bluuebunny/crossref_metadata_2025 huggingface dataset:
The fear of cancer progression and recurrence in patients with pancreatic cancer.
Authors: Pijnappel Esther N. , Dijksterhuis Willemieke P.M. , Sprangers Mirjam A.G. , Augustinus Simone , van de Poll-Franse Lonneke V , de Vos-Geelen Judith , van Santvoort Hjalmar , de Hingh Ignace H.J.T. , Molenaar I. Quintus , Busch Olivier R.C. , Besselink Marc G.H. , Wilmink Johanna , Van Laarhoven Hanneke W.M.
Published: June 2021

4132

Background: Patients with pancreatic cancer run a considerable risk of disease progression or, after resection, disease recurrence, ultimately leading to death. Therefore, it is plausible that pancreatic cancer patients experience fear of cancer recurrence or progression (FOP). The aim of this study was to compare FOP in patients with pancreatic cancer treated with surgery, palliative systemic treatment or best supportive care (BSC), and examine the association between quality of life (QoL) and FOP and between FOP and overall survival (OS), respectively. Methods: This prospective multicenter cohort study included patients diagnosed with pancreatic cancer between 2015 and 2018, who participated in the Dutch Pancreatic Cancer Project (PACAP). Data on FOP (worry of cancer progression scale [WOPS]) and QoL (EORTC QLQ-C30 summary scale score), were obtained from the PACAP database. Data regarding patient and tumor characteristics were derived from the nationwide Netherlands Cancer Registry. The association between QoL and WOPS was assessed with logistic regression analysis. OS was evaluated using Kaplan Meier curves with log-rank test and multivariable Cox proportional hazard analyses. Results: In total, 315 patients were included, of whom 111 patients underwent surgery, 138 received palliative systemic treatment, and 66 BSC. WOPS scores tended to decrease and stabilize over time in all subgroups. Patients who underwent surgery had significantly lower WOPS scores (i.e. less FOP) at initial diagnosis compared to patients in the palliative systemic treatment and BSC group (p = 0.004). Higher QoL scores were independently associated with a lower probability of high WOPS scores in patients receiving BSC only (OR 0.95, P = 0.006). Baseline WOPS score was not independently associated with OS. Conclusions: Pancreatic cancer patients reported FOP at diagnosis, which decreased and stabilized over time. Given the distress that FOP evokes, FOP should be explicitly addressed by health care providers when guiding pancreatic cancer patients through their treatment trajectory, especially those receiving palliative treatment or BSC.
Impact of the COVID-19 pandemic on care delivery and outcomes for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Paluri Ravi Kumar , Cockrum Paul , Laursen Ashley Ann , Gaeta Joseph Louis , Wang Shu , Surinach Andy
Published: June 2021

4137

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused abrupt changes to the US health system and disruption in cancer care delivery. Little has been reported on the impact of COVID-19 on patients with mPDAC and the care delivery. Our study aimed to characterize the impact of COVID-19 on healthcare utilization and outcomes for patients with mPDAC in the US in the community oncology setting. Methods: We performed a retrospective cohort study of adult patients diagnosed with mPDAC between March – September 2019 and March – September 2020 using the nationwide Flatiron Health EHR database, comprising data from over 280 (largely community based) cancer clinics. Patients were stratified into two cohorts based on the year of diagnosis (2019 vs. 2020). Clinical characteristics were summarized including age at metastatic diagnosis, stage at initial diagnosis, and ECOG performance score (PS). Overall survival (OS) from metastatic diagnosis was estimated using Kaplan-Meier methods. A sensitivity analysis limiting the follow-up time to November of each year was conducted. Results: Overall, 1,719 patients were included in the study (2019: n = 923, 2020: n = 796); both cohorts had similar demographic compositions in terms of age and sex (2019: median age = 70 (IQR: 62 – 76), 52.2% male; 2020: median age = 70 [IQR: 62 – 76], 53.5% male). In 2020, the number of newly diagnosed mPDAC patients decreased by 13.8% compared to 2019. A slightly higher proportion of patients were initially diagnosed with stage IV disease in 2020 (69.7%) vs 2019 (62.3%). A similar proportion of patients with ECOG PS 0-1 was observed between the two cohorts (2019: 48.5%; 2020: 47.9%). The number of visits recorded within the first 90 days after metastatic diagnosis was similar between the two cohorts (2019: median 8 [IQR: 3 – 14]; 2020: median 9 [IQR: 4 – 14]). For both cohorts, the proportion of patients who received 1L treatment was similar (2019: 75.8%; 2020: 76.5%), and the most common 1L treatment regimen was gemcitabine plus nab-paclitaxel (2019: 37.6%; 2020: 40.9%). Of the 1L treated populations, 37.6% of patients diagnosed in 2019 received second line (2L) compared to 17.9% of the 2020 cohort; 16.9% of 1L treated patients in 2019 received 2L in the sensitivity analysis. Patients diagnosed in 2020 had a significantly lower median OS of 6.1 months (95% CI: 5.4 – 6.9) compared to patients diagnosed in 2019: 8.4 months (7.5 – 9.0) (p < 0.001). Conclusions: During the COVID-19 pandemic era, the diagnoses of de novo mPDAC appears to have been impacted, with a higher number of patients diagnosed with advanced stage at presentation. Our analysis suggests that while patients diagnosed in 2020 received a similar level of care as those in 2019, their survival outcomes were adversely affected. Further research is necessary to characterize the impact of the COVID-19 pandemic on cancer care and outcomes.
TCOG T5217 trial: A phase II randomized study of SLOG versus modified FOLFIRINOX as the first-line treatment in locally advanced or metastatic pancreatic ductal adenocarcinoma.
Authors: Chiang Nai-Jung , Shan Yan-Shen , Bai Li-Yuan , Li Chung-Pin , Chen Jen-Shi , Yang Shih-Hung , Kuo Yung-Chia , Chao Yee , Hsieh Yao-yu , Kao Hsiang-fong , Hsiao Chin-Fu , Chen Li-Tzong
Published: June 2021

4143

Background: The triplet regimen of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG) has shown promising efficacy for metastatic pancreatic ductal adenocarcinoma (PDAC) in our previous study. Current multicenter randomized, phase II study compared the efficacy and safety of SLOG versus modified FOLFIRINOX (mFOLFIRINOX) in patients with advanced/metastatic PDAC. Methods: Patients with chemo-naïve, histologically confirmed advanced/metastatic PDAC, were randomly assigned to either SLOG (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2 on day 1, plus daily 40/50/60 mg of S-1 based on BSA and 30 mg of oral leucovorin, twice daily, on days 1-7, every 2 weeks) or mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 and leucovorin 400 mg/m2 on day 1 plus 5-FU 2400 mg/m2 for 46 hrs, every 2 weeks). Patients were stratified according to disease extent, ECOG PS and primary tumor location. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS) and safety profile. Tumor response was assessed by CT/MRI every 8 weeks according to RECIST v1.1. As an exploratory trial, 130 (65 per arm) patients were estimated to detect a two-sided 15% difference in 6-month PFS (60% in SLOG and 45% in mFOLFIRINOX) with a significant level of α = 0.1 and β = 0.25. Results: Between March 2018 and October 2019, 130 patients were accrued. One patient who was assigned to mFOLFIRINOX arm didn’t receive assigned treatment. Of them, 62.3% were male, 45.4% were ECOG PS0, 81.5% had metastatic diseases, and 16.9% had prior surgery. The 6-month PFS rate was 55.4% in SLOG arm (n = 65) and 50% in mFOLFIRINOX arm (n = 64) (p = 0.850). The ORR and DCR in the SLOG and the mFOLFIRINOX arms were 40% versus 26.6% (p = 0.135) and 76.2% versus 71.9% (p = 0.550), respectively. The median PFS was 7.5 months in SLOG arm and 6.5 months in mFOLFIRINOX arm (p = 0.395); while the median OS was 12.9 months in SLOG arm and 12.1 months in mFOLFIRINOX arm (p = 0.88). Ten patients underwent conversion surgery, of whom 7 had SLOG and 3 had mFOLFIRINOX. The incidence of grade 3/4 neutropenia was significantly higher in mFOLFIRINOX arm (53.2% vs. 16.9% in SLOG arm, p < 0.0001). Conclusions: SLOG could achieve comparable but numerically better ORR, and median PFS and OS as compared to mFOLFIRINOX in patients of advanced PDAC. SLOG can be an alternative first-line regimen for advanced PDAC patients. Clinical trial information: NCT03443492.
Prognostic and predictive factors in patients treated with ramucirumab (RAM) with advanced hepatocellular carcinoma (aHCC) and elevated alpha-fetoprotein (AFP): Results from two phase III trials.
Authors: Llovet Josep M. , Singal Amit G. , Villanueva Augusto , Finn Richard S. , Kudo Masatoshi , Galle Peter R. , Wang Chunxiao , Widau Ryan C , Gonzalez Gugel Elena , Zhu Andrew X.
Published: June 2021

4146

Background: Elevated AFP in patients with aHCC is a poor prognostic factor with distinct molecular features, including high vascular endothelial growth factor (VEGF) signalling and increased angiogenesis. RAM, a human IgG1 monoclonal antibody, VEGF receptor 2 (VEGFR2) inhibitor, demonstrated improved survival vs placebo among patients with elevated AFP in the REACH-2 trial and is accepted as a standard of care for management of aHCC. We analyzed prognostic factors in patients with AFP ≥400 ng/mL and predictors of clinical benefit to RAM in an individual participant data (IPD) meta-analysis of the REACH and REACH-2 Phase III trials. Methods: Patients with aHCC, Child-Pugh A, ECOG performance status (PS) ≤1, and prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to RAM 8 mg/kg or Placebo Q2W. Meta-analysis was conducted in patients with AFP ≥400 ng/mL (n = 542). Univariate (UV) and multivariate (MV) analyses were performed using a Cox proportional hazard regression model. MV used the cut-off p-value < 0.1 from UV, irrespective of treatment arm. Overall survival (OS) was evaluated by Kaplan-Meier estimator and Cox models. To define predictors of RAM benefit, treatment-by-covariate interactions terms were evaluated. Results: In terms of prognosis assessed by MV analysis in patients with AFP ≥400 ng/mL, 6 variables among demographic and baseline disease characteristics were associated with poor OS in the RAM cohort (ECOG PS 1, AFP > 1000 ng/mL, Child-Pugh > A5, Extrahepatic site > 1, neutrophil-to-lymphocyte ratio > 3.2 and aspartate aminotransferase > 57 U/L) with an additional 3 factors identified within the whole cohort (macrovascular invasion presence, etiology HCV vs. Other and alkaline phosphatase ≥146). RAM benefit was present across all subgroups, including patients with very aggressive HCCs (AFP > 4000 ng/mL; HR: 0.64; 95% CI: 0.49-0.84) and those with nonalcoholic steatohepatitis /alcohol related aHCC (HR: 0.56; 95% CI: 0.40-0.79). Of note, two treatment-emergent (TE) events were the only factors that were significantly associated with improved RAM-related survival: TE-hypertension (p interaction = 0.0392) and TE-ascites (p interaction = 0.0001). However, these results should be interpreted with caution given that TE events are factors only observed after randomization. Conclusions: Several poor prognostic factors for OS were identified in patients with aHCC and elevated AFP. RAM provided an OS benefit irrespective of baseline prognostic covariates, with greater benefit observed in patients with aggressive HCC and those who experienced TE-hypertension or TE-ascites. Clinical trial information: NCT01140347; NCT02435433.
Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Motzer Robert J. , Porta Camillo , Alekseev Boris , Rha Sun Young , Choueiri Toni K. , Mendez-Vidal Maria Jose , Hong Sung-Hoo , Kapoor Anil , Goh Jeffrey C. , Eto Masatoshi , Wang Jinyi , Pan Janice , Ayele Asfaw Alemseged , He Cixin Steven , Mody Kalgi , Cella David
Published: June 2021

4502

Background: LEN + PEMBRO improved PFS, OS and ORR vs SUN in the first-line treatment of pts with aRCC; LEN + EVE improved PFS and ORR vs SUN (Motzer R et al. NEJM. 2021). We report results of a secondary objective of the CLEAR trial comparing the impact of LEN + PEMBRO or EVE vs SUN, on HRQoL. Methods: Pts (N=1069) were randomized (1:1:1) to receive LEN 20 mg PO QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + EVE 5 mg PO QD; or SUN 50 mg PO QD (4 wks on/2 wks off). HRQoL was assessed per FKSI-DRS, EORTC QLQ-C30, and EuroQoL EQ-5D-3L, at baseline, on day 1 of subsequent 3 wk cycles starting with cycle 2, and at the off-treatment visit. HRQoL analyses (unless otherwise noted) were based on data from randomized pts with any HRQoL data who received ≥1 dose of study treatment. No adjustments for multiple testing or estimation were used; P-values and CIs are nominal and descriptive. Results: For comparisons of LEN + PEMBRO vs SUN, overall changes from baseline at mean follow-up (wk 46) favored LEN + PEMBRO with significant differences between treatments for physical functioning (least squares mean difference [LS MD] [95% CI]: 3.0 [0.5, 5.5]) and fatigue (−2.8 [−5.5, −0.1]), dyspnea (−2.8 [−5.3, −0.3]), and constipation (−2.2 [−4.2, −0.2]). LS MD of the FKSI-DRS total score was 0.2 (−0.4, 0.7). For comparisons of LEN + EVE vs SUN, overall changes from baseline at wk 46 favored SUN with significant differences in overall HRQoL (−2.8 [−5.1, −0.5] assessed by the EORTC QLQ-C30 GHS/QoL scale) and pain (2.8 [0.1, 5.5]), appetite loss (4.2 [1.3, 7.1]), and diarrhea (5.3 [2.6, 7.9]). LS MD of the FKSI-DRS total score was −0.4 (−1.0, 0.2). 14 of 18 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in LS MD comparisons. The LEN + PEMBRO arm is favored over SUN for the median time to first deterioration (TTD) for physical functioning, dyspnea, appetite loss and EQ-5D VAS (Table). 15 of 19 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in TTD comparisons. Conclusions: Compared with SUN, pts in LEN + PEMBRO group had similar or better symptoms and HRQoL. Clinical trial information: NCT02811861. [Table: see text]
Effect of Bacillus Calmette-Guerin (BCG) exposure on severity of COVID-19 infection: A COVID-19 and Cancer Consortium (CCC19) study.
Authors: Schmidt Andrew Lachlan , Bakouny Ziad , Labaki Chris , Bashir Babar , Clement Jessica M. , Edwin Natasha Catherine , Flora Daniel Blake , Girard Jennifer , Gulati Shuchi , Hwang Clara , Jani Chinmay , Lopes Gilberto , Mesa Ruben A. , Redelman-Sidi Gil , Mishra Sanjay , Warner Jeremy Lyle , Choueiri Toni K.
Published: June 2021

4529

Background: Oncology patients experience more severe disease outcomes from COVID-19 infection than the general population. BCG is a live bovine tuberculosis bacillus with immunotherapeutic effects in urothelial cancers; it is also used as vaccination against Mycobacterium tuberculosis in parts of the world. As BCG vaccination has been associated with broad protection against viral pathogens, BCG exposure through vaccination or intravesical therapy may modulate host immunity and reduce the severity of COVID-19 infection. We report the effect of BCG exposure on COVID-19 severity in oncology patients from the CCC19 registry. Methods: The CCC19 registry (NCT04354701) was used to identify patients with prior BCG exposure. Cohort A received intravesical treatment for bladder carcinoma, and cohort B received prior BCG vaccination. Each cohort was matched 3:1 to non-BCG-exposed controls by age, sex, race, primary cancer type, cancer status, ECOG performance status (PS) and calendar time of COVID-19 infection. The primary endpoint was COVID-19 severity reported on an ordinal scale (uncomplicated, hospitalized, admitted to ICU +/- ventilated, died within 30 days) of patients exposed to prior BCG compared to matched non-exposed controls. 2-sided Wilcoxon rank-sum tests were used. Results: As of 6-Feb-2021 we included 124 patients with BCG exposure, 68 patients with bladder carcinoma who had received intravesical BCG (Cohort A), and 64 cancer patients with prior BCG vaccination (Cohort B). Median age was 76 years, IQR 69-83 (Cohort A) and 67 years, IQR 62-74 (Cohort B). Bladder cancer pts were predominately male (78%) vs 55% for Cohort B. Patients with PS 2+ were uncommon, 18% in Cohort A and 16% in Cohort B. COVID-19 illness severity was no different in patients exposed to prior intravesicular BCG (p=0.87). COVID-19 illness severity was no different in patients exposed to prior intradermal BCG vaccination (p=0.60). Conclusions: Despite this being the largest such cohort reported to date, we failed to demonstrate an association of prior BCG exposure with modulation of severity of COVID-19 illness. Prospective trials evaluating the protective effect of BCG vaccination are ongoing and will add further insight into the effect of BCG on COVID-19 illness.[Table: see text]
Genomic predictors of response to PD-1 axis inhibitors in metastatic urothelial cancer (mUC) patients using machine learning analysis of tissue comprehensive genomic profiling (CGP).
Authors: Reisinger Raquel , Sacristan Santos Victor , Nussenzveig Roberto , Wesolowski Sergiusz , Hernandez Edgar Javier , Henrie Alexander Ryan , Maughan Benjamin L. , Swami Umang , Yandell Mark , Grivas Petros , Agarwal Neeraj
Published: June 2021

4542

Background: Immune check point inhibitors (ICI), specifically PD-1 axis inhibitors, are an established treatment for mUC patients (pts), though molecular markers of response are not well-established. Probabilistic Graphical Models (PGMs) are artificial intelligence (AI) algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that machine learning analysis can reveal biomarkers of response to ICI beyond Tumor Mutational Burden (TMB) and PD-L1 expression. Methods: Pts with mUC receiving systemic therapy and available tumor CGP were included in the analysis. CGP was performed by a CLIA validated NGS panel (Foundation Medicine). 17 clinically relevant variables were included in the analyses. Multilevel molecular and clinical interdependencies between ICI response were assessed using a Bayesian network (BN) machine learning approach. To account for high computational cost of the BN dependence structure discovery, variables were selected based on primary and secondary dependencies to ICI Objective Response Rate (ORR) via Hill Climbing Algorithm. Genes selected for analysis included those present in > 5% of the cohort . All variants of unknown significance were removed. Kaplan-Meyer (KM) survival analysis was also performed. Results: 174 pts were eligible and included: median age was 67 (33 – 86), 54.6% were smokers, 27.6% male, 14.4% had upper tract disease at diagnosis and 77 pts were treated with an approved ICI. Results from BN analysis revealed strong positive interdependencies between ICI ORR and TMB ≥ 10 or mutated PIK3CA gene. KM analysis was in agreement with BN results, a low TMB ( < 10 muts/MB) and wild-type PIK3CA were predictive of poor PFS (Table). PGMs will be presented at the meeting. Conclusions: BN and KM survival analysis supported TMB ≥ 10 as a biomarker of improved outcomes to ICI. Moreover, these results reveal mutated PIK3CA as a novel biomarker of improved outcomes to ICI. Study has limitations as expected in a retrospective analysis. These hypothesis-generating data require external validation.[Table: see text]
Programmed death ligand-1 (PD-L1) expression in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in NIVES study.
Authors: Masini Cristina , Carlinfante Gabriele , Iotti Cinzia , De Giorgi Ugo , Bellia Roberto Salvatore , Buti Sebastiano , Salaroli Francesco , Zampiva Ilaria , Mazzarotto Renzo , Mucciarini Claudia , Vitale Maria Giuseppa , Bruni Alessio , Procopio Giuseppe , Kinspergher Stefania , Vanoni Valentina , Nole Franco , Morelli Franco , Baier Susanne , Buttigliero Consuelo , Pinto Carmine
Published: June 2021

4558

Background: The NIVES study represents the first prospective trial with NIVO in combination with SBRT in pre-treated mRCC patients. This study did not meet the primary endpoint in terms of objective response rate (ORR) as previously reported. However this combination showed a faster time to treatment response, a long progression free survival and median duration of response without increasing toxicities. Here we have tested with an exploratory analysis the correlation between PD-L1 expression and clinical outcomes in pts treated with NIVO plus SBRT. Methods: PD-L1 expression was assessed in archival collected tumour samples in our central laboratory using 4 commercial kits for immunoistochemical (ICH) analysis (clone 22C3 pharm DX Dako Agilent, 28.8 Abcam and SP142 and SP263 Ventana Medical System). A tumor cell was considered positive if any membranous staining was found regardless of the intensity. In particular the immunostaining was scored 0 when all tumor cells were unstained (PD-L1-negative), 1+ when < 1% positive tumor cells were counted, 2+ when the percentage was between 1% and 50%,3+ when the number of stained cells was more than 50%. ORR and overall survival (OS) were correlated with PD-L1 staining. Results: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 44 of 69 pts enrolled in the NIVES study. Twenty-two pts of 44 (50%) were considered PD-L1-negative using all the 4 commercial kits for ICH analysis, while 14 of 44 pts (31,8%) were defined PD-L1 weakly positive (positive tumor cells < 1% at least in one kit for ICH). Eight of 44 pts (18.1%) were defined PD-L1 strong positive when at least one kit for ICH scored 2+ or 3+. About the correlation between ORR and PDL1 staining in the 42 pts (2/44 pts are not evaluable for ORR), ORR was 18.2% (95% CI, 5.2% to 40.3%) in the PD-L1-negative group vs 20% (95% CI, 5.7% to 43.7%) in weakly/strongly PD-L1 positive (p = 1.00). Among the 44 pts in the intention-to-treat population with available PD-L1 status, median OS was not significantly different between pts with PD-L1 negative (20.56 months, 95% CI, 7.16 to NR) and PD-L1 positive (18.33 months, 95% CI, 6.83 to NR) (p = 0.56). Conclusions: For the first time four commercial kits for ICH analysis were used to test PD-L1 expression in pretreated mRCC pts. Data from these small sample size seem to confirm that PD-L1 in pre-treated mRCC cancer is not a predictive biomarker for selecting pts to receive NIVO-based treatment. Clinical trial information: NCT03469713.
Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC).
Authors: Shah Amishi Yogesh , Motzer Robert J. , Apolo Andrea B. , Powles Thomas , Escudier Bernard , Zhang Joshua , Scheffold Christian , Karumanchi Sravan , Nguyen Linh Thuy , Choueiri Toni K.
Published: June 2021

4561

Background: In the phase 3 CM 9ER trial (NCT03141177), N+C significantly improved progression-free survival (PFS; HR 0.51, 95% CI 0.41–0.64; p < 0.0001), overall survival (OS; HR 0.60, 98.89% CI 0.40–0.89; p = 0.0010), and objective response rate (p < 0.0001) vs S in 1L aRCC (Choueiri, 2020). N+C was generally well tolerated with low rates of treatment-related discontinuations, indicating successful adverse event (AE) management with dose modification to maintain tolerability. Here the impact of C exposure on efficacy and safety outcomes in CM 9ER was evaluated using ER analysis. Methods: Patients (pts, N = 320) with previously untreated aRCC received C 40 mg QD in combination with N 240 mg Q2W; dose reductions of C to 20 mg QD or 20 mg Q2D were allowed to manage AEs. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between predicted C exposure or apparent clearance (CL/F) and specified endpoints, including PFS, dose modification, and select AEs (palmar-plantar erythrodysesthesia [PPE; Gr ≥1], diarrhea [Gr ≥3], hypertension [Gr ≥3], fatigue/asthenia [Gr ≥3], and ALT/AST elevation [Gr ≥3]). C exposure was defined as the overall average concentration from time zero to the time of event or censoring (CAVG) and estimated by population pharmacokinetic modeling for a typical patient. ER analysis for OS was not done due to the low number of events at the database lock date (March 30, 2020). Results: In the ER analysis of PFS, predicted C exposure at 40-mg and 20-mg QD doses was not significantly associated with the rate of progression or death (HR 1.00, 95% CI 0.78–1.27, for 20-mg vs 40-mg dose). In the ER analysis of AEs, lower predicted C exposure was significantly associated with lower rates of PPE (HR 0.63, 95% CI 0.50–0.78, for 20-mg vs 40-mg dose) and diarrhea (HR 0.48, 95% CI 0.29–0.80) but was not significantly associated with the rates of hypertension, fatigue/asthenia, or ALT/AST elevation. Higher predicted C CL/F was associated with a lower rate of C dose modification; however, this association was not statistically significant (HR 0.80, 95% CI 0.57–1.12, for CL/F 3.2 vs 1.2 L/hr). Conclusions: In ER models of pts with 1L aRCC treated with the combination of N+C, C exposure was not significantly associated with PFS; however, higher C exposure was associated with higher rates of PPE and diarrhea. ER modeling predicts that a starting dose of 40 mg QD C in combination with N with appropriate dose modifications to manage C AEs will not adversely affect the efficacy of the combination in 1L aRCC. Clinical trial information: NCT03141177.
Outcomes with novel combinations in non-clear cell renal cell carcinoma(nccRCC): ORACLE study.
Authors: Kilari Deepak , Szabo Aniko , Ghatalia Pooja , Rose Tracy L , Weise Nicole , Tucker Matthew D. , Nelson Ariel Ann , Dong Huaying , Hester Danubia , Acharya Luna , Jain Rohit K. , Maughan Benjamin L. , Alva Ajjai Shivaram , Tripathi Abhishek , Basu Arnab , Koshkin Vadim S , Emamekhoo Hamid , Davis Nancy B. , Desai Arpita , McKay Rana R.
Published: June 2021

4580

Background: Despite advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of new combination therapies (including immunotherapy (IO), anti-vascular endothelial growth factor inhibitors (VEGF), and mammalian target of rapamycin (mTOR) inhibitors) in metastatic nccRCC is not known. Methods: In this multicenter retrospective analysis, we explored the efficacy of combination systemic therapies in patients with nccRCC. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints include progression- free survival (PFS), disease control rate (DCR), median duration of response (DOR), overall survival (OS), and biomarker correlates. Results: Among 66 included patients, median age was 59 yr; 60% were male and 62% white. Histologies included papillary (38%), chromophobe (17%), unclassified (24%), translocation (12%), and other (9 %). Sarcomatoid and/or rhabdoid differentiation was present in 18%, 70% had prior nephrectomy, 86% were IMDC intermediate/poor risk, 29% and 32% had liver and bone metastasis respectively. 67% received combination treatment in the first line. Comparison of outcomes based on treatment regimen is shown in the table. Conclusions: Antitumor activity was observed with novel combinations in nccRCC which warrants further prospective studies. Response rates and survival with combination therapy in this dataset remain inferior to rates seen in clear cell RCC.[Table: see text]
Immunity to childhood vaccines following high dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) for germ cell tumors (GCT) with comparison to Hodgkin lymphoma (HL).
Authors: Feldman Darren R. , Lewis Akeem Ronell , Knezevic Andrea , Ali David , Bromberg Maria , Aronson Julia , Funt Samuel Aaron , McHugh Deaglan Joseph , Motzer Robert J. , Bajorin Dean F. , Patil Sujata , Shah Gunjan L. , Shah Monika , Seo Susan , Kamboj Mini , Perales Miguel-Angel , Papanicolaou Genofeva
Published: June 2021

5017

Background: HDCT/ASCT represents a curative salvage treatment for patients with GCT but is rarely used for other solid tumors. Patients undergoing HDCT/ASCT for hematologic neoplasms require revaccination for their childhood immunizations. Whether this is necessary in patients with GCT is unknown. Methods: In this prospective longitudinal study, patients with GCT undergoing HDCT-ASCT from 11/2010 to 5/2018 had serologies for Measles, Mumps, Rubella, Diphtheria, Tetanus, Polio, and Varicella Zoster measured before HDCT and at 3, 6, and in a subset, 12+ months after the last HDCT with results at these timepoints compared using descriptive statistics. In addition, titer levels at ≥6 months post-transplant were matched 1:1 for age and gender with HL patients who underwent HDCT/ASCT during the same time period. Immunity was compared between cohorts using the Cochran-Mantel-Haenszel test. Results: Of 80 patients with GCT (median age 30, 84% nonseminoma), 91% received 3 sequential transplants and 68 had repeat titers at ≥6 months. Immunity at baseline was >95% for Diphtheria, Tetanus and Polio and 89% for Varicella Zoster but lower for Measles (74%), Mumps (85%), and Rubella (83%) (Table). Compared to baseline, proportional immunity for all infections was similar at 3, 6, and 12 months post-transplant in the GCT population (≥6 months shown in Table). Matching resulted in 58 GCT-HL pairs. One-year immunity was numerically lower for most infections in the HL vs. GCT patients and significantly decreased for Measles and Rubella (Table). Conclusions: To our knowledge, this is the first study to assess vaccine titers following HDCT/ASCT for GCT. We demonstrate that HDCT/ASCT does not result in loss of immunity to childhood vaccines and that GCT patients retain protective titers more frequently than those with HL. However, 15-31% of GCT patients lack MMR immunity at baseline and at 1-year post-ASCT. Therefore, we recommend checking MMR titers at 1-year post-ASCT with revaccination of those lacking immunity. Titer evaluation and revaccination is not necessary for other childhood immunizations.[Table: see text]
Very late recurrence in germ cell tumor of the testis: Lessons and implications.
Authors: Moore Joseph A , Tidwell Rebecca , Campbell Matthew T , Shah Amishi Yogesh , Zhang Miao , Guo Charles , Ward John Francis , Karam Jose A. , Wood Christopher G. , Logothetis Christopher , Pisters Louis L. , Tu Shi-Ming
Published: June 2021

5030

Background: Up to 30% of patients with germ cell tumor of the testis (TGCT) develop recurrent disease after initial treatment. The majority of recurrences occur in the first 2 years after treatment. Very late recurrence (LR), i.e. > 5 years after initial presentation, occurs in about 1% of patients with TGCT and is associated with poor prognosis. Current guideline does not require follow-up after 5 years to detect LR, except in those presenting with metastatic NSGCT. Methods: We retrospectively reviewed the records of patients from the Genitourinary Medical Oncology clinic at the M. D. Anderson Cancer Center, who developed recurrent disease > 5 years after their initial diagnosis of TGCT. Specifically, we examined the pathology and location of their primary and recurrent tumors, treatments rendered (e.g., surgery, radiotherapy, chemotherapy), and overall survival after LR. Overall survival from the time of LR was estimated using Kaplan-Meier estimates and compared for patient subgroups with log rank tests. Fisher’s exact test was used to compare proportions in patient subgroups. Results: We identified 25 patients who developed LR between July 2007 and August 2020. Age at time of LR: median 46 years (range, 29-61); time of late LR: median 16.1 years (range, 6.8-33.1 years) after diagnosis. Stage at time of diagnosis: I – 5, II-IIIA – 13, IIIB-C – 7. Pathology of primary: nonseminoma with yolk sac tumor or teratoma – 15, nonseminoma without yolk sac tumor or teratoma – 1, not available – 9. Pathology of LR: somatic transformation to carcinoma – 9, somatic transformation to sarcoma – 2, nonseminoma with yolk sac tumor or teratoma – 10, nonseminoma without yolk sac tumor or teratoma – 2, not available – 2. Overall, 5 patients (20%) had LR in retroperitoneum alone, 6 patients (24%) had non-retroperitoneal nodal or pulmonary metastases, and 14 patients (56%) had non-pulmonary visceral metastases. Nine patients (36%) are deceased, ten patients (40%) are alive without evidence of disease (NED), and 6 patients are alive with disease (24%). With a median follow-up of 42 months, 68% of patients are alive 3 years after LR. Patients with prior post-chemotherapy consolidation surgery have longer survival, 80% vs. 53% at 3 years, respectively (p = 0.01). Additionally, at their last follow-up 9/12 vs. 1/13 patients were NED with vs. without prior post-chemotherapy consolidation surgery, respectively (p = 0.001). Conclusions: Patients with LR > 5 years after initial presentation tend to harbor nonseminoma (with yolk sac tumor and or teratoma). Among these patients, a majority who did not undergo surgery to remove residual disease after chemotherapy developed somatic transformation and succumbed to their LR. Further investigation into rates of LR among all patients may be warranted given the poor survival after LR.
Biomarker analysis of phase (Ph) IB trial of radium-223 (Rad) and niraparib (Nira) in patients (Pts) with metastatic castrate-resistant prostate cancer (mCRPC) (NiraRad).
Authors: Yang Eddy Shih-Hsin , Leiby Benjamin , Sonpavde Guru P. , Einstein David Johnson , Quinn Zachary L. , Szmulewitz Russell Zelig , Sartor A. Oliver , Kelly William Kevin
Published: June 2021

5036

Background: Rad is an alpha particle emitter that causes DNA double strand breaks and has been FDA-approved for use in mCRPC pts with bone metastases. PARP-1 activity critically supports androgen receptor (AR) activity in mCRPC and potentiates AR-dependent DNA damage response pathways that promote prostate cancer cell survival. Nira is a potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in mCRPC. We previously reported the safety of targeting the PARP-1/AR axis with Nira in combination with Rad. Herein we describe the results of an exploratory biomarker analysis. Methods: The primary objective of NiraRad is to determine the optimum Ph II dose of Nira plus Rad (55 kBq/kg of body weight IV every 4 weeks (wks) x 6) in pts with and without prior chemotherapy (docetaxel). Pts were enrolled to one of three dose levels of Nira (100, 200, or 300 mg PO daily). All cohorts were combined for exploratory biomarker analysis using Nanostring PanCancer Driver and Immune Pathways panels and the nSolver Advanced analysis module was performed on blood obtained from 23 pts at baseline, cycle (C) 1 day (D) 15, and C3D15. A favorable response was defined as any PSA reduction at week 12 or treatment (tx) duration > 18 wks, the median time on tx in the cohort of pts analyzed. A threshold of > 2 fold (X) differentially expressed genes was used. Results: Of the 23 pts with biomarker data, 7 (30%) experienced PSA reductions and 11 (48%) received tx for > 18 wks, 6 of which also had PSA reductions. Exploratory analysis revealed that the PI3K/Ras, MAPK, and transcriptional misregulation pathways were differentially regulated in pts who had favorable responses. The top downregulated gene, PAX5, which has been shown to promote prostate cancer growth, was decreased at C1D15 (2.7X, p < 0.01) and C3D15 (4.8X, p < 0.001) in pts with tx duration > 18 wks and at baseline in pts who had PSA reductions (3.1X, p < 0.05). Immune pathways analysis suggested downregulation of immunosuppressive B-cell (plasma cell) and upregulation of NK and T cell pathways in pts with tx duration > 18 wks. Conclusions: Previously Nira and Rad have been shown to have acceptable tolerability in mCRPC pts. This exploratory analysis suggests potential response biomarkers that warrant further investigation. Managed by: the Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Pharmaceuticals and Bayer Healthcare Pharmaceuticals, Inc. Clinical trial information: NCT03076203.
Association of plasma tumor DNA (ptDNA) with increased risk of venous thromboembolism (VTE) in metastatic castration resistant prostate cancer patients (mCRPC).
Authors: Conteduca Vincenza , Scarpi Emanuela , Wetterskog Daniel , Ferroni Fabio , Rossi Alice , Romanel Alessandro , Gurioli Giorgia , Bleve Sara , Gianni Caterina , Brighi Nicole , Schepisi Giuseppe , Lolli Cristian , Cortesi Pietro , Barone Domenico , Demichelis Francesca , Paganelli Giovanni , Beltran Himisha , Attard Gerhardt , De Giorgi Ugo
Published: June 2021

5048

Background: Cancer is a risk factor for VTE. In mCRPC, ptDNA is an independent predictor of outcome ( Romanel, Sci Transl Med 2015; Conteduca, Br J Cancer 2020). We firstly aimed to investigate the association between ptDNA and VTE in mCRPC men treated with androgen receptor signaling inhibitors (ARSI) Methods: This prospective biomarker study included mCRPC patients treated with abiraterone and enzalutamide from April 2013 to December 2018. We excluded patients with a previous VTE history and/or ongoing anticoagulation. Targeted next-generation sequencing was performed to determine ptDNA fraction from pre-treatment plasma samples. Assessment of VTE risk based on survival analysis was performed using cumulative incidence function and estimating sub-distributional hazard ratio (SHR) Results: Median age of 180 enrolled patients was 74 years (range 42-90). Of these, 60 (33.3%) were chemotherapy-naive. At a median follow-up of 58 months (range 0.5-111.0), 21 patients experienced VTE (venous thrombosis and/or pulmonary embolism) with a cumulative incidence of VTE at 12 months of 17.1% (95% CI 10.3-23.9). Before starting ARSI, ptDNA fraction above median value of 0.175, presence of visceral metastasis (mets), prior chemotherapy and serum lactate dehydrogenase (LDH) were significantly associated with higher incidence of VTE compared with patients with no thrombosis (12-month estimate, 18.6 vs 3.5%, P=0.0003; 44.4 vs 14.8%, P=0.015; 24.7 vs 4.5%, P=0.006; and 30.0 vs 13.5%, P=0.050, respectively). In the multivariate analysis (Table) including baseline ptDNA level, visceral, liver and lung mets, number of lesions, LDH, high ptDNA fraction was the only independent factor associated with the risk of thrombosis (HR 5.78, 95% confidence interval [CI] 1.63-20.44, P=0.006). All these patients received anticoagulant therapy for VTE. No ARSI discontinuation and VTE-related death were reported, and no significant difference in progression-free/overall survival was observed in mCRPC patients with and without VTE. Conclusions: These results suggest that baseline ptDNA fraction in mCRPC patients treated with ARSI is associated with increased risk of VTE. These patients may be followed up more closely for the risk of VTE and the need for a primary thromboprophylaxis should be taken into account in mCRPC with elevated ptDNA concentration. Validation of these findings in larger multicenter trials is warranted.[Table: see text]
Long-term adverse events (AE) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT).
Authors: Sun Michael , Thomas Charlene , Ho Benedict , Niaz Muhammad Junaid , Molina Ana M. , Sternberg Cora N. , Nanus David M. , Bander Neil Harrison , Tagawa Scott T.
Published: June 2021

5055

Background: PSMA-TRT is a promising investigational treatment for patients with mCRPC. Expected short-term toxicities associated with PSMA-TRT include dose-dependent myelosuppression and xerostomia. However, there is a lack of information regarding long-term effects of PSMA-TRT on marrow, renal, and liver function. Additionally, potential organ dose limits for radiation are derived from studies of external beam radiation, which may not be applicable to TRT. Methods: Men treated on prospective clinical trials of PSMA-TRT, from 2003 through 2020 with at least six months of follow-up were included. Variables included treatment, co-morbidities, baseline and most recent renal, liver, and marrow function, along with respective short-term ( < 6 months) and long-term toxicities. AEs were graded using CTCAE version 5 and attribution was assessed with most recent clinical follow up. Multivariable logistic regression was used to control for type of TRT, comorbidities, and subsequent therapies. Results: 71 (59.7%) patients who received 177Lu-J591, 30 (25.2%) 177Lu-PSMA-617, 11 (9.2%) 225Ac-J591, and 7 (5.9%) 90Y-J591 were included, with median follow up 18 months (range 6-133). Long-term (most recent) laboratory values and AEs are summarized in the table. A majority of AEs were attributed to alternate etiologies. 5 of 14 cases of grade (Gr) ≥2 creatinine increase, 3 of 36 cases of Gr ≥2 platelets, 2 of 14 cases of Gr ≥2 bilirubin, 1 of 15 cases of Gr ≥2 AST increase, and 1 of 5 cases of Gr ≥2 ALT increase were deemed possibly related to PSMA-TRT. Only two Gr ≥3 AEs were attributed to possibly being related to PSMA-TRT: one case of Gr 4 creatinine elevation and one case of Gr 3 ALT elevation. On multivariable analysis, alpha-TRT was associated with hepatic AEs (OR 4.38, p = 0.047), and there was a trend towards higher Charlson Comorbidity scores associating with hematologic AEs (OR 1.27, p = 0.095). Conclusions: This is the largest analysis to-date of long-term AEs in patients who have received PSMA-TRT. Long-term effects on renal, liver, and marrow function are infrequent.[Table: see text]
Impact of androgen deprivation therapy on mortality of prostate cancer patients with COVID-19: A propensity score-based analysis.
Authors: Duarte Mateus Bringel Oliveira , Leal Frederico , Argenton Juliana Luz Passos , Carvalheira Jose Barreto Campello
Published: June 2021

5067

Background: Previous studies suggested that androgen deprivation therapy (ADT) may reduce severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infectivity. However, it is unknown whether there is an association between ADT and a higher survival in prostate cancer patients with COVID-19. Methods: We performed a retrospective analysis of prostate cancer (PC) patients hospitalized to treat COVID-19 in Brazil’s public health system. We compared patients with the active use of ADT versus those with non-active ADT, past use. We constructed propensity score models of patients in active versus non-active use of ADT. All variables were used to derive propensity score estimation, and for the outcome analysis we performed a multivariate backward elimination process to select variables to add to the propensity score model. Results: We analyzed 109 PC patients with COVID-19 that presented past or current use of ADT. In total, 52.8% of our patients were less than 75 years old, 44.0% (48/109) were in active ADT, and most were using a GnRH analog (73%, 35/48). Also, 63.3% of our cohort died from COVID-19. ADT active use were protective factor in our logistic regression model (OR 0.28, 95% CI 0.12–0.66, P = 0.0036). We noticed a significant imbalance in the propensity score of patients in active and those in non-active ADT. Then, when we performed a propensity score-based inverse weight double robust estimation model, we observed that ADT remained statistically associated with improved overall survival (average treatment effect [ATE] -0.26, 95% CI -0.45 to -0.08, P = 0.0058). Conclusions: The active use of ADT was associated with a reduced risk of death in patients with COVID-19.
Retrospective cohort study of estrogen receptor low positive early breast cancer using real world data.
Authors: Bari Shahla , Khong Hung T. , Czerniecki Brian J. , Costa Ricardo L
Published: June 2021

525

Background: Estrogen receptor (ER) positive breast cancer (BC) is a heterogeneous disease, with ongoing debate on the optimal cut off point for clinically relevant ER expression. Tumors harboring ≤10% ER expression are associated with poor outcomes. We used a real-world database to assess prognostic and predictive value of an alternative ER expression cut points. Methods: This retrospective cohort study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). We evaluated the association between ER expression (assessed locally by immunohistochemistry according to ASCO/CAP guidelines) with tumor characteristics, and treatment patterns of patients with early-stage BC (stage I-III) using descriptive statistics. Recurrence free survival and overall survival was defined as time in months from date of surgery until the data of documented cancer recurrence or death respectively. We used Kaplan Myer survival curves to calculate recurrence free (RFS) and overall survival (OS) of patients with ER low, ER intermediate and ER high tumors. To define an alternative ER expression cut point, the data set was divided into 2/3 training and 1/3 test data. A cut point analysis was performed on the training data set to find the optimum cut point of ER+ staining based on correlation with recurrence free survival as the outcome. Results: Among 4,697 ER positive early-stage BC patients, 83 (1.8%) had ER low (ER expression :1-10%) and 36 (0.8%) had ER intermediate BC (11-20%). Median follow up time was 63 months (range 24-84). ER low tumors were associated with higher tumor grade, larger size, and higher axillary tumor burden compared to ER high positive tumors ( > 20% ER expression). African American patients had a higher prevalence of both triple negative and ER low positive BCs compared to ER high tumors- 21%, 22%, and 8% respectively. No significant differences in patient- or tumor-associated characteristics were observed between Low ER and intermediate-ER positive BC patients. Both ER low and intermediate positive tumor patients had survival outcomes similar to patients with TNBC and worse than ER high positive tumors (p < 0.001). No significant correlations between endocrine therapy and RFS or OS were observed among patients with either ER low or intermediate BCs (HR 1.47 and 2.57, p > 0.05; respectively). Sensitivity analysis showed that tumors with ≤ 20% ER expression were associated with worse RFS in both univariate and multivariate analyses (p < 0.05). Conclusions: These findings suggest that patients with ER expression rates ≤ 20% have poor outcomes and derive minimal benefit from endocrine therapies.