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BACKGROUND The immune profile of sarcomatoid renal cell carcinoma (sRCC), including the programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) status, has not been well characterized. METHODS An immunohistochemical digital analysis of PD-L1, PD-1, CD4, and CD8 was performed on nephrectomy specimens from 118 sRCC patients and 92 nonsarcomatoid clear cell renal cell carcinoma (ccRCC) patients. The clinical characteristics of the population were compared between sRCC and ccRCC. Overall survival was estimated, and comparisons were made between PD-L1–positive and PD-L1–negative groups as well as tumor-infiltrating lymphocyte (TIL)–high and TIL-low groups. RESULTS The PD-L1 H-score of sRCC (mean, 3.7; range, 0-192.1) was significantly higher than the score of grade 4 ccRCC (P = .001), and 41.3% of sRCC cases showed a PD-L1 H-score ≥ 10. The PD-1–positive cell density was significantly higher in sRCC versus ccRCC within the tumor and at the invasive front. The intratumoral CD8-positive cell density was significantly higher in sRCC versus ccRCC. Forty-one percent in the sarcomatoid component of sRCC and 8% in the epithelioid component of sRCC had an adaptive immune resistance phenotype (PD-L1–positive and TIL-positive), whereas only 1% in ccRCC had the type I phenotype. CONCLUSIONS sRCC showed higher PD-L1 expression and higher PD-1– and CD8-positive cell density than grade 4 ccRCC. The results indicate a notable immunosuppressive environment in sRCC. Despite advances in the treatment of advanced-stage renal cell carcinoma, sRCC still has a poor prognosis. This work describes highly immunosuppressive characteristics of sRCC in comparison with an appropriate ccRCC control. The results suggest PD-1/PD-L1 blockade therapy as a potential therapeutic approach for sRCC. Cancer 2017. © 2017 American Cancer Society.

Background: Approximately 16% of patients with renal cell carcinomas (RCC) present with stage IV disease at time of diagnosis. Treatment options for metastatic clear cell RCC, the most common histologic subtype, have proliferated over the past decade and include a combination of surgery and systemic therapy. The selection of systemic agent and best timing of systemic therapy in relation to nephrectomy is an area of active research. Objective: To evaluate the evidence for perioperative systemic therapy, including presurgical and postsurgical, for metastatic RCC. Methods: A systematic literature search using PubMed and MEDLINE databases was performed in January 2017 for articles related to perioperative systemic therapy in metastatic RCC using key word search terms. The authors screened the search results and identified selected publications by predetermined inclusion criteria and consensus. Expert opinion was obtained to assess for publications missed by search. Results: Early phase clinical trials of antiangiogenic tyrosine kinase inhibitors prior to cytoreductive nephrectomy in select patients show that these systemic agents are safe and effective in the presurgical setting. There are no randomized data evaluating pre- or post-surgical systemic therapy in metastatic RCC. Conclusions: Retrospective and early-phase prospective studies on the use and timing of systemic therapy in relation to cytoreductive nephrectomy in metastatic RCC show that standard of care antiangiogenic agents are safe and effective in the perioperative setting, though randomized data are still lacking. Pre-surgical immune checkpoint therapy for metastatic RCC has strong biologic rationale and holds promise. Sequential tumor sampling in neoadjuvant and presurgical trials is necessary to determine biomarkers of response and resistance.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.

Background Pazopanib is associated with increased progression-free survival (PFS) in clear-cell renal cell carcinoma (RCC) and has become a standard of care in this disease. The drug is used in metastatic non–clear-cell RCC, but data on outcomes in this setting are limited. Patients and Methods We conducted a retrospective data analysis of records of consecutive metastatic non–clear-cell RCC patients who received pazopanib in front-line and salvage settings between November 2009 and November 2012. Tumor response rate was assessed by a blinded radiologist using Response Evaluation Criteria in Solid Tumors version 1.1. PFS and overall survival (OS) times were estimated using Kaplan–Meier methods. Results Twenty-nine patients were identified with non–clear-cell metastatic RCC, 9 received pazopanib in the front-line setting, 20 in the salvage setting after progression of disease with other targeted therapies. Seven patients (24%) had papillary RCC, 4 (14%) had chromophobe, 5 (17%) had unclassified histopathology, and 13 (45%) had other subtypes including collecting duct, translocation Xp11.2, and various subtypes with sarcomatoid differentiation. All patients discontinued pazopanib before analysis. Median PFS was 8.1 months (95% CI, 5.7-NA [not available]) in the front-line group, and 4 months (95% CI, 2.1-9.9) in the salvage group. Median OS was 31 months (95% CI, 9.2-NA) in the front-line group, and 13.6 months (95% CI, 6.4-NA) in the salvage group. Conclusion Pazopanib showed efficacy in patients with metastatic non–clear-cell RCC in the front-line and salvage settings. Toxicity was mild to moderate and manageable. Further studies are needed to evaluate pazopanib's role in non–clear-cell RCC in terms of efficacy and safety.

Second-line targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKIs). This study compares the effectiveness of these therapies in a multi-practice chart review and synthesizes the findings with those of a similarly designed study. Medical oncologists/hematologists (N = 36) were recruited to review charts for patients aged ≥18 years, received a first-line TKI and initiated second-line targeted therapy in 2010 or later. The primary outcome was time from second-line initiation to treatment failure (TTF; discontinuation, physician-assessed progression, or death, whichever occurred first). TTF was compared among patients receiving second-line everolimus (EVE), temsirolimus (TEM), or TKI as a class, using a Cox proportional hazards model adjusting for type of initial TKI and response, histological subtype, performance status, and sites of metastasis. Hazard ratios (HRs) for TTF were pooled, in a meta-analysis, with previously reported HRs for progression-free survival from a chart review with a similar design. A total of 138, 64 and 79 patients received second-line therapy with EVE, TEM or a TKI, respectively. Adjusting for baseline characteristics, EVE was associated with numerical, but not statistically significant, reductions of 28% (HR = 0.72; 95% CI [0.45–1.16]) and 26% (HR = 0.74; 95% CI [0.48–1.15]) in the hazard of TTF compared to TEM and TKI, respectively. After pooling the HRs from both studies, EVE was associated with significantly reduced hazards of TTF compared to TEM and TKI (HR = 0.73; 95% CI [0.57–0.93]; and HR = 0.75; 95% CI [0.57–0.98], respectively). Limitations include retrospective analyses with possible missing or erroneous chart data, confounding of unobserved factors due to non-randomization, and limited data for axitinib during the study period. In pooled results from two independent multi-practice chart reviews of second-line mRCC treatment, EVE was associated with significantly reduced hazards of treatment failure compared to TEM and to TKIs as a class.

Several updates were made to the 2018 NCCN Guidelines for Kidney Cancer. Adjuvant sunitinib is the first adjuvant therapy to be endorsed by the panel for patients with stage II and III clear cell histology renal cell carcinoma (RCC; category 2B). A promising new treatment-ipilimumab plus nivolumab for patients at intermediate and poor risk in the frontline setting-was added to the guidelines as well. Cabozantinib was added as a first-line option for poor- and intermediate-risk patients with advanced RCC.

Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient variability in drug clearance and exposure that can significantly impact safety and tolerability across a patient population. To optimize cabozantinib exposure (maintaining efficacy and tolerability) for the individual, patients may require treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall survival, progression-free survival and the objective response rate compared with everolimus in patients with advanced RCC who had received previous treatment with a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib (60%) but effective as only 9% discontinued treatment due to adverse events (AEs). In this review, we discuss pharmacometric analyses that evaluated the impact of cabozantinib dose on efficacy and safety outcomes during the METEOR study. Exposure-response models demonstrate that the risk of experiencing adverse events and dose reduction is increased in patients with low cabozantinib clearance versus typical clearance and decreased in patients with high clearance. Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact on efficacy as AEs are more likely to occur in patients with low clearance and higher exposure to cabozantinib. These analyses further support a dose modification strategy to optimize cabozantinib exposure for individual patients.

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

Patients with intermediate-risk advanced renal cell carcinoma are a heterogeneous population, having either 1 or 2 risk factors. It is unclear whether all patients in this risk category should be treated similarly. A secondary analysis of the PRINCIPAL study of pazopanib found that patients can be stratified by number of risk factors and Eastern Cooperative Oncology Group performance status to more accurately predict outcomes. Introduction: The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778). Patients and Methods: Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients. Results: Three hundred sixty three and 343 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS >= 2 (vs. PS = 2) to more accurately predict outcomes. (C) 2019 Published by Elsevier Inc.

Purpose To provide an update summarizing the biologic pathways governing von Hippel-Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations. Methods A PubMed search of the English language literature was reviewed using the following search terms: von Hippel-Lindau, von Hippel-Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review. Results von Hippel-Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs. Conclusion The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.

Background A von Hippel Lindau (VHL) mutation or functional inactivation occurs in the a large proportion of patients with clear-cell renal cell carcinoma (ccRCC), which results in the dysregulation of a number of key cellular functions. A high throughput screen and candidate compound assessment revealed that agents with proteasome inhibition properties were able to stabilize point-mutated VHL and restore some of its functions. Patients and Methods Nine patients with histologically confirmed metastatic ccRCC with disease progression during at least 1 previous systemic therapy were treated with carfilzomib at a dose of 20 mg/m2 over 30 minutes via intravenous (I.V.) infusion on days 1 and 2 and a dose of 56 mg/m2 over 30 minutes via I.V. infusion on days 8, 9, 15, and 16 of each 4-week cycle. Results The study was stopped after 9 patients were enrolled because of futility. Of the 9 patients treated in the study, all patients had disease progression within 4 months, with a median time of 1.8 months (95% confidence interval, 0.8-3.6 months). No patient showed a response according to Response Evaluation Criteria In Solid Tumors. Three patients showed a best response of stable disease. The most common side effects were musculoskeletal pain, elevated creatinine level, anemia, hyperkalemia, leukopenia, lymphopenia, and fatigue. Conclusion Although the negative safety and efficacy results of this study do not favor the use of carfilzomib for the treatment of ccRCC, previous studies have shown selected patients achieved partial or complete response to this class of agent. Further preclinical investigations to evaluate the molecular characteristics of the patients who respond to proteasome inhibitors will better characterize the underlying mechanism of response, and might allow for the selection of an appropriate patient population in future studies.

In the original version of [this article][1] ([1][2]), the wrong files were supplied for Figs. 5B and C. The figures and related article text have been corrected in the latest online HTML and PDF versions of this article. The authors regret these errors. 1. 1.[↵][3]1. Cowman SJ, 2. Fuja

4555 Background: Inactivation of VHL leads to aberrant stabilization and accumulation of HIF-2α, which drives tumor growth. Patients (pts) with VHL disease are at risk for ccRCC, pancreatic neuroendocrine tumors (pNETs), and hemangioblastomas. Repeated surgeries are often needed to control ccRCC and other VHL disease manifestations. Prior results of this ongoing open-label phase 2 study (NCT03401788) showed activity with belzutifan in VHL disease. Updated results are presented. Methods: Adults with germline VHL alterations, measurable and localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS 0 or 1 received belzutifan 120 mg once daily until progression, intolerable toxicity, or decision to withdraw. The primary end point is ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent review committee (IRC). Secondary end points include DOR, time to response (TTR), PFS, and safety. Results: As of June 1, 2020, 61 pts enrolled. Most pts (82%) had ECOG PS 0, and the median number of prior tumor reduction procedures (eg, partial nephrectomy, craniotomy, radiation therapy) per pt was 5 (range, 0-15). Lesions outside the kidney (non-RCC tumors) evaluable by IRC included pNETs (33%) and CNS hemangioblastomas (82%). Median follow-up was 69 wk (range, 18-105), median duration of treatment was 68 wk (range, 8-105), and 56 pts (92%) remain on therapy. There were 22 confirmed responses (ORR, 36% [95% CI, 24-49]) and 7 (11%) unconfirmed responses (documented at 1 time point, to be confirmed at subsequent time point); all were PRs. In pts with confirmed PR, median DOR was not reached (range, 12+ to 62+ wk), median TTR was 31 wk (range, 12-61), and 56 pts (92%) had some reduction in the sum of all target lesion diameters. PFS rate at 52 wk was 98% (95% CI, 89-100). For non-RCC tumors, ORR was 80% (16/20; 1 CR) in pNETs and 32% (16/50; 1 CR) in CNS hemangioblastomas. Of 16 pts with evaluable retinal hemangioblastomas at baseline, 11 (69%) showed improvement per IRC. In those 16 pts, 29 eyes were monitored for retinal hemangioblastomas: 16 eyes (55%) showed improvement, 12 (41%) were stable, and no evaluation was available for 1 eye (3%). All 61 pts (100%) had at least one AE. The most common all-cause AE was anemia (90%), which is considered an on-target toxicity. Treatment-related AEs (TRAE) were reported by 60 pts (98%), and 8 pts (13%) had a grade 3 TRAE. No pts had grade 4/5 TRAEs. One pt discontinued treatment because of a TRAE (grade 1 dizziness). Conclusions: Belzutifan demonstrates clinical benefit and has a favorable safety profile in patients with VHL disease–associated ccRCC, pNETs, and hemangioblastomas. Clinical trial information: NCT03401788.

4579 Background: The sustained increased global prevalence of kidney cancer (renal cell carcinoma, RCC) has increased the burden to health systems, and most of all, to individual patients and their families. Although individual national surveys have been held, no conclusions could be drawn about country-level variation in patient experience or best practice. Here, we report on the second biennial Global Patient Survey on the diagnosis, management, and burden of RCC. Conducted by the International Kidney Cancer Coalition (IKCC) and involving its Affiliate Organizations worldwide, the survey aims to improve collective understanding and to contribute toward the reduction of the burden of kidney cancer around the world. Methods: A 35-question survey on the diagnosis, management, and burden of RCC was designed by a multi-country steering committee of patient leaders to identify geographic variations in 6 key dimensions: patient education, experience and awareness, access to care and clinical trials, best practices, quality of life, and unmet psychosocial needs. The survey was distributed in 13 languages to patients with kidney cancer and their caregivers, through IKCC’s 46 Affiliate Organisations and social media. It was completed online or in paper form between 29 Oct 2020 and 5 Jan 2021. Results: 2,012 (1,586 patients, 417 carers, 9 undisclosed) responses were recorded from 41 countries in 13 languages. Survey results were analyzed using cross-tabulations by an independent third-party organization. The full global report will be publicly available, as well as 7 individual country reports where at least 100 responses were received. 52% lacked understanding of subtype at diagnosis. 42% reported that the likelihood of surviving their cancer beyond 5 years was not explained. 51% reported that they were involved as much as they wanted to be in developing their treatment plan. 41% indicated that “No one” discussed cancer clinical trials with them. 31% were invited to take part in a clinical trial. 56% experienced barriers to their treatment. 45% self-reported that they were insufficiently physically active; 15% were completely sedentary. 50% indicated that they ‘very often’ or ‘always’ experienced disease-related anxiety. 55% indicated that they ‘very often’ or ‘always’ experienced a fear of recurrence. 52% reported having talked to their doctor/healthcare professional about their concerns. Conclusions: The IKCC and its global affiliates will use these results to ensure that patient and caregiver voices are heard and acted upon, with ultimate incorporation of these findings by much broader communities into care pathways, clinical practice, or health technology assessments. Furthermore, individual countries can use their reports to advance understanding of patient experiences and to drive improvements in providing care locally.

We conducted a retrospective analysis of two clinical trials in treatment-naïve patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT18 months (longer DT) versus ≤18 months (shorter DT).DT, objective response rate (ORR), tumor shrinkage, and overall survival (OS) were summarized for patients with longer and shorter DT.Overall, 152 patients (37.8%) had longer DT and 250 (62.2%) had shorter DT (median, 34.7 vs. 6.5 months, respectively). ORR in all 402 patients with advanced RCC was 43.5%. ORR was 75% for longer DT versus 24.4% for shorter DT (p 0.0001). More patients with longer DT versus shorter DT had ≥10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment-related adverse events (AEs) grade ≥3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT.Longer duration (18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS.

// Pavlos Msaouel 1, * , Amado J. Zurita 1, * , Shixia Huang 2 , Eric Jonasch 1 and Nizar M. Tannir 1 1 Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 2 Dan L. Duncan Cancer Center & Department of Molecular and Cellular Biology and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Nizar M. Tannir, email: ntannir@mdanderson.org Keywords: biomarkers, cytokines and angiogenic factors, everolimus, non-clear cell renal cell carcinoma, sunitinib Received: September 20, 2016 Accepted: January 16, 2017 Published: February 02, 2017 ABSTRACT No biomarkers are available to predict relative clinical benefit from targeted therapies in patients with non-clear cell renal cell carcinoma (nccRCC). To identify candidate predictive markers, we investigated a set of cytokines and angiogenic factors (CAFs) in previously untreated patients with nccRCC participating in the phase II ESPN trial comparing first-line sunitinib to everolimus. Pre-treatment concentrations of 30 CAFs were measured in plasma from 37 patients treated with everolimus (n=16) or sunitinib (n=21), and associated with progression-free (PFS) and overall survival (OS) after adjusting for potential confounders. High (>median) concentrations of soluble glycoprotein 130 (sgp130) were predictive of a longer PFS with sunitinib compared with everolimus (HR = 0.30; 95% CI: 0.11-0.85; P = 0.024). Significantly shorter PFS was noted, independently of treatment arm, in patients with high (>median) levels of IL-8 (HR = 3.13; 95% CI: 1.41-6.92), IL-13 (HR = 3.36; 95% CI: 1.49-7.58), and soluble tumor necrosis factor receptor II (HR = 2.21; 95% CI: 1.04-4.72). High IL-8 levels were also associated with significantly shorter OS (HR = 3.55; 95% CI: 1.55-8.14). Thus, using CAF profiling we identified candidate prognostic and predictive circulating biomarkers that can be used to inform therapeutic decisions in nccRCC.

The hypoxia-regulated tumor-suppressor von Hippel-Lindau (VHL) is an E3 ligase that recognizes its substrates as part of an oxygen-dependent prolyl hydroxylase (PHD) reaction, with hypoxia-inducible factor α (HIFα) being its most notable substrate. Here we report that VHL has an equally important function distinct from its hypoxia-regulated activity. We find that Aurora kinase A (AURKA) is a novel, hypoxia-independent target for VHL ubiquitination. In contrast to its hypoxia-regulated activity, VHL mono-, rather than poly-ubiquitinates AURKA, in a PHD-independent reaction targeting AURKA for degradation in quiescent cells, where degradation of AURKA is required to maintain the primary cilium. Tumor-associated variants of VHL differentiate between these two functions, as a pathogenic VHL mutant that retains intrinsic ability to ubiquitinate HIFα is unable to ubiquitinate AURKA. Together, these data identify VHL as an E3 ligase with important cellular functions under both normoxic and hypoxic conditions.

10.2217/fon-2016-0028 © 2016 Future Medicine Ltd Cancer initiation and progression is the result of an accumulation of mutations in key tumor suppressor genes, mismatch repair genes and oncogenes which alter cancer cell growth, death and differentiation. Mutations occurring in cancer tissue are termed somatic; whereas, heritable mutations that may be passed on to subsequent generations occur in germline DNA. Deleterious germline mutations in certain genes can lead to hereditary cancer syndromes whereby family members carrying the mutation have an increased susceptibility to certain tumor phenotypes. Germline mutations in the von HippelLindau (VHL) gene, a tumor suppressor found on chromosome 3p25, are inherited in an autosomal dominant fashion giving way to the potential development of a spectrum of tumor types including: renal and pancreatic cysts, clear cell renal cell carcinoma (ccRCC), hemangioblastomas (HB), pheochromocytomas, retinal angiomas and pancreatic neuroendocrine tumors (PNETs) [1,2]. VHL disease occurs in approximately one in 35,000 births, and the morbidity and mortality associated with VHL disease primarily centers around the neurologic complications of HBs and the progression of ccRCC [3,4]. VHL lesions, despite different anatomic origins, are in general highly vascular owing to the loss of the underlying anti-angiogenic function of the VHL gene. Given the variety of tumor types within a single individual with VHL disease, treatment necessitates a personalized, multidisciplinary approach; and, given that the most frequent alterations in sporadic ccRCC involve loss of the 3p chromosomal arm including the VHL gene, treatment discoveries for this rare, heritable disease have implications for a much wider patient population [5]. In this article, we discuss the current state of treatment options for VHL disease across anatomic sites of expression in the context of its molecular underpinnings. COMMENTARY

Objective To identify groups most likely to benefit from an Expressive Writing (EW) intervention, we examined psychosocial variables as intervention moderators. We hypothesized that EW would be particularly effective for participants with high levels of depressive symptoms and social support at study entry. Methods Patients (n = 277; 60.6% male) with kidney cancer were randomly assigned to either an expressive (EW) or neutral writing (NW) condition. Intervention outcomes included measures of depressive symptoms (CESD), cancer-related symptoms (MDASI), fatigue (BFI), and sleep disturbances (PSQI) assessed at baseline, 1, 4, and 10 months later. Moderators were measured at baseline. Results As hypothesized, depressive symptoms and social support moderated intervention efficacy. When examining both moderators simultaneously, EW appeared to be most effective in terms of cancer-related symptoms (p

303 Background: RMC is a rare and highly aggressive malignancy with a median overall survival (OS) of only 13 months from diagnosis. RMC is thought to be completely refractory to the targeted therapies used against clear cell renal cell carcinoma and the recommended standard of care therapy is platinum-based cytotoxic chemotherapy, which only produces a best response rate of 29% in the first line setting (Shah et al. BJU Int., 2017). Comprehensive molecular profiling of RMC tissues revealed a decrease in genes related to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation and an increase in genes involved in fatty acid synthesis, demonstrating a reliance on aerobic glycolysis to meet cellular bioenergetics needs (Msaouel et al. Cancer Cell, 2020). The combination of B+E is particularly effective in tumors such as fumarate hydratate – deficient renal cell carcinomas, which also rely on aerobic glycolysis. We therefore hypothesized that B+E would show clinical efficacy against RMC. Methods: We analyzed 10 pts with RMC treated with B+E at our institution. A blinded board-certified radiologist reviewed all restaging images to assess best radiographic response as defined by RECIST v1.1 and, when applicable, date of progression. Adverse events (AEs) were evaluated using the CTCAE version 5.0 grading estimated from chart documentation. Clinical-grade next generation genome sequencing for gene mutations, copy number alterations and fusions was performed in 6/10 pts using the Oncomine platform. Results: Between 05/2005 and 09/2020, we identified 10 pts with RMC that were treated with B+E (Table). B+E produced a partial response in 2/10 pts (20%) and stable disease as best response in 6/10 pts (60%), resulting in a median progression-free survival of 3.5 months (mo) with 95% CI 1.8 – 5.2 mo. Decrease in tumor burden was noted even in patients that had received 3+ prior therapies and irrespective of genomic alterations. The median overall survival (OS) from B+E initiation was 7.3 mo (95% CI 5.4 – 9.1) and the median OS from diagnosis was 20.8 mo (95% CI 15.4 – 26.1). B+E was well tolerated with no grade ≥ 4 AEs and only one grade 3 AE (skin rash). Dose reduction was only needed in 1/10 pts. Conclusions: B+E is clinically active and well tolerated in heavily pre-treated pts with RMC and is therefore a viable therapeutic option for this lethal disease. However, pts ultimately relapse and further investigation is needed to elucidate mechanisms of resistance and determine how to optimally target metabolic vulnerabilities in RMC. [Table: see text]

273 Background: Clear cell RCC (ccRCC) accounts for ~70% of kidney cancer cases in the US. Several first-line therapies are approved for ccRCC, but few patients respond completely and most progress within 5-11 mo. A key oncogenic driver in RCC is the transcription factor hypoxia-inducible factor 2α (HIF-2α). MK-6482 is a small molecule HIF-2α inhibitor that blocks the heterodimerization of HIF-2α with HIF-1β, inducing tumor regression in mouse xenograft RCC models. Updated data presented here include additional follow-up from the expansion cohort of patients with ccRCC from the first-in-human phase 1/2 study of MK-6482 in advanced solid tumors (NCT02974738). Methods: Patients were aged ≥18 y with advanced ccRCC, received ≥1 prior therapy, and had RECIST v1.1 measurable disease, ECOG status 0 or 1, adequate organ function, and life expectancy ≥6 mo. They received 120 mg of MK-6482 orally once daily. Tumors were assessed at baseline, within 7 days before week 9, and then every 8 weeks; response was assessed using RECIST v1.1. The primary end point was safety. Secondary end points included ORR, duration of response (DOR), and PFS. Results: Fifty-five patients with ccRCC were treated with MK-6482 120 mg (52 in expansion and 3 in dose-escalation cohorts). The median number of prior therapies was 3 (range 1-9). Forty-two patients (81%) previously received PD-1/L1 inhibitors and 48 (92%) previously received VEGF inhibitors. Thirteen patients (24%) were classified as favorable risk and 42 (76%) as intermediate or poor risk per IMDC criteria. With a median follow-up of 28 mo, the most common all-grade, all-cause AEs >30% were anemia (76%), fatigue (71%), dyspnea (49%), nausea (36%), cough (31%), and hypoxia (31%). Anemia (27%) and hypoxia (16%) were the most common grade 3 AEs. Two patients (4%) experienced grade 4 AEs, and 4 patients (7%) experienced grade 5 AEs. No grade 4 or 5 AEs were related to treatment. ORR was 25%, with 14 confirmed PRs. Thirty patients (55%) had SD, with a disease control rate (CR+PR+SD) of 80%. Median DOR was not reached; 77% had a response ≥6 mo. By IMDC risk, 4 of 13 patients with favorable risk had PR (ORR = 31%) and 10 of 42 with intermediate or poor risk had PR (ORR = 24%); disease control rate was 92% and 76%, respectively. Median PFS for the total population was 14.5 mo; 51% had a PFS of 12 mo. As of June 1, 2020, 33 patients (60%) discontinued because of PD and 2 (4%) because of AEs; 11 patients (20%) had ongoing treatment. Conclusions: MK-6482 remained well tolerated with a favorable safety profile and promising single-agent activity in patients with ccRCC for all IMDC risk groups after further follow-up. A phase III trial in a similar population is underway. Clinical trial information: NCT02974738 .

TPS365 Background: Sitra is a spectrum-selective receptor tyrosine kinase inhibitor (TKI) that targets TAM receptors (TYRO3, AXL, MERTK), VEGFR2, c-Kit, and c-MET. Sitra has shown antitumor activity in accRCC, and reduces type 2 tumor-associated macrophages, regulatory T-cells and myeloid-derived suppressor cells and enhances T cell–mediated antitumor immune responses. The combination of sitra with anti-PD1 immune checkpoint inhibitors (ICIs), such as nivo, has an acceptable safety profile and demonstrates efficacy across multiple tumor types, including accRCC (Msaouel et al. J Clin Oncol, 2020, abstr 612). Ipi enhances the efficacy of nivo through distinct but complementary pathways to those targeted by sitra. We hypothesize that the triple combination of sitra + nivo + ipi will lead to more potent antitumor responses. This study is designed to determine the optimal dose of sitra when combined with nivo + ipi, and assess the safety as well as the preliminary efficacy of this combination in accRCC, and potentially other cancers, that have shown favorable responses to nivo + ipi. Methods: This phase I/Ib study (NCT04518046) is evaluating sitra + nivo + ipi in frontline advanced or metastatic ccRCC or other solid malignancies. The primary endpoint of the trial is safety and tolerability of this regimen. Secondary endpoints include: objective response rate (RECIST 1.1), duration of response, progression-free survival, overall survival, and pharmacokinetic measurements. The phase I dose escalation portion of the trial will enroll approximately 30 pts with intermediate- or poor-risk accRCC by International Metastatic RCC Database Consortium (IMDC) criteria, who will receive escalating doses of sitra (starting dose 35 mg orally QD) following the Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design (Yuan et al. Clin Cancer Res, 2018), combined with nivo 3 mg/kg and ipi 1 mg/kg (NIVO3/IPI1) every 3 weeks (wks) for up to 4 doses, followed by maintenance nivo (240 mg every 2 wks or 480 mg every 4 wks). The phase Ib dose expansion cohorts will be initiated following identification of the recommended dose of sitra in combination with NIVO3/IPI1 and will enroll up to 31 pts for each of 2 cohorts: pts with intermediate-/poor-risk accRCC (Cohort A) and pts with favorable-risk accRCC (Cohort B). Pts will receive study treatment until disease progression, unacceptable adverse events, or pt withdrawal of consent. Future dose expansion cohorts may be added to include other solid tumors in which favorable activity has been previously demonstrated with nivo + ipi, such as metastatic urothelial carcinoma, melanoma, non–small-cell lung cancer, hepatocellular carcinoma, and colorectal cancer. The study is currently enrolling at 1 US site and additional sites may be added at dose expansion. At the time of the abstract submission, 3 pts have been enrolled. Clinical trial information: NCT04518046 .

333 Background: Patients (pts) with VHL disease are at risk of developing benign and malignant tumors, including ccRCC, pancreatic lesions tumors, CNS hemangioblastomas, and retinal lesions. Inactivation of VHL leads to stabilization of HIF-2α, which drives tumor growth. In a phase 1/2 study, MK-6482, a potent, selective, oral small molecule HIF-2α inhibitor, demonstrated favorable safety and antitumor activity in advanced ccRCC. We present results of the open-label phase 2 study of MK-6482 for VHL disease–associated ccRCC (NCT03401788). Methods: Adults with germline VHL alterations, measurable, localized/non-metastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS 0/1 received MK-6482 120 mg once daily until progression, intolerable toxicity, or decision to withdraw. Primary end point: ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent review committee (IRC). Secondary end points: DOR, time to response (TTR), PFS, and safety. Results: As of June 1, 2020, 61 pts enrolled. The majority (82%) of pts had ECOG PS 0, and median number of prior surgeries per pt was 5 (range, 1-15). Lesions outside the kidney (non-RCC tumors) evaluable by IRC included pancreatic lesions (100%) and CNS hemangioblastomas (70%). Median duration of treatment was 68 wk (range, 8-105), and 92% of pts remain on therapy. There were 22 confirmed responses (ORR, 36% [95% CI, 24%-49%]) and 7 (11%) unconfirmed (documented at 1 time point, to be confirmed at subsequent time point) responses; all PRs. In pts with confirmed PR, median DOR was not reached (range, 12-62 wk) and median TTR was 31 wk (range, 12-61); 14 (64%) pts had response duration of ≥26 wk. 56 pts (92%) had any decrease in size of target lesions. PFS rate at 52 wk was 98% (95% CI, 89%-100%). Overall, pretreatment median linear growth rate of ccRCC tumors was +3.6 mm/y (range, −3.4 to +33.1), compared with −4.5 mm/y (range, −12.8 to +5.1) while on treatment. For non-RCC tumors, ORR in pancreatic lesions was 64% (39/61, including 4 CRs) and in CNS hemangioblastomas was 30% (13/43, including 5 CRs). Median (range) TTR was 35 wk (11-60) and 12 wk (10-60) for pancreatic lesions and CNS hemangioblastomas, respectively. 11/16 (69%) pts with evaluable retinal lesions at baseline showed improvement. Of those 16 pts, 29 eyes were followed for retinal lesions; 16 eyes (55%) showed improvement, 12 (41%) remained stable, and no follow-up evaluation was available for 1 (3%) eye. Treatment-related AEs (TRAEs) occurred in 98% of pts, none grade 4/5. Most common TRAE was anemia (87%), considered to be an on-target toxicity. One pt discontinued treatment due to a TRAE (grade 1 dizziness). As of data cutoff, 1 pt (2%) required surgery for ccRCC tumors after treatment. Conclusions: MK-6482 is an active and well-tolerated therapy for VHL disease–associated ccRCC, pancreatic lesions, as well as CNS and retinal hemangioblastomas. Clinical trial information: NCT03401788 .

5003 Background: Patients (pts) with Von Hippel-Lindau disease (VHL) are at risk for several cancers, including clear cell renal cell carcinoma (ccRCC). Inactivation of VHL results in constitutive activation of the HIF-2α transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, has shown favorable safety and antitumor activity in a phase 1/2 study. We present initial results of the open-label phase 2 study of MK-6482 for treatment of VHL-associated ccRCC (NCT03401788). Methods: Adult pts with a pathogenic germline VHL variation, measurable localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS of 0/1 received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/pt decision to withdraw. Primary end point was ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent radiology review. Secondary end points were DOR, time to response (TTR), PFS, and safety and tolerability. Results: As of December 6, 2019, 61 pts were enrolled; median (range) age was 41 years (19-66) and most pts were male (52.5%) and had ECOG PS of 0 (82.0%). The most common lesions outside the kidney (non-RCC tumors) were CNS hemangioblastomas (80.3%) and pancreatic lesions (50.8%). Median (range) duration of treatment was 9.9 mo (1.9-18.2) and 95.1% of pts remain on therapy. Three pts discontinued (AE, n = 1; death [fentanyl toxicity], n = 1; pt decision, n = 1). There were 17 confirmed responses (ORR, 27.9% [95% CI, 17.1-40.8%]) and 8 (13.1%) unconfirmed (documented at 1 timepoint and to be confirmed at subsequent timepoint) responses; all responses were PRs. Of 61 pts, 53 (86.9%) had decrease in size of target lesions. In 17 pts with confirmed response, median (range) DOR was not reached (2.1-9.0 mo) and median (range) TTR was 5.5 mo (2.7-14.0). Responses were also observed in CNS, retinal, and pancreatic lesions. Median PFS was not reached; 12-mo PFS rate was 98.3%. Treatment-related AEs (TRAEs) occurred in 96.7% of pts, mostly grade 1 (44.3%) or grade 2 (42.6%) and primarily (≥20%) anemia (83.6%; considered an on-target-toxicity), fatigue (49.2%), and dizziness (21.3%). Grade 3 TRAEs occurred in 9.8% of pts, primarily fatigue (4.9%) and anemia (3.3%). There were no grade 4 or 5 TRAEs. One pt discontinued because of a TRAE (dizziness). Conclusions: MK-6482 showed promising efficacy and tolerability in pts with VHL-associated ccRCC and responses in other VHL-related lesions. These data support further investigation of MK-6482 in VHL disease. Clinical trial information: NCT03401788 .

e17090 Background: Two immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations are FDA-approved for patients (pts) with metastatic renal cell carcinoma (mRCC). Here we present a multicenter off-protocol experience with IO/TKI combinations after progression on monotherapy. Methods: We performed a retrospective analysis of pts with mRCC who received combination non-FDA approved off-protocol IO/TKI combination therapy from 11/2015 – 1/2019 at MD Anderson Cancer Center and Duke Cancer Institute. Results: 48 pts met criteria for study inclusion. At therapy start: median (med) age 65 years; 75% clear cell histology; 68.8% IMDC intermediate risk (20.8% favorable, 10.4% poor); 81.3% prior nephrectomy; med metastatic sites: 2; med prior systemic treatments: 2; most common metastatic sites: lung (58.3%), lymph node (52.1%), and bone (43.8%). Pts received nivolumab (nivo) in combination with the following: cabozantinib (n = 24, 50%), pazopanib (13, 27.1%), axitinib (6, 12.5%), lenvatinib (2, 4.2%), ipilimumab/cabozantinib (3, 6.3%). Med PFS was 13.7 months and med OS was not reached. The two largest cohorts received nivo + cabozantinib (N+C; med dose 40 mg daily) or nivo + pazopanib (N+P; med dose 400 mg daily). The N+C cohort had higher med metastatic sites (3 vs 2) and was more pretreated with agents unique to their IO/TKI combination (med 2 vs 0). In the N+P group, more pts had started on TKI prior to addition of nivo at progression (69.2% vs 45.8%), and fewer had IO monotherapy with TKI addition (30.8% vs 50%). With a med follow up of 14.0 months after combination start, the N+C cohort had a med PFS of 7.3 months (initiated TKI first: 4.8, IO first: 8.2) and med OS of 18.2 months (TKI first: 11.8, IO first: 24.3). The N+P cohort had med follow up of 20.5 months after combination, med PFS of 21.3 months (TKI first: 16.5, IO first: 21.8), and med OS was not reached. In the N+C group, 87.5% experienced any grade adverse event (AE), most common included fatigue (79.2%), diarrhea (42.7%), nausea (29.2%), hypertension (29.2%), and weight loss (25.0%). In the N+P group, 92.3% experienced any grade AE, including fatigue (76.9%), hypertension (38.5%), diarrhea (30.8%), nausea (30.8%), and weight loss (30.8%). There were no grade ≥3 AEs. Conclusions: Slow disease progression on nivo or TKI may be safely controlled with addition of IO/TKI therapy. Med PFS after addition of nivo to TKI appears similar (N+C) and improved (N+P) compared to nivo monotherapy (Checkmate-025). Med PFS after addition of TKI to IO was also similar (N+C) and improved (N+P) compared to historical controls.

5073 Background: Immune checkpoint inhibitors, multi-kinase VEGF agents, and mTOR inhibitors are approved for mRCC. Due to the overlapping mechanisms of action of the twelve approved therapies for mRCC, select patients are referred for phase I clinical trials after progression on multiple lines of treatment. We sought to evaluate the efficacy of phase I trials in patients with mRCC. Methods: Patients with all histologies of mRCC were included if they received treatment on a phase I clinical trial at MD Anderson Cancer Center. Baseline clinical characteristics and outcomes data were retrospectively collected. The historical control was a study of 1112 patients with mRCC who received third-line treatment in the IMDC database (PMID: 27318422). Time to event endpoints were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Between 2014 and 2019, there were 106 cases where 82 patients with mRCC were enrolled in a phase I clinical trials (40 unique trials). 30% (32/108) of the cases were in patients with non-clear cell RCC (nccRCC), and the most prevalent nccRCC histologies were papillary (n = 7) and renal medullary carcinoma (n = 7). The median number of prior systemic therapies was 2 (range 0-9). Across the entire cohort, median PFS was 5.9 months (m), median OS was 31.2 m, and the ORR was 23% (Table). In patients who received at least two prior lines of therapy (n = 70), the median PFS was 4.8 m and median OS was 24.9 m. In patients with metastatic nccRCC, median OS, PFS, and ORR were numerically lower, but statistically did not contradict the supposition that these outcomes did not differ from ccRCC (Table). Conclusions: In the largest pooled phase I clinical trial experience for patients with mRCC, phase I trials may have therapeutic value when compared to historical controls, where median PFS was 3.9 m, median OS was 12.4 m, and ORR was 10.5%. Patients with all histologies of mRCC may derive clinical benefit from phase I clinical trials, yet patients with ccRCC had numerically better outcomes. Patients with mRCC should be considered for phase I clinical trials. [Table: see text]

Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can lead to tumorigenesis; however, the functional impact of the high mutation burden resulting from this phenotype remains poorly explored. Here, we demonstrate that dMMR-induced destabilizing mutations lead to proteome instability in dMMR tumors, resulting in an abundance of misfolded protein aggregates. To compensate, dMMR cells utilize a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins. Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfolded protein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells. To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibition and found the combination was synergistic, significantly improving efficacy over either treatment alone.

Despite numerous therapeutic advances in renal cell carcinoma (RCC), little is known about patients' perspectives on cancer care. An international survey was conducted to identify points of frustration associated with cancer care reported by patients with RCC. Data were obtained from an online survey, conducted from April 1 to June 15, 2017, through social media and patient networking platforms. This survey obtained baseline demographic, clinicopathologic, and treatment-related information. Open-ended questions accessed sources of frustration in cancer-related care and patients' suggestions for amelioration. Responses were categorized and reviewed by independent reviewers. A qualitative analysis was performed and the Kruskal-Wallis test was used to define associations between baseline characteristics and sources of frustration. Among 450 patients surveyed, 71.5% reported sources of frustration, classified as either emotional (48.4%) or practical (23.1%). The most common were fear of recurrence/progression (15.8%), distrust of their cancer care system (12.9%), and lack of appropriate information (9.8%). Female gender and non-clear cell histology were associated with both types of frustration, and older age was linked to practical sources of frustration. Patients suggested solutions included greater compassion among health care practitioners (20.7%), better access to information (15.1%) and research to improve their chances of being cured (14.7%). Sources of frustration related to emotional and practical causes were identified amongst patients with RCC. Certain demographic and clinical characteristics were associated with more sources of frustration. This study provides the first characterization of specific ways to improve the patient experience by addressing common frustrations.

PBRM1 is a subunit of a SWI/SNF chromatin remodeling complex, and more than 30% of clear cell RCCs show PBRM1 mutations. The function of PBRM1 in tumor immune microenvironment, tumor prognosis and response to immune checkpoint therapies still remain unclear. Here we found that Pbrm1 knockout in mouse Renca RCC cells decreased the activity of IFNγ-STAT1 signaling pathway and consequently the expression of chemokines that recruit effector CD8+ T cells. Pbrm1 deficient murine RCC tumors showed reduced infiltration of CD8+ T cells, which was associated with less PD-1 expression. Pbrm1 deficient tumors demonstrated longer latency but they were more resistant to anti-PD1 treatment. This study provided mechanistic insights and therapeutic guideline to manage ccRCC associated with PBRM1 inactivation. Citation Format: Xian-De Liu, Wen Kong, Anh Hoang, Xuesong Zhang, Lijun Zhou, Patrick G. Pilie, Sevinj Isgandrova, Margie M. Moczygemba, Eric Jonasch. PBRM1 loss promotes resistance to immunotherapy in RCC [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B48.

Cancer initiation and progression is the result of an accumulation of mutations. Mutations occurring in cancer tissue are termed somatic, whereas mutations in germline DNA may be passed onto subsequent generations and are often termed hereditary. Deleterious germline mutations in key tumor suppressor genes can lead to hereditary cancer syndromes whereby family members carrying the mutation have an increased susceptibility to developing certain tumor phenotypes. Common features of hereditary cancer syndromes include early age of onset, multiple affected generations, rare tumor types, and/or multiple primary malignancies.

CRISPR-Cas9 gene editing technology has considerably facilitated the generation of mouse knockout alleles, relieving many of the cumbersome and time-consuming steps of traditional mouse embryonic stem cell technology. However, the generation of conditional knockout alleles remains an important challenge. An earlier study reported up to 16% efficiency in generating conditional knockout alleles in mice using 2 single guide RNAs (sgRNA) and 2 single-stranded oligonucleotides (ssODN) (2sgRNA-2ssODN). We re-evaluated this method from a large data set generated from a consortium consisting of 17 transgenic core facilities or laboratories or programs across the world. The dataset constituted 17,887 microinjected or electroporated zygotes and 1,718 live born mice, of which only 15 (0.87%) mice harbored 2 correct LoxP insertions in cis configuration indicating a very low efficiency of the method. To determine the factors required to successfully generate conditional alleles using the 2sgRNA-2ssODN approach, we performed a generalized linear regression model. We show that factors such as the concentration of the sgRNA, Cas9 protein or the distance between the placement of LoxP insertions were not predictive for the success of this technique. The major predictor affecting the method’s success was the probability of simultaneously inserting intact proximal and distal LoxP sequences, without the loss of the DNA segment between the two sgRNA cleavage sites. Our analysis of a large data set indicates that the 2sgRNA–2ssODN method generates a large number of undesired alleles (>99%), and a very small number of desired alleles (

Background Cabozantinib prolongs overall survival (OS) and progression-free survival (PFS) in patients with metastatic clear cell renal cell carcinoma (RCC) that progressed on first-line vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI). The role of cabozantinib has not been established in non-clear cell renal cell carcinoma (nccRCC). Methods This is a retrospective study of 30 patients with nccRCC who received cabozantinib from January 2013 to January 2017. Information collected included baseline characteristics, toxicity, dose reductions, PFS and OS. A fellowship trained abdominal radiologist, blinded to patient history and clinical data, assessed radiographic response using RECIST, v1.1. Results With a median follow-up of 20.6 months (95% confidence interval [CI]: 11.4–28.8), median PFS was 8.6 months (95% CI: 6.1–14.7), and median OS was 25.4 months (95% CI: 15.5–35.4). Of the 28 patients with measurable disease, 4 had partial responses (2 papillary, 1 chromophobe and 1 unclassified RCC), 18 had stable disease (64.2%) and 6 had progressive disease (21.4%), resulting in a 14.3% objective response rate and a 78.6% disease control rate. Two patients with papillary RCC who had experienced disease progression on savolitinib achieved durable partial response and stable disease, respectively, following treatment with cabozantinib. Of the 21 patients who started cabozantinib at 60 mg/d, 12 (57.1%) required dose reduction due to toxicity. Conclusion In this retrospective study, cabozantinib produced a clinically meaningful benefit in patients with metastatic nccRCC, the majority of whom had disease progression on prior VEGFR-TKIs. Prospective trials of cabozantinib in nccRCC are warranted.

Loss of von Hippel Lindau (VHL) protein function is a key driver of VHL diseases, including sporadic and inherited clear cell renal cell carcinoma. Modulation of the proteostasis of VHL, especially missense point-mutated VHL, is a promising approach to augmenting VHL levels and function. VHL proteostasis is regulated by multiple mechanisms including folding, chaperone binding, complex formation and phosphorylation. Nevertheless, many details underlying the regulations of VHL proteostasis are unknown. VHL is expressed as two variants, VHL30 and VHL19. Furthermore, the long-form variant of VHL was often detected as multiple bands by western blotting. However, how these multiple species of VHL are generated and whether the process regulates VHL proteostasis and function are unknown. We hypothesized that the two major species are generated by VHL protein cleavage, and the cleavage regulates VHL proteostasis and subsequent function. We characterized VHL species using genetical and pharmacological approaches and showed that VHL was first cleaved at the N-terminus by chymotrypsin C before being directed for proteasomal degradation. Casein kinase 2-mediated phosphorylation at VHL N-terminus was required for the cleavage. Furthermore, inhibition of cleavage stabilized VHL protein and thereby promoted HIF downregulation. Our study reveals a novel mechanism regulating VHL proteostasis and function, which is significant for identifying new drug targets and developing new therapeutic approaches targeting VHL deficiency in VHL diseases.

Background Second targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin inhibitors (mTORis) and tyrosine kinase inhibitors (TKIs). This observational study compares overall survival (OS) and progression-free survival (PFS) of patients treated with everolimus (an mTORi) and axitinib (a TKI) following first TKI, and assesses the impact of type and duration of first TKI on the relative effectiveness of these second targeted therapies. Methods Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Included patients with mRCC were required to have discontinued a first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons, and to have initiated everolimus or axitinib as second targeted therapy between February 2012 and January 2013. OS and PFS were compared between patients treated with everolimus vs. axitinib using multivariable Cox proportional hazards regression models. Comparative results were also stratified by type and duration of first TKI. Results Included patients (n = 325 for everolimus and n = 127 for axitinib) had a mean age of 61 years and 31% were female. Sunitinib was the most commonly used first TKI (73%). After adjusting for patient characteristics, no statistically significant differences were observed in OS or PFS between everolimus and axitinib. When stratifying by type and duration of first TKI, there was no statistically significant difference in OS between everolimus and axitinib in all subgroups except for patients with

Sequencing of clear cell renal cell carcinomas identified loss-of-function mutations of SETD2, a gene that encodes a nonredundant methytransferase responsible for histone H3 lysine 36 trimethylation (H3K36me3), and H3K36me3 is progressively deregulated in metastases. However, few data exist regarding the impact of loss of H3K36me3 on outcomes. We assessed the association of SETD2 DNA alterations and messenger RNA (mRNA) expression with overall survival using The Cancer Genome Atlas clear cell renal carcinoma data (N=411). Additionally, we assessed the association of H3K36 loss of methylation with renal cell carcinoma-specific survival and progression-free survival using an independent cohort at Mayo Clinic (N=1,454). Overall survival, renal cell carcinoma-specific survival and progression-free survival were estimated using Kaplan-Meier method and differences in survival across groups was compared using Cox regression models, adjusted for age and the Mayo SSIGN (stage, size, grade, and necrosis) score. In The Cancer Genome Atlas cohort, SETD2 DNA alterations or mRNA expression was not associated with overall survival (P>.05). In the Mayo cohort, patients with H3K36me3-negative tumors were 2 times more likely to experience renal cell carcinoma-specific death than patients with H3K36me3-positive tumors (hazard ratio, 2.23; 95% confidence interval, 1.77–2.81); P

Clear cell renal cell carcinoma (ccRCC) is composed of cells whose cytoplasm filled with lipid droplets, subcellular organelles coated with adipocyte differentiation-related protein (ADFP) for the storage of triacylglycerol converted from excess free fatty acids. Mammalian cells primarily use the autophagy-lysosome system to degrade misfolded/aggregated proteins and dysfunctional organelles such as lipid droplets. MAP1S (originally named C19ORF5) is an autophagy activator and promotes the biogenesis and degradation of autophagosomes. Previously, we reported that MAP1S suppresses hepatocellular carcinogenesis in a mouse model and promoted the survival of patients with prostate adenocarcinomas by increasing the degradation of aggregated proteins and dysfunctional mitochondria. Here we show that a suppression of MAP1S in renal cells causes an impairment of autophagic clearance of lipid droplets. In contrast, an overexpression of MAP1S causes an activation of autophagy flux and a reduction of lipid droplets so less DNA double strand breakage is induced. The levels of MAP1S in normal renal cells are dramatically higher than those in the ccRCC tissues and cell lines derived from renal cell carcinomas. High levels of MAP1S are associated with a reduced malignancy and metastasis of ccRCC and predict a better survival of ccRCC patients. Therefore, autophagy defects in the degradation of lipid droplets triggered by the MAP1S deficiency may enhance the initiation and development of ccRCC and reduce the survival of ccRCC patients.

To evaluate the feasibility of constructing radiogenomic-based surrogates of molecular assays (SOMAs) in patients with clear-cell renal cell carcinoma (CCRCC) by using data extracted from a single computed tomographic (CT) image.In this institutional review board approved study, gene expression profile data and contrast material-enhanced CT images from 70 patients with CCRCC in a training set were independently assessed by two radiologists for a set of predefined imaging features. A SOMA for a previously validated CCRCC-specific supervised principal component (SPC) risk score prognostic gene signature was constructed and termed the radiogenomic risk score (RRS). It uses the microarray data and a 28-trait image array to evaluate each CT image with multiple regression of gene expression analysis. The predictive power of the RRS SOMA was then prospectively validated in an independent dataset to confirm its relationship to the SPC gene signature (n = 70) and determination of patient outcome (n = 77). Data were analyzed by using multivariate linear regression-based methods and Cox regression modeling, and significance was assessed with receiver operator characteristic curves and Kaplan-Meier survival analysis.Our SOMA faithfully represents the tissue-based molecular assay it models. The RRS scaled with the SPC gene signature (R = 0.57, P.001, classification accuracy 70.1%, P.001) and predicted disease-specific survival (log rank P.001). Independent validation confirmed the relationship between the RRS and the SPC gene signature (R = 0.45, P.001, classification accuracy 68.6%, P.001) and disease-specific survival (log-rank P.001) and that it was independent of stage, grade, and performance status (multivariate Cox model P.05, log-rank P.001).A SOMA for the CCRCC-specific SPC prognostic gene signature that is predictive of disease-specific survival and independent of stage was constructed and validated, confirming that SOMA construction is feasible.

Isolated local retroperitoneal recurrence after radical nephrectomy for renal cell carcinoma poses a therapeutic challenge. We investigated outcomes in patients with localized retroperitoneal recurrence treated with surgical resection.This was a retrospective, single institutional study of 102 patients with retroperitoneal recurrence treated with surgery from 1990 to 2014. Demographics, clinical and pathological features, location of retroperitoneal recurrence and perioperative complications are reported using descriptive statistics. We studied recurrence-free and cancer specific survival using univariate and multivariate analyses.Median age at retroperitoneal recurrence diagnosis was 55 years (IQR 49-64). Cancer was pT3-4 in 62 patients (60.8%) and pN1 in 20 (19.6%). No patients had distant metastatic disease at retroperitoneal recurrence surgery. Median time from nephrectomy to retroperitoneal recurrence diagnosis was 19 months (IQR 5-38.8). The median size of the resected retroperitoneal recurrence was 4.5 cm (IQR 2.7-7). Median followup after recurrence surgery was 32 months (IQR 16-57). Metastatic progression was observed in 60 patients (58.8%) postoperatively. Neoadjuvant and salvage systemic therapy was administered in 46 (45.1%) and 48 patients (47.1%), respectively. On multivariate analysis pathological nodal stage at original nephrectomy and maximum diameter of retroperitoneal recurrence were identified as independent risk factors for cancer specific death.Clinicopathological factors at nephrectomy as well as retroperitoneal recurrence surgery are important prognosticators. Aggressive surgical resection offers potential cure in a substantial number of patients with retroperitoneal recurrence with acceptable complications and still has a dominant role in the management of isolated locally recurrent RCC.

Sarcomatoid transformation, wherein an epithelioid carcinomatous tumour component coexists with a sarcomatoid histology, is a predictor of poor prognosis in clear cell renal cell carcinoma. Our understanding of sarcomatoid change has been hindered by the lack of molecular examination. Thus, we sought to characterize molecularly the biphasic epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma and compare them to non-sarcomatoid clear cell renal cell carcinoma. We examined the transcriptome of the epithelioid and sarcomatoid components of advanced stage sarcomatoid clear cell renal cell carcinoma (n=43) and non-sarcomatoid clear cell renal cell carcinoma (n=37) from independent discovery and validation cohorts using the cDNA microarray and RNA-seq platforms. We analyzed DNA copy number profiles, generated using SNP arrays, from patients with sarcomatoid clear cell renal cell carcinoma (n=10) and advanced non-sarcomatoid clear cell renal cell carcinoma (n=155). The epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma had similar gene expression and DNA copy number signatures that were, however, distinct from those of high-grade, high-stage non-sarcomatoid clear cell renal cell carcinoma. Prognostic clear cell renal cell carcinoma gene expression profiles were shared by the biphasic components of sarcomatoid clear cell renal cell carcinoma and the sarcomatoid component showed a partial epithelial-to-mesenchymal transition signature. Our genome-scale microarray-based transcript data were validated in an independent set of sarcomatoid and non-sarcomatoid clear cell renal cell carcinomas using RNA-seq. Sarcomatoid clear cell renal cell carcinoma is molecularly distinct from non-sarcomatoid clear cell renal cell carcinoma, with its genetic programming largely shared by its biphasic morphological components. These data explain why a low percentage of sarcomatoid histology augurs a poor prognosis; suggest the need to modify the pathological grading system and introduce the potential for candidate biomarkers to detect sarcomatoid change preoperatively without specifically sampling the histological sarcomatoid component.

The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a cancer driver. More importantly, the PI3K/AKT pathway is composed of multiple bifurcating and converging kinase cascades, providing many potential targets for cancer therapy. Renal cell carcinoma (RCC) is a high-risk and high-mortality cancer that is notoriously resistant to traditional chemotherapies or radiotherapies. The PI3K/AKT pathway is modestly mutated but highly activated in RCC, representing a promising drug target. Indeed, PI3K pathway inhibitors of the rapalog family are approved for use in RCC. Recent large-scale integrated analyses of a large number of patients have provided a molecular basis for RCC, reiterating the critical role of the PI3K/AKT pathway in this cancer. In this review, we summarizes the genetic alterations of the PI3K/AKT pathway in RCC as indicated in the latest large-scale genome sequencing data, as well as treatments for RCC that target the aberrant activated PI3K/AKT pathway.

Background Clinical trials have demonstrated that pazopanib prolongs progression-free survival (PFS), with an acceptable safety profile, for patients with advanced renal cell carcinoma (aRCC). The efficacy of second-line mammalian target of rapamycin (mTOR) inhibitors in pazopanib-treated patients has also been evaluated in clinical trials; however, few studies have evaluated first-line pazopanib or second-line mTOR inhibitors in real-world settings. The present study evaluated the outcomes of first-line pazopanib, and pazopanib followed by mTOR inhibitors, in a community oncology setting. Patients and Methods The present study was a retrospective analysis of eligible patients in US Oncology's iKnowMed electronic health records database who had been treated for aRCC from November 1, 2009 to August 31, 2012. The patients received first-line therapy with pazopanib (cohort 1), followed by second-line therapy with either everolimus or temsirolimus (cohort 2). The key outcomes included overall survival (OS), PFS, adverse events (AEs), treatment patterns, and healthcare resource use. Results The median OS in cohort 1 (n = 177) was 22 months, and the median PFS was 8.5 months. The most common AEs were fatigue (56%), diarrhea (52%), vomiting (44%), and nausea (40%). The median persistence was 151 days with pazopanib. The median OS in cohort 2 (n = 35) was 16 months; the median PFS was 5.7 months. The most common AEs were fatigue (51%) and nausea (34%). The median persistence was 93 days with everolimus and 49 days with temsirolimus. Conclusion The outcomes for the patients treated with first-line pazopanib in the community setting were consistent with those reported by previous prospective and retrospective studies. Although the second-line cohort was small, the results of mTOR inhibitors after pazopanib were also consistent with those of previous observations.