bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive genomic profiling of urethral cancer to reveal distinctive features compared to bladder cancer.
Authors: Dorff Tanya B. , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Ali Siraj Mahamed , Schrock Alexa Betzig , Fisher Hugh A.G. , Mian Badar , Nazeer Tipu , Fabrizio David , Frampton Garrett Michael , Miller Vincent A. , Stephens Phil , Gay Laurie M. , Ross Jeffrey S. , Pal Sumanta K.
Published: March 2017

429

Background: Relapsed and refractory urethral cancer (UrethC) is a rare form of genito-urinary malignancy that includes urothelial carcinoma (UC), squamous cell carcinoma (SCC), adenocarcinoma (AC) and clear cell carcinoma (CCC) subtypes. No standard treatment exists. Methods: DNA was extracted from 40 microns of FFPE specimen from 46 cases of mUrethC. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of >500X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: The clinical features, GA, TMB findings in the mUrethC patients and the subtypes of UrethC are shown in the Table. In comparison with 1,183 similarly profiled UC of the bladder (UCB), all 46 mUrethC and the 21 urothelial mUrethC as a separate group widely differed in GA frequencies. With the exception of similar TP53 GA frequencies, there were significantly lower GA in ERBB2, FGFR1-3 and PIK3CAin the mUrethC cases (p<0.0001 for all comparisons) In addition, mUrethC featured as significantly lower frequency of TMB > 20 mut/Mb (4%; p=0.0001). Conclusions: CGP of mUrethC reveals distinctive genomic alteration frequencies among the 4 disease subtypes with higher numbers of GA in the AC than in the UC, SCC and CCC. The TMB appears to be lower in mUrethC than classically seen in UCB where checkpoint inhibition is now approved. Further study of this rare form of genitourinary cancer appears warranted. [Table: see text]
Index lesion tumor volume on MRI to predict adverse pathologic outcomes following radical prostatectomy.
Authors: Sugano Dordaneh , Sidana Abhinav , Calio Brian P. , Gaur Sonia , Jain Amit L , Maruf Mahir , Merino Maria J , Choyke Peter L. , Turkbey Baris , Wood Bradford J. , Pinto Peter A.
Published: March 2017

43

Background: Tumor volume measured on postoperative pathology has been shown to be associated with adverse pathologic and oncologic outcomes. Advances in imaging technology may facilitate the prediction of these outcomes prior to surgery. In this study, we evaluated the predictive value of tumor volume of the index lesion (ILTV) calculated from prostate MRI in analyzing adverse pathologic outcomes following radical prostatectomy (RARP). Methods: Clinical and pathologic data from a prospectively maintained, single-institution database was analyzed for patients who underwent 3T MRI prior to RARP (without prior therapy) between 2007 and 2016. ILTV was calculated from T2W MRI by multiplying length by width by depth by 0.52. Adverse pathologic outcomes were determined on whole mount prostatectomy specimens, and defined as positive margins (PM), extracapsular extension (ECE), positive lymph nodes (LNI), and seminal vesicle invasion (SVI). Logistic regression was used to assess associations of clinical, imaging, and histopathological variables with adverse pathologic features. Results: From the 501 patients who underwent RARP, 490 received MRI prior to surgery. The median age of our cohort of was 60 years (IQR 10), and median PSA was 6.21 ng/ml (IQR 6). There were 74/480 patients (15.4%) with PM, 112/474 (23.6%) with ECE, 30/478 (6.4%) with LNI, and 32/482 (6.7%) with SVI. Patients with adverse outcomes had larger ILTV compared to those without (PM: 1.038cc vs 0.807cc, p=0.041; ECE: 1.388cc vs 0.765cc, p<0.001; LNI: 2.970cc vs 0.797cc, p<0.001; SVI: 2.269cc vs 0.798cc, p<0.001). On multivariate analysis, ILTV was found to be an independent predictor of PM (OR: 1.149, p=0.036), ECE (OR: 1.269, p=0.001), LNI (OR: 1.387, p<0.001), and SVI (OR: 1.341, p<0.001). Conclusions: We demonstrate that Index Lesion Tumor Volume measured on T2W MRI is an independent predictor of PM, ECE, LNI, and SVI following RARP, and serves as a preoperative marker that may facilitate and inform patient counseling and decision making.
Evolution of circulating tumor DNA (ctDNA) profile from first-line (1L) to second-line (2L) therapy in metastatic renal cell carcinoma (mRCC).
Authors: Pal Sumanta K. , Sonpavde Guru , Agarwal Neeraj , Vogelzang Nicholas J. , Srinivas Sandy , Haas Naomi B. , Signoretti Sabina , Lanman Richard B. , Banks Kimberly , Choueiri Toni K.
Published: March 2017

434

Background: Treatment of mRCC typically entails mechanistically distinct agents across the 1L and 2L setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. ctDNA is a platform to conveniently ascertain temporal changes in genomic profile. Methods: Data was obtained from pts with mRCC who received ctDNA profiling as a part of routine clinical care at progression using a CLIAA-certified platform evaluating 70 genes. Genomic alterations (GAs) were pooled for the entire cohort. A comparison of 1L vs. 2L was performed, with grouping based on conventional practice patterns (1L regimens included sunitinib, pazopanib and bevacizumab, and 2L regimens included everolimus, axitinib, cabozantinib, and nivolumab). Results: ctDNA results from 224 pts with mRCC were assessed (gender: 149 M, 75 F; average age: 62; histology: 89 clear cell, 37 non-clear cell, 98 unknown). GAs were detected in 78.6% of pts. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). 64 and 56 pts were coded as receiving 1L and 2L agents, respectively. The average number (range) of ctDNA alterations detected was 2.9 (1-14) in 1L and 3.7 (1-16) in 2L with median (range) ctDNA variant allele fractions of 0.23 (0.05-9.92) in 1L and 0.24 (0.04-47.14) in 2L. The highest disparity in GA frequencies in 2L vs. 1L were in TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%). Isolating 2L pts who specifically had 1L VEGF-therapy documented, these differences were even more prominent in comparison to 1L pts: TP53 (64% vs. 31%), PIK3CA (29% vs. 8%), and NF1 (29% vs. 4%). Conclusions: In the largest assessment of ctDNA in mRCC to date, the majority of pts demonstrated clinically relevant GAs. Increasing p53 and mTOR pathway (e.g, NF1, PIK3CA) alteration in 2L pts with 1L VEGF-directed therapy may underlie mechanisms of resistance. Increasing GA frequency from 1L to 2L pts may have implications for immunotherapeutic approaches.
Correlation of insulin-receptor expression with efficacy of axitinib in patients with advanced renal cell carcinoma.
Authors: Takahashi Masayuki , Daizumoto Kei , Tsuda Megumi , Kusuhara Yoshito , Mori Hidehisa , Shintani Terumichi , Fukawa Tomoya , Yamamoto Yasuyo , Yamaguchi Kunihisa , Fukumori Tomoharu , Kanayama Hiroomi
Published: March 2017

442

Background: Axitinib has demonstrated high efficacy with well-controlled adverse events (AEs) for advanced renal cell carcinoma (RCC). Recently, nivolumab has been approved for advanced RCC. However, it is very expensive in Japan and may cause severe immune-related AEs. There is no clue to choose axitinib or nivolumab as the second-line for advanced RCC. Previously we identified the gene set which may predict poor prognosis of RCC patients (Takahashi m et.al., Proc Natl Acad Sci U S A., 98: 9754, 2001) and have sought to elucidate whether insulin receptor (INSR) expression in the gene set may predict the resistance for axitinib as a biomarker. Methods: Axitinib was administered in 36 patients in our department between January 2008 and April 2015. Median age was 70 (36-84) years old with 22 males and 14 females. Histological subtype included clear cell RCC (n=27, 75.0%), clear cell + sarcomatoid component (n=3), collecting duct carcinoma (n=2), papillary, sarcomatoid, mucinous tubular and spindle cell carcinoma (MTSCC), and unknown in each one. Axitinib was administered in two patients as the first line, 21 patients as the second line, and 13 patients as ≥ the third line. Tissue of primary tumor was available in 20/36 patients, including 16 clear cell RCC and 4 other subtypes. Immunohistochemical INSR expression was examined and correlated with survival of the patients with axitinib. Results: Objective response rate was 27.6%, progression-free survival (PFS) was 16.3 months, and overall survival (OS) was 41.9 months in clear cell RCC patients. Patients with low INSR expression (n=7) had significantly shorter PFS (68 vs. 586 days, p<0.001) and OS (169 vs. 1027 days, p=0.004) compared with those with high INSR expression (n=13). If only clear cell RCC was evaluated, patients with low INSR expression (n=3) had significantly shorter PFS (77 vs. 586 days, p=0.008) and OS (294 vs. 1027 days, p=0.016) compared with those with high INSR expression (n=13). Conclusions: Axitinib was highly effective for advanced clear cell RCC. However, immunohistochemically low expression of INSR in the primary tumor may predict the resistance for axitinib and those patients may be more suitable for immune checkpoint inhibitors.
Intra-individual genomic diversity between circulating tumor cell-free DNA (cfDNA) and tumor tissue testing in metastatic renal cell carcinoma (mRCC).
Authors: Hahn Andrew W. , Gill David Michael , Streeter Jessica , Bailey Erin B. , Carroll Emma , Aryal Lubina , Batten Julia A. , Gupta Sumati , Agarwal Neeraj , Maughan Benjamin Louis
Published: March 2017

444

Background: Multiple approved targeted therapies are available for treatment of mRCC. Though some clinical trials guide treatment selection, there are many gaps without high-level evidence. Both tumor tissue and cfDNA based next-generation sequencing (NGS) testing are frequently performed to help guide treatment. Our objective was to assess type and number of genomic aberrations among tumor tissue and cfDNA. Methods: 14 sequential pts with both tissue and cfDNA NGS testing were selected and genomic profiles were compared. The total number of aberrations detected was statistically evaluated using comparison of the means. The Mann-Whitney test was used to compare the incidence of mutations in identified mutation pathways. Results: There was a discordance in the genetic aberrations detected among tumor versus cfDNA NGS tests, confirming intra-individual genetic diversity. Specifically, alterations in the DNA repair, PI3K, and epigenetic pathways were more common in tissue based testing (Table). Additionally, the median number of mutations identified was significantly lower for cfDNA based NGS testing (median 1.5) compared to tissue based NSG testing (median 10.0) (p < 0.0001). Conclusions: Discordance in the type of genomic aberrations in tissue versus cfDNA testing suggests intra-individual genetic diversity and may have implications in treatment selection when using these tests. Lower number of aberrations detected by the cfDNA testing may have occurred due to lower sensitivity of NGS by cfDNA compared to the tissue based NGS. The higher frequency of aberrations on tissue based testing suggests that tissue based testing should be used preferentially in clinical trials and practice. This data is hypothesis generating and needs further investigation in a larger cohort. [Table: see text]
Development of a novel patient-derived preclinical model from malignant effusions in patients with tyrosine kinase inhibitor resistant clear cell renal cell carcinoma.
Authors: Kang Jung Hun , Heo Mi Hwa , Kim Hee Kyung , Cho Jinhyun , Kim Youjin , Lee Hansang , Lee Sang-Cheol , Park Se Hoon
Published: March 2017

445

Background: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood and there is a need to develop new therapeutic options overcoming them. Methods: To develop a preclinical model that predicts clinical activity of novel agents.We established patient-derived cell (PDC) and xenograft (PDX) models from malignant effusions (n = 15) or surgical specimen (n = 4).Genomic features of the PDX model were compared with those of the primary tumor. Drug effects of cell viability were then tested with PDC and PDX models. Results: Successful PDCs, defined as cells that maintained growth following 2 passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro. Conclusions: The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations. We show that novel preclinical models are developed using malignant effusions derived from patients with kidney cancer. The preclinical models can be used to test anti-tumor activity of novel therapeutics. The preclinical model we developed can be used to interrogate sensitivity to targeted agents based on genomic alterations. The PDC model from malignant effusions of patients was successfully converted to a PDX model, and represents an important and feasible platform for future cancer research.
The impact of UGT1A1 and SLCO1B1 genetic polymorphisms and pharmacokinetics of axitinib on clinical safety and efficacy in patients with metastatic renal cell carcinoma.
Authors: Narita Shintaro , Igarashi Ryoma , Tsuchiya Norihiko , Inoue Takamitsu , Fujiyama Nobuhiro , Numakura Kazuyuki , Tsuruta Hiroshi , Kagaya Hideaki , Saito Mitsuru , Niioka Takenori , Miura Masatomo , Satoh Shigeru , Habuchi Tomonori
Published: March 2017

448

Background: We investigated the impact of genetic polymorphisms and pharmacokinetics of axitinib on adverse events, objective responses, and survival in patients with metastatic renal cell carcinoma (mRCC). Methods: In total, 53 patients with mRCC treated with axitinib were analyzed. Patient was classified as favorable (n = 5), intermediate (n = 36), and poor (n = 12) using the MSKCC risk classification system. High-performance liquid chromatography was used to measure serum axitinib levels. AUC0–12 (ng∙h/mL) was calculated using various serum levels at 0 to 12 h (C0–C12) following administration on day 7 of treatment. The genetic polymorphisms related to the drug pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed using PCR-RFLP analysis. Results: The most frequently reported ≥ G3 adverse events were hypertension (43.3%), proteinuria (30.2%), and anorexia (20.1%). The axitinib trough levels (C0) were significantly correlated with AUC0–12 of axitinib. Patients with axitinib C0 ≥ 10 ng/mL had a significantly higher rate of hand-foot syndrome ≥ G2 and hypothyroidism ≥ G2 than those with axitinib C0 < 10 ng/mL (p = 0.013, p = 0.005). The overall survival in patients with axitinib C0 ≥ 5 ng/mL was significantly better than that in those with axitinib C0 < 5 ng/mL (p = 0.022). The mean C0 and AUC0–12 values in patients with a poor metabolizer (*6/*6, *6/*28, and *28/*28) of UGT1A1 polymorphism were significantly higher than those in patients with an extensive metabolizer (p = 0.045, p = 0.035, respectively). The mean AUC0–12 value in patients with the SLCO1B1 *15 was significantly higher than that in those without the SLCO1B1 *15 (p = 0.038). Conclusions: Serum axitinib levels were associated with adverse events and overall survival of patients with mRCC. The genetic polymorphisms in UGT1A1 and SLCO1B1 may affect serum axitinib levels in patients with mRCC. Pharmacokinetics and genetic polymorphisms play important roles in the outcomes of patients with mRCC treated with axitinib.
Impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the obesity paradox.
Authors: Narita Shintaro , Ito Ryuichi , Huang Mingguo , Numakura Kazuyuki , Tsuruta Hiroshi , Maeno Atsushi , Saito Mitsuru , Inoue Takamitsu , Tsuchiya Norihiko , Satoh Shigeru , Habuchi Tomonori
Published: March 2017

449

Background: Obesity increases the risk of renal cell carcinoma (RCC); however, obese patients experience longer survival than non-obese patients. The mechanism of this “obesity paradox” is unknown. We examined the impact of obesity, total adiponectin (AD) level, and intratumoral AD receptors expression on RCC aggressiveness and survival, and also investigated the mechanism underlying enhanced cancer aggressiveness in RCC cells with exogenous adiponectin stimulation. Methods: A total of 129 RCC patients treated with surgery were included in the analyses. Preoperative BMI, serum total adiponectin (AD) level, total AD secretion from perinephric adipose tissue, and intratumoral AD receptors mRNA and protein expression were analyzed. Caki-2 and 786- cells were used for in vitro functional analyses. Results: Overweight and obese patients had significantly lower grade cancers than normal patients in all patients and in those without metastasis (p = 0.003, and p = 0.027, respectively). Cancer-specific survival in overweight and obese patients was significantly better than in normal patients in all patients (p = 0.035). A weak inverse correlation existed between serum AD level and BMI in RCC patients (r = −0.344). Tumor size was slightly correlated with serum AD level, and high serum AD was significantly associated with poor overall survival in patients without metastasis (p = 0.035). The AD level of perinephric adipose tissue and intratumoral AdipoR1/R2 expression in tumors did not correlate with RCC aggressiveness and survival. Exogenous AD significantly enhanced proliferation, but not invasion or migration in 786-O and Caki-2 cells. Exogenous AD significantly inhibited starvation- and metformin-induced apoptosis, and up-regulated p-AMPK and Bcl-xL in these cells. Conclusions: Low BMI and high AD level are associated with cancer aggressive and poor survival in RCC patients treated surgically. AD modulates proliferation and apoptosis, which may underlie the “obesity paradox” of RCC.
Combined inhibition of autophagy with mTOR inhibitor to enhance cell death in renal cell carcinoma.
Authors: Chen Hua , Potts Kyle , Murray Allan , Hitt Mary , Moore Ron
Published: March 2017

450

Background: mTOR (mammalian target of rapamycin) and autophagy are increasingly recognized as being a central cellular and pathological process for numerous human diseases, including renal cell carcinoma (RCC). Depending on the cellular context, autophagy may promote cancer cell survival or cell death. However, little is known about the mechanisms of regulating mTOR activity and autophagic function in RCC. We hypothesize that autophagy promotes cell survival via mTOR mediated-phosphatidylinositol 3-kinase (PI3K)/AKT pathway and is regulated by the von Hippel-Lindau (VHL) tumor suppressor. Methods: RCC cells were stably lentiviral transduced with expression of VHL or mCherry-EGFP tandemfluorescent-tagged LC3B for studying autophagic flux. Cell viability was evaluated by cytotoxic XTT and clonogenic assays and flow cytometry. The efficacy of PI3K/AKT/mTOR pathway inhibition by RAD001, PI-103, MK2206, AZD8055, and/or lysosomotropic inhibitors were evaluated by immunoblots and immunofluorescence for autophagy process of autophagosome and lysosome. Results: We show that mTOR is hyperactive in VHL-deficient cells compared to cells with wild-type VHL or VHL-expressing cells. AZD8055-induced toxicity occurs in a VHL-independent manner via cell cycle arrest and clonogenic senescent cell death, but results in significantly increased expression of autophagic marker LC3-II and the formation of autophagic vacuoles. Pharmacologic inhibition or siRNA silencing of autophagy pathway components promotes AZD8055-induced cell death in VHL-deficient cells. Interestingly, defective autophagy marked by the presence of sustained p62 expression in VHL-deficient cells appears to contribute to cell survival via mTOR signaling, which in turn influences autophagosome-lysosome fusion, and thus controls autophagic flux by acting at the termination stage of the process. Conclusions: These results support mTOR and autophagy pathways as potential targets of anticancer drugs and reveal VHL in control of the autophagic program in RCC. Further, this work suggests that combined inhibition of autophagy along with mTOR inhibitors could be a novel therapeutic strategy for the treatment of RCC.
An evaluation of abemaciclib activity in combination with sunitinib in renal cell carcinoma.
Authors: Holder Sheldon L. , Small Jeffrey
Published: March 2017

452

Background: The majority of therapeutic agents used in renal cell carcinoma (RCC) target the vascular endothelial growth factor and mammalian target of rapamycin pathway. Exceptions include the immunotherapy agents interleukin-2 and nivolumab. To change the natural history of RCC and improve upon current treatment regimens we believe new therapeutic targets are necessary. CDK4/6 and PIM1 kinase have both been identified as possible therapeutic targets in RCC. Abemaciclib is a potent inhibitor of both CDK4/6 and PIM1 kinases. We have demonstrated that abemaciclib causes increased apoptosis and decreased cellular viability in RCC cell lines and tumor responses in mice (submitted). Here we report the results of an additional pre-clinical study of the effects of abemaciclib alone and in combination with sunitinib. Methods: Tumors were established in nude mice by subcutaneous flank injection of 786-O cells. Tumors were allowed to establish and grow to about 1 cm. Mice were treated by oral gavage with vehicle, sunitinib, abemaciclib, or combination. Tumors were measured with calipers to determine response. Mice that received sunitinib were subsequently treated with combination therapy and response determined by caliper measurement. At the conclusion of the course of treatment mice were euthanized and the tumors removed, weighed, fixed, and embedded in paraffin. Results: Mice treated with vehicle had continued tumor growth during the course of therapy. Mice treated with sunitinib showed mostly disease stabilization, paralleling the response seen in clinic. Mice in the abemaciclib cohort showed gradual decline in tumor size over the course of treatment. Mice in the combination therapy cohort exhibited a rapid reduction in tumor size with sustained response. Interestingly mice in the sunitinib cohort experiencing stable disease or growing tumor had rapid decrease in tumor size with the initiation of combination therapy. Conclusions: Abemaciclib is active in a mouse model of RCC. The combination of abemaciclib/sunitinib causes rapid reduction in tumor size in treatment naïve and sunitinib pre-treated mice. These data support the use of combination abemaciclib/sunitinib therapy in a human clinical trial.
Development of a prognostic nomogram for liver toxicity in patients treated with pazopanib.
Authors: Kattan Michael W. , Van Der Graaf Winette T.A. , Powles Thomas , Lam Simon , Ahmad Qasim , Dezzani Luca , Han Jackie , Sternberg Cora N.
Published: March 2017

455

Background: Potential liver toxicity associated with pazopanib treatment has provided a challenge for decision-making regarding patient selection and monitoring. The goal of this study was to develop a tool for predicting liver toxicity for patients receiving pazopanib. Methods: Data was pooled from several clinical trials in patients with renal cell carcinoma, soft tissue sarcoma, or ovarian carcinoma; the dataset consisted of 2,051 patients treated with pazopanib in these trials. Liver toxicity was defined as an ALT level > 3 times the upper limit of normal (ULN) and a bilirubin level > 2 times ULN. Predictors of hepatotoxicity included were age, gender, race, hypertension, performance status, indication (tumor type), prior antineoplastic treatment, concomitant treatment with CYP450, P-gp, or BCRP inhibitors, and baseline clinical characteristics of weight, ALT, AST, ALP, and bilirubin. The statistical modeling was performed using logistic regression. Continuous predictors were modeled with restricted cubic splines to permit potentially nonlinear effects. The performance of the model was evaluated using discrimination (measured by concordance index) and calibration (assessed graphically). Results: Calibration plots suggested adequate congruence between predicted probabilities and actual proportions of liver toxicity. The model had a bootstrap corrected concordance index of 0.739. The calibration of the model was excellent for predicted probabilities up to 30% (Table). The prediction model was represented as a nomogram. Conclusions: This appears to be the first nomogram that predicts, with reasonable accuracy, liver toxicity in patients receiving pazopanib based on their baseline clinical characteristics. Although nomograms are limited by the degree of uncertainty that is inherent in the estimates of probability, the findings may aid clinicians in selecting patients for treatment and monitoring. Validation in a separate dataset is needed to confirm the nomogram’s accuracy. [Table: see text]
Clinicopathologic characterization and outcomes for patients with renal medullary carcinoma: Results from the National Cancer Database.
Authors: Zaid Harras B. , Thompson Robert Houston , Leibovich Bradley C. , Parker William P. , Costello Brian Addis , Pagliaro Lance C. , Boorjian Stephen A.
Published: March 2017

456

Background: Renal medullary carcinoma (RMC) is a rare, aggressive malignancy for which relatively limited characterization exists to date. We evaluated clinicopathologic features, treatment patterns, and variables associated with outcomes for patients with RMC. Methods: We reviewed the National Cancer Database to identify patients diagnosed with RMC between 1998-2012. Overall survival (OS) was estimated using the Kaplan-Meier method. Clinicopathologic features associated with all-cause mortality (ACM) were assessed using Cox regression analysis. Results: We identified 153 patients with RMC, comprising approximately 0.04% of renal malignancies during this time period. Median age at diagnosis for RMC was 24 years (IQR 20, 31). The majority of RMC patients were black (135; 88%), male (108; 71%), and presented with unilateral, right-sided tumors (101; 66%). Notably, nearly half (72; 48.9%) presented with metastatic disease. A total of 92 (64.3%) patients underwent radical nephrectomy (RN), and 2 (1.3%) were treated with partial nephrectomy. Pathologic stage at nephrectomy was ≤pT2 in 30 patients (32.6%), pT3 in 43 (46.7%), pT4 in 7 (7.6%), and N+ in 50 (55.6%). Of the patients who underwent RN, 60 (65.2%) received multimodal therapy (MMT), including radiation (3; 3.3%), systemic therapy (49; 53.3%), and radiation + systemic therapy (8; 8.7%). Of the 59 patients who did not undergo surgical resection, the majority (46; 77.8%) presented with M1 disease. Median OS was 7.8 months for the entire RMC cohort, with 1- and 3-year OS of 34% and 11%, respectively. Notably, median OS for patients presenting with M1 and M0 disease was 5.2 months versus 11.2 months, respectively (p< 0.01). On multivariable analysis, treatment with RN (HR 0.40; p=0.003) or RN+MMT (HR 0.44; p<0.001) were associated with decreased ACM, whereas the presence of metastatic disease at diagnosis remained associated with an increased risk of ACM (HR 1.74; p=0.02). Conclusions: The prognosis for patients with RMC is dismal, with a median OS under 8 months. Further studies, including the development of novel therapies, are needed to establish the optimal multimodal management approach for these patients.
Dose adjustment of axitinib based on AUC in sunitinib-pretreated metastatic renal cell carcinoma.
Authors: Miura Yuji , Imamura Chiyo K. , Uchino Keita , Kishida Takeshi , Matsubara Nobuaki , Shinojima Toshiaki , Kondo Keiichi , Hongo Fumiya , Yoshimura Kenichi , Tanigawara Yusuke , Takano Toshimi
Published: March 2017

457

Background: Axitinib is one of the standard second-line therapies after sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC). The previous study showed that higher exposure and diastolic blood pressure (dBP) were independently associated with better clinical outcomes. However, many factors, such as antihypertensive agents use, usually affect dBP. Therefore, axitinib dose adjustment based on its exposure could be more adequate than that based on dBP. Methods: We conducted a prospective phase II trial of axitinib dose adjustment for Japanese pts with mRCC previously treated with sunitinib. Starting dose of axitinib was 5 mg BID. We assayed blood axitinib levels on day 1 and calculated the area under concentration-time curve from 0 to 12 hours (AUC0-12). We determined the individual sufficient dose (SD) to reach AUC0-12 value at the steady state of 150 ng*hr/mL. After day 15, axitinib dose was adjusted to keep over SD according to adverse drug reaction for each patient. The primary endpoint is 6-month progression-free survival (6m-PFS) rate. Secondary endpoints include toxicity and objective response rate. With power of 80% and one-sided alpha of 10%, thirty-two pts were required to reject 48% of 6m-PFS rate under expected 69% 6m-PFS rate. Results: Between May 2013 to March 2015, 26 pts were enrolled when the trial closed for poor accrual. Pts’ characteristics were: median age 71 years, male 20 (77%), PS 0 19 (73%), and International Metastatic RCC Database Consortium intermediate risk 24 (92%). Median SD of axitinib was 3 mg BID (range 1-16). SD was given at a median of 78% (range 0-100) of total administration day until 6 months. Two pts did not receive the planned SD because their SD was over 10 mg BID. Therefore, the two pts were excluded from safety analysis; meanwhile all pts were included in efficacy analysis. The 6m-PFS rate was 85% (95% CI 66-94, p < 0.01). The median PFS was 10.6 months (95% CI 7.2-16.7). The most common grade 3 to 4 adverse events during the first 6 months were hypertension (79%), decrease appetite (29%), fatigue (13%), and hand-foot syndrome (13%). Conclusions: The individual dose adjustment of axitinib to keep over 150 ng*hr/mL of AUC0-12 on day 1 for sunitinib-pretreated mRCC is feasible. Clinical trial information: UMIN000009579.
Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors.
Authors: Derosa Lisa , Routy Bertrand , Enot David , Baciarello Giulia , Massard Christophe , Loriot Yohann , Fizazi Karim , Escudier Bernard J. , Zitvogel Laurence , Albiges Laurence
Published: March 2017

462

Background: Preclinical data demonstrated that microbiota modulates activity of immune checkpoint inhibitors (ICB) and broad-spectrum antibiotics (ATB) damper their efficacy. However, the impact of ATB in patients (pts) treated with ICB remains unknown. Our study evaluates the effect of ATB use in metastatic renal cell carcinoma (mRCC) pts treated with ICB. Methods: We conducted a retrospective analysis of mRCC pts treated in prospective trials at Gustave Roussy with PD1/PD-L1 inhibitors alone or in combination. ATB (+)/(-) group were defined as pts treated or not with ATB at baseline (up to 1 month prior to the 1st injection of ICB). Progression-Free survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS) were compared in each group (ATB (+) vs ATB (-)). Statistical analyses were performed using Kaplan-Meier method and Cox regression adjusted for risk factors. Results: We enrolled 80 mRCC pts treated with anti-PD-1/PD-L1 monotherapy (n=67), anti-PD-1 plus CTLA-4 (n=10) or anti-PD-L1 plus bevacizumab (n=3) with available data on ATB. Majority of pts were male (65%), clear-cell histology (88%), and had prior nephrectomy (80%). With regard to IMDC risk groups, 21%, 57%, and 22% had favorable, intermediate, and poor-risk disease, respectively. Sixteen (20%) pts belonged to the ATB (+) group (mostly receiving beta-lactamases and fluoroquinolones). ATB (+) had decreased PFS compared to ATB (-), 2.3 vs. 8.1 months, p<0.001. This statistical association was maintained after multivariate analysis adjusted for age, gender, IMDC risk groups, tumour burden and proton pomp inhibitors. In addition, ORR was lower in ATB (+) compared with ATB (-) (p<0.002). Even though it is too early to conclude on OS (median follow-up <6 months), there was already a negative trend driven in ATB (+). Conclusions: This is the first analysis evaluating the impact of ATB in mRCC pts treated in the era of ICB. Recent use of ATB prior to ICB, negatively influences responses even after multivariable analysis for prognostic risk factors. Further studies are warranted to investigate whether the alteration of gut microbiota compositions is responsible for this different outcome.
Individualized treatment with sunitinib versus standard dosing with sunitinib or pazopanib in patients with metastatic renal cell carcinoma (mRCC): Results from the Canadian Kidney Cancer information system (CKCis).
Authors: Basappa Naveen S. , Lalani Aly-Khan A. , Li Haocheng , Kalirai Austin , Wood Lori , Kollmannsberger Christian K. , Sim Hao-Wen , Kapoor Anil , Hotte Sebastien J. , Czaykowski Piotr , Canil Christina M. , Reaume M. Neil , Bjarnason Georg A. , Vanhuyse Marie , Soulieres Denis , Levesque Eric , North Scott A. , Heng Daniel Yick Chin
Published: March 2017

468

Background: Recent analysis using CKCis, a prospective database, showed that mRCC patients receiving first-line sunitinib (S) had better survival than patients receiving pazopanib (P) and greater than expected absolute survival in the real world setting. We conducted further analyses to see if an individualized approach (treatment starting at standard dose/schedule with subsequent schedule/dose alterations based on toxicity) using S results in better outcomes in mRCC patients. Methods: Patients within CKCis diagnosed with clear cell mRCC treated with first-line S or P between January 2011 to December 2015 were analyzed by three treatment groups: 1) S as per individualized approach (SI), 2) S as per product monograph (SS), or 3) P as per product monograph (PS). Overall survival (OS) and time-to-treatment failure (TTF) were calculated. Cox regression analysis allowed for adjustment of International Metastatic RCC Database Consortium (IMDC) criteria with age as a continuous variable. Results: A total of 573 patients were identified, 261 patients in SI, 201 patients in SS, and 111 patients in PS. Differences in baseline characteristics were noted (Table). Median OS was improved in SI vs. SS (40.8 vs. 22.6 months (m), p<0.001) and SI vs. PS (40.8 vs. 20.3 m, p<0.001). TTF was better in SI vs. SS (16.6 vs. 5.4 m, p<0.001) and SI vs. PS (16.6 vs. 7.0 m, p<0.001). SS vs. PS showed no difference in median OS (22.6 vs. 20.3 m, p=0.76) or TTF (5.4 vs. 7.0 m, p=0.11). Adjusted hazard ratio showed significance in SS vs. SI (OS 1.81, p=0.004 TTF 2.42, p<0.001) and PS vs. SI (OS 3.16, p<0.001; TTF 2.03, p<0.001). Conclusions: Significant improvement in OS and TTF is seen using an individualized approach to mRCC patients, further supporting the growing body of evidence endorsing this practice. Further prospective validation awaits from the NCT01499121 study. [Table: see text]
Acute and late toxicity in high-risk prostate cancer patients treated with androgen suppression and hypofractionated pelvic radiotherapy.
Authors: Faria Sergio , RUO Russel , Cury Fabio , Duclos Marie , Souhami Luis
Published: March 2017

47

Background: Two recent large randomized trials confirm that 60Gy in 20 fractions is an effective regimen compared to conventionally fractionated escalated doses in localized prostate cancer. However, in these two trials the prostate was the only target volume irradiated. The purpose of this study is to report acute and late toxicity in patients with high-risk prostate cancer treated with the same moderate hypofractionated radiotherapy (HypoRT) to two target volumes at the same time: prostate and pelvic nodes. Methods: High-risk prostate cancer patients received 60Gy/20 fractions (4 weeks) to the prostate while the pelvic-nodes received 44Gy delivered with intensity modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) during the same 20 fractions. ADT started 2-3 months before HypoRT. Acute and late toxicity were prospectively assessed according to CTCAE.v3. Results: 105 patients treated between September/2010 and November/2013 were reviewed. Median follow up is 41 months. Median ADT duration was 18 months. Acute grade > 2 gastrointestinal (GI) or genitourinary (GU) toxicity was seen in 17% and 17% respectively, with only 1 and 3 patients experiencing GI and GU acute grade 3 toxicity, respectively. The worst grade > 2 late GI and GU toxicity was seen in 7% and 8% of patients, respectively. There was no grade 4-5 toxicity. At the last follow-up, the rates of grade = 2 GI and GU toxicity were 5% and 3%, respectively with no residual grade > 3 toxicity. The 48-month actuarial progression free survival is 82%. We found only 8 publications on this topic, all delivered the HypoRT in 25-28 fractions, but only one has long-term toxicity. Conclusions: ADT with HypoRT delivered with IMRT and SIB to the prostate (60Gy) and pelvic nodes (44Gy) in 20 fractions is feasible and well tolerated after 41months of median follow-up. Our approach shortens treatment duration, is convenient and its results support a needed randomized trial. Clinical trial information: NCT02107287.
The role of microRNAs (miRNAs) as predictive biomarker in advanced renal cell carcinoma (mRCC) patients (pts) with “extreme response” to tyrosine kinase inhibitors (TKIs) treatment.
Authors: Garrigos Carmen , Molina-Pinelo Sonia , Montano Marta Espinosa , Lerma Antonio , Osman Ignacio , Ávila Rainiero , Medina Rafael , Melendez Ricardo , Salinas Ana , Garcia-Donas Jesus , Rodriguez-Antona Cristina , Duran Ignacio
Published: March 2017

470

Background: MiRNAs play an important role as modulators of gene expression in a multitude of biological processes, being closely linked to the regulation of development and cell differentiation. Promising results about their value as predictors of drug response have been published in lung, colorectal cancer [Molina-Pinelo] and RCC [García-Donas]. This study aims to determine whether miRNAs can predict TKIs “extreme responses” in mRCC pts. Methods: RNA from formalin fixed paraffin embedded tumor and non-tumor samples from 15 pts with mRCC was extracted with mirVana miRNA isolation kit (Ambion). We defined as TKI “extreme responders” those pts that either had a long-term response (LR) (PFS˃11 months, n=7) or that were primary refractory (PR) (progression as best response, n=8). The expression of 754 miRNAs was analyzed with TaqMan Low Density Array Human MicroRNA Panel (TLDA) (ThermoFisher). QPCR was carried out in the System of Gene Expression and Genotyping Arrays module ViiA7. A qPCR ThermoFisher software specifically designed was used to calculate the ΔCt, cluster analysis, comparison between groups and primary analysis of the results. MiRNAs differentially expressed were analyzed independently by individual qPCR assays in the same cohort. A validation in an external cohort is being currently conducted. Results: Four miRNAs were significantly associated with patient response and differentially expressed in PR vs. LR (up-regulated in PR: miR-425-5p, down-regulated in PR: miR-139-3p, let-7d, and let-7e). Validation in our cohort was successful with let-7d and let-7e (p<0.05). Regarding differential expression in tumor vs non-tumor samples 14 miRNAs were identified by TLDA. Seven of those were validated in our series (tumor up-regulated: miR-146b, miR-21, miR-155, miR-122; tumor down-regulated: miR135a, miR-200c, miR-187) (p<0.05). These miRNAs were located in genes related with apoptosis, proliferation, metastasis, migration, and oncogenic pathways. Conclusions: MiRNAs could represent a valid predictive biomarker in mRCC treatment. These results need further validation in an independent cohort [work in progress].
The genomic landscape of metastatic non-clear cell renal cell carcinoma.
Authors: Carlo Maria Isabel , Khan Nabeela , Chen Yingbei , Hsieh James , Hakimi A. Ari , Lee Chung-Han , Feldman Darren R. , Motzer Robert J. , Voss Martin Henner
Published: March 2017

474

Background: Non-clear cell renal cell carcinoma (nccRCC) encompasses about 20% of RCC cases and includes a number of subtypes that vary clinically and molecularly. Compared to ccRCC, these tumors have more limited sensitivity to conventional anti-VEGF agents and mTOR inhibitors, and there is clear need for better therapies. Analysis of genomic alterations in potentially targetable pathways may lead to novel therapeutic development strategies. Methods: We retrospectively analyzed tumors from 112 patients with metastatic nccRCC with targeted next-generation sequencing (NGS) across a panel of >340 cancer-relevant genes. Matched tumor and normal was used to facilitate somatic calling. We report on recurrent alterations observed for nccRCC variants. Results: Median age was 53 years (range 12-77), 67% were male; 47% presented with metastatic disease and 53% with localized disease that later metastasized. NGS was performed on tissue from primary tumors (57%) or metastatic sites (43%). Subtype classifications included unclassified (44%), papillary (21%), chromophobe (13%), translocation (12%), and other (9%). The most frequently altered genes by subtype are included in table. 36% of unclassified or papillary tumors had a mutation in a putative driver gene amenable to targeted therapies, including MET, NOTCH1, SMARCB1, TSC1, TSC2, PIK3CA, and FGFR3. 3 chromophobe tumors and 1 translocation tumor had a mutation in a potentially targetable pathway. Conclusions: The mutation profiles of metastatic nccRCC vary by papillary, chromophobe, and translocation subtype, with unclassified tumors most approximating papillary subtype. Unclassified and papillary subtypes harbor frequent mutations in potentially targetable pathways that merit further investigation. [Table: see text]
The efficacy and safety in elderly patients with advanced renal cell carcinoma: Real-world use of sorafenib in Japan.
Authors: Tatsugami Katsunori , Oya Mototsugu , Kabu Koki , Akaza Hideyuki
Published: March 2017

476

Background: Multiple treatment options are available for patients with advanced renal cell carcinoma (RCC). However, the safety and efficacy data of these agents in elderly patients are limited. In this study, the data, which prospectively collected practical use of sorafenib amongst all RCC patients as a nationwide post-marketing surveillance, were analyzed using propensity-matched cohorts. Methods: A total of 3,255 patients with advanced RCC were enrolled and 772 patients selected by propensity score were matched for <75 (n=386) and ≥75 year old patients (n=386). Progression free survival (PFS), tumor response, adverse events (AEs), doses of sorafenib, and estimated glomerular filtration rate (eGFR) were analyzed. Results: The median PFS in <75 and ≥75 year old patients was 233 days (194, 274) vs. 219 days (190, 263), respectively. The mean starting dose (702 mg vs. 688 mg) and median treatment duration (222 days vs. 175 days) were similar in two groups, but mean dose intensity (70.3% vs. 61.4%, p<0.001) was lower in ≥75 year old patients than that in <75 year old patients. Complete response rates were 0.9% and 3.7%, partial response rates were 27.9% and 27.1%, stable disease rates were 58.4% and 55.6%, progressive disease rates were 12.8% and 12.8% in <75 and ≥75 year old patients, respectively. Objective response rate (CR+PR) was comparable in both groups (28.8% and 30.8%). Safety was analyzed for 772 patients, and any grade AEs observed ≥20% were hand-foot skin reaction (HFSR) (55.8%), hypertension (36.7%), rash (27.4%), and increase in lipase / amylase (26.2%), and diarrhea (21.8%). The common serious AEs were rash (7.4%), HFSR (6.0%), hepatic dysfunction (5.6%), cytopenia (4.9%), and hypertension (2.8%). The incidence of these common AEs was similar between the two groups. The discontinuation due to AE and drug related death rates were 65.3% vs. 74.9% (p<0.01) and 3.4% vs. 4.9% in <75 and ≥75 year old patients, respectively. In both groups, the eGFR value did not change from the baseline, and even slightly increased after 12 months of sorafenib treatment. Conclusions: This study indicated that sorafenib provides clinical benefits and is tolerable amongst patients with advanced RCC regardless of age.
Cabozantinib for the treatment of patients with metastatic variant histology renal cell carcinoma (vhRCC): A retrospective study.
Authors: Campbell Matthew T. , Bilen Mehmet Asim , Duran Cihan , Altinmakas Emre , Lim Zita Dubauskas , Jonasch Eric , Tannir Nizar M.
Published: March 2017

478

Background: Cabozantinib (C) prolongs overall survival (OS) and progression-free survival (PFS) in patients with metastatic clear-cell renal cell carcinoma (ccRCC) that progressed on first-line VEGFR-TKI. No standard of care systemic therapy exists for the management of patients with metastatic vhRCC. Methods: This is a retrospective, IRB approved study of patients with vhRCC who received C at MD Anderson Cancer Center from January 2014 till June 2016. Information collected from the medical records included the baseline characteristics, toxicity, dose reductions, and OS. A blinded radiologist assessed the radiographic response using RECIST v1.1. Descriptive statistics, the Kaplan Meier method and the log rank test were applied using Microsoft Excel and GraphPad Prism version 6 software. Results: Median PFS was 8.1 months (mos) (95% CI: 5.8-17.8), and median OS was 22.7 mos (95% CI:11-NR), median follow up 13.3 months (95% CI: 9.6-17) . There were no significant differences detected between patients with papillary versus non-papillary histologies with respect to PFS or OS. At last follow-up, 7 patients remain on treatment with median time on therapy for all patients of 17.7 months. There were 2 confirmed PRs (both P) for a 12% ORR, 2 unconfirmed PRs (1 chr, 1 sarc), 10 of 17 (59%) with stable disease, and 5 of 19 with progressive disease (26%), for a disease control rate of 14 of 19 (74%). Of 15 patients who started C at 60 mg/d, 10 (67%) required dose reduction due to toxicity. Multiple patients required treatment breaks but none discontinued therapy due to toxicity. Conclusions: In this retrospective study, cabozantinib produced a clinically meaningful benefit in patients with metastatic vhRCC, the majority of whom had PD on prior VEGFR-TKIs. Prospective trials of cabozantinib in vhRCC are warranted.[Table: see text]