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Prostate cancer progression is significantly affected by its tumor microenvironment, in which mesenchymal cells play a crucial role. Stromal cells are modified by cancer mutations, response to androgens, and lineage plasticity, and in turn, engage with epithelial tumor cells via a complex array of signaling pathways and ligand-receptor interactions, ultimately affecting tumor growth, immune interaction, and response to therapy. The metabolic rewiring and interplay in the microenvironment play an additional role in affecting the growth and progression of prostate cancer. Finally, therapeutic strategies and novel clinical trials with agents that target the stromal microenvironment or disrupt the interaction between cellular compartments are described. This review underscores cancer-associated fibroblasts as essential contributors to prostate cancer biology, emphasizing their potential as prognostic indicators and therapeutic targets.

Background: Recent studies have highlighted the importance of the cell-free DNA (cfDNA) methylation profile in detecting breast cancer (BC) and its different subtypes. We investigated whether plasma cfDNA methylation, using cell-free Methylated DNA Immunoprecipitation and High-Throughput Sequencing (cfMeDIP-seq), may be informative in characterizing breast cancer in patients with BRCA1/2 germline mutations for early cancer detection and response to therapy., Methods: We enrolled 23 BC patients with germline mutation of BRCA1 and BRCA2 genes, 19 healthy controls without BRCA1/2 mutation, and two healthy individuals who carried BRCA1/2 mutations. Blood samples were collected for all study subjects at the diagnosis, and plasma was isolated by centrifugation. Cell-free DNA was extracted from 1 mL of plasma, and cfMeDIP-seq was performed for each sample. Shallow whole genome sequencing was performed on the immuno-precipitated samples. Then, the differentially methylated 300-bp regions (DMRs) between 25 BRCA germline mutation carriers and 19 non-carriers were identified. DMRs were compared with tumor-specific regions from public datasets to perform an unbiased analysis. Finally, two statistical classifiers were trained based on the GLMnet and random forest model to evaluate if the identified DMRs could discriminate BRCA-positive from healthy samples., Results: We identified 7,095 hypermethylated and 212 hypomethylated regions in 25 BRCA germline mutation carriers compared to 19 controls. These regions discriminate tumors from healthy samples with high accuracy and sensitivity. We show that the circulating tumor DNA of BRCA1/2 mutant breast cancers is characterized by the hypomethylation of genes involved in DNA repair and cell cycle. We uncovered the TFs associated with these DRMs and identified that proteins of the Erythroblast Transformation Specific (ETS) family are particularly active in the hypermethylated regions. Finally, we assessed that these regions could discriminate between BRCA positives from healthy samples with an AUC of 0.95, a sensitivity of 88%, and a specificity of 94.74%., Conclusions: Our study emphasizes the importance of tumor cell-derived DNA methylation in BC, reporting a different methylation profile between patients carrying mutations in BRCA1, BRCA2, and wild-type controls. Our minimally invasive approach could allow early cancer diagnosis, assessment of minimal residual disease, and monitoring of response to therapy., (© 2024. The Author(s).)

Background: Androgen receptor signalling inhibitors (ARSIs) abiraterone acetate (AA) enzalutamide (Enza), are currently the standard first-line (L1) treatments for metastatic castration-resistant prostate cancer (mCRPC), and docetaxel (D) is reserved as second-line (L2) after ARSI failure. Nonetheless, D use in men ≥ 75 years old is restricted owing to treatment toxicities and patient comorbidities, and a L2 alternative ARSI is frequently used. We aimed to evaluate real-life survival and toxicity outcomes of these elderly patients after failure of L1 ARSI treatment., Material and Methods: We retrospectively evaluated efficacy and safety in a real-world international cohort of consecutive patients ≥ 75 years old when starting L1 ARSI for mCRPC according to the choice of L2 treatment (D versus alternative ARSI)., Results: Of the 122 identified patients, 57 (46.7%) had received L2 ARSI and 65 (53.3%) L2 D. No difference was found in the L1 overall survival (OS) for the ARSI and D groups (32.8 vs. 30.0 months, respectively; Hazard ratio [HR] = 1.22; 95% CI, 0.77-1.95; P = .40) or in the L2 OS (18.5 vs. 17.8 months, respectively; HR = 1.09; 95% CI, 0.69-1.74; P = .71). No difference was observed for rPFS from L2 (P = .12), although a trend was observed for a numerically improved rPFS on D., Conclusion: Within the limitations of a retrospective design and small population, our study suggests that D or ARSI after failure of L1 alternative ARSI are clinically comparable L2 options for elderly patients with mCRPC., Competing Interests: Disclosure Loana Bueno Valencia received consulting fees from Janssen and travel grants from Janssen, Astellas, and Bayer. The other authors report no competing interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Managing metastatic castration-resistant prostate cancer (mCRPC) in men aged ≥ 75 is challenging due to limited data. Regardless of age, in real-world clinical practice, most mCRPC still derive from failure of androgen deprivation therapy (ADT) with or without docetaxel (D) for metastatic castration-sensitive prostate cancer (mCSPC). As abiraterone acetate plus prednisone (AA) and enzalutamide (Enza) are common first-line treatments for mCRPC. The impact of prior use of D for mCSPC on the efficacy and safety of AA or Enza in this older population remains unclear., Methods: A cohort of patients aged ≥ 75 years starting AA or Enza as first-line therapy for mCRPC from January 2015 to April 2019 was identified from the registries of 10 institutions. Patients were categorized into 2 groups based on previous use of D for mCSPC. Primary endpoints were cancer-specific survival (CSS) from AA or Enza start, CSS from ADT onset, and safety. We used Kaplan-Meier method to estimate the endpoints distribution, including median values with 95% confidence intervals (95% CI)., Results: Of the 337 patients identified, 24 (7.1%) received ADT+D and 313 (92.9%) received ADT alone for mCSPC. Median follow-up from AA/Enza start was 18.8 months. Median CSS from ADT or AA/Enza was not significantly different between ADT+D and ADT alone cohorts (71.9 vs. 52.7 months, P = .97; 25.4 vs. 27.2 months, P = .89, respectively). No statistically significant difference in adverse events (AEs) of any grade rate (58.3% vs. 52.1%, respectively; P = .67) or grade ≥ 3 (12.5% vs. 15.7%, respectively; P = 1.0) was found between ADT+D and ADT alone cohorts., Conclusions: Despite the innate limitations of a retrospective design and relatively small size of the ADT+D cohort, this analysis suggests that elderly men receiving AA or Enza as first-line therapy for mCRPC have similar survival outcomes and tolerability, regardless of previous D for mCSPC., Competing Interests: Disclosure Loana Valenca received consulting fees from Janssen and travel grants from Janssen, Astellas, and Bayer. The other authors report no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC)., Patients and Methods: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected., Results: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS., Conclusion: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC., Competing Interests: Disclosure Parvaneh Fallah Scientific advisor/consultant: BMS, Seagen, Pfizer, Astrazeneca, EMD Sereno Canada Honoraria: Astrazeneca, EMD Sereno Canada, Gilead, Merck, Janssen Rohit K Jain Receiving honoraria from FLASCO, Curio Science, DAVA Oncology, NCCN/Pfizer, and OncLive/MJH Life Sciences Consulting for AVEO, Bristol Myers Squibb, Sanofi, EMD Serono, Gilead Sciences, IDEOlogy Pfizer, and Seattle Genetics/Astellas In the speakers’ bureau of Gilead Sciences, Seagen, and Seattle Genetics/Astellas Receiving research funding from Bristol Myers Squibb, Gilead Sciences, and NCI. Praful Ravi Research funding to institution: Lilly, Bayer, Telix Speaker's fees: OncLive Charlene Mantia Consulting/advisory role: Aadi Bioscience, Synthekine, Nextech Institutional research funding: Bristol Myers Squibb Bradley Alexander McGregor Received funds for consulting: Arcus, BMS, Eisai, Exelixis, Gliead, Pfizer, SeaGen Funding to institution - BMS, Exelixis, Gilead, Pfizer, SeaGen Roger Li Research support: Predicine; Veracyte; CG Oncology; Valar labs; Merck. Clinical trial protocol committee: CG Oncology; Merck; Janssen. Scientific advisor/consultant: BMS, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, Janssen, Thericon. Honoraria: SAI MedPartners, Solstice Health Communications, Putnam Associates, UroToday. Wassim Kassouf Consultant or advisory roles: Sesen Bio, Ferring, Roche, BMS, Merck, Janssen, Bayer, Astellas, Seagen, Pfizer/EMD Serono, Photocure Clinical trials: BMS, Roche, Janssen, Theralase, Pfizer, CG Oncology Gregory Russell Pond Received honorariums from Astra-Zeneca and Takeda Received consulting fees from Merck and Profound Medical. Close family member who is employed by Roche Canada, and who owns stock in Roche Ltd. Raskesh K. Jain Received consultant fees from Cur, DynamiCure, Elpis, Merck, SPARC, SynDevRx Owns equity in Accurius, Enlight, SynDevRx Served on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund Received grants from Boehringer Ingelheim and Sanofi. Research is supported by NIH R01CA259253, R01CA269672, R01-NS118929, U01CA261842, and grants from the National Foundation for Cancer Research, Jane's Trust Foundation, Niles Albright Research Foundation, and Harvard Ludwig Cancer Center. Guru Sonpavde Advisory Board: EMD Serono, BMS, Merck, Seattle Genetics/Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly/Loxo Oncology, Vial, PrecisCa, Atkis, Kura Oncology, Daiichi-Sankyo Consultant/Scientific Advisory Board (SAB): Syapse, Merck, Servier, Syncorp Research Support to institution: EMD Serono, Jazz Therapeutics, BMS Speaker: Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Merck, Pfizer Data safety monitoring committee (honorarium): Mereo Employment: Spouse employed by Myriad Travel: BMS, Astellas, (Copyright © 2024 Elsevier Inc. All rights reserved.)

We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men., (© 2024. The Author(s).)

Prostate cancer (PCa) is currently the most commonly diagnosed cancer and second leading cause of cancer-related death in men in the United States. The development of metastases is associated with a poor prognosis in PCa patients. Since current clinicopathological classification schemes are unable to accurately prognosticate the risk of metastasis for those diagnosed with localized PCa, there is a pressing need for precise and easily attainable biomarkers of metastatic risk in these patients. Primary tumor samples from 1239 individuals with PCa were divided into development (n=1000) and validation (n=239) cohorts. In the development cohort, we utilized a meta-analysis workflow on retrospective primary tumor gene expression profiles to identify a subset of genes predictive of metastasis. For each gene, we computed Hedges' g effect size and combined their p-values using Fisher's combined probability test. We then adjusted for multiple hypothesis testing using the Benjamini-Hochberg method. Our developed gene signature, termed Meta-Score, achieved a robust performance at predicting metastasis from primary tumor gene expression profiles, with an AUC of 0.72 in the validation cohort. In addition to its robust predictive power, Meta-Score also demonstrated a significant prognostic utility in two independent cohorts. Specifically, patients with a higher risk-score had a significantly worse metastasis-free survival and progression-free survival compared to those with lower score. Multivariate cox proportional hazards model showed that Meta-Score is significantly associated with worse survival even after adjusting for Gleason score. Our findings suggest that our primary tumor transcriptional signature, Meta-Score, could be a valuable tool to assess the risk of metastasis in PCa patients with localized disease, pending validation in large prospective studies., Author Summary: Metastasis is the leading cause of death in patients diagnosed with prostate cancer (PCa), underscoring the need for reliable prediction tools to forecast the risk of metastasis at an early stage. Here, we utilize the gene expression profiles of 1,000 unique primary tumors from patients with localized PCa to develop a gene signature capable of predicting metastasis. Our signature, termed Meta-Score, comprises forty-five genes that can accurately distinguish primary tumor with high propensity for metastasis across different patient cohorts. Notably, Meta-Score maintained its robust predictive performance in an internal validation cohort of comprising primary tumor samples from 239 patients. In addition to its robust predictive performance, Meta-Score demonstrates a significant association with survival, independent of Gleason score in two independent patient cohorts, underscoring its prognostic utility. Taken together, Meta-Score is a robust risk-stratification tool that can be leveraged to identify patients at high-risk of metastasis and unfavorable survival using their primary tumor gene expression profiles.

In the complex tumor microenvironment (TME), mesenchymal cells are key players, yet their specific roles in prostate cancer (PCa) progression remain to be fully deciphered. This study employs single-cell RNA sequencing to delineate molecular changes in tumor stroma that influence PCa progression and metastasis. Analyzing mesenchymal cells from four genetically engineered mouse models (GEMMs) and correlating these findings with human tumors, we identify eight stromal cell populations with distinct transcriptional identities consistent across both species. Notably, stromal signatures in advanced mouse disease reflect those in human bone metastases, highlighting periostin's role in invasion and differentiation. From these insights, we derive a gene signature that predicts metastatic progression in localized disease beyond traditional Gleason scores. Our results illuminate the critical influence of stromal dynamics on PCa progression, suggesting new prognostic tools and therapeutic targets., (© 2024. The Author(s).)

Background: While the efficacy of neoadjuvant chemotherapy (NACT) in treating triple-negative breast cancer (TNBC) is generally accepted, not all patients derive benefit from this preoperative treatment. Presently, there are no validated biomarkers to predict the NACT response, and previous attempts to develop predictive classifiers based on gene expression data have not demonstrated clinical utility. However, predictive models incorporating biological constraints have shown increased robustness and improved performance compared to agnostic classifiers., Methods: We used the preoperative transcriptomic profiles from 298 patients with TNBC to train and test a rank-based classifier, k-top scoring pairs, to predict whether the patient will have pathological complete response (pCR) or residual disease (RD) following NACT. To reduce overfitting and enhance the signature's interpretability, we constrained the training process to genes involved in the Notch signaling pathway. Subsequently, we evaluated the signature performance on two independent cohorts with 75 and 71 patients. Finally, we assessed the prognostic value of the signature by examining its association with relapse-free survival (RFS) using Kaplan‒Meier (KM) survival estimates and a multivariate Cox proportional hazards model., Results: The final signature consists of five gene pairs, whose relative ordering can be predictive of the NACT response. The signature has a robust performance at predicting pCR in TNBC patients with an area under the ROC curve (AUC) of 0.76 and 0.85 in the first and second testing cohorts, respectively, outperforming other gene signatures developed for the same purpose. Additionally, the signature was significantly associated with RFS in an independent TNBC patient cohort even after adjusting for T stage, patient age at the time of diagnosis, type of breast surgery, and menopausal status., Conclusion: We introduce a robust gene signature to predict pathological complete response (pCR) in patients with TNBC. This signature applies easily interpretable, rank-based decision rules to genes regulated by the Notch signaling pathway, a known determinant in breast cancer chemoresistance. The robust predictive and prognostic performance of the signature make it a strong candidate for clinical implementation, aiding in the stratification of TNBC patients undergoing NACT., (© 2023. The Author(s).)

To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits., (© 2023. Springer Nature Limited.)

Liquid biopsy has the potential to drastically change clinical practice, paving the way to a novel non-invasive approach for cancer diagnosis and treatment. One of the limitations for the implementation of liquid biopsy in clinical practice is the lack of shared and reproducible standard operating procedures (SOPs) for sample collection, processing and storage. Here, we present a critical review of the literature focusing on the available SOPs to guide liquid biopsy management in research settings and describe SOPs that our laboratory developed and employed in the context of a prospective clinical-translational trial (RENOVATE, NCT04781062). The main aim of this manuscript is to address common issues, towards the implementation of interlaboratory shared protocols for optimized preanalytical handling of blood and urine samples. To our knowledge, this work is one of the few up-to-date, freely available comprehensive reports on trial-level procedures for the handling of liquid biopsy., Competing Interests: Conflicts of Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The genomic, epigenetic and metabolic determinants of prostate cancer pathobiology have been extensively studied in epithelial cancer cells. However, malignant cells constantly interact with the surrounding environment-the so-called tumour microenvironment (TME)-which may influence tumour cells to proliferate and invade or to starve and die. In that regard, stromal cells-including fibroblasts, smooth muscle cells and vasculature-associated cells-constitute an essential fraction of the prostate cancer TME. However, they have been largely overlooked compared to other cell types (i.e. immune cells). Indeed, their importance in prostate physiology starts at organogenesis, as the soon-to-be prostate stroma determines embryonal epithelial cells to commit toward prostatic differentiation. Later in life, the appearance of a reactive stroma is linked to the malignant transformation of epithelial cells and cancer progression. In this Review, we discuss the main mesenchymal cell populations of the prostate stroma, highlighting their dynamic role in the transition of the healthy prostate epithelium to cancer. A thorough understanding of those populations, their phenotypes and their transcriptional programs may improve our understanding of prostate cancer pathobiology and may help to exploit prostate stroma as a biomarker of patient stratification and as a therapeutic target., (© 2022. The Author(s).)

Background: Androgen receptor signaling inhibitors (ARSis) abiraterone acetate (AA) plus prednisone and enzalutamide (Enza), are currently the most administered first-line treatments for metastatic castration-resistant prostate cancer (mCRPC). AA and Enza have shown similar overall survival (OS) benefits and there is no consensus upon the best option for mCRPC first-line treatment. Volume of disease may represent a useful biomarker to predict response to therapy in such patients., Objectives: In this study, we seek to evaluate the impact of volume of disease on patients treated with first-line AA versus Enza for mCRPC., Design and Methods: We retrospectively evaluated a cohort of consecutive patients with mCRPC categorized by volume of disease [high volume (HV) or low volume (LV) per E3805 criteria] at ARSi onset and treatment type (AA or Enza), assessing OS and radiographic progression-free survival (rPFS), from therapy start, as co-primary endpoints., Results: Of the 420 patients selected, 170 (40.5%) had LV and received AA (LV/AA), 76 (18.1%) LV and had Enza (LV/Enza), 124 (29.5%) HV and were given AA (HV/AA), and 50 (11.9%) HV and received Enza (HV/Enza). Among patients with LV, OS was significantly longer when treated with Enza [57.2 months; 95% confidence interval (CI): 52.1-62.2 months] versus AA (51.6 months; 95% CI, 42.6-60.6 months; p  = 0.003). Consistently, those with LV receiving Enza showed increased rPFS (40.3 months; 95 CI, 25.0-55.7 months) than those having AA (22.0 months; 95% CI, 18.1-26.0 months; p  = 0.004). No significant difference in OS or rPFS was observed in those with HV treated with AA versus Enza ( p  = 0.51 and p  = 0.73, respectively). In multivariate analysis of patients with LV, treatment with Enza was independently associated with better prognosis than AA., Conclusion: Within the intrinsic limitations of a retrospective design and small population, our report suggests that volume of disease could be a useful predictive biomarker for patients starting first-line ARSi for mCRPC., Competing Interests: Loana Bueno Valenca received consulting fees from Janssen and travel grants from Janssen, Astellas, Bayer. The other authors report no conflict of interest., (© The Author(s), 2023.)

Background: Metastatic castration-resistant prostate cancer remains a challenging condition to treat. Among the available therapeutic options, the androgen receptor signaling inhibitors abiraterone acetate plus prednisone (AA) and enzalutamide (Enza), are currently the most used first-line therapies in clinical practice. However, validated clinical indicators of prognosis in this setting are still lacking. In this study, we aimed to evaluate a prognostic model based on the time of metastatic disease presentation (after prior local therapy [PLT] or de-novo [DN]) and disease burden (low volume [LV] or high-volume [HV]) at AA/Enza onset for mCRPC patients receiving either AA or Enza as first-line., Methods: A cohort of consecutive patients who started AA or Enza as first-line treatment for mCRPC between January 1st, 2015, and April 1st, 2019 was identified from the clinical and electronic registries of the 9 American and European participating centers. Patients were classified into 4 cohorts by the time of metastatic disease presentation (PLT or DN) and volume of disease (LV or HV; per the E3805 trial, HV was defined as the presence of visceral metastases and/or at least 4 bone metastases of which at least 1 out the axial/pelvic skeleton) at AA/Enza onset. The endpoint was overall survival defined as the time from AA or Enza initiation, respectively, to death from any cause or censored at the last follow-up visit, whichever occurred first., Results: Of the 417 eligible patients identified, 157 (37.6%) had LV/PLT, 87 (20.9%) LV/DN, 64 (15.3%) HV/PLT, and 109 (26.1%) HV/DN. LV cohorts showed improved median overall survival (59.0 months; 95% CI, 51.0-66.9 months) vs. HV cohorts (27.5 months; 95% CI, 22.8-32.2 months; P = 0.0001), regardless of the time of metastatic presentation. In multivariate analysis, HV cohorts were confirmed associated with worse prognosis compared to those with LV (HV/PLT, HR = 1.87; p = 0.029; HV/DN, HR = 2.19; P = 0.002)., Conclusion: Our analysis suggests that the volume of disease could be a prognostic factor for patients starting AA or Enza as first-line treatment for metastatic castration-resistant prostate cancer, pending prospective clinical trial validation., (© 2023. The Author(s).)

While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation., (© 2023. The Author(s).)

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10 -8 ) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10 -11 ; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10 -8 ; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10 -8 , HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The familial aggregation of bladder cancers has been observed, but the incidence and association of familial bladder cancer with germline pathogenic and likely pathogenic (P/LP) variants is unknown., Patients and Methods: A retrospective analysis was conducted of patients with bladder cancer treated at the Dana-Farber Cancer Institute to identify those with a first-degree relative with bladder cancer. A second cohort of patients referred to DFCI for suspicion of a cancer predisposition syndrome was analyzed for candidate P/LP germline variants. Descriptive statistics were generated., Results: Among 885 patients with bladder cancer, 38 patients (4.3%) had a family history of bladder cancer in a first-degree relative. No significant association of age of diagnosis was observed between patients with and without a first-degree family history of bladder cancer (P = .3). In the second cohort, 27 of 80 (34%) patients with bladder cancer evaluated for cancer predisposition syndromes harbored a P/LP germline variant. P/LP variants were identified most commonly in the following genes: BRCA1 (n = 5), MSH2 (n = 5), MLH1 (n = 4), ATM (n = 3), and CHEK2 (n = 2). Of the 27 patients with identified germline P/LP variants, 20 (74%) had a family history of a tumor component syndrome in a first- or second-degree relative and 3 were subsequently diagnosed with another genetically-linked associated cancer., Conclusion: Familial bladder cancer defined as bladder cancer in the proband and a first-degree relative, was present in 4.3% of patients with bladder cancer and was not associated with age of diagnosis. Additionally, among patients suspected to have a familial cancer syndrome, one-third harbored a germline P/LP variant. Further study of germline variants in patients with familial bladder cancer including somatic testing for loss of heterozygosity may provide insights regarding disease pathogenesis and inform therapy., (Copyright © 2022. Published by Elsevier Inc.)

The immune checkpoint inhibitor (ICI) pembrolizumab is US FDA approved for treatment of solid tumors with high tumor mutational burden (TMB-high; ≥10 variants/Mb). However, the extent to which TMB-high generalizes as an accurate biomarker in diverse patient populations is largely unknown. Using two clinical cohorts, we investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing in solid tumors. TMB estimates from tumor-only panels substantially overclassified individuals into the clinically important TMB-high group due to germline contamination, and this bias was particularly pronounced in patients with Asian/African ancestry. Among patients with non-small cell lung cancer treated with ICIs, those misclassified as TMB-high from tumor-only panels did not associate with improved outcomes. TMB-high was significantly associated with improved outcomes only in European ancestries and merits validation in non-European ancestry populations. Ancestry-aware tumor-only TMB calibration and ancestry-diverse biomarker studies are critical to ensure that existing disparities are not exacerbated in precision medicine., Competing Interests: Declaration of interests G.S. reports the following disclosures: advisory boards of BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics/Gilead, Scholar Rock, and G1 Therapeutics; research support to Sanofi, Astrazeneca, Immunomedics/Gilead, QED, Predicine, and BMS; steering committee of studies of BMS, Bavarian Nordic, Seattle Genetics, QED, and G1 Therapeutics (all unpaid) and Astrazeneca, EMD Serono, Debiopharm (paid); data safety monitoring committee of Mereo; travel costs from BMS (2019) and Astrazeneca (2018); writing/editor fees from UpToDate and as editor of the Elsevier PracticeUpdate Bladder Cancer Center of Excellence; speaking fees from Physicians Education Resource (PER), Onclive, Research to Practice, and Medscape (all educational). M.G. receives research funding from Bristol-Myers Squibb, Merck, Servier, and Janssen. F.S.H. reports grants and other from Bristol-Myers Squibb; personal fees from Merck; personal fees from EMD Serono; grants, personal fees, and other from Novartis; personal fees from Surface; personal fees from Compass Therapeutics; personal fees from Apricity; personal fees from Aduro; personal fees from Sanofi; personal fees from Pionyr; personal fees from Torque; personal fees from Bicara; other from Pieris Pharmaceuticals; personal fees from Eisai; personal fees from Checkpoint Therapeutics; personal fees from Idera; personal fees from Genentech/Roche; personal fees from BioEntre; personal fees from Gossamer; personal fees from Phio; personal fees from Iovance; personal fees from Trillium; personal fees from Abcuro; personal fees from Catalym; personal fees from Immunocore; outside the submitted work. In addition, F.S.H. has the following patents: Methods for Treating MICA-Related Disorders (20100111973) with royalties paid; Tumor Antigens and Uses Thereof (7250291) issued; Angiopoiten-2 Biomarkers Predictive of Anti-immune Checkpoint Response (20170248603) pending; Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (20160340407) pending; Therapeutic Peptides (20160046716) pending; Therapeutic Peptides (20140004112) pending; Therapeutic Peptides (20170022275) pending; Therapeutic Peptides (20170008962) pending; Therapeutic Peptides (9402905) issued; Methods of Using Pembrolizumab and Trebananib pending; Vaccine Compositions and Methods for Restoring NKG2D Pathway Function against Cancers (10279021) issued; Antibodies That Bind to MHC Class I Polypeptide-Related Sequence A (10106611) issued; and Anti-galectin Antibody Biomarkers Predictive of Anti-immune Checkpoint and Anti-angiogenesis Responses. T.K.C. reports the following disclosures: research/advisory boards/consultancy/honoraria (institutional and personal, paid and unpaid) for or from AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, and Tempest; travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; stock options in Pionyr and Tempest; and other: UpToDate royalties, CME-related events (e.g., OncLIve, PVI, MJH Life Sciences) honoraria, NCI GU steering committee. T.K.C. also has patents filed, royalties, or other intellectual properties (no income as of this writing) related to biomarkers of immune checkpoint blockers and ctDNA. No speaker’s bureau. T.K.C. is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Tumor biopsy is still the gold standard for diagnosing and prognosis renal cell carcinoma (RCC). However, its invasiveness, costs, and inability to accurately picture tumor heterogeneity represent major limitations to this procedure. Analysis of circulating cell-free DNA (cfDNA) is a non-invasive cost-effective technique that has the potential to ease cancer detection and prognosis. In particular, a growing body of evidence suggests that cfDNA could be a complementary tool to identify and prognosticate RCC while providing contemporary mutational profiling of the tumor. Further, recent research highlighted the role of cfDNA methylation profiling as a novel method for cancer detection and tissue-origin identification. This review synthesizes current knowledge on the diagnostic, prognostic, and predictive applications of cfDNA in RCC, with a specific focus on the potential role of cell-free methylated DNA (cfMeDNA).

Background: COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct., Patients and Methods: This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations., Results: The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded., Conclusions: Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial., Competing Interests: Disclosure The authors report the following conflicts of interest: ZB non-financial support, Bristol Myers Squibb (BMS); research support, Genentech/imCore. Honoraria from UpToDate. CL research support, Genentech/imCore. AS educational travel support, Pfizer and Astellas. MMA research support, BMS Lilly, AstraZeneca, and Genentech; consulting/advisory role, BMS, Lilly, AstraZeneca, Genentech, Merck, Achilles, and Abbvie. RH consulting/advisory role, BMS, Merck, Pfizer, Genetech, AstraZeneca, and GSK; research grant/funding, Merck, BMS, Pfizer, Genentech, GSK, and AstraZeneca. ST institutional research funding from AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, BMS, Eisai, Nanostring, Cyclacel, Odonate, and Seattle Genetics; has served as an advisor/consultant to AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, BMS, Eisai, Nanostring, Puma, Sanofi, Celldex, Paxman, Puma, Silverback Therapeutics, G1 Therapeutics, AbbVie, Athenex, OncoPep, Outcomes4Me, Kyowa Kirin Pharmaceuticals, Daiichi-Sankyo, and Samsung Bioepsis Inc. MDG reports: Stock, Rappta Therapeutics; consulting/advisory role, BioMotiv, Janssen, Dendreon, Merck, GlaxoSmithKline, Lilly, Astellas, Genentech, BMS, Novartis, Pfizer, EMD Serono, AstraZeneca, Seattle Genetics, Incyte, Alleron Therapeutics, Dracen, Inovio Pharmaceuticals, Numab, Dragonfly Therapeutics; institutional research funding, Janssen, Dendreon, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca, Genentech/Roche. TKC research support, AstraZeneca, Alexion, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda; honoraria, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc. (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly Oncology; consulting or advisory role, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest, Lilly Ventures; Stocks: Pionyr, Osel, and Tempest; leadership role, Director of Genitourinary Oncology Division at Dana-Farber and past President of Medical Staff at Dana-Farber, member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee, KidneyCan Advisory board, Kidney cancer Research Summit co-chair (2019-); patents, royalties or other intellectual properties related to checkpoint inhibitors biomarkers and ctDNA (no royalties made as to date); travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria; medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others). TKC’s institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. TKC has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. DD Consulting/Advisory role, Mirati, Ipsen, Boehringer Ingelheim, Atheneum Partners, Boston Healthcare Associates, Dedham Group, Guidepoint Global Advisors; travel expenses, Ipsen. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Renin-angiotensin system inhibitors (RASi) have been shown to improve outcomes in studies of multiple malignancies by effects on the tumor microenvironment to enhance the immune repertoire and improve drug delivery. Repurposing RASi to treat metastatic renal cell carcinoma (mRCC) in combination with immune-checkpoint inhibitors (ICI) may improve survival coupled with tolerability and cost efficacy. We evaluated the impact of RASi on outcomes in mRCC patients receiving ICI., Methods: This multicenter, retrospective cohort study included mRCC patients treated with ICI with or without RASi. The patients from Dana-Farber Cancer Institute (DFCI) were used as a discovery cohort, and the patients from University of California San Diego (UCSD) were used for validation. Receipt of an ICI (PD1/L1 and/or CTLA-4 inhibitors) was required. RASi use was defined as receipt of a RASi at baseline and for a minimum of 30 days after ICI initiation. For both the discovery and validation cohorts, the primary outcome assessed was overall survival (OS) and the secondary endpoints were time-to-treatment failure (TTF), and objective response rate (ORR)., Results: Overall, 229 patients who received an ICI were included: 100 patients from DFCI and 129 patients from UCSD. Concomitant RASi were administered in 30 patients (30%) in the DFCI cohort and 59 (45%) in the UCSD cohort. Median age at ICI initiation was 62.5 years in both cohorts. Median follow-up was 3.8 [IQR 3-5.3] years in the DFCI cohort, and 2.3 [IQR 1.4-3.6] years in the UCSD cohort. In the DFCI cohort, RASi was significantly associated with longer OS (adjusted-HR 0.35 [95% CI, 0.17-0.70], P = .003) and TTF (adjusted-HR 0.57 [0.36-0.92], P = .02). In the validation cohort, RASi was associated with TTF (adjusted HR, 0.60 [0.39-0.92], P = .02) and not statistically associated with OS (adjusted-HR 0.60 [0.34-1.06], P = .07). The propensity analysis, matching 83 patients from both cohorts receiving RASi while on ICI with 83 who did not, showed that RASi significantly improved OS (HR 0.59 [0.37-0.95], P = .03) and TTF (HR 0.60 [0.43-0.85], P = .0034)., Conclusions: RASi was associated with improved OS and TTF in mRCC patients receiving ICI. This provides a rationale for prospective randomized studies combining ICI and RASi in mRCC patients., Competing Interests: Disclosures Ziad Bakouny: Research support from Bristol-Myers Squibb and Genentech/imCORE. Honoraria from UpToDate. Toni K: Choueiri reports grants, personal fees, nonfinancial support, and other from BMS, Merck, Roche, Pfizer, EMD, Exelixis, Novartis, and AstraZeneca [advisory board, consultancy, honorarium, payments (personal and for institution)], and a patent for IO biomarkers pending, issued, and licensed to DFCI (related to IO). Rana R: McKay received research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion. Guru Sonpavde: Advisory Board: BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics/Gilead, Scholar Rock, G1 Therapeutics; Research Support to Institution: Sanofi, Astrazeneca, Immunomedics/Gilead, QED, Predicine, BMS; Steering committee of studies: BMS, Bavarian Nordic, Seattle Genetics, QED, G1 Therapeutics (all unpaid), and Astrazeneca, EMD Serono, Debiopharm (paid).; Data safety monitoring committee: Mereo; Travel costs: BMS (2019), Astrazeneca (2018); Writing/Editor fees: Uptodate, Editor of Elsevier Practice Update Bladder Cancer Center of Excellence; Speaking fees: Physicians Education Resource (PER), Onclive, Research to Practice, Medscape (all educational). Rakesh Jain has received an Honorarium from Amgen; Consultant fees from Elpis, SPARC, SynDevRx; Owns equity in Accurius, Enlight, SynDevRx; Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund and received a Research Grant from Boehringer Ingelheim. The remaining authors have stated that they have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Neuroendocrine prostate cancer (NEPC) is a resistance phenotype that emerges in men with metastatic castration-resistant prostate adenocarcinoma (CR-PRAD) and has important clinical implications, but is challenging to detect in practice. Herein, we report a novel tissue-informed epigenetic approach to noninvasively detect NEPC., Experimental Design: We first performed methylated immunoprecipitation and high-throughput sequencing (MeDIP-seq) on a training set of tumors, identified differentially methylated regions between NEPC and CR-PRAD, and built a model to predict the presence of NEPC (termed NEPC Risk Score). We then performed MeDIP-seq on cell-free DNA (cfDNA) from two independent cohorts of men with NEPC or CR-PRAD and assessed the accuracy of the model to predict the presence NEPC., Results: The test cohort comprised cfDNA samples from 48 men, 9 with NEPC and 39 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 4.3 × 10-7) and discriminated between NEPC and CR-PRAD with high accuracy (AUROC 0.96). The optimal NEPC Risk Score cutoff demonstrated 100% sensitivity and 90% specificity for detecting NEPC. The independent, multi-institutional validation cohort included cfDNA from 53 men, including 12 with NEPC and 41 with CR-PRAD. NEPC Risk Scores were significantly higher in men with NEPC than CR-PRAD (P = 7.5×10-12) and perfectly discriminated NEPC from CR-PRAD (AUROC 1.0). Applying the predefined NEPC Risk Score cutoff to the validation cohort resulted in 100% sensitivity and 95% specificity for detecting NEPC., Conclusions: Tissue-informed cfDNA methylation analysis is a promising approach for noninvasive detection of NEPC in men with advanced prostate cancer., (©2021 American Association for Cancer Research.)

Background: The renin-angiotensin system is involved in the regulation of angiogenesis and cell proliferation. Angiotensin inhibition may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Because TGF-β is associated with resistance in patients with metastatic urothelial carcinoma (mUC) receiving programmed cell death protein 1/programmed cell death ligand 1 (PD1/L1) inhibitors, we hypothesized that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may enhance the outcomes of patients with mUC who receive PD1/L1 inhibitors., Patients and Methods: Data from patients with mUC who received PD1/L1 inhibitors as monotherapy were obtained; patients from the Dana-Farber Cancer Institute constituted the discovery dataset, and data from Moffitt Cancer Center served as the validation dataset. A logistic regression investigated the impact of concurrent ACEI/ARB primarily on any regression of tumor (ART) after controlling for prognostic factors., Results: Data were available for 178 patients from the discovery dataset, of whom 153 (86%) had received prior platinum and 33 (18.5%) concurrent ACEIs/ARBs. Multivariable logistic regression analysis revealed that ACEIs/ARBs were associated with greater probability of ART (odds ratio [OR] = 2.69; 95% confidence interval [CI], 1.15-6.30; P = .022). In the validation dataset, 101 patients were available, of whom 59 (58.4%) had received prior platinum and 22 (21.8%) concurrent ACEIs/ARBs. ACEI/ARB demonstrated a trend for association with ART (OR = 3.28; 95% CI, 0.98-10.99; P = .054) on multivariable analysis of the validation dataset., Conclusions: Concurrent angiotensin blockade was associated with a higher rate of tumor regression in patients with mUC receiving PD1/L1 inhibitors. Validation is warranted in a prospective trial, especially given the cost efficacy of ACEIs/ARBs., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: In the current era of personalized medicine, liquid biopsy has acquired a relevant importance in patient management of advanced stage non-small cell lung cancer (NSCLC). As a matter of fact, liquid biopsy may supplant the problem of inadequate tissue for molecular testing. The term 'liquid biopsy' refers to a number of different biological fluids, but is most clearly associated with plasma-related platforms. It must be taken into account that pre-analytical processing and the selection of the appropriate technology according to the clinical context may condition the results obtained. In addition, novel clinical applications beyond the evaluation of the molecular status of predictive biomarkers are currently under investigation., Areas Covered: This review summarizes the available evidence on pre-analytical issues and different clinical applications of liquid biopsies in NSCLC patients., Expert Opinion: Liquid biopsy should be considered not only as a valid alternative but as complementary to tissue-based molecular approaches. Careful attention should be paid to the optimization and standardization of all phases of liquid biopsy samples management in order to determine a significant improvement in either sensitivity or specificity, while significant reducing the number of 'false negative' or 'false positive' molecular results.

Introduction: Patients with lung cancer (LC) are susceptible to severe outcomes from COVID-19. This study evaluated disruption to care of patients with LC during the COVID-19 pandemic., Methods: The COVID-19 and Cancer Outcomes Study (CCOS) is a prospective cohort study comprised of patients with a current or past history of hematological or solid malignancies with outpatient visits between March 2 and March 6, 2020, at two academic cancer centers in the Northeastern United States (US). Data was collected for the three months prior to the index week (baseline period) and the following three months (pandemic period)., Results: 313 of 2365 patients had LC, 1578 had other solid tumors, and 474 had hematological malignancies. Patients with LC were not at increased risk of COVID-19 diagnosis compared to patients with other solid or hematological malignancies. When comparing data from the pandemic period to the baseline period, patients with LC were more likely to have a decrease in in-person visits compared to patients with other solid tumors (aOR 1.94; 95% CI, 1.46-2.58), but without an increase in telehealth visits (aOR 1.13; 95% CI 0.85-1.50). Patients with LC were more likely to experience pandemic-related treatment delays than patients with other solid tumors (aOR 1.80; 95% CI 1.13-2.80) and were more likely to experience imaging/diagnostic procedure delays than patients with other solid tumors (aOR 2.59; 95% CI, 1.46-4.47) and hematological malignancies (aOR 2.01; 95% CI, 1.02-3.93). Among patients on systemic therapy, patients with LC were also at increased risk for decreased in-person visits and increased treatment delays compared to those with other solid tumors., Discussion: Patients with LC experienced increased cancer care disruption compared to patients with other malignancies during the early phase of the COVID-19 pandemic. Focused efforts to ensure continuity of care for this patient population are warranted., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Immune checkpoint inhibitors (ICI) have shown clinical benefit in many types of metastatic cancers with only a few predictive biomarkers identified so far. CDKN2A is commonly altered in human cancers, but prior studies have provided conflicting evidence regarding the association between CDKN2A genomic alterations (GA) and response to ICIs. Herein, we examined the impact of loss-of-function CDKN2A alterations on response and survival in patients treated with ICIs., Experimental Design: We studied the association between loss-of-function CDKN2A alterations and the response to ICIs in two independent cohorts of six different cancer types. Seven hundred and eighty-nine patients treated at Dana-Farber Cancer Institute (DFCI; Boston, MA) and 1,250 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY) were included in the final analysis. Patients' tumors were sequenced using Oncopanel or MSK-IMPACT. RNA sequencing data from The Cancer Genome Atlas and IMvigor210 were used to investigate differences in the tumor microenvironment., Results: In the DFCI cohort, CDKN2A GAs were associated with poor response and survival in patients with urothelial carcinoma treated with ICIs, but not those treated with platinum-based therapy. Similarly, CDKN2A GAs were associated with worse outcomes in the MSKCC urothelial carcinoma cohort treated with ICIs. There was no association of CDKN2A status with ICI treatment outcome in five other cancers: esophagogastric, head and neck, non-small cell lung, renal cell carcinoma, and melanoma. Immuno-inflammatory pathways were significantly reduced in expression in CDKN2A- altered tumors., Conclusions: Our data show that CDKN2A GAs were associated with reduced benefit from ICI therapy in urothelial carcinoma as well as changes in the tumor-immune microenvironment., (©2021 American Association for Cancer Research.)

Importance: Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown., Objective: To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy., Design, Setting, and Participants: This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019., Exposures: Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy., Main Outcomes and Measures: The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used., Results: Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001)., Conclusions and Relevance: In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Prior data have variably implicated the inactivation of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex with increased tumor sensitivity to immune checkpoint inhibitors (ICI). Herein, we examined the association between mSWI/SNF variants and clinical outcomes to ICIs. We correlated somatic loss-of-function (LOF) variants in a predefined set of mSWI/SNF genes ( ARID1A, ARID1B, SMARCA4, SMARCB1, PBRM1 , and ARID2 ) with clinical outcomes in patients with cancer treated with systemic ICIs. We identified 676 patients from Dana-Farber Cancer Institute (DFCI, Boston, MA) and 848 patients from a publicly available database from Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY) who met the inclusion criteria. Multivariable analyses were conducted and adjusted for available baseline factors and tumor mutational burden. Median follow-up was 19.6 (17.6-22.0) months and 28.0 (25.0-29.0) months for the DFCI and MSKCC cohorts, respectively. Seven solid tumor subtypes were examined. In the DFCI cohort, LOF variants of mSWI/SNF did not predict improved overall survival (OS), time-to-treatment failure (TTF), or disease control rate. Only patients with renal cell carcinoma with mSWI/SNF LOF showed significantly improved OS and TTF with adjusted HRs (95% confidence interval) of 0.33 (0.16-0.7) and 0.49 (0.27-0.88), respectively, and this was mostly driven by PRBM1 In the MSKCC cohort, where only OS was captured, LOF mSWI/SNF did not correlate with improved outcomes across any tumor subtype. We did not find a consistent association between mSWI/SNF LOF variants and improved clinical outcomes to ICIs, suggesting that mSWI/SNF variants should not be considered as biomarkers of response to ICIs., (©2020 American Association for Cancer Research.)

Background: Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1-based ICBs., Methods: We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated., Results: Eighty-six patients were included in the analysis; the median age was 63 years (range 33-84) and the median number of prior therapies was 2 (range 1-10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval [CI] = 26-47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3-8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41-66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%)., Conclusions: Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies., Competing Interests: Conflict of interest statement B.A.M. is reports serving as a consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech and EMD Serono and reports receiving research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis andSeattle Genetics. A.-K.AL. reports serving as a consultant for AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche and TerSera and reports receiving research grants (institution or personal) from Bristol-Myers Squibb, Novartis, Roche andIpsen. D.A.B. reports receiving non-financial support from Bristol-Myers Squibb and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group and Insight Strategy, outside the submitted work. X.X.W. reports receiving research support to DFCI from Bristol Myers Squibb. L.C.H. reports serving as a consultant for Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano and Ology Medical Education; reports receiving research funding to the institution (DFCI) from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer and Endocyte (Novartis) and reports receiving financial support for research travel from Bayer and Genentech. M.A.B. reports serving as a consultant for Exelixis, Seattle Genetics, EMD Serono, Nektar and Sanofi and receiving institutional research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Xencor, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton and Pfizer. T.K.C. reports serving as a consultant for Analysis Group, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Heron Therapeutics, Lilly, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology and receiving research support to DFCI from Analysis Group, AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Sanofi/Aventis andTakeda. All remaining authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Plasma cell-free DNA (cfDNA) variant analysis is commonly used in many cancer subtypes. Cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) has shown high sensitivity for cancer detection. To date, studies have not compared the sensitivity of both methods in a single cancer subtype., Methods: cfDNA from 40 metastatic RCC (mRCC) patients was subjected to targeted panel variant analysis. For 34 of 40, cfMeDIP-seq was also performed. A separate cohort of 38 mRCC patients were used in cfMeDIP-seq analysis to train an RCC classifier., Results: cfDNA variant analysis detected 21 candidate variants in 11 of 40 mRCC patients (28%), after exclusion of 2 germline variants and 6 variants reflecting clonal hematopoiesis. Among 23 patients with parallel tumor sequencing, cfDNA analysis alone identified variants in 9 patients (39%), while cfDNA analysis focused on tumor sequencing variant findings improved the sensitivity to 52%. In 34 mRCC patients undergoing cfMeDIP-seq, cfDNA variant analysis identified variants in 7 (21%), while cfMeDIP-seq detected all mRCC cases (100% sensitivity) with 88% specificity in 34 control subjects. In 5 patients with cfDNA variants and serial samples, variant frequency correlated with response to therapy., Conclusion: cfMeDIP-seq is significantly more sensitive for mRCC detection than cfDNA variant analysis. However, cfDNA variant analysis may be useful for monitoring response to therapy.

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).

Purpose: To date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC)., Methods: We evaluated the frequency of germline pathogenic and likely pathogenic variants in 1038 patients with high-risk UC who underwent targeted clinical germline testing. Case-control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals., Results: Among 1038 patients with UC, the cumulative frequency of patients with pathogenic variants was 24%; 18.6% of patients harbored ≥1 actionable germline variant with preventive or therapeutic utility. MSH2 (34/969, 3.5%) and BRCA1/2 (38/867, 4.4%) germline variants had the highest frequency. Germline variants in DNA damage repair genes accounted for 78% of pathogenic germline variants. Compared to the cancer-free cohort, UC patients had significant variant enrichment in MSH2 (odds ratio [OR]: 15.4, 95% confidence interval [CI]: 7.1-32.7, p < 0.0001), MLH1 (OR: 15.9, 95% CI: 4.4-67.7, p < 0.0001), BRCA2 (OR: 5.7, 95% CI: 3.2-9.6, p < 0.0001), and ATM (OR: 3.8, 95% CI: 1.8-8.3, p = 0.02)., Conclusion: In this study, 24% of UC patients harbored pathogenic germline variants and 18.6% had clinically actionable variants. MLH1 and MSH2 were validated as UC risk genes while ATM and BRCA2 were highlighted as potential UC predisposition genes. This work emphasizes the utility of germline testing in selected high-risk UC cohorts.

Background: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs., Methods: We identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method., Results: A total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (p<0.001), first-line ICI therapy (p=0.011), and PD-1 inhibitor therapy (p=0.007) were all significantly associated with irAE development., Conclusions: This study quantitates the incidence of developing irAEs due to ICI conditioned on time elapsed without irAE development. Although the monthly incidence of irAEs decreased over time on therapy, patients can still develop delayed irAEs beyond ICI discontinuation, and thus, continuous vigilant monitoring is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations., Methods: This multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months., Results: Of 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%)., Conclusions: Patients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD., Competing Interests: Competing interests: NM-C reports support for research travel from Pfizer and Ipsen, and consulting fees for BMS and Bayer. AT reports advisory fee from Foundation medicine and research funding to institution from EMD Serono, Aravive, Bayer, Corvus, WindMil Therapeutics. BB received an unrestricted research grant from Bristol-Myers Squib and speakers' fee from Bristol-Myers Squib, Pfizer, Ipsen and Merck. EL reports research clinical trial funding from Bristol-Myers Squib, Exelixis, Pfizer, Merck, Calithera, Peloton, Genentech, Roche; and consultant fees from Calithera. YZ reports advisory board: Amgen, Roche Diagnostics, Novartis, Jansen, Eisai, Exelixis, Castle Bioscience, Array, Bayer and Pfizer. RM reports consulting fees for Bristol-Myers Squib, Dendreon, Exelixis, Jannsen, Novartis, Pfizer, Tempus; RM receives research funding from Pfizer and Bayer. SS reports consulting fees from Jannsen, and receives research funding from Genentech. AM reports advisory board fees from Seattle Genetics and Debiopharm Group and institution research funding from Acerta Pharma, Genentech, Roche, Merck, Novartis, Seattle Genetics, Acerta Pharma, Mirati Therapeutics and Bristol-Myers Squibb. MH reports consulting fees from AstraZeneca, Bayer, BMS, Exelixis FujiFilm, Genentech and Pfizer; speaking fees from Exelixis; and research funding from BMS, Clovis, Exelixis, Genentech, Merck and Pfizer. TC reports honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS, Cerulean, Eisai, Foundation Medicine, Heron Therapeutics, Exelixis, Genentech, Roche, Lilly, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates (Healthcare Communications Company with several brands such as OnClive and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology; Consulting fees from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS, Cerulean, Eisai, Foundation Medicine, Exelixis, Heron therapeutics, Genentech, Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group; support for research travel from Part of Consulting, Advisory role and Honoraria; research funding (Institutional and personal) from AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine, Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Takeda. LH reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serono, Ology Medical Education; research funding from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis), and support for research travel from Bayer and Genentech., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We previously showed that alterations in mTOR pathway genes were correlated with response to rapalog therapy in metastatic renal cell carcinoma (mRCC), when the analysis focused on extremes of response. Herein, we expand on the prior cohort and examine genetic correlations with rapalog response in a dataset not selected for extremes of response. Tumors from 58 patients from the phase III trial of temsirolimus and 51 local patients with mRCC treated with rapalogs were studied. Somatic mutations were investigated using a targeted sequencing platform covering 27 genes. Clinical benefit (CB) was defined as patients with complete remission, partial response, or stable disease lasting at least 22 weeks. Mutational analyses focused on 5 mTOR pathway genes ( TSC1, TSC2, MTOR, PTEN, PIK3CA ) and 6 genes commonly mutated in RCC ( BAP1, KDM5C, PBRM1 SETD2, TP53 , and VHL ). Among the 109 patients, 93 (85%) patients had clear cell histology, and 31 (28%) showed CB. Nine of 30 (30%) patients harboring mTOR pathway mutations in their tumor achieved CB versus 22 of 79 (28%) in the wild-type group. There was no distinct association between any individual or combination of mTOR pathway gene mutations and CB. Three of 7 patients with TSC1 mutations showed CB. In addition, none of the 6 genes commonly mutated in RCC showed a mutation pattern that correlated with CB. Overall, in this large and diverse population of patients with mRCC, there is no suggestion of a correlation between response to rapalog therapy and mutation status for mTOR pathway genes., (©2019 American Association for Cancer Research.)

Background: Immune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized., Methods: This multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had >1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively., Results: Of 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2-31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3-13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively., Conclusions: Despite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks., Competing Interests: Competing interests: WX reports consulting role with Bayer. NM-C reports support for research travel from Pfizer and Ipsen, and consulting fees for BMS. BAM reports advisory roles for Astellas/Seattle Genetics, Astra Zeneca, Nektar, Exelixis, Pfizer and consultant roles for Astellas, Bayer, Genentech, Janssen and EMD Serono. DYCH reports consulting roles with BMS, Novartis, Pfizer, Ipsen and Exelixis. MAB has a consulting/advisory role with Exelixis, Seattle Genetics, EMD Serono, Nektar and Sanofi and receives institutional research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Xencor, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton and Pfizer. TKC reports research (institutional and personal) funds from AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takedal Honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly; consulting or advisory Role for AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest; stock ownership in Pionyr, Tempest; no leadership or employment in for-profit companies; other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee); patents, royalties or other intellectual properties: International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response,” filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017 and International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy,” filed October 31, 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed November 3, 2017; travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria; medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others).The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. CV provided upon request for scope of clinical practice and research. He reports mentoring several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. LCH reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, Ology Medical Education; Research funding from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis), and support for research travel from Bayer and Genentech., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Overexpression of periostin (POSTN) is associated with prostate cancer (PCa) aggressiveness. We investigated the prognostic significance of POSTN expression in tumor biopsy samples of patients with PCa., Methods: We scored POSTN expression by immunohistochemistry analysis on 215 PCa biopsy samples using an anti-POSTN-specific antibody. A total immunoreactive score (T-IRS) was calculated by adding the POSTN staining scores of stromal and epithelial tumor cells. Prostate-specific antigen (PSA) progression/recurrence-free survival (PFS), radiographic progression/recurrence-free survival (rPFS), and overall survival (OS) were the study end points., Results: A total of 143 patients received therapy with radical attempt, whereas 72 had locally advanced or metastatic disease and received hormone therapy alone. Median T-IRS was 9 and 12 (range, 0-20), respectively (P = .001). Overall, we found a weak positive correlation of T-IRS with prebiopsy PSA levels (r = 0.166, P = .016) and Gleason score (r = 0.266, P < .000). T-IRS ≥ 8 independently predicted for shorter PSA-PFS and OS (hazard ratio [HR] [95% confidence interval (CI)] ≥ 8 versus < 8: 1.50 [1.06-2.14], P = .024 and 1.92 [1.20-3.07], P = .007, respectively). In the subgroup analysis, the association between T-IRS and patient outcome was retained in patients who received therapy with radical attempt (HR [95% CI] ≥ 8 vs. < 8: rPFS: 2.06 [1.18-3.58], P = .01; OS: 2.36 [1.24-4.50], P = .009) and in those with low to intermediate Gleason scores (HR [95% CI] ≥ 8 vs. < 8: PSA-PFS: 1.65 [1.06-2.59], P = .028; rPFS: 2.09 [1.14-3.87], P = .018; OS: 2.57 [1.31-5.04], P = .006)., Conclusion: POSTN T-IRS on PCa biopsy samples independently predicted the risk of recurrence, progression, and death in patients with localized disease and in those with low to intermediate Gleason scores., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Abiraterone and enzalutamide are currently approved for mCRPC patients. Both drugs have distinct mechanisms of action and may have different toxicity profile. There are limited data comparing the side effects of abiraterone and enzalutamide. We performed a meta-analysis of randomized controlled trials (RCT) to better characterize the risk of adverse events associated with both drugs., Methods: We performed a literature search on MEDLINE for studies reporting abiraterone and enzalutamide side effects from January 1966 to July 31, 2015. Abstracts presented at ASCO meetings from 2004 to 2015 were selected manually. Phase III RCT were included in analysis. We assessed the risk of adverse events reported in RCT by performing two meta-analyses: abiraterone-prednisone vs. placebo-prednisone (2,283 pts) and enzalutamide vs. placebo (2,914 pts). Summary of incidence, relative-risks (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies., Results: Overall, enzalutamide was not associated with all-grade (RR 1.06 - 95% CI 0.67-1.65) or grade ≥3 (RR 0.81 - 95% CI 0.28-2.33) cardiovascular events, but was associated with increased risk of all-grade fatigue (RR 1.29 - 95% CI 1.15-1.44). On the other hand, abiraterone was associated with increased risk of all-grade (RR 1.28 - 95% CI 1.06-1.55) and grade ≥3 (RR 1.76 - 95% CI 1.12-2.75) cardiovascular events, but was not associated with all-grade (RR 0.85 - 95% CI 0.58-1.23) or grade ≥3 (RR 1.07 - 95% CI 0.97-1.19) fatigue., Conclusions: In this meta-analysis, abiraterone was associated with an increased risk of cardiovascular events, while enzalutamide was associated with an increased risk of fatigue., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Background: PN is a secreted cell adhesion protein critical for carcinogenesis. In breast cancer, it is overexpressed compared to normal breast, and a few reports suggest that it has a potential role as a prognostic marker., Methods: Tumour samples obtained at the time of mastectomy from 200 women followed for a median time of 18.7 years (range 0.5-29.5 years) were investigated through IHC with a polyclonal anti-PN antibody using tissue microarrays. Epithelial and stromal PN expression were scored independently according to the percentage of coloured cells; the 60th percentile of PN epithelial expression, corresponding to 1%, and the median value of PN stromal expression, corresponding to 90%, were used as arbitrary cut-offs. The relationships between epithelial and stromal PN expression and clinical-pathological features, tumour phenotype and the risk of mortality following surgery were analysed. Appropriate statistics, including the Fine and Gray competing risk proportional hazard regression model, were used., Results: The expression of PN in tumour epithelial cells was significantly lower than that which was observed in stromal cells (p < 0.000). No specific association between epithelial or stromal PN expression and any of the clinical-pathological parameters analysed was found as it was observed in respect to mortality when these variables were analysed individually. However, when both variables were considered as a function of the other one, the expression of PN in the stromal cells maintained a statistically significant predictive value with respect to both all causes and cancer-specific mortality only in the presence of high epithelial expression levels. No significant differences in either all causes or BCa-specific mortality rates were shown according to epithelial expression for tumours displaying higher stromal PN expression rates. However, the trends were opposite for the higher stromal values and the patients with high epithelial expression levels denoted the group with the worst prognosis, while higher epithelial values in patients with lower stromal expression levels denoted the group with the best prognosis, suggesting that PN epithelial/stromal interactions play a crucial role in breast carcinogenesis, most likely due to functional cross-talk between the two compartments. On the basis of PN expression in both compartments, we defined 4 subgroups of patients with different mortality rates with the group of patients characterized by positive epithelial and low stromal PN expression cells showing the lowest mortality risk as opposed to the groups of patients identified by a high PN expression in both cell compartments or those identified by a low or absent PN expression in both cell compartments showing the worst mortality rates. The differences were highly statistically significant and were also retained after multiparametric analysis. Competing risk analysis demonstrated that PN expression patterns characterizing each of previous groups are specifically associated with cancer-specific mortality., Conclusions: Although they require further validation through larger studies, our findings suggest that the patterns of expression of PN in both compartments can allow for the development of IHC "signatures" that maintain a strong independent predictive value of both all causes and, namely, of cancer-specific mortality.

MALDI-TOF MS was used to recognise serum peptidome profiles predictive of mortality in women affected by early BCa. Mortality was analysed based on signal profiling, and appropriate statistics were used. The results indicate that four signals were increased in deceased patients compared with living patients. Three of the four signals were individually associated with all-cause mortality, but only one having mass/charge ratio (m/z) 1,046.49 was associated with BCa-specific mortality and was the only peak to maintain an independent prognostic role after multivariate analysis. Two groups exhibiting different mortality probabilities were identified after clustering patients based on the expression of the four peptides, but m/z 1,046.49 was exclusively expressed in the cluster exhibiting the worst mortality outcome, thus confirming the crucial value of this peptide. The specific role of this peak was confirmed by competing risk analysis. MS findings were validated by ELISA analysis after demonstrating that m/z 1,046.49 structurally corresponded to Angiotensin II (ATII). In fact, mortality results obtained after arbitrarily dividing patients according to an ATII serum value of 255 pg/ml (which corresponds to the 66(th) percentile value) were approximately comparable to those previously demonstrated when the same patients were analysed according to the expression of signal m/z 1,046.49. Similarly, ATII levels were specifically correlated with BCa-related deaths after competing risk analysis. In conclusion, ATII levels were increased in women who exhibited worse mortality outcomes, reinforcing the evidence that this peptide potentially significantly affects the natural history of early BCa. Our findings also confirm that MALDI-TOF MS is an efficient screening tool to identify novel tumour markers and that MS findings can be rapidly validated through less complex techniques, such as ELISA., (© 2015 UICC.)

PN is a secreted cell adhesion protein critical for carcinogenesis. Elevated serum levels of PN have been implicated as playing an important role in different types of cancer, and a few reports suggest a potential role as a prognostic marker. We evaluated the prognostic significance of preoperative serum PN concentration in patients with BCa receiving curative surgery. Enzyme-Linked Immunosorbent Assay (ELISA) was performed to determine the preoperative serum PN level in 182 patients. The correlations between serum PN concentration with clinical pathological features and PN expression in primary tumor samples were analyzed. The prognostic impact of serum PN levels with all-cause and BCa-specific mortality was also investigated. Appropriate statistics were used. Elevated serum PN levels were significantly associated with patient age (p = 0.005), adjuvant systemic therapy (p = 0.04) and progesterone receptor (PgR) status (p = 0.02). No correlation between PN preoperative serum levels and other clinical-pathological parameters, including either the epithelial or the stromal PN expression of primary tumor or the combination of the two, was found. Similarly, no association between serum PN levels and either all-cause or BCa-specific mortality was found. However, subgroup analysis revealed a correlation between higher PN serum levels and all-cause mortality in patients with node-negative disease (p = 0.05) and in those with a low PgR expression (p = 0.03). Higher levels of serum PN were also found to correlate with BCa-specific mortality in the subgroup of patients who did not receive any adjuvant systemic therapy (p = 0.04). Our findings suggest that PN was detectable in the serum of early BCa patients before surgery and increased base-line serum levels predicted worse long-term survival outcomes in specific subgroups of patients.

Renal cell carcinoma (RCC) is responsible for 4% of all neoplasms in adults and for 80% of all primary renal tumors. Metastatic RCC is resistant to all cytotoxic agents and generally prognosis is poor. However, the clinical behavior of RCC is unpredictable, and late recurrences of disease can occur even after several years from the initial surgical approach, so response to the currently available targeted agents is uncertain, due to the lack of reliable prognostic and predictive factors. We report the case of a patient who developed a metastatic recurrence of RCC 16 years after primary treatment, in spite of metastatic disease at diagnosis. At the time of relapse, the disease showed a surprisingly long-term response to Sunitinib, which is maintained after 74 months of treatment. This case report highlights the unpredictable behavior of RCC and underlines the presence of a subset of patients with metastatic RCC achieving long-term response to Sunitinib, despite poor clinical features. In this subset of patients, an important clinical question arises about the appropriate duration of treatment and the need to continue it indefinitely.