bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of PSMA-PET in focal dose-escalated radiotherapy of primary prostate cancer patients: Results of a planned safety analysis of a phase II trial.
Authors: Spohn Simon K.B. , Gainey Mark , Kamps Marius , Mix Michael , Ruf Juri , Benndorf Matthias , Zschaeck Sebastian , Ghadjar Pirus , Baltas Dimos , Grosu Anca L. , Zamboglou Constantinos
Published: February 2022

260

Background: Positron emission tomography targeting prostate specific membrane antigen (PSMA-PET) changes treatment management of primary prostate cancer (PCa) patients and might improve focal dose escalation in radiotherapy (RT) due to superior coverage of intraprostatic tumour burden. The 2-armed, non-randomized HypoFocal phase II trial investigates the safety of implementation of PSMA-PET-based focal therapy planning in external beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT). Here we present results from the planned safety analysis after 6 months of follow-up (FU). Methods: Intermediate- and high risk PCa Patients with cN0 and cM0 staged by mpMRI and PSMA PET were included. EBRT was delivered in 20 fractions with 60 Gy to the prostate and up to 75 Gy to mpMRI- and PSMA-PET defined boost volumes (arm A). HDR-BT was delivered with 15 Gy to the prostate and a boost of up to 19 Gy, followed by EBRT with 44Gy in 20 fractions (arm B). 36% of patients received androgen deprivation therapy. Volumes, treatment plans, gastrointestinal (GI) and genitourinary (GU) toxicities according to CTCAE v5.0 and Quality of Life (QoL) was assessed. Results: 25 patients were enrolled in each study arm in two centers (Freiburg and Berlin). Clinical T stage was significantly different between mpMRI and PSMA-PET (p=0.007) with upstaging towards ≥ cT2c stages in PET. GTV-PET and GTV-Union were significantly larger than GTV-MRI, resulting in large boost volumes (see table). Boost volumes received a median mean dose of 70 Gy in EBRT and a median D90 of 19 Gy in HDR-BT At 6 months FU, prevalence of ≥ grade 2 GU and GI toxicity was 4% and 0% for arm A and 12 and 4% for arm B. Two patients experienced grade 3 GI toxicitiy 9 and 12 months after RT, related to biopsy. No signification change of QoL was observed after 6 months of FU. cT stages and target volumes. Conclusions: Implementation of PSMA-PET in primary PCa patients relevantly alters cT-stage and RT treatment management with significantly larger GTVs and subsequent boost volumes. Still, boost delivery was feasible with acceptable acute toxicities and good QoL. Putative oncological benefits should be evaluated in larger cohorts. Clinical trial information: DRKS00017570. [Table: see text]
Impact of lymph node yield at prostatectomy on outcomes in NRG/RTOG 9601.
Authors: Chan Emily , Pugh Stephanie L. , Simko Jeff , Feng Felix Y , Shipley William U. , Lukka Himanshu , Bahary Jean-Paul , Pisansky Thomas Michael , Zeitzer Kenneth Lee , Lawton Colleen Anne , Efstathiou Jason A. , Rosenthal Seth A. , Balogh Alexander G. , Lovett Richard Dana , Wong Anthony C. , Dess Robert Timothy , McGinnis Scott , Kuettel Michael R. , Demora Lyudmila , Sandler Howard M.
Published: February 2022

265

Background: A recent study ( Fossati et al, 2018) found that higher lymph node count at radical prostatectomy was associated with improved outcomes in patients treated with salvage radiation for elevated prostate-specific antigen (PSA) after surgery. We sought to validate these results in NRG/RTOG 9601, a randomized controlled trial of men with pT2/T3 disease who underwent either radiation (RT) alone or RT+antiandrogen (bicalutamide) therapy for PSA elevation following radical prostatectomy from 1998-2003. Methods: We reviewed available pathology reports for all patients in NRG/RTOG 9601 to determine the nodal count at radical prostatectomy. Clinical data was as of 11/5/2015, same as the primary endpoint for the trial. Cox proportional hazards models were used to assess the effect of number of positive lymph nodes, treatment arm (RT alone or RT+bicalutamide), Gleason score, positive margins, and seminal vesicle invasion on the following endpoints: times to local and distant failure and overall and disease specific survival. Results: Out of the 760 patients originally eligible in the trial, 552 (73%, 276 in each arm) had complete data available. Median node count in the entire cohort was 6 (range 0-33, Q1-Q3 3-9). There were no significant differences between treatment arms in terms of patient demographic or clinical characteristics, including total lymph nodes removed in either arm (RT alone vs RT+bicalutamide median 5 vs 6, p = 0.11). There was no significant association between total lymph nodes and overall survival with both arms combined (HR = 1.00, 95% CI:0.97-1.03, p = 0.87) or in the individual arms alone (RT+Casodex: HR = 1.01, 95% CI:0.97-1.05, p = 0.65; RT+Placebo: HR = 0.98, 95% CI: 0.94-1.03, p = 0.45). There was also no significant association between total lymph nodes and disease-specific survival with both arms combined (HR = 1.00, 95% CI:0.95-1.04, p = 0.84) and in the arms alone (RT+Casodex: HR = 1.00, 95% CI:0.95-1.05, p = 0.92; RT+Placebo: HR = 0.99, 95% CI: 0.92-1.07, p = 0.86). In multivariable analysis performed on the two arms, Gleason score was the only feature associated with worse overall and disease-specific survival, seen only in the RT alone arm. Similar findings were seen when evaluating times to local and distant failure. Conclusions: Lymph node yield in NRG/RTOG 9601 did not show any association with adverse outcomes in the entire cohort, or in either treatment arm alone. The therapeutic benefit of an extensive lymph node dissection in this population remains uncertain. Clinical trial information: NCT00002874.
Molecular characterization to delineate the clonal evolution of primary prostate cancer with synchronous lymph node metastasis.
Authors: Singhal Udit , Nallandhighal Srinivas , Tosoian Jeffrey J. , Pham Trinh , Liu Chia-Jen , Kareem Razeen , Kunder Komal Ramesh , Morgan Todd Matthew , Lucianò Roberta , Shariat Shahrokh F , Dambrosio Lucia , Doglioni Claudio , Tomlins Scott A. , Briganti Alberto , Palapattu Ganesh S. , Udager Aaron M. , Salami Simpa
Published: February 2022

266

Background: Primary prostate cancers (PCa) harbor multiple spatially distinct tumors with significant inter-lesion molecular heterogeneity. This diversity can result in many subclones that compete for biological and clinical dominance. The defining features of primary PCa that give rise to lymph node (LN) metastases is unknown. We performed multiregional targeted DNA/RNA next generation sequencing (NGS) of primary PCa with synchronous LN metastases to identify primary PCa foci capable of metastasis. Methods: Patients who underwent radical prostatectomy and LN dissection with pathologic node positive disease were identified. Punch biopsies were performed from pre-identified regions of cancer on formalin fixed paraffin embedded (FFPE) prostate and LN specimens and DNA/RNA samples were co-isolated. Targeted NGS was performed to characterize the genomic profile of each tumor region and to evaluate gene fusion status of each sample. We compared somatic DNA mutations, copy number alterations (CNA), and gene fusion status between primary and LN disease. Phylogenetic analysis was performed using the Phylip’s dollo and parsimony, neighbor-joining method to determine the likely clonal source of LN metastasis. Results: We analyzed 88 primary tumor (1°) and 23 LN-metastases samples from 14 patients. After quality control, 11 patients (69 and 18 primary and LN tumor samples, respectively) had sufficient quality data for analyses. Seven had evidence of extraprostatic extension (EPE), with phylogenetic analysis supporting this as the source of LN-metastasis in 4 cases. One patient had concordant TP53 and TPR non-synonymous mutations and broad CNAs between all 1°and two LN-metastasis foci, with two of the 1° regions showing high-level CNAs with both LN-metastasis foci. In two patients with pT2N1 disease, sub-clonal seeding and clonal evolution was observed with metastases arising from a GG5 area. Seven had cribriform pattern in both LN and 1° foci. One patient showed CDK12 mutation within the 1° and LN foci. FOXA1 was mutated in two patients within 1° and LN foci. Conclusions: Using targeted DNA/RNA NGS to assess primary PCa and synchronous LN metastases, we demonstrate that LN metastases is related to a combination of histopathologic and genomic factors. This highlights the need to develop robust prognostic biomarkers for identification of novel therapeutic targets for LN metastasis.
Temporal changes in the screening, diagnosis and surgical treatment of genitourinary (GU) malignancies during the COVID-19 pandemic.
Authors: Labaki Chris , Schmidt Andrew Lachlan , Bakouny Ziad , Labban Muhieddine , El Zarif Talal , Chang Steven Lee , McGregor Bradley Alexander , Kibel Adam S. , Rebbeck Timothy , Trinh Quoc-Dien , Choueiri Toni K.
Published: February 2022

281

Background: The COVID-19 pandemic has been associated with a significant disruption in healthcare services including cancer screening and diagnosis. Delays in cancer screening and treatment may lead to increased mortality. We aimed to analyze changes in screening, diagnosis and surgical treatment of common GU malignancies in relation to the COVID-19 pandemic. Methods: We evaluated screening, novel diagnoses, and surgical management modalities of prostate cancer (PCa), urothelial carcinoma (UC) and renal cell carcinoma (RCC) within Massachusetts General Brigham, the largest healthcare system in the Northeastern United States, over four 3-month time periods during the pandemic (March 2020- March 2021). The percentage change in screening, diagnoses and management modalities during pandemic periods as compared to the immediate pre-pandemic period (December 2019-March 2020) was calculated as (Nperiod – Ncontrol)/Ncontrol. The difference in “predicted” versus “observed” diagnoses in each pandemic period was compared to the average of the four preceding 3-month periods (March 2019-March 2020) to account for seasonal variation. Results: The first pandemic peak (March-June 2020) was associated with a significant decline across screening, diagnosis and treatment, ranging from -15.7 to -64.8%, followed by a progressive recovery, ranging from -5.9 to +25.1% in the latest period (December 2020-March 2021) (Table). Although 725 diagnoses were “missed“ between March and June 2020 as compared to the previous 12 months, 971 diagnoses were “recovered” between June 2020 and March 2021. Conclusions: A substantial disruption in the screening, diagnosis and treatment of GU malignancies was observed early in the pandemic, followed by a progressive rebound and recovery. The highest declines were observed for PSA screening, and the lowest for cystectomy procedures, reflecting triaging of care based on severity during the pandemic.[Table: see text]
Distribution of NCCN risk classifications using MRI-ultrasound fusion versus systematic 12 core biopsies.
Authors: Khajir Ghazal , Press Benjamin , Levi Angelique W. , Sprenkle Preston C. , Leapman Michael S.
Published: February 2022

283

Background: The widely-used National Comprehensive Cancer Network (NCCN) risk criteria for prostate cancer are impactful for patient and clinicians, particularly when assessing suitability for initial active surveillance. However, in the era of MRI-guided biopsy, fewer patients may meet stringent “very-low risk” criteria due to improved sampling, which may lead to over-treatment of non-lethal cancers. We evaluated the distribution of prostate cancer risk classification obtained using MRI-ultrasound fusion versus systematic 12 core biopsy. Methods: We performed a retrospective study of patients who underwent prostate MRI-ultrasound fusion biopsy at a single institution from January 2017 to July 2021. The primary study objective was to characterize the proportion of patients meeting NCCN “very-low risk” designation within a contemporary biopsy cohort. We calculated NCCN risk classifications (very low, low, favorable intermediate, unfavorable intermediate, high, and very high) based on constituent components (PSA, PSA density, number of biopsy cores positive, greatest extent of core positivity). We conducted comparisons within patients based on findings obtained through MRI-ultrasound fusion biopsy versus systematic biopsy only. Results: We identified 1,132 patients, including 1,014 (89.5%) and 118 (10.5%) who underwent first-time biopsy and surveillance biopsies. The median PSA was 7.15 (interquartile range: 5.2-10.8). Using data obtained through systematic biopsy alone, 123 (10.9%) and 242 (21.4%) were classified as very-low and low NCCN risk, respectively. Incorporating data from MRI-ultrasound fusion biopsy, 86 (7.6%) and 255 (22.5%) were classified as very-low and low NCCN risk, respectively. Among patients initially electing active surveillance as management, 7.4%, 60.2%, 26.9% met very-low, low, and favorable-intermediate risk criteria, respectively. Conclusions: A small proportion of patients undergoing MRI-ultrasound fusion biopsy will be classified as ‘very-low risk’ by the NCCN definition, and the majority of patients managed initially with active surveillance fall outside of this criteria. These findings imply a need to broaden support for active surveillance outside of “very-low risk” criteria to promote greater uptake.[Table: see text]
Survival of young black males with metastatic clear cell renal cell carcinoma.
Authors: Grigg Claud , Trufan Sally J. , Riggs Stephen Boyd , Clark Peter E , Matulay Justin T. , Kearns James T , Zhu Jason , Raghavan Derek , Burgess Earle F
Published: February 2022

294

Background: Black men have the highest incidence of clear cell renal cell carcinoma (ccRCC) and have a worse prognosis than women or White patients in the curative setting. We previously reported that women with metastatic ccRCC have an inferior prognosis to men which is dynamic with age. The prognosis of Black patients with metastatic ccRCC is not well described. Methods: Clinicopathologic features and survival of patients diagnosed with clinical stage IV ccRCC between 2004-2016 were obtained from the National Cancer Database (NCDB). Patients were stratified according to their age at diagnosis, race, and sex. Uni- and multi-variable chi-square, logistic regression, and overall survival (OS) analyses were used for comparisons. Results: In this cohort, there were 900 Black men, 461 Black women, 13,422 White men, and 6363 White women. Black patients were less likely to have private insurance, lung metastases, or to live in high income zip codes and were more likely to have liver metastases. Compared to White race, Black race was associated with worse OS in the overall cohort (HR 1.17 [95% CI 1.10-1.24], p<0.001; multivariate HR 1.14 [95% CI 1.06-1.21], p<0.001) and in a smaller cohort limited to patients receiving systemic therapy as their initial treatment modality (n=10,869; HR 1.22 [95% CI 1.11-1.33], p<0.001). Within age groups, the highest disparity was observed among younger patients (<50yr: median OS 12.0 vs 22.1mo, p=0.004; 50-64yr: 14.6 vs 20.7mo, p=0.0001; >65yr 9.7 vs 14.5mo, p=0.002). When stratified by age and race, males had similar or superior survival compared to females in most subgroups, however Black males under 50yrs had markedly inferior OS compared with Black females (median OS 10.4mo vs 17.1mo for Black females, p=0.0083) and compared with White patients (Table). Conclusions: Young Black males with metastatic ccRCC demonstrate remarkably poor OS in this cohort; whereas males otherwise have a more favorable prognosis. Potential hypotheses to explain this disparity include differences in obesity and smoking incidence in this population as well as unmeasured factors impacting access to care.[Table: see text]
Racial differences in the natural history of small renal masses: A prospective registry study.
Authors: Cheaib Joseph G. , Patel Sunil H. , Alam Ridwan , Metcalf Meredith , Trock Bruce , Jing Yuezhuo , Ged Yasser , Allaf Mohamad , Pierorazio Phil , Singla Nirmish
Published: February 2022

295

Background: Patients with small renal masses (SRM) can be managed conservatively by active surveillance (AS) or active treatment. A subset of patients who elect for AS undergo delayed intervention, either due to progression or other factors. Using a large, prospective registry of patients with SRMs we characterize differences in SRM growth trajectories on AS and pathologic differences among resected SRMs between African Americans (AA) and Caucasians. Methods: We stratified patients enrolled in the prospective Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry by race. DISSRM includes AS, primary intervention (PI), and delayed intervention (DI). The growth rate for patients who elected for AS was compared between AA and Caucasian patients. Pathologic features among patients who underwent PI or DI were compared by race. Results: We enrolled 745 patients in DISSRM who were either AA (n = 117, 15.7%) or Caucasian (n = 628 (84.3%)), with median follow-up of 3.3 years [IQR 1.5-6.6]. 410 patients elected for AS (84% Caucasian, 16% AA) and 401 opted for PI (n = 335) or DI (n = 66) (86% Caucasian, 14% AA). Within the AS cohort, no differences were seen in age, comorbidities, or tumor size, though Caucasians were more male-predominant (60.9% vs. 38.5%, p = 0.001), and body mass index was higher among AA (p = 0.03). Median overall growth rate for AA vs Caucasian was 0.04 cm/year [-0.03-0.3] vs 0.1 cm/year [0-0.33], p = 0.2 (Figure).In the DI arm, median time to intervention was 12.5 months, with HR (AA vs Caucasian) being 0.32 (0.13-0.82), p = 0.02. There were no differences in baseline clinical characteristics or tumor size in the DI or PI arm, however AA were more likely to undergo radical nephrectomy (24.6% vs. 10.4%, p = 0.01). pT stage and grade were similar between groups, and papillary histology was more common among AA (34.1% vs 19.9%, p = 0.007). There were 31 deaths among patients undergoing intervention, which was significantly worse for AA after multivariable adjustment (HR 2.51, p = 0.025). Conclusions: Using the largest prospective registry of SRM, we found the natural history of SRM on AS to be similar between AA and Caucasians. However, histology, surgical approach, and survival differed between groups, with worse OS among AA. Further socioeconomic and molecular analyses will help elucidate biological differences and identify strategies to improve outcomes among patients with SRM.
Clinical characteristics of patients with collecting duct carcinoma.
Authors: Zhou Li , Li Siming , Yan Xieqiao , Xu Huayan , Li Juan , Wu Xiaowen , Chi Zhihong , Si Lu , Cui Chuanliang , Kong Yan , Guo Jun , Sheng Xinan
Published: February 2022

297

Background: Collecting duct carcinoma (CDC) is traditionally classified as a rare renal cell carcinoma. It comprised less than 2% of all renal cell carcinoma but presented a highly aggressive clinical course1. The natural history of CDC was merely described in small-sample retrospective studies because of its low incidence. Methods: We retrospectively collected clinicopathological data of patients (pts) diagnosed with CDC in our center from 2006 to the present. Histological diagnoses of all patients with CDC were confirmed by two senior urologic pathologists. Results: CDC was found in 58 pts (60% males and 22% over 65 years old). Most started with hematuria, low back pain, or systemic symptoms; 7 pts (12%) had no clinical symptoms. 67% pts underwent partial or radical resection of the kidney. 39.7% pts had distant metastases at diagnosis. Among the 35 pts with no distant metastasis at diagnosis, 18 (51%) had positive regional lymph nodes, 22 (63%) had locally advanced T stage (T3 or T4), and 18 (51%) were G3/4 by Fuhrman or WHO/ISUP. For pts undergoing radical nephrectomy, the median disease-free survival (DFS) was 6.3 mos (95%CI: 0.2, 12.4), and the median OS was 22.5 mos (95%CI: 16.6, 28.4), which were significantly related to T stage (P = 0.033 and 0.001). For pts after metastasis (56 cases), the most common sites of recurrence and metastasis were lymph nodes (55%), lung (46%), bone (36%), liver (16%), adrenal glands (7%), and local recurrence (20%). The median OS after metastasis was 11.3 mos (95%CI: 9.5, 13.0). Among the locally advanced or metastatic pts, 33 received gemcitabine + cisplatin combined with sorafenib as the first-line therapy. There were 8 PR and 17 SD. The ORR was 24.2%, DCR was 75.8%, and median PFS was 6.1 mos (95% CI: 4.7, 7.5). The median OS was 12.1 mos (95% CI: 8.6, 15.5). In 2 pts receiving anti-PD-1 monoclonal antibody combined with axitinib, 1 case had PR and 1 obtained SD with tumor shrinking. They are still under follow-up. Conclusions: CDC is prone to be diagnosed at a late stage and develop metastases. There is currently no standard treatment for metastatic patients; gemcitabine + cisplatin combined with sorafenib can be tried in the first-line setting. Anti-PD-1 plus axitinib showed promising efficacy in cases of CDC, and a larger sample is needed for verification.
Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC): CheckMate 9ER updated results.
Authors: Cella David , Motzer Robert J. , Blum Steven I. , Ejzykowicz Flavia , Hamilton Melissa , Wallace Joel , Zhang Joshua , Simsek Burcin , Ivanescu Cristina , Choueiri Toni K.
Published: February 2022

323

Background: In CheckMate 9ER, patients (pts) with aRCC were randomized 1:1 to nivolumab 240 mg IV Q2W + cabozantinib 40 mg PO QD (N+C; n = 323) or sunitinib (S) 50 mg PO (4 weeks of 6-week cycles; n = 328). As reported previously, at a median follow-up of 18.1 months, N+C led to superior progression-free and overall survival and more favorable HRQoL than S. We report results of HRQoL analyses for 32.9-months follow-up. Methods: Disease-related symptoms (DRS) were evaluated using the FKSI-19 instrument and HRQoL with the EQ-5D-3L visual analogue scale (VAS). Change from baseline (BL) was assessed using mixed-model repeated measures (MMRM), adjusting for baseline scores and stratification factors, and included all common timepoints (at BL and every 6 wks) through week 151. Time to deterioration analysis was conducted for first (TFD), confirmed (TCD) and definitive (TDD) deterioration events using Kaplan-Meier estimates and Cox proportional hazards models. Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (not at all or a little bit) vs notable bother (somewhat, quite a bit, and very much). HRQoL endpoints were exploratory and P-values are nominal and descriptive. Results: Group mean scores over time show that HRQoL was maintained or improved from BL with N+C while reductions were observed with S. Overall changes from BL though week 151 favored N+C with nominal significant differences between treatments observed for all scores except functional well-being (FWB; Table). Similarly, decreased risk of deterioration was observed with N+C vs S for all scores except FWB, irrespective of the deterioration definition used (TFD, TCD, TDD). Pts in N+C arm were 48% (odds ratio: 0.52 [95% CI, 0.35-0.77]) less likely to be notably bothered by side effects than pts in S arm. Conclusions: Pts continued to report improved HRQoL with N+C compared to S. Treatment with N+C reduced the risk of meaningful deterioration in HRQoL scores, regardless of the definition of deterioration and showed a decreased risk of being bothered by treatment side effects in contrast to S. These results suggest that the superior efficacy of N+C over S with the additional benefit of improved HRQoL is maintained with longer follow-up. Clinical trial information: NCT03141177. [Table: see text]
Early primary tumor response in metastatic RCC patients treated with immune checkpoint inhibitors-based combinations.
Authors: Ciccarese Chiara , Bimbatti Davide , Atzori Francesco , Bonato Adele , Scagliarini Sarah , Pellegrini Ilaria , Bracarda Sergio , De Giorgi Ugo , Masini Cristina , Santoni Matteo , Massari Francesco , Buti Sebastiano , Damassi Alessandra , Zampiva Ilaria , Strusi Alessandro , Sparagna Ileana , Rebuzzi Sara Elena , Tortora Giampaolo , Iacovelli Roberto
Published: February 2022

349

Background: 25-30% of renal cell carcinoma presents with metastases (mRCC) at diagnosis. The activity of immune checkpoint inhibitor (ICI)-combinations on the primary tumor (PT) is debated. Patients and Methods: mRCC patients (pts) with PT who received first-line nivolumab plus ipilimumab (N/I) or pembrolizumab plus axitinib (P/A) were included. We investigated the early primary tumor response (EPTR) at the first radiological assessment. Results: 73 pts were included. The median early reduction of the PT longest diameter was 12.4% with P/A versus 6.2% with N/I (p = 0.42). We evaluated if the type of EPTR could affect the metastases response. Among pts with PT stable disease (SD), 8.3% had metastatic disease progression (PD) with P/A and 34.8% with N/I. Early PT partial response (PR) was associated with no metastatic PD with both N/I and P/A. The 2 pts with PT PD had also metastatic PD to P/A. Of the 3 PT with PD to N/I, 1 had metastatic SD and 2 PD. In the overall population, of the 94.1% without PT progression (PR+SD), 47.5% had metastatic PR, 35.6% SD, 16.9% PD. Conclusions: ICIs-combinations achieved an early PT PR in about 10-20%, without any complete responses. Only a small percentage of PT had an early PD, mainly associated with metastatic PD. However, among those PT without an early progression, metastatic PR can be achieved in approximately 50% of cases.[Table: see text]
A systematic review of immune checkpoint inhibitors (ICI) in non-clear cell renal cell cancer (nccRCC) subtypes.
Authors: Reis Ana Filipa , Odeny Thomas A , Simão Diana , Fontes-Sousa Mario , Rodrigues Ysel Chiara Vina , Paller Channing Judith , Barata Pedro C.
Published: February 2022

353

Background: ICI were approved for advanced RCC treatment either alone or combined with another ICI or a tyrosine kinase inhibitor. While most trial data derive from clear cell (cc) histology, the differential activity of ICI in nccRCC subtypes is not entirely known. The aim of this analysis is to summarize the reported activity of ICI-based therapies in ncc-subtypes or in tumors with sarcomatoid/rhabdoid features. Methods: A systematic literature search following PRISMA guidelines was performed. PubMed, GoogleScholars and ASCO Database were searched for the key-words “renal cell cancer” and “immune check point inhibitors” and equivalents. Publications between July 2016 - July 2021 were considered. All original articles reporting outcomes of ICI in at least 5 patients with an advanced nccRCC were eligible. Case reports, reviews, out of scope publications and articles with no full text available were excluded. Results: This study included a total of 14 publications, mostly case series except one phase II and one phase IIIb/IV trial. The table below summarizes the different histological subtypes included in these studies, more frequently papillary (10-88%), chromophobe (0-34%) and unclassified (4-27.5%) RCC. As for first line (L), ICI monotherapy elicited an overall response ratio (ORR) of 5-26.7%, a median progression free survival (mPFS) of 2.2-4.2 months (m) and a median overall survival (mOS) of 16.3-28.9m. ICI combination therapy associated with a higher ORR of 14.2-33%, a mPFS of 2.4-8.3m and a mOS not reached (NR). In ≥2ndL, ICI alone elicited an ORR of 9.4-22.6%, a mPFS of 3.5-7.1m and a mOS of 11.6m-NR. ICI combination therapy was superior, with a reported ORR of 31-44.4%, a mPFS of 4.3-5.6m and a mOS NR. Overall, ICI therapy elicited a higher ORR in papillary tumors (5-50%). Unclassified RCC response was more variable (0-66.7%). Chromophobe tumors had a lower ORR of 0-20%. ICI therapy outcomes among nccRCC with sarcomatoid/rhabdoid features were of an ORR of 0-42.1%, a mPFS of 2.3-6.9m and a mOS of 25.5m–NR. Nonetheless, outcomes were inferior in ncc comparing to cc tumors. Conclusions: The observed activity of ICI-based therapies was heterogenous among nccRCC subtypes. Combination regimens, papillary subtype and sarcomatoid/rhabdoid features were associated with higher responses. These findings might help treatment decisions and require further validation.[Table: see text]
Impact of cytoreductive nephrectomy (CN) on survival in metastatic renal cell cancer (mRCC) treated with immune checkpoint inhibitors (ICI).
Authors: Perimbeti Stuthi , Jiang Changchuan , Deng Lei , Roy Arya , Gopalakrishnan Keerthy , Chatta Gurkamal S. , George Saby , Gopalakrishnan Dharmesh
Published: February 2022

359

Background: The advent of ICIs has dramatically changed the treatment paradigm in mRCC. Although CN was demonstrated to improve survival in combination with cytokine-based therapies, its role is not well-defined in the ICI era. We aimed to compare survival outcomes of patients treated with ICIs, based on their CN status. Methods: The National Cancer Database was queried to identify all patients older than 18 years with mRCC who received ICIs from 2015 to 2018. Chi-Square and Mann-Whitney U tests were used to compare frequency distributions. Cox proportional hazards regression was employed for multivariate analysis of factors associated with overall survival (OS). Results: A total of 4,369 patients were identified- 36.4% (n=1589) had undergone CN. Among patients who got CN, 85.3% were treated with upfront surgery while 13.8% received prior systemic therapy ( P = 0.001). The study population was predominantly Caucasian (89.2%) and male (70.6%). Patients who underwent CN were younger (median age 61 vs. 65 years, P = <0.001). Large primary tumors and clinically node-negative status were associated with higher odds of CN (T4 disease - odds ratio (OR) for 1.49, 95% CI 1.13-3.44, P = 0.03; cN0 disease - OR 1.56, 95% CI 1.23-4.56, P = 0.04). OS after 1 year was significantly higher in patients who underwent CN (66.8% vs 33.2%. P <0.001). On multivariate analysis, CN was independently predictive of improved OS with a hazard ratio (HR) of 0.53 and 95% CI 0.41-0.68, P <0.001. Conclusions: In this large retrospective analysis, CN was associated with improved OS among patients with mRCC receiving ICI-based therapies. Our findings suggest that despite recent advances in systemic therapies for mRCC, CN retains an important role in carefully selected patients.[Table: see text]
Tumor genomic landscape in younger compared to older patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Tripathi Nishita , Li Haoran , Jo Yeonjung , Sayegh Nicolas , Tandar Clara , Nussenzveig Roberto , Haaland Benjamin , Cheney Jackson , Goel Divyam , Nordblad Blake , Gupta Sumati , Maughan Benjamin L. , Agarwal Neeraj , Swami Umang
Published: February 2022

373

Background: Renal cell carcinoma is predominant in 6th to 8th decade of life. Younger pts are more likely to have symptomatic tumors on presentation but with favorable pathological features and disease specific survival (PMID: 17092632). Herein, we hypothesized that the genomic landscape for pts with onset of renal cell cancer at a younger age is distinct from those with late age of onset. Methods: In this IRB-approved retrospective study, pts with mccRCC and tumor comprehensive genomic profiling (CGP) available from a CLIA-certified laboratory were evaluated. Among these, the pts in the first and fourth quartiles of age were included in this study. Variants of unknown significance and gene with alterations (GA) present in less than 5% of pts were excluded from the analysis. A chi-square test was used to compare gene aberration frequency and p-values were adjusted for false discovery rate (FDR) using Benjamini-Hochberg (BH) correction. The median number of genomic aberrations per pt was compared using Wilcoxon rank-sum test. Results: 78 pts were eligible and included: first quartile (Range: 25-53 years; n=54) and fourth quartile (Range: 68-77 years; n=38); male vs female: 30/13 vs 20/15. The genomic aberrations observed in both groups is listed in the table. GA in VHL and PBRM1 were the most commonly observed in both groups . Most commonly observed genomic alterations in first quartile was TP53, BAP1, CDKN2B and TSC1; and fourth quartile of age was SETD2, TSC1, KDM5C and TP53. Tumor mutation burden and the frequency of gene aberrations was similar across both the cohorts. Conclusions: In these hypothesis generating data, there was no significant difference in prevalence of targetable genomic aberrations, tumor mutational burden and frequency of genomic alterations in younger vs older pts with mccRCC. The numerically higher GA in KDM5C and SETD2 (both of which contribute to epigenetic dysregulation) in older pts warrant interrogation in a larger data set. Future directions may include the investigation of epigenomic changes and transcriptomic profiling. Detailed genomic landscape of these pts will be presented in the meeting.[Table: see text]
Stage I testicular cancer: Five-year follow-up rates and reasons for non-adherence.
Authors: Karmas Tim , Holland Patrick , Matheson Kara , Wood Lori
Published: February 2022

412

Background: For stage I testicular cancer patients, active surveillance or follow up (f/u) post treatment is an integral part of quality care. Most guidelines recommend a minimum of 5 years of f/u however, it is known that a significant proportion of patients do not meet this milestone. The goal of this project was to determine what proportion of patients did not undergo ≥ 5 years of f/u in Nova Scotia (NS) and to document the reasons why. This would allow one to develop strategies to improve compliance and quality care. Methods: A review of all patients from NS diagnosed with testicular cancer between 2006-2015 was conducted. REB approval was obtained. Data from the provincial registry and electronic medical records was used to determine date of diagnosis, relapse/death, and f/u dates. Complete f/u was defined as: a patient having tumor markers, imaging studies, and/or clinical documentation ≥ 5 after initial diagnosis or relapse. The adequacy of f/u investigations was not recorded. If follow up was < 5 years, the reason for this was recorded. Results: In this cohort, 151 patients had stage I testicular cancer; 108 with seminoma (75% on surveillance) and 43 with nonseminoma (93% on surveillance). The median age was: 35.8 years. 48 pts (31.8%) were not seen at a cancer center (until relapse in 5 pts). Excluding 2 pts who died of unrelated causes, 44 patients (29.5%) had < 5 years f/u in NS. The most common reasons were: moved or probably moved in 17 (38.6%) and patient compliance/missing ≥2 appointments in 10 (22.7%). Modifiable reasons for incomplete f/u include: discharged too early from the cancer center in 3 patients, f/u never arranged post orchiectomy in 2 patients, and care transferred to primary care which did not occur in 1 patient. 22 patients relapsed: 3 in patients with lack of ≥ 5 years of f/u causing excess morbidity in 1 case. No patients died of testicular cancer. Conclusions: The majority of men with stage I testicular cancer had ≥ 5 years of f/u in NS as recommended by guidelines. However, 30% did not, with the most common reason being that the patient moved in 39% (where they may or may not have had f/u) and noncompliance in 23%. This study reinforces the need to have a seamless transition of care for this young, mobile patient population and easy, automated, regular appointment reminders. These results have led us to explore the creation of a phone-based app to improve follow up care and transition of care.
GAMMA: Results from a phase II study for relapsed germ cell tumors using an oxaliplatin-based treatment regimen.
Authors: Ng Kenrick , Prendergast Aaron , Carter Abigail , Yogeswaran Yathushan , Alexander Susanna B. , Rudman Sarah , Wong Han Hsi , Alifrangis Constantine , Nowosinska Ewa , Berney Daniel , Shamash Jonathan
Published: February 2022

417

Background: Following relapse from first line chemotherapy, 30-60% of patients with germ cell tumors (GCTs) can be salvaged with further chemotherapy. Oxaliplatin-based therapies may offer reduced toxicity. Methods: Eligible patients with GCTs who progressed following cisplatin-based chemotherapy were recruited into this single-arm, phase II clinical trial (NCT01782339). Participants were recruited from six centers and received four 21-day cycles of: Actinomycin D 1mg/m2, high dose Methotrexate 5-8g/m2 day 1, Paclitaxel 80mg/m2 days 1, 8 and 15, Oxaliplatin 85mg/m2 days 4 and 8 with Pegfilgrastim support. Participants underwent an FDG-PET scan at baseline, prior to cycle 2 and on completion of treatment. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Results: 44 patients received at least one dose of the study medication between November 2012 and February 2020. In this full analysis set (FAS) population, the median age was 38 (range 20-57), with 9 (20%) with seminoma, 23 (52%) non-seminoma and 12 (27%) of other histology. 31 (70%) patients had at least intermediate risk disease by IPFSG risk group criteria (n = 16, 36% intermediate risk, n = 6, 14% high risk, n = 9, 20% very high risk). 39 patients received 2 or more cycles of the treatment regimen and were deemed part of the subgroup of patients in the evaluable population. The ORR of the FAS population was 52.3% and 59.0% in the evaluable population. The metabolic response rate (MRR) was 52.3% in the FAS population and 59.0% in the evaluable population. The median radiological PFS in the FAS population was 17.0 months (95% CI, 5.7 months- not reached, NR) with a radiological PFS rate at two years of 38.7% (95% CI, 22.3%-54.9%). The median combined radiological or tumour marker PFS in the FAS population was 8.3 months (95% CI, 2.6 months-17.4 months) with a combined radiological or tumour marker PFS rate at two years of 28.9% (95% CI, 16.0%-43.1%). At a median follow-up of 26.8 months, the median OS in the FAS population was not reached (95% confidence interval [CI], 17.0 months-NR) with an OS rate at two years of 62.5% (95% CI, 46.1%-75.2%). Toxicity data and correlation between early metabolic response and outcomes will be presented at the meeting. Conclusions: The GAMMA chemotherapy regimen has demonstrated encouraging anti-tumor activity in relapsed GCT, despite recruiting a cohort of patients with relatively unfavorable outcomes. Clinical trial information: NCT01782339.
Molecular analysis of primary testicular germ cell tumor and matched metastatic teratomas.
Authors: Savelyeva Anna , Wang Feng , Guo Lei , Lafin John T. , Jia Liwei , Medvedev Kirill , Lewis Cheryl , Kapur Payal , Margulis Vitaly , Woldu Solomon L. , Meng Xiaosong , Grishin Nick , Amatruda James F. , Xu Lin , Bagrodia Aditya
Published: February 2022

425

Background: Metastastic teratoma (MT) is a unique germ cell tumor (GCT) subhistology characterized by resistance to platinum-based chemotherapy. Metastatic teratoma requires complete surgical excision, usually via retroperitoneal lymph node dissection (RPLND), following chemotherapy as a part of multidisciplinary GCT care. Molecular characterization of post-chemotherapy metastatic teratoma along with companion pre-chemotherapy testicular primary tumors could inform 1) the origin and differentiation site of metastatic teratomas, 2) mechanisms of platinum-resistance, 3) novel therapeutic options for patients with unresectable teratomas. Methods: We performed integrated molecular analysis for 16 primary germ cell tumors and 18 metastatic teratomas, 11 were matched tumor/metastasis pairs. All teratomas in our cohort were collected after induction platinum-based chemotherapy. In addition to SNV analysis, we conducted a chromosomal copy number gain and loss analysis for selected teratomas, matched primary tumors and primary teratomas from the TCGA. Results: Metastatic teratomas as well as their tumors of origin had low tumor mutation burden (0.65 and 0.47 accordingly). Amongst 583 SNVs detected in the study cohort, only two (KRAS p.Gly12Asp and KRAS p.Gly12Val) were previously described as oncogenic. Analysis of SNVs in proteins playing key roles in oncogenic signaling [1] showed that TP53 and Ras pathways were the most affected in metastatic teratomas. The majority of metastatic teratomas possess gain of 3p11.1 and loss of 10q26.3, 16p11.2, 19p13.2, 19q12 and 22q12.3 loci. Within 3p11.1 we did not identify any previously described oncodrivers. However, 5 chromosomal loci with lost heterozygosity contained 16 previously annotated tumor suppressor genes (15 protein coding and 1 microRNA, MIR199A1). Amongst those, GADD45GIP1 inhibition (growth arrest and DNA-damage-inducible, gamma interacting protein 1) is known for playing a role in cisplatin resistance through mechanism of cellular senescence [2]. Conclusions: Metastatic teratoma in our cohort is characterized by low tumor mutational burden, recurring copy number changes, and lack of recurring SNVs. Molecular insight of teratoma may inform disease biology and treatment. References: Sanchez-Vega, Francisco et al. “Oncogenic Signaling Pathways in The Cancer Genome Atlas.” Cell vol. 173,2 (2018): 321-337.e10. Nakayama, Kentaro et al. “Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer.” Oncology letters vol. 13,6 (2017): 4713-4719.
Inherited germline variants in urothelial cancer: A multicenter whole-exome sequencing analysis.
Authors: Kohlmann Wendy , Nix David , Atkinson Aaron , Boucher Kenneth M , Kolesar Jill , Singer Eric A. , Edge Stephen B. , Quintana Branda , Churchman Michelle L. , Feng Bingjian , Graham Laura , Carpten John D. , Sanchez Alejandro , Zakharia Yousef , Byrne Lindsey , Jain Rohit K. , Nepple Kenneth G. , Shabsigh Ahmad , Chahoud Jad , Gupta Sumati
Published: February 2022

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Background: Outside of Lynch syndrome, few genetic factors have been associated with urothelial cancer (UC). This project seeks to describe the frequency of germline variants in a multi-center UC cohort. Methods: Patients diagnosed with UC from 1980 to 2019 and consented to the Total Cancer Care protocol by members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. The ORIEN program includes a convenience sample of cases with both germline and tumor samples available, though this analysis was germline only. Whole exome sequencing data were analyzed using a GATK best practices for germline variant analysis. A series of quality control (allele frequency > = 0.3, read depth > = 20, genotype quality > = 20), annotation, functional impact (loss of function/splicing), and region (cancer predisposition genes/pathways) filters were applied to identify variants of significant consequence. Results: 348 exomes were evaluated. This identified 60 variants classified as pathogenic/likely pathogenic (P/LP) and 17 novel, high impact variants in genes associated with high, moderate, or recessively inherited cancer risk in 77 individuals (22.1%). 15 (4.5%) had P/LP variants in genes associated with a high or moderate cancer risk, and 10 (3%) of these variants were considered to be clinically actionable with associated with cancer screening, risk reduction or treatment recommendations. The high/moderate risk genes with P/LP variants included CHEK2 (n = 5), FANCM (n = 4), MSH6 (n = 2) and single cases of MSH2, BRCA2, ERCC3, and BRIP1. The average age of diagnosis in those with and without a high/moderate risk P/LP variant was 67.6 (57-80 yrs) and 68.9 (45-91 yrs). Family history of cancer was reported for 73% of those with a germline LP/PV and 60% of those without, but this trend was not significant (p =.44). Conclusions: Individuals with UC have a high frequency of germline variants that warrant further study for association with cancer risk. A smaller, but significant portion also carry germline variants that may be clinically relevant to them and/or family members. Currently UC is not included in genetic testing criteria. This study adds to the growing body of research indicating that diverse types of cancer patients harbor germline variants. Strategies for expanding testing should be considered.
Impact of care fragmentation in patients receiving neoadjuvant chemotherapy and radical cystectomy for bladder cancer.
Authors: Riveros Carlos , Chalfant Victor , Balaji KC
Published: February 2022

468

Background: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for muscle-invasive bladder cancer (MIBC). However, the impact of care fragmentation on the outcomes of patients receiving NAC and RC for MIBC is not well defined. Methods: The National Cancer Database was queried for adult (≥18 years old) patients with cT2-T4aN0M0 urothelial carcinoma of the bladder receiving NAC followed by RC between 2004 and 2017. Patients were dichotomized based on whether they received fragmented care (FC, defined as receiving NAC at a different facility from RC) or integrated care (IC, defined as receiving NAC and RC at a single facility). Descriptive statistics were used to characterize the two groups based on demographic and therapeutic profiles. Overall survival was compared between patients who received FC versus IC. Statistical analyses include Chi-squared tests, t-tests, Kaplan-Meier with log-rank test, and Cox regression analysis. Results: A total of 5054 patients received NAC followed by RC: 1848 (36.6%) received FC and 3206 (63.4%) received IC. Greater travel distance, private insurance, and treatment at a community cancer program were associated with FC whereas age, sex, race, median income, education level, rurality, and comorbidity burden were not. While patients who received FC had a longer time to initiation of NAC (40 vs. 37 days, p< 0.001), there was no significant difference in median overall survival (OS) (84.3 vs. 92.8 months, p= 0.37). On multivariable Cox regression analysis, age, comorbidity burden, stage, lymphovascular invasion, and surgical margins were associated with OS, while FC was not (hazard ratio: 1.03; 95% confidence interval 0.94-1.13; p= 0.51). Conclusions: Although care fragmentation was associated with a slight delay in the initiation of NAC, long-term survival rates were similar between the FC and IC groups.[Table: see text]