bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic profiling of prostate cancer at a diverse academic center.
Authors: Lopez Robert , Ferrari Anna C. , Goel Sanjay , Peeke Stephen , Sharma Janaki Neela , Shenoy Niraj Konchady , Gartrell Benjamin Adam
Published: February 2020

64

Background: According to recent reports, ~1 in 4 patients with metastatic prostate cancer may harbor alterations in DNA damage repair (DDR) genes. Clinical trial data demonstrates that prostate cancer patients with DDR mutations may respond to poly-ADP ribose polymerase (PARP) inhibitors. Less is known about the mutational profile in minority patients with prostate cancer. We sought to determine the genomic profile of prostate cancer in an ethnically diverse patient population at a single center. Methods: We performed a retrospective review of men with prostate cancer at the Montefiore-Einstein Cancer Center who had next generation sequencing (NGS) with FoundationOne solid tumor testing between 2/2016 - 8/2019. Individual chart review was used to obtain clinical and demographic data including self-reported race/ethnicity. Results: NGS was attempted on archival tissue from 95 patients and results were obtained for 85. Among patients with results, the self-reported race/ethnicity was: Hispanic (H) 37.6%, Non-Hispanic Black (NHB) 52.9%, Non-Hispanic White (NHW) 4.7%, and Other (O) 4.7%. At the time of tissue sampling, 61 patients had metastatic disease and 10 were castration-resistant. 63 samples were from the prostate, 7 from bone, 7 from lymph node, 3 from liver and 5 from other soft tissue sites. The most commonly altered genes included: TP53 (26%), TMPRSS2-ERG fusion (23%), and PTEN (17%). Alterations in the androgen receptor were identified in 5 samples (all with CRPC). 32.8% had alterations in DDR genes including BRCA2 9 (10.6%), ATM 7 (8.2%), ATR 4 (4.7%), BRIP1 2 (2.3%), CDK12 3 (3.5%), FANCA 2 (2.3%), and PALB2 1 (1.2%). Alterations in mismatch repair genes (MSH2, MLH1, MSH6, PMS2) were present in 4 (4.7%) patients (3 of these were MSI-H). In samples where tumor mutational burden (TMB) was reported, 4 (4.7%) were TMB-high (3 MSI-H and 1 with POLE mutation). Conclusions: DDR gene mutations are common in this primarily minority population. As DDR mutations become more common in the CRPC setting, our data may underestimate the frequency of DDR mutations as only 10 patients had CRPC at the time of tissue sampling. Minority men, like all men, with prostate cancer should be considered for genomic analysis as results are likely to guide therapeutic decisions.
Sites of metastasis and survival in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).
Authors: Dudani Shaan , de Velasco Guillermo , Wells Connor , Gan Chun Loo , Donskov Frede , Porta Camillo , Fraccon Anna , Pasini Felice , Hansen Aaron Richard , Bjarnason Georg A. , Beuselinck Benoit , Pal Sumanta K. , Hotte Sebastien J. , Lalani Aly-Khan A. , Yuasa Takeshi , Kanesvaran Ravindran , Reaume M. Neil , Canil Christina M. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2020

642

Background: Across a variety of malignancies, sites of metastatic involvement are known to be associated with differences in survival. We sought to characterize the frequency and survival of patients with different sites of metastases in mRCC. Methods: Patients with mRCC starting treatment between 2002-2019 were identified and sites of metastatic involvement at time of systemic therapy initiation were documented. The primary outcomes of interest were prevalence of metastatic site involvement and overall survival (OS). Multivariable Cox regression models were performed to adjust for imbalances in IMDC risk factors. Results: A total of 10,320 patients were included. Median age at diagnosis was 60, 73% were male, 87% had clear-cell histology and 80% underwent nephrectomy. The most common sites of metastases were: lung (71%), lymph nodes (49%), bone (36%), liver (21%), adrenal (9%), brain (9%), pancreas (5%), pleura (4%) and thyroid (0.6%). Survival by metastatic site and adjusted hazard ratios are presented in Table. Conclusions: Metastases to endocrine organs (pancreas, thyroid, adrenal) are infrequent but are associated with the longest median OS, whereas bone, liver, pleura and brain metastases are associated with median OS < 18 months. These benchmark values are useful for patient counseling and study design. Sites of metastatic involvement may reflect differences in underlying disease biology, and further work to investigate differences in immune, molecular and genetic profiles between metastatic sites is encouraged.[Table: see text]
Treatment duration and response of advanced renal cell carcinoma (aRCC) patients (pts) who have completed first-line (1L) treatment (tx): Results from a cross-sectional real-world study.
Authors: Zanotti Giovanni , Kim Ruth , Krulewicz Stan , Hall Jennifer P. , Leith Andrea , Bailey Abigail , Liu Frank Xiaoqing , Kearney Mairead
Published: February 2020

643

Background: In 2019, there was an estimated 73,820 new cases of kidney cancers in the US. The tx landscape for aRCC is changing rapidly. Recently approved txs for 1L aRCC include new targeted agents and immuno-oncology (IO) therapies. We examine outcomes for pts who completed 1L tx. Methods: Real-world data were drawn from the RCC Disease Specific Programme; a cross-sectional survey administered to US oncologists, nephrologists and urologists. Physicians completed pt record forms (PRFs) for up to the next 8 consulting aRCC pts receiving drug tx, from February - September 2019, plus additional optional PRFs for pts receiving/who had received either 1L tx of nivolumab/ipilimumab combination or cabozantinib, where these pts were available. Results: Physicians (n=82) provided data on 687 pts; 230 had progressed from 1L tx and were on 2L tx at time of data collection. Of those receiving 2L tx, 61% male; mean age was 66.4 years (SD=11.0); 43% stage IV at diagnosis. At 1L, 72% (n=165) had received tyrosine kinase inhibitor (TKI) monotherapy; 16% (n=37) IO+IO, 3% (n=7) TKI+IO and 9% (n=20) other regimens. Mean 1L duration was 10.3 months (SD=9.4) and mean time to 2L initiation was 13.7 months (SD=21.1). 1L treatment responses were: 6% complete response, 21% partial response, 16% stable disease, and the remainder relapsed/progressed (44%) or unknown response (13%). Most common 2L regimens were TKI (37%) or IO (34%) monotherapy. 47% of 1L TKI monotherapy pts received 2L IO monotherapy. 86% of 1L IO+IO pts received 2L TKI monotherapy. Conclusions: Some pts with aRCC progress to 2L; many experience poor clinical outcomes with 1L txs, highlighting high unmet need in 1L for more efficacious txs. Optimal tx strategy (and sequencing) continues to evolve. Approval of IO+TKI therapies, approved during the fieldwork period, has broadened the therapeutic landscape for 1L aRCC. Whilst the proportion of 1L pts receiving IO+TKI therapies is still low, the adoption of these in 1L is likely to transform the management of aRCC. Further research is needed to determine the optimum tx sequence in these pts with high unmet need.
A real-world experience of immune checkpoint inhibitors (ICI) in metastatic renal cell carcinoma (mRCC).
Authors: Elias Roy , Levonyak Nicholas , Christie Alana , Bowman Isaac Alexander , Kapur Payal , Hannan Raquibul , Hammers Hans J. , Brugarolas James
Published: February 2020

647

Background: ICI therapy has changed the treatment landscape in mRCC. Here we present the safety and efficacy of ICIs used in an academic medical center (UT Southwestern Medical Center) and affiliated county hospital (Parkland Hospital). Methods: All mRCC patients (pts) treated with at least one dose of ICI from 2014 - 2018 were identified. Baseline characteristics were collected at the start of ICI. Outcomes included objective response rate (ORR) as determined by RECISCT v1.1, time to next treatment (TNT) and overall survival (OS). Immune-related adverse events (irAE) were graded according to CTCAE v4.0. Kaplan-Meier methods and Cox proportional hazards regression models were used to estimate survival and generate hazard ratios (HR). Results: We identified 177 pts with mRCC, including 31 at the county hospital, who received at least one dose of ICI. 140 (79.1%) pts were intermediate or poor risk by IMDC, and 149 (84.2%) had clear cell histology. 127 (71.8%) received nivolumab monotherapy, 40 (22.6%) received ipilimumab and nivolumab, and 10 (5.6%) received ICI with a tyrosine kinase inhibitor. ICI was given in the 1st line in 34 (19.2%) pts, 2nd line in 77 (43.5%) pts, and the 3rd or later line in 29 (16.4%) pts. The ORR was 18.6% (33/177), and there were 6 (3.4%) complete responses. The median TNT and OS was 8.9 (95% CI; 7.1-10.6) and 26.7 (95% CI; 22.4-30.9) months, respectively. In multivariate analysis (MVA) of TNT including sex, nephrectomy status, IMDC risk group, histology, and number of organs involved, only number of organs involved (HR: 1.27; 95% CI: 1.12-1.45; p = 0.0003) and non-ccRCC subtype (HR: 2.63; 95% CI: 1.63-4.24; p <0.0001) retained statistical significance. MVA of OS revealed similar findings, with number of involved organs (HR: 1.49; 95% CI: 1.97-7.45; p < 0.0001) and non-ccRCC subtype (HR: 3.83; 95% CI: 1.97-7.45; p <0.0001) correlating with worse survival. irAEs were observed in 77 pts (43.5%) with 42 (23.7%) pts experiencing a grade 3/4 irAE. Conclusions: ICI therapy is safe and efficacious in the real world setting. Clinical and laboratory variables, including the IMDC risk score, do not consistently predict outcomes in this heterogeneous cohort.
Fear of cancer recurrence among patients and survivors diagnosed with localized renal cell carcinoma.
Authors: Bergerot Cristiane Decat , Battle Dena , Philip Errol James , Bergerot Paulo Gustavo , Smith Allan 'Ben' , Rathmell Kimryn , Shuch Brian M. , Derweesh Ithaar , Jonasch Eric , Msaouel Pavlos , Pal Sumanta K. , Staehler Michael D. , Stern Adam P.
Published: February 2020

649

Background: Fear of cancer recurrence (FCR) is considered one of the most pervasive and burdensome sources of distress for patients. Whereas it can be considered an adaptive response to real threats associated with diagnosis, treatment and disease, numerous studies have suggested that elevated levels can be dysfunctional. Despite this extensive body of research, little is known regarding FCR among individuals diagnosed with renal cell carcinoma (RCC). The current study sought to describe the prevalence of FCR among patients with RCC. Methods: Patients with localized RCC participated in an international survey from 07/19 to 09/19, through an online platform devised by a non-profit patient advocacy group (KCCure). Patients were assessed for FCR using the FCR-7, a 7-item measure, ranging from 0 to 28. A cutoff score of 17 indicates a moderate level of FCR, while a cutoff of 27 indicates severe level of FCR. Linear regression was used to determine the association between FCR and patients’ characteristics. Results: A total of 1150 patients participated in this survey, of which 412 had localized disease and were assessed for FCR. The majority were female (79%), with a median age of 54 years old (range, 30-80), and well-educated (58%). Patients were predominantly from US (85%), Canada (4%) and Germany (2%) and lived in suburban (48%) or rural areas (32%). More than half of participants were diagnosed with disease stage I (56%) and the remainder were divided between stage II (19%) and III (24%). More than half of patients (55%) reported a moderate or severe level of FCR. Younger patients (p=0.001) and those of female gender (p=0.004) were more likely to report higher levels of FCR. Conclusions: To our knowledge, this is the first study to quantify the degree of FCR among patients and survivors diagnosed with localized RCC. Importantly, high rates of FCR were associated with female gender and younger age, possibly driven by the fact that women may be more open to disclosing emotional symptoms and younger patients are still to pass through many life milestones and thus fear may be more pronounced. Targeted assessment and interventions are needed to address this highly prevalent form of distress among those diagnosed with RCC.
Retrospective study to identify clinical factors related to a high benefit of axitinib in mRCC: Results from AXILONG Spanish real-world study.
Authors: Pinto Alvaro , Iglesias Gomez Clara , Climent Miguel Ángel , Gallardo Diaz Enrique , Garcia del Muro Xavier , Alonso Gordoa Teresa , Llinares Legido Julia Inmaculada , Suarez Rodriguez Cristina , Anguera Georgia , Muñoz-Langa José , Lainez Nuria , Rodriguez Sanchez Angel , Martínez Ortega Esther , Villalobos Maria L. , Reig Torras Oscar
Published: February 2020

650

Background: AXILONG is a Pfizer observational multi-institutional retrospective study, evaluating clinical factors which could be related with a higher benefit of axitinib in pretreated mRCC patients in two pre-specified subgroups with extreme response to axitinib. Methods: Medical records from 157 patients treated in 40 Spanish hospitals with axitinib under clinical practice were retrospectively reviewed and included in the study. Of note, patients had to had an extreme response with axitinib, which means being a long responder (LR) to axitinib, defined as those patients who achieved a median Progression Free Survival (mPFS) of 9 months or longer, or refractory patients (RP) those who achieved a Progression Disease (PD) as best response. Results: In this analysis, we describe the results of a subgroup of patients who received axitinib in second-line after sunitinib, which represents the 68,2% (n=107) of the patients included in the whole study. The 55,1% (n=59) of this subgroup were LR and the 44,9% (n=48) were RP. In this sub-group of patients, the mPFS in LR was 18,7 months (95%CI; 12,9-24,4) and the overall response rate (ORR) was 43,9% (3,5% CR). Median overall survival (mOS) since the start of axitinib was 28,2 months for both sub-groups included, being 44,8 months in the LR patients and 7,3 months in the RP (95% CI, 12.79–34.65; p <0,001). In this population the 1st line mPSF was 27,2 months in LR and 10,9 months in RP (95%CI; 12,97-20,15; p ≤0,001). Conclusions: Despite the limitations of the AXILONG study there were a subgroup of patients who can be considered long responders o axitinib in whom we can obtain a high benefit in terms of efficacy, when treating with the sequence sunitinib-axitinib. Clinical trial information: NCT03538717 .[Table: see text]
Association of robotic partial nephrectomy for clinical T2a renal mass with improved trifecta outcome compared to open partial nephrectomy: A single surgeon comparative analysis.
Authors: Ghali Fady , Elbakry Amr A. , Hamilton Zachary , Nasseri Ryan , Eldefrawy Ahmed , Ryan Stephen T. , Yim Kendrick , Patel Sunil , Bradshaw Aaron , Meagher Margaret , Reddy Madhumitha , Lee Hak J. , Derweesh Ithaar
Published: February 2020

653

Background: We compared surgical quality and functional outcomes of robotic partial nephrectomy (RPN) and open PN (OPN) for cT2a renal masses (cT2aRM). Methods: Retrospective analysis of 150 consecutive patients [RPN 59/OPN 91] from 6/2008 to 6/2016. Main outcome was achievement of Trifecta [negative surgical margin, no major urologic complications, and ≥90% preservation of estimated glomerular filtration rate (eGFR)]. Multivariable analysis was performed to identify factors of Trifecta attainment. Results: Mean tumor size (RPN 7.9 vs. OPN 8.4 cm, p=0.139) and median RENAL score (p=0.361) were similar. No difference was noted for positive margins (RPN 3.4% vs. OPN 1.1%, p=0.561), DeGFR (RPN -6.2 vs. OPN -7.8, p=0.543), and ≥90% eGFR recovery (RPN 54.1% vs. OPN 47.2%, p=0.504). RPN had lower blood loss (p=0.015), hospital stay (p=0.013), and Clavien ≥3 complications (RPN 5.1% vs. OPN 16.5%, p=0.041). Trifecta rate was significantly higher in RPN (47.5% vs. 34.0%, p=0.041). Multivariable analysis demonstrated decreasing RENAL score (OR 1.11, p<0.001), RPN (OR 1.2, p=0.013), and decreasing EBL (OR 1.02, p=0.016) to be associated with Trifecta attainment. Conclusions: RPN provided similar functional and oncologic precision to OPN, while being associated with improvements in major complications, the latter of which was reflected in a higher rate of Trifecta achievement for RPN. RPN may be considered to be a first-line option for select patients with cT2aRM when feasible and safe.
Cost analysis of post-nephrectomy follow-up schedules from three North American clinical practice guidelines for localized renal cell carcinoma (RCC).
Authors: Thana Myuran , Dragomir Alice , Kassouf Wassim , Wood Lori
Published: February 2020

657

Background: Several guidelines have been developed for follow up of patients after nephrectomy for RCC. The direct financial cost of following recommendations in three North American guidelines were estimated in this analysis. Methods: Recommendations from the American Urological Association (AUA), Canadian Urological Association (CUA), and National Comprehensive Cancer Network (NCCN) for post-radical nephrectomy care were compiled. Data regarding costs of testing and physician visits were obtained from the Ontario Health Insurance Plan Schedule of Benefits. Both the cost per patient completing five years of surveillance (scenario A), and the estimated cost adjusted for attrition from predicted recurrences (scenario B) were calculated. A sensitivity analysis was performed and will be presented. Results: For five years of follow up of a single patient in both scenarios, the costs are summarized in the table. For scenario A, follow up costs ranged from $515-1112 for T1N0, $1639-2746 for T2N0, $1856-2746 for T3/4 and $1918-2746 TxN+. For scenario B, costs were $497-1051 for T1N0, $1259-2198 for T2N0, $1008-1595 for T3/4N0 and $1043-1595 for TxN+. Conclusions: The AUA, CUA, and NCCN guidelines showed considerable differences in their associated costs, particularly when expected recurrences were accounted for. The NCCN recommendations are predicted to be the costliest to implement, irrespective of stage.[Table: see text]
Prevalence of pathogenic germline risk variants (PVs) in 1,829 renal cell carcinoma (RCC) patients (pts).
Authors: Abou Alaiwi Sarah , Nassar Amin , Adib Elio , Akl Elie , Groha Stefan , Esplin Edward D. , Nielsen Sarah , Yang Shan , McGregor Bradley Alexander , Pomerantz Mark , Gusev Alexander , Rana Huma Q. , Sonpavde Guru , Garber Judy Ellen , Freedman Matthew L. , Choueiri Toni K.
Published: February 2020

659

Background: Hereditary RCCs account for 3-5% of all RCC cases. The prevalence and significance of germline PVs of RCC have not been fully characterized. Methods: We evaluated the frequency of pathogenic and likely pathogenic variants, referred to as PVs, in 1829 high-risk RCC pts who underwent targeted clinical germline testing (1-134 genes) at a commercial laboratory. PVs, including single nucleotide variants/indels/ copy number variants, were confirmed using orthogonal technology in accordance with Invitae’s standard operating practices. Actionable genes were defined as established cancer-predisposition genes that confer a higher risk for any cancer phenotype and for which enhanced screening and family genetic testing are recommended by the National Comprehensive Cancer Network. We focused our analysis on genes tested in more than 100 pts (n=93). Results: Among 1892 pts, 54.9% were male, and 68.9% were Caucasians, with median age 50 (range:1-87) years at RCC diagnosis. 11.8% (n=215) of pts had at least 2 primary RCCs, and 30.7% (n= 561) had a personal history of another cancer. The cumulative frequency of pts with PVs was 17.7%. PVs in known RCC susceptibility genes such as FH, FLCN, and SDHB were detected in 1.8% (29/1622), 1.22% (120/1634) and 0.64% (11/1727) of pts respectively. PVs in other cancer-associated genes were most frequently reported in CHEK2 (loss-of-function variants, 30/1276, 2.4%), MUTYH (19/1124, 1.7%), and BRCA2 (17/1276, 1.33%). PVs in DNA-damage repair genes (DRG) accounted for 71.8% of PVs and, overall, were detected in 12.7% of pts. Among the DRG, PVs in the homologous recombination pathway (ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, RECQL4, WRN) were the most prevalent (7.8%) whereas the mismatch repair pathway (MLH1, MSH2, MSH6, PMS2) was altered in only 0.7% of pts. Of the examined cohort, 9.7% of pts had ≥1 actionable PV. In non-Caucasians, BRCA2 PVs were the most common (6/273, 2.20%). Conclusions: PVs were identified in 17.7% of RCC subjects, most of which (71.8%) were in DRG, with »10% of pts having actionable variants. Our work is concordant with known RCC susceptibility genes and potentially highlights novel risk genes that should be validated in future studies.
Hospital-level quality indicators for kidney cancer surgery: A Veteran’s Affairs national health system validation of concept.
Authors: Aguilar Palacios Diego , Wilson Brigid , Saarela Olli , Ascha Mustafa , Song Sunah , DeWitt-Foy Molly Elmer , Lawson Keith , Barnholtz-Sloan Jill , Finelli Antonio , Campbell Steven , Abouassaly Robert
Published: February 2020

667

Background: Validation and implementation of quality indicators (QIs) for oncological surgical care is imperative in national health care systems. However, QIs must be adjusted for significant case-mix variations among hospitals and to capture disparate patient outcomes. Here, we explore and validate a compound quality score (CQS) as a metric for hospital-level quality of care in kidney cancer patients. Methods: Kidney cancer patients (n = 8233) treated at the VA (2005-2015) were identified. Two previously described and validated process QIs were explored: the proportion of patients with a) T1a tumors undergoing partial nephrectomy; and b) T1-T2 tumors undergoing minimally invasive radical nephrectomy. Demographics, comorbidity, tumor characteristics and treatment year were used for case-mix adjustment using indirect standardization / multivariable regression models. The predicted vs observed ratio of cases was calculated to generate each QI score. CQS represents the sum of both QIs scores. Ninety-six hospitals were benchmarked by CQS and patient-level outcomes were regressed on CQS levels to assess for length of stay (LOS), 30 days complications/readmission, 90 days overall mortality and total cost of surgical admission. Results: CQS identified 25, 33 and 38 hospitals with higher, lower and average performance, respectively. Total CQS score was independently associated with LOS [β = -0.04, p< 0.01, predicted LOS 0.84 days shorter for CQS = 2 vs. CQS = -2], 30 days surgical complications [OR = 0.88, p < 0.01] or 30 days medical complications [OR = 0.93, p < 0.01] and total cost of surgical admission [β = -0.014, p< 0.01, predicted 12% lower cost for CQS = 2 vs. CQS = -2]. No association was found between CQS and 30 day readmissions or 90 days mortality (all p>0.05), although low event rates were observed (8.9% and 1.7%, respectively). Conclusions : Variability in quality of surgical care at a hospital-level can be captured with the CQS among kidney cancer patients. CQS is associated with length of stay, post-operative complications and total cost of surgical admission. Quality indicators should be used to identify, audit and implement quality improvement strategies across health systems.
Association of checkpoint inhibitor monotherapy with less cardiac toxicity than combination therapy.
Authors: Cone Eugene Blanchard , Reese Stephen , Marchese Maya , Nabi Junaid , Kilbridge Kerry L. , Trinh Quoc-Dien
Published: February 2020

671

Background: Immune checkpoint inhibitors (ICIs) demonstrate impressive clinical benefit across a variety of cancers. NCCN guidelines for several cancers including renal cell carcinoma now support ICI monotherapy and combination therapy with ipilimumab. Cardiac toxicity is a rare but catastrophic adverse event associated with ICIs. We sought to define the comparative cardiac risk profile of ICI combination versus monotherapy in a real world setting. Methods: We used VigiBase, the World Health Organization database of case safety reports, which collects data from more than 130 countries to identify drug-associated adverse events. Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac adverse events (AE) related to monotherapy (nivolumab, ipilimumab, pembrolizumab) or combination therapy (ipilimumab/nivolumab). To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected due to chance. Results: We found 7,644, 25,016, and 14,681, and 5,191 AEs for ipilimumab, nivolumab, pembrolizumab, and combination therapy respectively. No signal existed for overall cardiac events, but combination therapy was associated with significantly higher odds of pericarditis or myocarditis (ROR 6.9, 95% CI 5.7—8.3) versus pembrolizumab (5.6, 4.9—6.4), nivolumab (5.1, 4.6-5.7), or ipilimumab monotherapy (1.9, 1.4-2.7). Pericarditis and myocarditis with combination therapy was fatal for 23% of reported AEs, compared to 14%, 14%, and 20% for ipilimumab, nivolumab, and pembrolizumab (p = 0.003) respectively. Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of myocarditis and pericarditis for all ICI, with the highest odds for combination therapy. These adverse events were often fatal. Further research is needed to identify patients at high risk for immunotherapy related cardiac toxicity.
Second-line VEGF TKI after IO combination therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Stukalin Igor , Dudani Shaan , Wells Connor , Gan Chun Loo , Pal Sumanta K. , Dizman Nazli , Powles Thomas , Donskov Frede , Wood Lori , Bakouny Ziad , Kollmannsberger Christian K. , Basappa Naveen S. , Hansen Aaron Richard , de Velasco Guillermo , Beuselinck Benoit , Canil Christina M. , Vaishampayan Ulka N. , Agarwal Neeraj , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2020

684

Background: Immuno-Oncology (IO) combinations are standard of care first-line treatment for metastatic renal cell carcinoma (mRCC). Data on therapy with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) post-progression on IO-combination therapy are limited. Methods: Using the IMDC, a retrospective analysis was done on mRCC patients treated with second-line VEGF TKIs after receiving IO combination therapy. Patients received first-line ipilimumab+nivolumab (IOIO) or anti-PD(L)1+anti-VEGF (IOVE). Baseline variables and second-line IMDC risk factors were collected. Overall response rates (ORR), time to treatment failure (TTF) and overall survival (OS) were determined. Multivariable Cox regression analysis was performed. Results: 142 patients were included. 75 patients received IOIO and 67 received IOVE pretreatment. The ORR of 2nd line therapy was 17/46 (37%) and 7/57 (12%) in the IOIO and IOVE pretreated groups, respectively (p<0.01). 2nd-line TTF was 5.4 months (95% CI 4.1-8.3) for the IOIO- and 4.6 months (95% CI 3.7-5.8) for the IOVE-pretreated group (p=0.37). 2nd-line median OS was 17.2 months (95% CI 10.8-35.1) and 11.8 months (95% CI 9.9-21.3) for the prior IOIO and IOVE groups, respectively (p=0.13). The hazard ratio adjusted by IMDC for IOVE vs IOIO pretreatment was 1.22 (95% CI 0.73-2.07, p=0.45) for 2nd line TTF and 1.43 (95% CI 0.74-2.8, p=0.29) for 2nd line OS. Conclusions: VEGF TKIs show activity after combination IO therapy. Response rates are higher in patients treated with VEGF TKIs after first-line IOIO compared to after IOVE. In patients with VEGF TKI after IOIO or IOVE, no difference in OS and TTF was observed.[Table: see text]
Individualized dosing schedule of sunitinib switched through plasma concentration monitoring in patients with metastatic renal cell carcinoma.
Authors: Zhu Xudong , Zhang Xingming , Zhang Haoran , Ni Yuchao , Dai Jindong , Sun Guangxi , Zhu Sha , Chen Junru , Zhao Jinge , Wang Zhipeng , Zeng Hao
Published: February 2020

694

Background: The aim of this study was to investigate the survival benefit and safety of switched dosing schedules for sunitinib in Chinese patients with metastatic renal cell carcinoma through plasma concentration monitoring. Methods: One hundred and twelve patients with mRCC were enrolled who were treated with Sunitinib. Patients were classified into 3 groups: switched dosing schedule through plasma concentration monitoring (4/2-2/1 schedule, 4/2-2/1-individualized and 2/1-individualized schedule), switched dosing schedule empirically due to severe adverse events (AEs)(4/2-2/1 schedule) and dosing schedule without switching (initial 4/2 or 2/1 schedule).The blood samples of patients in monitoring group were collected at different medication points consecutively within one or two course of treatment. In monitoring group, dosing schedule was switched according to plasma concentration curve. For patients whose dosing schedule was switched empirically, the switching was from 4/2 to 2/1 schedule because of intolerance to initial 4/2 schedule. The survival benefit and safety were compared among these 3 groups. Results: From plasma concentration curves, dosing schedules were switched in 17 patients. The dosing schedule was switched from 4/2 to 2/1 in 37 patients empirically, while 58 patients were administrated with a 4/2 or 2/1 schedule without switching. Among the monitoring, empirical and initial group, the median PFS was 30.0,20.0 and 9.0 months,respectively(P = 0.001), and the median OS was not-reach, 37.0, and 18.0 months, respectively (p = 0.004). Moreover, patients with a switched schedule through monitoring had better tolerance after switching. The incidence of grade 3/4 AEs fell from 88.2% to 41.2% (p = 0.001).In empirical group, the incidence of grade 3/4 AEs fell from 73.0% to 37.8% (p = 0.001). Conclusions: Treatment-related toxicities could be minimized through plasma concentration monitoring. Patients with switched schedules by monitoring could achieve a better survival benefit.
Endoscopic Ultra Sound-guided RadioFrequency Ablation (EUSRFA) as focal treatment for pancreatic metastases from renal cell carcinoma: A monocentric experience.
Authors: Chanez Brice , Caillol Fabrice , Ratone Jean-Philippe , Bories Erwan , Pesenti Christian , Pignot Geraldine , Brunelle Serge , Walz Jochen , Thomassin Jeanne , Salem Naji , Giovannini Marc , Gravis Gwenaelle
Published: February 2020

695

Background: Pancreatic metastases (PM) from renal cell carcinoma (RCC) are rare but associated with long survival. The usual management of PM is surgery or tyrosine kinase inhibitor (TKI) with sides effects. Endoscopic radiofrequency ablation (EUSRFA) is an innovative approach to focally treat deep metastasis and could be a relevant technic to control PM from RCC. Methods: This analysis addressed the local control and toxicity in patients treated by EUSRFA for progressive PM from RCC. EUSRFA was done with a linear EUS scope and a 19 G needle delivering short ablation time. Response was assessed by CT-scan using both size and contrast enhancement of the PM treated every 2 to 3 months. Results: 8 pts from Paoli-Calmettes Institute (France) were treated between May 2017 and August 2019. Age was 70.5y [61-75], 5/8 female, ECOG 0-1 (100%). The median time from diagnosis to PM was 14.5 years [9.35-22.18], median number of PM was 2 [1-3], 6/8 was documented by histology and all were classified as progressive before EUSRFA. PM localizations was: head in 40%, body 40% and average size was 14 mm [4 - 35]. 75% of pts (6/8) had other mRCC spread, 5/8 had received systemic treatment and 2 were on therapy at EUSRFA time. 3 pts had EUSRFA as the only treatment for RCCm. We performed 18 EUSRFA procedures over 16 PM. Patient received in median 2 EUSRFA sessions [1-3]. Follow up of 22.4 months [2.3-42.6], 50% of treated PM was evaluated as complete response, 17.5% as partial response and 20% as stable disease at the last CT-scan evaluation. 2 pts were considered as progressive disease and PM focal control was 87.5%. One patient treated with TKI during EURFA developed a paraduodenal abscess 2 months after EUSRFA. Another patient with biliary prothesis developed hepatic abscesses few days after EUSRFA. No other acute side effects were experienced. Interestingly, all PM treated with diameter of < 20mm was locally control versus only 75% of PM> 20mm. Conclusions: Though larger studies have to corroborate our data, EUSRFA is feasible and displays a good local control for PM. It could be a valuable option, less morbid than pancreas resection, for well selected patients with progressive PM.
Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma (S/R RCC) to reveal potential determinants of poor prognosis and response to immune checkpoint inhibitors (ICI).
Authors: Bakouny Ziad , Braun David A. , Shukla Sachet A. , Pan Wenting , Gao Xin , Hou Yue , Flaifel Abdallah , Nassar Amin , Abou Alaiwi Sarah , Flippot Ronan , Steinharter John A. , Nuzzo Pier Vitale , Ishii Yuko , Ross-Macdonald Petra , Lee Gwo-Shu Mary , McDermott David F. , Heng Daniel Yick Chin , Signoretti Sabina , Van Allen Eliezer Mendel , Choueiri Toni K.
Published: February 2020

715

Background: S/R RCC are highly aggressive tumors but recent pilot clinical data have suggested that these tumors respond well to ICI. Our aim was to perform integrative molecular characterization of S/R RCC tumors in order to characterize potential features that underlie their poor prognosis and responses to ICI. Methods: We compared genomic (1), transcriptomic (2) and immune microenvironment (3) data between S/R and non-S/R tumors. (1) S/R patients from 3 cohorts [N = 209]: The Cancer Genome Atlas [TCGA], CheckMate 010/025 & panel sequencing from Dana-Farber/Harvard Cancer Center [DF/HCC]. (2) RNA-seq on S/R from 2 cohorts [N = 98]: TCGA & CheckMate 010/025. (3) Immunofluorescence for CD8+ T cells [N = 17] & Immunohistochemistry for PD-L1 expression on tumor cells [N = 118] from CheckMate 010/025. Overall Response Rate (ORR), Progression Free Survival (PFS), and Overall Survival (OS) in S/R RCC was compared between ICI and non-ICI in clinical cohorts (Table). Results: S/R tumors were significantly enriched in mutations in BAP1, NF2, RELN, and MUTYH, deletions of CDKN2A/B & amplifications of EZH2 (q < 0.05) compared to non-S/R tumors. Gene Set Enrichment Analysis showed upregulation of epithelial-mesenchymal transition, immune pathways, and proliferation programs compared to non-S/R tumors in both RNA-seq cohorts independently (q < 0.25). S/R tumors exhibited greater infiltration by CD8+ T cells at the tumor margin (p = 0.048) and PD-L1 expression on tumor cells (43.2% vs 21.0%, p < 0.01) compared to non-S/R. S/R had improved ORR, PFS, and OS on ICI vs. non-ICI (Table). Conclusions: S/R RCC tumors have distinctive molecular features that may account for their association with poor prognosis and outcomes on ICI.[Table: see text]
AGAP2-AS1 as a potential marker for development of distant metastases in surgically treated low-risk clear cell renal cell carcinoma.
Authors: Nakken Sigrid , Eikrem Øystein , Marti Hans-Peter , Beisland Christian , Bostad Leif , Scherer Andreas , Flatberg Arnar , Beisvag Vidar , Strauss Philipp
Published: February 2020

732

Background: Historically, 30 % of patients with localized kidney cancer develop distant metastases during follow-up. There is an urgent need to improve the individual risk assessment for clear cell renal cell carcinoma (ccRCC) patients. We therefore aim to characterize the gene expression profile of low-risk patients both with and without progressive disease to define predictive outcome candidate markers. Methods: Formalin-fixed tissue blocks from ccRCC patients (n=24, eight progressors and 16 non-progressors) with a low Leibovich score were collected. Patients had a mean age of 65 years (5 females and 19 males). The non-progressors were matched 2:1 to the progressors for gender, age, pT tumor stage, size, Fuhrman grade, and eGFR. Total RNA was extracted(miRNeasy FFPE Kit, Qiagen) and sequenced (TruSeq RNA Access Library Kit, Illumina). RNA-seq results were analyzed by ingenuity pathway analysis, K Nearest Neighbors algorithm, and survival analysis. Results: 1167 differentially expressed genes (abs.FC≥2, p≤0.05) were detected. Progressors overexpressed genes related to cancer, B-cell infiltration and other immune-system related pathways. Principal component analyses and hierarchical clustering depicted a systematic transcriptomic difference between progressors and non-progressors. Combinations of up to 10 genes were evaluated as classifiers. The AGAP2-AS1 mRNA classified 23 out of 24 samples correctly, without the need for a larger gene panel. The trend of expression was confirmed with RT-PCR.The correlation between sample status as either progressor or non-progressor and AGAP2-AS1 level was R2 =0.69, p <0.01. Patients were split into groups based on AGAP2-AS1 expression (cut-off log2cpm>1), where higher expression correlated with shorter survival; Wilcoxon (p<0.0001),Log-rank test (p<0.0001), Hazard ratio; 9.24E-11. Immunohistochemistry of AGAP2, USP10 and KI-67 confirmed results from the mRNA level. Conclusions: RNA-seq results show a transcriptomic difference between low-risk ccRCC progressors and low-risk non-progressors. AGAP2-AS1 may serve as a potential classifier for the identification of low-risk progressors.
Identification of genomic aberrations associated with overall survival in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Kessel Adam , Tran Summer , Rivers Zachary , Hahn Andrew W , Nussenzveig Roberto , Rathi Nityam , Maughan Benjamin Louis , Sirohi Deepika , Stenehjem David D. , Agarwal Neeraj
Published: February 2020

745

Background: Tumor comprehensive genomic profiling (CGP) in addition to risk stratification by IMDC criteria may aid in improving risk stratification. The objective of this study was to assess the prognostic impact of somatic mutations in addition to IMDC risk criteria. Methods: All patients with mccRCC treated with first line with VEGFR-TKI with CGP data available through a CLIA certified lab were included. Kaplan-Meier methodology and Cox proportional hazard ratios were used to test the association of overall survival with genomic alterations present in at least 7% of the population in this dataset. Genomic data were correlated with outcome by univariate analysis and subsequent multivariate testing, integrating genomic data with IMDC risk criteria. Results: A total of 58 patients met eligibly. The presence of any mutation in VHL, PBRM1, and MLL2 were prognostic in terms of overall survival (Table). The mutation status for these three prognostic genes was added to the IMDC risk model to test for the prognostic correlation. The mutations status of these 3 genes significantly correlated with overall survival (VHL: 0.32 [95% CI 0.11-0.95], PBRM1: 0.36 [0.14-0.96], and MLL2: 7.60 [1.35-24.6]) independent of the IMDC risk criteria. Conclusions: In mccRCC, VHL, PBRM1, and MLL2 mutations each predict overall survival independent of IMDC criteria. Further studies are warranted to assess alterations with low prevalence in this data set. Upon external validation, these data provide the rationale for integration of mutation status of these three genes in to the IMDC risk criteria.[Table: see text]
Multicenter comparison of outcomes for clinical and pathologic T3a renal cell carcinoma.
Authors: Bradshaw Aaron , Ghali Fady , Miller Nathan , Keiner Cathrine , Dutt Raksha , Meagher Margaret , Yim Kendrick , Patel Devin , Uzzo Robert Guy , Lane Brian R. , Capitanio Umberto , Derweesh Ithaar
Published: February 2020

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Background: The identification of venous thrombus in patients with renal cell carcinoma (RCC) is particularly challenging, with a substantial number upstaged to pathologic T3a following intervention. We compared survival outcomes between patients with initial cT3a status versus those upstaged to pT3a. Methods: This is a retrospective, multicenter analysis of patients with cT3a or pT3a RCC who underwent operative management. Primary outcome was recurrence-free survival (RFS). Secondary outcomes were overall survival (OS) and cancer-specific survival (CSS). Cox regression multivariable analysis (MVA) was utilized for primary outcome. Kaplan-Meier analyses (KMA) were conducted to describe RFS, OS, and CSS with log-rank test comparing clinical and upstaged pathologic T3a groups. Results: 770 patients were analyzed (cT3a 184, pT3a 586, median follow-up 28 months). Average pathologic tumor size was smaller in pT3a (7.2 cm vs 8.7 cm, p < 0.01), with no significant differences in clinical variables. A similar proportion underwent radical nephrectomy (vs. partial) (89.7% cT3a and 85.0% pT3a, p = 0.11) with no significant different in positive margin rate (3.8% cT3a, 4.8% pT3a, p = 0.23). However, a higher proportion of patients with cT3a disease were pathologically node positive (19.0% vs. 10.8%, p < 0.01) and demonstrated a higher rate of recurrence (cT3a 51.1% vs. pT3a 34.1%, p < 0.01) despite shorter mean follow-up (cT3a 33.0 vs. pT3a 50.7 mo, p < 0.01). MVA for RFS revealed cT3a staging (pT3a referent, HR 1.72, p < 0.01), positive margins (HR 2.85, p < 0.01), and clear cell histology (HR 1.68, p < 0.01) to be independently associated with higher recurrence rate, while partial nephrectomy (radical referent, HR 0.259, p < 0.01) was associated with a decreased rate. KMA revealed 5-year RFS of 34.4% and 60.6% for cT3a and pT3a respectively (p < 0.01). KMA for secondary outcomes revealed 5-year OS rates of 56.7% and 62.0% (p = 0.02) and 5-year CSS of 74.4% and 67.7% for cT3a and pT3a respectively (p = 0.01). Conclusions: Patients with cT3a RCC have poorer oncologic outcomes than those with upstaged pT3a RCC. Suspected venous involvement on pre-operative imaging may indicate more aggressive or advanced disease than that found during surgery.
ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastasized castration-resistant prostate cancer (mCRPC): A multicenter phase I study.
Authors: Vermunt Marit , Robbrecht Debbie , Devriese Lot , Janssen Julie , Keessen Marianne , Eskens Ferry , Beijnen Jos H. , Mehra Niven , Bergman Andre M.
Published: February 2020

79

Background: ModraDoc006 is a novel formulation of docetaxel and to enhance bioavailability, this tablet is co-administered with ritonavir (r), an inhibitor of cytochrome p450 3A4 and P-glycoprotein. The safety, anti-tumor activity and pharmacokinetics (PK) of ModraDoc006/r were investigated by dose-escalation in patients with mCRPC, to propose a recommended phase 2 dose (RP2D). Methods: Progressive mCRPC patients, who were treatment naïve or previously treated with either abiraterone or enzalutamide, received a maximum of 30 weekly cycles of ModraDoc006/r in a bi-daily once weekly (BIDW) schedule. Plasma docetaxel concentrations were determined at the first 2 cycles up to 48h after intake of ModraDoc006/r. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Serum Prostate Specific Antigen (PSA) levels were assessed every 6 weeks. Results: 23 patients were included, of whom 20 were evaluable for safety and PK. In 5 patients, the initial 30-20/100-100 dose was explored, with observation of one dose limiting toxicity (DLT) (grade 3 alanine aminotransferase increase). The next dose level of 30-20/200-200 resulted in 2 DLTs in 6 patients (grade 3 diarrhea and mucositis). Subsequently, two intermediate dose levels: 30-20/200-100 and 20-20/200-100 were explored in 6 and 3 patients. At the 30-20/200-100 dose, an adequate docetaxel exposure was achieved and 1 DLT (grade 3 diarrhea) was observed, with no DLTs at the 20-20/200-100 dose. Common treatment-related AEs (occurring in > 30% of all patients) were diarrhea, nausea, vomiting, anorexia and fatigue. Five patients completed the maximum of 30 weekly treatments. In 10 patients, evaluable for anti-tumor activity after treatment with ≥9 cycles, 4 confirmed and 2 non-confirmed PSA responses ( > 50% decrease) were observed. Conclusions: The RP2D of BIDW ModraDoc006/r in mCRPC was established as 30-20/200-100 mg. These results are encouraging for further development of ModraDoc006/r as a convenient, safe and effective alternative to IV docetaxel for mCRPC patients. A phase 2b study is currently being conducted. Clinical trial information: NCT03136640.
Abiraterone acetate (AA) with or without cabazitaxel (CBZ) in treatment of chemotherapy naive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Slovin Susan F. , Knudsen Karen E. , Halabi Susan , Fleming Mark T. , Molina Ana M. , Wolf Steven Paul , de Leeuw Renee , Fernandez Celina , Kang Praneet , Southwell Traci , Jones Carol L. , Fernandez Escarleth , Kelly William Kevin
Published: February 2020

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Background: Loss of retinoblastoma tumor suppressor (RB) function has been shown to lead to CRPC and is strongly associated with poor outcome. RB functions as a transcriptional repressor; as such, loss of RB causes de-repression of pro-tumorigenic gene networks, including deregulation of the androgen receptor (AR) locus, excessive AR production, and castration-resistant (ligand independent) AR activity that can bypass hormone therapy. Our hypothesis is that leveraging RB status can direct treatment decisions. The primary objective of the trial (NCT02218606) was to determine the radiographic progression free survival (rPFS) of AA/prednisone (AAP) with and without CBZ in mCRPC patients (pts) that have progressed on primary androgen deprivation therapy and no prior AR directed therapy or chemotherapy. Methods: This is a multicenter non-comparative randomized phase 2 trial. Pts were randomized 1:1 to AAP with crossover to CBZ upon AAP failure (Arm 1), or the combination of AAP + CBZ (Arm 2). Randomization was stratified by the CALGB 90401 prognostic risk groups. The primary endpoint was rPFS (time from randomization to radiographic progression or death, whichever occurs first). Arms were analyzed separately. Results: Between October 2014 and March 2019, 93 pts were accrued; 81 were randomized. Median age was 68 years and ECOG performance status was 0 or 1. Endpoints are shown in Table. Therapies were well tolerated. Conclusions: Results of AAP + CBZ (Arm 2) in chemotherapy naïve pts suggest that men may derive benefit from the earlier use of CBZ with acceptable toxicity, supporting further study of this combination in mCRPC pts. Circulating Tumor Cells are being analyzed for changes in RB/AR expression. Managed by: Prostate Cancer Clinical Trials Consortium; Funding: Sanofi US; Support: Prostate Cancer Foundation. Clinical trial information: NCT02218606. [Table: see text]