bluuebunny/crossref_metadata_2025_split huggingface dataset:
KRAS wild-type pancreatic ductal adenocarcinoma: Molecular and therapeutic opportunities.
Authors: Desai Aakash , Walden Daniel , Halfdanarson Thorvardur Ragnar , Alberts Steven R , McWilliams Robert R. , Mahipal Amit , Ahn Daniel H. , Babiker Hani M. , Tella Sri Harsha , McGarrah Patrick Walsh , Kizilbash Sani Haider , Adjei Alex A. , Bekaii-Saab Tanios S. , Ma Wen Wee 
Published: June 2022

4130 Background: KRAS is mutationally activated in over 90% of pancreatic ductal adenocarcinoma (PDAC). Compared to pts with KRAS mutation, KRAS wild-type (wt) PDAC seem to have better response to therapy and may harbor potentially actionable molecular alterations. Here, we analyze the molecular profile and clinical outcome of a cohort of pts with KRAS wt PDAC. Methods: A retrospective review was conducted on pts with PDAC who underwent CLIA-certified Next Generation Sequencing (NGS) testing at Mayo Clinic between December 1, 2018 and December 1, 2021. Pts with KRAS wt PDAC with available reports were included. Their genomic drivers, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcome data were collected. The study was approved by the institutional IRB. Results: Of the 241 eligible pts, 8% (19) has KRAS wt PDAC. Among those, 2 pts had no mutation identified by the gene/molecular panel used. Of the 17 pts (89%) with identified alterations, mutations found in ³ 2 pts were TP53 (53%), CDKN2A (16%) and CDKN2B/ERBB2/PTEN/MSH3/RNF43/FBXW7/KMT2D/GNAS (11% each). Chromosomal rearrangements were identified in 5 (26%): CADPS2-BRAF, GP2-ERBB2, PTPRK-RSPO3, EML4-NTRK3 and TFG-MET. RNA expression results were available in 12 pts: common overexpression were ERBB2 (27%) and MET/NRAS/MYC/CCDN1/CCNE1/AR (18% each); and the under-expression MGMT (18%). Among the 13 pts with available MSI status via NGS, 2 (11%) were MSI-high (both had high TMB [28.4 and 23.7 m/MB]) while all others were TMB < 10 m/MB. The median age at diagnosis was 61 years (68% males). 8/19 (42%) were Stage IV at diagnosis with 15/19 (79%) pts ultimately diagnosed with metastatic disease. Among metastatic pts, median lines of treatment received was 2.5 (range:0-4). 4 pts received FOLFIRINOX (FFX), 2 gemcitabine/ nab-paclitaxel (GP) and tumor response were comparable to previously reported results. 1 received 1st-line pembrolizumab and remained on therapy at the time of analysis. The median length of follow up from diagnosis was 29 months. A patient with TFG-MET re-arrangement previously progressed on FFX and GP was treated using a MET inhibitor, and achieved significant CA19-9 drop and pancreas tumor shrinkage at 1st restaging, with ongoing response. Conclusions: The molecular profile of KRAS wt PDAC is highly heterogeneous and difficult to generalize. Novel approaches (e.g., basket trials) are needed to develop therapy for this rare PDAC subgroup.
Comparison of systematic inflammatory prognostic scores in patients with advanced pancreatic adenocarcinoma.
Authors: Ma Lucy Xiaolu , Espin-Garcia Osvaldo , Wang Yifan , Allen Michael J , Jang Gun Ho , Zhang Amy , Dodd Anna , Ramotar Stephanie , Hutchinson Shawn , Tehfe Mustapha , Ramjeesingh Ravi , Biagi James Joseph , Wilson Julie , Notta Faiyaz , Fischer Sandra , Zogopoulos George , Gallinger Steven , Grant Robert C. , Knox Jennifer J. , O'Kane Grainne M. 
Published: June 2022

4149 Background: Systemic inflammatory scores have been developed as tools to aid clinicians in prognostication and patient (pt) selection for clinical trials. We compared the accuracy of five prognostic scores to predict overall survival (OS) in pts with advanced pancreatic adenocarcinoma (PDAC). Methods: Pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657) from 2015 to 2020 were included. All pts had biopsies for whole genome and RNA sequencing prior to standard first-line chemotherapy in the advanced setting. Prognostic risk was calculated using: neutrophil-to-lymphocyte ratio (NLR; >5 = high), platelet-to-lymphocyte ratio (PLR; > 150 = high), Prognostic Nutritional Index (PNI = albumin + 5 x lymphocytes. PNI < 45 = high risk), Gustave Roussy Immune Score (GRIm-S; NLR>6 = 1 point, albumin <35 = 1 point, LDH > upper limit of normal [ULN] = 1 point. GRIm-S ≥2 = high risk), and Memorial Sloan Kettering Prognostic Score (MPS; NLR >4 and albumin < 40 = high risk). OS was estimated using the Kaplan-Meier method and compared between risk groups (high vs. not-high) for each scoring system using the log-rank test. Cox proportional hazards models were used to analyze the association between each prognostic score and OS, adjusting for baseline clinical and genomic factors. Results: In total, 263 pts with advanced PDAC cancer were included, with median follow up of 32.9 (95% CI 15.9-64.2) months. Median OS in the intention to treat population was 9.3 months (95% CI 8-10.2). PLR and PNI were not prognostic. High risk NLR (N=85, 32%), GRIm-S (N=47, 18%) and MPS (N=46, 17%) identified pts with poor prognosis. The GRIm-S and MPS were most significant: median OS in high vs low risk pts 6.4 vs. 10 months p<0.001 (GRIm-S) and 6.3 vs. 10 months p=0.002 (MPS). On multivariable analyses, high risk NLR, GRIm-Score and MPS were each associated with poor OS after adjusting for baseline clinical and genomic factors (Table). For all models, ECOG ≥1 (N=165, 63%); the basal-like Moffitt RNA subtype (N=49, 20% vs 80% classical) and low HRDetect scores (N=31, 13%) were significantly associated with poor OS. However these scores did not associate with RNA based classifiers or HRD scores and can therefore provide additional prognostic information. Conclusions: Both the GRIm-S and MPS are highly prognostic in PDAC and are scores easily used in the clinical setting and may help in clinical trial selection. Genotypic correlates are being explored.[Table: see text]
Neoadjuvant chemotherapy is associated with improved outcomes in patients with stage 1A and 1B pancreatic cancer undergoing surgery: An NCDB study.
Authors: Rozich Noah , Singh Maharaj , Kriley Isaac , Weese James L. , FACS Aaron Chevinsky , Papenfuss Wesley Allan , Bellini Geoffrey 
Published: June 2022

4157 Background: The use of neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC) has shown clear advantages in locally advanced and borderline resectable disease. The benefit in upfront resectable PDAC is debated. Moreover, in early clinical stages IA/IB, potential benefits including improved R0 resection rate, decreased tumor upstaging, and survival, are not clear. We hypothesize that NAC will be associated with improved outcomes and survival compared to adjuvant therapy in patients with clinical stage IA/IB PDAC. Methods: The National Cancer Database (NCDB) PUFs (2004-2017) were used to perform a retrospective review of patients with clinical stage IA or IB PDAC undergoing surgery. Treatment groups were selected based on timing of chemotherapy. Patients receiving chemotherapy or surgery alone were excluded. Results: We identified 6,613 patients with clinical stage IA or IB PDAC who underwent surgery. The neoadjuvant therapy group (NAT) included 1,533 patients who received neoadjuvant or perioperative chemotherapy, and the adjuvant therapy group (AT) contained 5080 patients who received chemotherapy after surgery. Patients in the NAT had higher rates of T1 and T2 disease and lower rates of T3 pathology compared to the AT (pT1: 18.7% vs 7.8%; pT2: 20.1 vs 18.6%; pT3: 59.3% vs 72.1%, p<0.0001). Additionally, the NAT had significantly higher rates of N0 disease and less N1 pathology (pN0: 54.6% vs 37.5%; pN1: 45.4% vs 62.5%, p<0.0001). The R0 resection rate was higher in the NAT (83.2% vs 62.3%, p=0.0197) and there was less lymphovascular invasion (LVI) compared to the AT (34.8% vs 48.1%, p<0.0001). Using Kaplan Meier estimates, the NAT was associated with improved overall survival (OS) compared to the AT (median OS: 33.4 vs 27.5 months, p<0.0001). On multivariable analysis, R0 resection (HR=0.715, CI: 0.619-0.825, p<0.0001), LVI (HR=1.126, 95% CI: 1.038-1.222, p=0.0043) but not receipt of NAC (HR=0.94, 95% CI: 0.852-1.038, p=0.2229) were independent risk factors for OS. Conclusions: NAC is beneficial in patients with stage IA/IB PDAC undergoing surgical resection as it is associated with improved oncologic outcomes including increased R0 resection rate, decreased tumor upstaging, lymph node metastasis, and LVI. Furthermore, patients receiving NAC were found to have improved survival over those getting adjuvant therapy. Based on these results, we recommend all patients diagnosed with PDAC be considered for NAC prior to surgery. [Table: see text]
Association between depth of response (DepOR) and clinical outcomes: Exploratory analysis in patients with previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 9ER.
Authors: Suárez Cristina , Choueiri Toni K. , Burotto Mauricio , Powles Thomas , Bourlon Maria Teresa , Shah Amishi Yogesh , Tomita Yoshihiko , Bedke Jens , Zhang Joshua , Simsek Burcin , Scheffold Christian , Escudier Bernard , Motzer Robert J. , Apolo Andrea B. 
Published: June 2022

4501 Background: Among patients (pts) with untreated aRCC in the CheckMate 9ER trial, superior progression-free survival (PFS; hazard ratio [HR], 0.56) and overall survival (OS; HR, 0.70) were maintained, and objective response and complete response (CR) rates were doubled for nivolumab plus cabozantinib (N+C) vs sunitinib (SUN) with extended 25.4 mo minimum (32.9 mo median) follow-up. This exploratory analysis evaluated the relationship between DepOR and clinical outcomes in CheckMate 9ER. Methods: Eligible pts received N (240 mg) every 2 weeks plus C (40 mg) once daily or SUN (50 mg once daily; 4 weeks of each 6-week cycle). In this analysis, DepOR subgroups were based on best overall response (blinded independent central review [BICR] per RECIST v1.1) and best tumor reduction threshold, as follows: CR; partial response subdivided by a tumor reduction of ≥80%–<100% (PR1); ≥60%–<80% (PR2); or ≥30%–<60% (PR3); stable disease (SD); and progressive disease (PD). PFS (per BICR) and OS by DepOR subgroups were analyzed after a 6-mo post-randomization landmark. Treatment-related adverse events (TRAEs) were assessed in DepOR subgroups. Results: Of 323 and 328 pts randomized to N+C or SUN, 236 and 157 pts were progression-free and alive and 293 and 253 pts were alive at the 6-mo landmark and were categorized by DepOR subgroup. Overall, greater proportions of pts receiving N+C had deeper responses vs SUN (CR, PR1, PR2; Table). Deeper responses with N+C were associated with improved 12-mo PFS rate vs SUN for CR (94.9% vs 82.4%), PR1 (81.3% vs 37.5%), and PR2 (72.1% vs 53.2%). In both arms, increasingly deeper response led to better OS outcome; yet OS rates and medians were comparable between arms for CR, PR1, PR2, and PR3 (Table). No meaningful patterns for overall TRAE rates by DepOR subgroup were identified in either arm. Conclusions: In CheckMate 9ER, more pts receiving N+C achieved deeper responses vs SUN. Deeper responses were generally associated with improved PFS and OS. Clinical trial information: NCT03141177. [Table: see text]
Association between decline of neutrophil-to-eosinophil ratio (NER) at week 6 after ipilimumab plus nivolumab initiation and improved clinical outcomes in metastatic renal cell carcinoma (mRCC).
Authors: Chen Yu-Wei , Tucker Matthew D , Brown Landon Carter , Yasin Hesham Abdallah , Ancell Kristin Kathleen , Armstrong Andrew J. , Beckermann Katy , Davis Nancy B. , Harrison Michael Roger , Kaiser Elizabeth , McAlister Renee , Schaffer Kerry , Wallace Deborah , George Daniel J. , Rathmell Wendy Kimryn , Rini Brian I. , Zhang Tian 
Published: June 2022

4527 Background: Low baseline NER has been associated with improved response to immunotherapy in mRCC (PMID:34732251). The current study aimed to investigate the early decline of NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. Methods: Retrospective chart review of ipi/nivo-treated mRCC patients at Vanderbilt-Ingram Cancer Center and Duke Cancer Institute was conducted. Landmark analysis at week 6 after ipi/nivo initiation was performed to assess the association between change in NER and clinical responses [progression-free survival (PFS)/overall survival (OS)]. Results: There were 150 mRCC patients included in the analysis: 78% had clear cell histology, 78% were IMDC intermediate/poor risk, and 74% were male. The median follow-up time was 11.9 months. After ipi/nivo initiation, the median NER decreased from 23.8 (interquartile range: 15.0-57.1) at baseline to 19.8 (10.6-40.8) at week 6; 102 (68%) patients had decreased NER. The NER at week 6 was grouped by percent change (≥ 50% decrease vs <50% decrease vs increase). In multivariable regression analysis after adjustment for age, sex, race, IMDC risk group, baseline NER, histology, prior systemic therapy, and prior nephrectomy (Table), decreased NER ≥ 50% was associated with improved PFS [adjusted hazard ratio (AHR): 0.55, p-value: 0.03] and OS (AHR: 0.38, p-value: 0.02) (Table). Stratified analysis was conducted by baseline NER [≥vs < baseline median NER (23.8)]: decreased NER ≥ 50% was associated with improved PFS (AHR: 0.46, p-value: 0.048) and OS (AHR: 0.29, p-value: 0.01) in the subgroup with high baseline NER. These associations were not observed in the subgroup with low baseline NER (p-value for PFS: 0.25; p-value for OS: 0.61). Conclusions: The decline of NER ≥50% at week 6 after ipi/nivo initiation was associated with improved PFS/OS in mRCC patients with high baseline NER. Prospective studies are warranted to validate NER change as a biomarker to predict response to ICIs in mRCC. [Table: see text]
Sequential immunotherapy in rare variant renal cell carcinomafinal report of UNISoN (ANZUP 1602): Nivolumab then ipilimumab + nivolumab in advanced nonclear cell renal cell carcinoma.
Authors: Conduit Ciara , Kichenadasse Ganessan , Harris Carole A. , Gurney Howard , Ferguson Tom , Parnis Francis , Goh Jeffrey C. , Morris Michelle Frances , Underhill Craig , Pook David William , Davis Ian D. , Roncolato Felicia , Harrison Michelle L. , Begbie Stephen , Joshua Anthony M. , Link Emma , Hovey Elizabeth J. , Gedye Craig ,   The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2022

4537 Background: Immune checkpoint immunotherapy (ICI) is active against many cancers. Many people are failed by PD1 inhibition alone, but not all patients benefit, nor require combination ICI treatment. UNISoN (NCT03177239) previously reported outcomes in people with non-clear cell renal cell carcinoma (nccRCC) receiving nivolumab (N) monotherapy, and N plus ipilimumab (I) in those whose cancers progressed after N alone. We present the final planned report. Methods: Population, Intervention, Analysis: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1) received N 240mg q2w alone (Part 1). Those with cancers refractory to N at 3 months were offered combination I (1mg/kg) + N (3mg/kg) q3w for up to 4 doses, followed by N 240mg q2w for a maximum total of 12 months of N (Part 2). UNISoN was powered to identify a clinically-relevant objective tumor response rate (OTRR) of 30% (assuming 15% was not relevant) among people receiving I+N in Part 2. Results: 85 pts with a representative spectrum of nccRCC histologies were enrolled and received N. Amongst the total population enrolled to UNISoN Part 1/2, mOS was 24 (16-28) months and 12m OS was 65% (54%-74%); of those proceeding to Part 2, the mOS was 10 (6-17) months only. Overall, 17% (10%-27%; 14/83) and 10% (3%-23%; 4/41) of pts experienced a response from N alone or I+N, respectively. 41 pts refractory to N received I+N. Overall in Part 2, the median time on treatment was 2.1 (95% CI 1.8, 2.8) months, the median number of cycles was 3; median follow-up at final analysis was 22 (16-30) months. In this population, the median PFS was 2.6 (2.2-3.8) months and 12m PFS was 11% (4%-23%). 13% (7%-22%) of patients were free of progression or death at 24 months. The primary endpoint was not met; only 80% of pts failed by N were assessable for response in Part 2. Overall tumor responses from N alone or I+N were more common in pts with papillary histology; pts with chromophobe histology had poor outcomes. No late toxicity safety signals were observed. Conclusions: Some pts with nccRCC benefit from N alone, or addition of I when disease is inadequately controlled by N alone, however most pts have limited benefit from ICI. More effective therapeutic options are needed for the majority of people with rare variant renal cell carcinomas. Novel markers of response are required to more rapidly predict pts who will progress on N. Translational research to identify predictive biomarkers of response is ongoing. Clinical trial information: NCT03177239.
Molecular characterization of the tumor microenvironment in chromophobe renal cell carcinoma (ChRCC) and related oncocytic neoplasms.
Authors: Labaki Chris , Zhang Long , Hou Yue , Bi Kevin , Hobeika Charbel , Bakouny Ziad , Camp Sabrina Yvonne , Priolo Carmen , Khabibullin Damir , Schindler Nicholas , Alchoueiry Michel , Denize Thomas , Saliby Renee Maria , Matar Sayed , Signoretti Sabina , Van Allen Eliezer Mendel , Shukla Sachet A. , Braun David A. , Henske Elizabeth , Choueiri Toni K. 
Published: June 2022

4549 Background: ChRCC represents about 5% of all kidney cancer and has a dismal prognosis in the metastatic setting, with limited response to immune checkpoint inhibitors (ICI) and targeted therapy. We evaluated the molecular properties of ChRCC and related oncocytic neoplasms to define the tumor immune microenvironment and identify potential therapeutic strategies. Methods: ChRCC, renal oncocytoma (RO) and low-grade oncocytic tumor (LOT) samples with matched normal kidney specimens were evaluated using single-cell RNA sequencing (scRNA-seq) and single-cell T-cell receptor sequencing (scTCR-seq). T-cell antigenic specificities from scTCR-seq were inferred using a comprehensive database of annotated T-cell receptor sequences (VDJdb). The infiltration of CD45+ immune cells in renal oncocytic tumors and ccRCC samples was quantified using immunohistochemistry (IHC). Bulk RNA-sequencing (RNA-seq) data of clear cell RCC (ccRCC) and ChRCC were further analyzed using The Cancer Genome Atlas (TCGA) KIRC and KICH cohorts, respectively, with immune cell fractions calculated using CIBERSORTx. Results: After quality-control, 46,817 cells from 5 tumor (ChRCC: n = 3, RO: n = 1 and LOT: n = 1) and 4 normal samples were isolated for scRNA-seq analysis. Renal oncocytic tumors (ChRCC, RO, and LOT) had a low density of CD45+ cells (mean: 739 ± 114 cells/mm2; n = 5) compared to ccRCC (mean: 3,420 ± 1,979 cells/mm2; n = 5) (p < 0.05). Across all tumors, CD8+ T-cell clusters displayed a low expression of immune exhaustion markers (i.e. PDCD1 [PD-1], CTLA4, LAG3, HAVCR2 [TIM-3], and TIGIT). Analysis of TCGA bulk RNA-seq data after adjustment for CD8 T-cell fraction showed no difference in the expression of most immune exhaustion markers (i.e. PDCD1, CTLA4, LAG3) in ChRCC compared to normal samples (p > 0.05), contrasting with a substantially higher expression in ccRCC versus normal kidney (p < 0.05). Analysis of the T-cell repertoire (scTCR-seq) of ChRCC, RO and LOT samples did not identify a pattern of clonal expansion, and a considerable proportion of clonotypes were inferred to have specificity for viral antigens (range: 1.3 to 34.4% among all samples; 11.3 to 34.4% after filtering out two samples with a low ( < 300) number of T-cells). Conclusions: Renal oncocytic tumors, including ChRCC, exhibit a low infiltration of immune cells, a non-exhausted immune phenotype and, a lack of clonally expanded tumor-specific T-cells. These findings may partially explain the molecular basis for the lack of response to ICIs in advanced ChRCC and outline the unique exhaustion phenotype of renal oncocytic tumors.
Association between molecular subtype membership or hypoxia-associated gene expression signatures and clinical outcomes in the CALGB 90601 (Alliance) phase 3 clinical trial of gemcitabine and cisplatin (GC) plus bevacizumab (B) or placebo (P).
Authors: McConkey David James , Choi Woonyoung , Halabi Susan , Luo Bin , Al-Ahmadie Hikmat A. , Rosenberg Jonathan E. , Mountain Jack , Regazzi Ashley Marie , Fong Megan , Iyer Gopa , Van Allen Eliezer Mendel , Mouw Kent William , Wen Yujia , McCart Linda , Ballman Karla V. , Beltran Himisha , Morris Michael J. 
Published: June 2022

4562 Background: Our previous work showed that basal tumors were associated with the best clinical outcomes in a Phase 2 clinical trial of neoadjuvant dose-dense MVAC plus B, and in other work we showed that basal tumors were enriched with hypoxia-associated gene expression signatures. Here we attempted to validate these findings in the C90601 Phase 3 clinical trial of GC plus B versus GC plus P. Methods: Whole transcriptome RNAseq was performed on all available tumors using Ion Torrent’s Ampliseq platform (n = 189). Tumors were assigned to molecular subtypes using 3 different classifiers - BASE47 (k=2), MDA oneNN (k=3), and the Consensus classifier (k=6). Tumor hypoxia signature enrichment was determined using 2 different gene expression signatures and gene set variation analysis (GSVA). The proportional hazards model was used to correlate molecular subtype calls and hypoxia signature enrichment with overall survival (OS) and progression-free survival (PFS) adjusting for stratification factors and treatment arm (for PFS). Results: The median OS & PFS by different signatures and the hazard ratios (HR) are presented in the Table. Conclusions: Predefined signatures associated with clinical benefit in the Phase-2 neoadjuvant clinical trial were not associated with benefit in C90601. Possible explanations include the lack of strong therapeutic effects of the treatments, potential heterogeneity (“subtype plasticity”) between the profiled tissue samples and the metastatic lesions under treatment pressure, and differences in biology associated with the disease states (muscle-invasive vs advanced/metastatic disease). Support: U10CA180821, U10CA180882, Department of Defense (CA160312), Genentech; ClinicalTrials.gov Identifier: NCT00942331. [Table: see text]