with progression-free survival (PFS) in each treatment group using Cox proportional hazards with and without controlling for Memorial Sloan Kettering Cancer Center (MSKCC) risk group. Overall survival (OS) was also tested where these data were available. RESULTS: A high 15G score was associated with significantly worse PFS in four of the six treatment groups: atezolizumab plus bevacizumab, sunitinib, atezolizumab, and everolimus (hazard ratios [HRs], 1.7 [95% CI, 1.4 to 2.2], 1.7 [1.4-2.0] 2.8, [95% CI, 1.6 to 4.9], and 1.5 [95% CI, 1.1 to 2.2], respectively; all P < .05). Within IMM151 and CM009/010/025 , where MSKCC risk stratification were available for multivariable analyses, high 15G score remained independently associated with worse PFS in atezolizumab plus bevacizumab, sunitinib, and everolimus (HR, 1.5 [95% CI, 1.2 to 2.0], 1.7 [95% CI, 1.4 to 2.2], 1.6 [95% CI, 2.3], respectively; all P < .05). A 15G high score was also associated with worse OS, which was significant in everolimus and near significant in nivolumab (HR, 1.5 [95% CI, 1.1 to 2.2] and 1.4 [95% CI, 0.9 to 2.0]). CONCLUSION: The 15G score was independently prognostic in metastatic ccRCC among patients receiving different systemic therapy regimens.

The 18-gene MyProstateScore 2.0 (MPS2) test was previously validated for detection of grade group (GG) ≥ 2 prostate cancer using post-digital rectal examination (DRE) urine. To improve ease of testing, we validated MPS2 using first-catch, non-DRE urine. Patients provided first-catch urine before biopsy. MPS2 values were calculated using previously validated models differing only by extent of clinical data included biomarkers alone (BA; no clinical data), biomarkers and clinical factors (BA + CF), and biomarkers, clinical factors, and prostate volume (BA + CF + PV). The primary outcome was GG ≥ 2 cancer on biopsy. MPS2 performance and clinical consequences of testing were compared with PSA and the Prostate Cancer Prevention Trial risk calculator (PCPTrc). The cohort included 266 men with median PSA 6.6 ng/mL (IQR, 4.9-9.1) of whom 103 (39%) had GG ≥ 2 cancer on biopsy. The AUC for GG ≥ 2 cancer was 57% for PSA, 62% for PCPTrc, and 71%, 74%, and 77% for MPS2 models. Under a testing approach detecting > 90% of GG ≥ 2 cancers, MPS2 testing would have avoided 36% to 42% of unnecessary biopsies, as compared with 13% using the PCPTrc. In patients with a prior negative biopsy, MPS2 testing would have avoided 44% to 53% of repeat biopsies, as compared with only 2.6% using PCPTrc. Using first-catch urine, MPS2 meaningfully improved the proportion of biopsies avoided relative to PCPTrc while maintaining highly sensitive detection of GG ≥ 2 cancer. Non-DRE testing provides a convenient, objective, and highly accurate testing option to reduce the need for imaging and biopsy in men with elevated PSA.

Darolutamide plus androgen-deprivation therapy (ADT) with docetaxel is one of the standards of care for metastatic hormone-sensitive prostate cancer (mHSPC), based on the phase III ARASENS study. To provide the option to use darolutamide without docetaxel to meet patients' needs and preferences, the phase III placebo-controlled ARANOTE study was undertaken. Reflecting evolving treatment guidelines for mHSPC, the complementary US-based ARASEC study was designed with a single, prospectively-enrolled investigational arm (darolutamide plus ADT) and an ADT monotherapy arm derived from the previous phase III CHAARTED study. ARASEC was designed with the same eligibility criteria and assessments as CHAARTED, and patients were matched 1:1 using propensity scores calculated from key prognostic baseline variables: age, ECOG performance status, extent of disease, prior local therapy, Gleason score, and prostate-specific antigen level. ARASEC enrolled 223 patients who received darolutamide plus ADT, with 393 patients in the CHAARTED ADT control arm available for matching. Matching yielded 160 patients in each arm with minimal differences in prognostic variables between the matched groups, who will be compared to evaluate the efficacy and safety of darolutamide plus ADT in mHSPC. This novel study design may inform future single-arm trials with historical control arms, with potentially faster accrual and reduced costs.Clinical Trial Registration: NCT05059236.