Kidney Cancer - Volume 1, issue 1

Authors: Lara Jr., Primo N. | Mulders, Peter F.A.

Article Type: Editorial

DOI: 10.3233/KCA-179001

Citation: Kidney Cancer, vol. 1, no. 1, pp. 1-1, 2017

Authors: Casuscelli, Jozefina | Vano, Yann-Alexandre | Fridman, Wolf Herve | Hsieh, James J.

Article Type: Review Article

Abstract: Renal cell carcinoma (RCC) encompasses a wide spectrum of morphologically and molecularly distinct (>10) cancer subtypes originated from the kidney epithelium. Metastatic RCC (mRCC) is lethal and refractory to conventional chemotherapeutic agents. The incorporation of targeted therapies and immune checkpoint inhibitors into the current practice of mRCC has markedly improved the median overall survival of clear cell RCC (ccRCC) patients, the most common subtype, but not rare kidney cancer (RKC or non-ccRCC, nccRCC). Varied treatment response in mRCC patients is observed, which presents clinical challenges/opportunities at the modern mRCC therapeutic landscape consisting of 12 approved drugs representing 6 different effective …mechanisms. Key contributing factors include inter- and intra-RCC heterogeneity. With the advances in pan-omics technologies, we now have a better understanding of the molecular pathobiology of individual RCC subtype. Here, we attempt to classify ccRCC based on contemporary molecular features with emphasis on their respective potential significance in clinical practice. Show more

Keywords: Kidney cancer, genomics, transcriptomics, proteomics, metabolomics, therapeutics, molecular classification, biomarkers, precision medicine

DOI: 10.3233/KCA-170008

Citation: Kidney Cancer, vol. 1, no. 1, pp. 3-13, 2017

Authors: Maia, Manuel Caitano | Dizman, Nazli | Salgia, Meghan | Pal, Sumanta Kumar

Article Type: Review Article

Abstract: The influx of multiple novel therapeutic options in the mRCC field has brought a challenge for treatment sequencing in this disease. In the past few years, cabozantinib, nivolumab and the combination of lenvatinib and everolimus have been approved in the second-line setting. As there is no direct comparison between these agents and the studies have failed to show improved benefit among a biomarker-selected patient population, appropriate patient selection based on clinical factors for individualized therapy is critical. Herein we provide a comprehensive overview of current data from each agent through the discussion of disease biology, clinical trials, potential biomarkers and …distilling future perspectives in the field. Show more

Keywords: Metastatic renal cell carcinoma, treatment, immunotherapy, cabozantinib, nivolumab, everolimus, lenvatinib

DOI: 10.3233/KCA-170006

Citation: Kidney Cancer, vol. 1, no. 1, pp. 15-29, 2017

Authors: Harshman, L.C. | Drake, C.G. | Haas, N.B. | Manola, J. | Puligandla, M. | Signoretti, S. | Cella, D. | Gupta, R.T. | Bhatt, R. | Van Allen, E. | Lara, P. | Choueiri, T.K. | Kapoor, A. | Heng, D.Y.C. | Shuch, B. | Jewett, M. | George, D. | Michaelson, D. | Carducci, M.A. | McDermott, D. | Allaf, M.

Article Type: Review Article

Abstract: In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A P hase 3 R andO mized S tudy Comparing PER ioperative Nivolumab vs. Observation in …Patients with Localized R enal C ell C arcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes. Show more

Keywords: Renal cell carcinoma, adjuvant, neoadjuvant, priming, nivolumab, PD-1 blockade, nephrectomy, recurrence-free survival, PROSPER RCC, EA8143

DOI: 10.3233/KCA-170010

Citation: Kidney Cancer, vol. 1, no. 1, pp. 31-40, 2017

Authors: Yip, Steven M. | Ruiz Morales, Jose M. | Donskov, Frede | Fraccon, Anna | Basso, Umberto | Rini, Brian I. | Lee, Jae Lyun | Bjarnason, Georg A. | Sim, Hao-Wen | Beuselinck, Benoit | Kanesvaran, Ravindran | Brugarolas, James | Koutsoukos, Kostas | Fu, Simon Yuen Fai | Yuasa, Takeshi | Davis, Ian | Alva, Ajjai | Kollmannsberger, Christian | Choueiri, Toni K. | Heng, Daniel Y.C.

Article Type: Research Article

Abstract: Background: Treatment outcomes are poorly characterized in patients with metastatic chromophobe renal cell cancer (chrRCC), a subtype of renal cell carcinoma. Objective: This retrospective series aims to determine metastatic chrRCC treatment outcomes in the targeted therapy era. Methods: A retrospective data analysis was performed using the IMDC dataset of 4970 patients to determine metastatic chrRCC treatment outcomes in the targeted therapy era. Results: 109/4970 (2.2%) patients had metastatic chrRCC out of all patients with mRCC treated with targeted therapy. These patients were compared with 4861/4970 (97.8%) clear cell mRCC (ccRCC) patients. Patients with …metastatic chrRCC had a similar OS compared to patients with ccRCC (23.8 months (95% CI 16.7 – 28.1) vs 22.4 months (95% CI 21.4 – 23.4), respectively (p  = 0.0908). Patients with IMDC favorable (18%), intermediate (59%) and poor risk (23%) had median overall survivals of 31.4, 27.3, and 4.8 months, respectively (p  = 0.028). Conclusions: To the authors’ knowledge, this is the largest series of metastatic chrRCC patients and these results set new benchmarks for survival in clinical trial design and patient counseling. The IMDC criteria risk categories seem to stratify patients into appropriate favourable, intermediate, and poor risk groups, although larger patient numbers are required. It appears that outcomes between metastatic chrRCC and ccRCC are similar when treated with conventional targeted therapies. Patients with metastatic chrRCC can be treated with tyrosine kinase inhibitors and enrolled in clinical trials to further measure outcomes in this rare patient population. Show more

Keywords: Metastatic, renal, chromophobe, international, targeted

DOI: 10.3233/KCA-160002

Citation: Kidney Cancer, vol. 1, no. 1, pp. 41-47, 2017

Authors: Carlo, M.I. | Manley, B. | Patil, S. | Woo, K.M. | Coskey, D.T. | Redzematovic, A. | Arcila, M. | Ladanyi, M. | Lee, W. | Chen, Y.B. | Lee, C.H. | Feldman, D.R. | Hakimi, A.A. | Motzer, R.J. | Hsieh, J.J. | Voss, M.H.

Article Type: Research Article

Abstract: Background: Mutations in VHL , PBRM1 , SETD2 , BAP1 , and KDM5C are common in clear cell renal cell carcinoma (ccRCC), and presence of certain mutations has been associated with outcomes in patients with non-metastatic disease. Limited information is available regarding the correlation between genomic alterations and outcomes in patients with metastatic disease, including response to VEGF-targeted therapy. Objective: To explore correlations between mutational profiles and cancer-specific outcomes, including response to standard VEGF-targeted agents, in patients with metastatic cc RCC. Methods: A retrospective review of 105 patients with metastatic ccRCC who had received …systemic therapy and had targeted next-generation sequencing of tumors was conducted. Genomic alterations were correlated to outcomes, including overall survival and time to treatment failure to VEGF-targeted therapy. Results: The most frequent mutations were detected in VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%). Time to treatment failure with VEGF-targeted therapy differed significantly by PBRM1 mutation status (p  = 0.01, median 12.0 months for MT versus 6.9 months for WT) and BAP1 mutation status (p  = 0.01, median 6.4 months for MT versus 11.0 months for WT). Shorter overall survival was associated with TERT mutations (p  = 0.03, median 29.6 months for MT versus 52.6 months for WT) or BAP1 mutations (p  = 0.02, median 28.7 months for MT versus not reached for WT). Conclusions: Genomic alterations in ccRCC tumors have prognostic implications in patients with metastatic disease. BAP1 and TERT promoter mutations may be present in higher frequency than previously thought, and based on this data, deserve further study for their association with poor prognosis. Show more

Keywords: Clear cell renal cell carcinoma, VEGF-targeted therapy, genomics, prognosis

DOI: 10.3233/KCA-160003

Citation: Kidney Cancer, vol. 1, no. 1, pp. 49-56, 2017

Authors: Pilié, Patrick G. | Jonasch, Eric

Article Type: Research Article

Abstract: 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. Show more

Keywords: Renal cell carcinoma, RCC, presurgical therapy, nephrectomy, toxicity, immune therapy

DOI: 10.3233/KCA-170009

Citation: Kidney Cancer, vol. 1, no. 1, pp. 57-64, 2017

Authors: Maia, Manuel Caitano | Bergerot, Paulo Gustavo | Dizman, Nazli | Hsu, JoAnn | Jones, Jeremy | Lanman, Richard B. | Banks, Kimberly C. | Pal, Sumanta K.

Article Type: Research Article

Abstract: Background: In a series of 224 patients with advanced renal cell carcinoma (RCC), we have previously reported circulating tumor DNA (ctDNA) detection in 79% of patients. Clinical factors associated with detection are unknown. Methods: Data was obtained from patients with radiographically confirmed stage IV RCC who received ctDNA profiling as a part of routine clinical care using a CLIA-certified platform evaluating 73 genes. Detailed clinical annotation was performed, including assessment of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, previous and current treatments and calculation of tumor burden using scan data most proximal to ctDNA …assessment. Tumor burden was equated to the sum of longest diameter (SLD) of all measurable lesions. Results: Thirty-four patients were assessed (18 male and 16 female) with a median age of 62 (range, 34–84). Twenty-six patients, 4 patients and 4 patients had clear cell, sarcomatoid and papillary histologies, respectively. IMDC risk was good, intermediate and poor in 14, 19 and 1 patient, respectively. ctDNA was detected in 18 patients (53%) with a median of 2 genomic alterations (GAs) per patient. No associations were found between IMDC risk, histology or treatment type and presence/absence of ctDNA. However, patients with detectable ctDNA had a higher SLD compared to patients with no detectable ctDNA (8.81 vs 4.49 cm; P  = 0.04). Furthermore, when evaluated as a continuous variable, number of GAs was correlated with SLD (P  = 0.01). Conclusions: With the caveat of a limited sample size, it appears that SLD (a surrogate for tumor burden) is higher in mRCC patients with detectable ctDNA. Confirmation of these findings in larger series is ongoing and may suggest a capability for ctDNA to either complement or supplant radiographic assessment. Show more

Keywords: Biomarkers, cell-free DNA, circulating tumor DNA, tumor burden, renal cell carcinoma, Guardant360

DOI: 10.3233/KCA-170007

Citation: Kidney Cancer, vol. 1, no. 1, pp. 65-70, 2017

Authors: Morris, Cyllene R. | Lara Jr., Primo N. | Parikh-Patel, Arti | Kizer, Kenneth W.

Article Type: Research Article

Abstract: Background and Objective: Since the 1990s, multiple studies have reported on an increased incidence of renal cell carcinomas (RCC), which has been considered incidental to the high use of abdominal diagnostic imaging. This population-based study used data from the California Cancer Registry to (i) update trends in RCC incidence and mortality by several tumor and demographic characteristics after reports of decreased use of diagnostic imaging in recent years, and (ii) examine changes in surgical treatment for early-stage RCC. Methods: Records of patients diagnosed with RCC from 1988 through 2013 and mortality data from the same period were …examined. Joinpoint regression was used to estimate annual percent changes in age-adjusted RCC incidence and mortality rates, stratified by sex, race/ethnicity, stage at diagnosis, grade, and tumor size. Trends in the proportion of partial or total/radical nephrectomies were evaluated by Cochran-Armitage tests. Results: A total of 77,363 incident cases of RCC and 28,590 deaths were evaluated. While mortality rates significantly decreased, the incidence of small localized RCC increased in virtually all groups examined after the mid-1990s until 2008-2009, when incidence trends stabilized in all groups concomitant with a decrease in imaging. The proportion of partial nephrectomies among patients with small localized tumors increased from 13.8% in 1988 to 74.6% in 2013. Conclusions: Earlier trends in RCC were consistent with the incidental discovery of small tumors. In parallel with the increase in early-stage RCC, the use of partial nephrectomies increased markedly. Following the decreased use of advanced diagnostic imaging, the trend of increasing RCC incidence appears to have ended in California. Show more

Keywords: Kidney cancer, Renal Cell Carcinoma, incidence, mortality, trends

DOI: 10.3233/KCA-170005

Citation: Kidney Cancer, vol. 1, no. 1, pp. 71-81, 2017

Authors: Nakajima, Erica | Leger, Paul | Mayer, Ingrid A. | Neuss, Michael N. | Chism, David D. | Rathmell, W. Kimryn

Article Type: Case Report

Abstract: We report a case of severe type B lactic acidosis (LA) in a 51-year-old male, 12 days after he received his first dose of nivolumab for metastatic Von Hippel Lindau (VHL) -mutated, clear cell renal cell carcinoma. Throughout his hospital course, infection, hypoperfusion, and tissue necrosis were not identified. We propose that his LA may have resulted from either inherent tumor glycolysis or immune activation and enhanced metabolism. The patient’s course was complicated by acute renal failure, and his LA rose progressively, eventually necessitating daily hemodialysis (HD). After receiving five consecutive days of HD, the patient started everolimus daily with …the intent of reducing glycolytic metabolism. Subsequently, the rate of lactic acid production slowed, and HD was no longer required after two doses of everolimus. To our knowledge, this is the first reported case of type B LA following nivolumab administration, and the use of everolimus to treat type B LA in a patient with renal cancer. Show more

Keywords: Renal cell carcinoma, acidosis, everolimus

DOI: 10.3233/KCA-160004

Citation: Kidney Cancer, vol. 1, no. 1, pp. 83-88, 2017