bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of cell-free DNA dominant clone allele frequency with poor outcomes in advanced biliary cancers treated with platinum-based chemotherapy.
Authors: Majeed Umair , Uson Junior Pedro Luiz Serrano , Yin Jun , Sonbol Mohamad Bassam , Ahn Daniel H. , Bekaii-Saab Tanios S. , Starr Jason S. , Jones Jeremy C , Inabinett Samantha R , Wylie Natasha , Boyle Ashton WR , Borad Mitesh J. , Mody Kabir 
Published: June 2021

4079 Background: Cell-free circulating tumor DNA (ctDNA) holds significant promise and is being used for clinical decision making in multiple tumors. This study aimed to evaluate the prognostic value of pre-treatment ctDNA in metastatic biliary tract cancers (BTC) treated with platinum based first-line chemotherapy treatment. Methods: We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis we considered the detected gene with highest variant allele frequency (VAF). Results of ctDNA analysis were correlated with patients’ demographics, progression-free survival (PFS) and overall survival (OS). Results: The median age of patients was 67 y/o (27-90). 54 (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma and six gallbladder cancer. 46 (68.6%) of the patients were treated with cisplatin plus gemcitabine, 14 (21%) patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations while 7 (10.4%) patients were treated on a clinical trial with gemcitabine and cisplatin plus additional targeted agents (CX4945 or PEGPH20). TP53, KRAS, APC, FGFR2 and IDH1 were the genes with highest frequency as dominant clone. The median dominant clone allele frequency (DCAF) was 3% (0-97%). DCAF >3% was associated with statistically significant worse PFS (median PFS: 4.05 vs. 7.70 months, p=0.046) and OS (median OS: 10.8 vs. 18.8 months, p=0.056). Each 1% increase in DCAF is associated with a hazard ratio of 26.21 in OS when adjusting for subtypes, age, treatment type, and CA19-9 [Table]. Conclusions: Patients with metastatic BTC with DCAF > 3% at diagnosis have worse PFS and OS compared to patients with low ctDNA when treated with upfront platinum-based chemotherapy.[Table: see text]
A multicenter randomized controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF trial): Analysis of overall survival.
Authors: Kudo Masatoshi , Hasegawa Kiyoshi , Kawaguchi Yoshikuni , Takayama Tadatoshi , Izumi Namiki , Yamanaka Naoki , Shimada Mitsuo , Inomata Masahumi , Kaneko Shuichi , Baba Hideo , Koike Kazuhiko , Omata Masao , Makuuchi Masatoshi , Matsuyama Yutaka , Kokudo Norihiro 
Published: June 2021

4093 Background: The initial report of the multicenter SURF trial (surgery vs. radiofrequency ablation [RFA] for small hepatocellular carcinoma [HCC]) showed that recurrence-free survival (RFS) did not differ significantly between patients undergoing surgery and RFA. The focus of the present report was to assess the effect on overall survival (OS). Methods: The SURF trial was a multicenter, open-label, randomized, controlled, phase 3 trial conducted in 49 institutions in Japan. Patients (aged between 29 and 79 years) with Child-Pugh scores ≤ 7, largest HCC diameter ≤ 3 cm, and ≤ 3 HCC nodules were considered eligible. Before enrollment, both liver surgeons and hepatologists who perform RFA confirm that all the patients can be treated using both surgery and RFA. Patients were then randomly assigned in a 1:1 ratio to undergo surgery or RFA, stratified by age, hepatitis-C virus infection, numbers of HCC, largest HCC diameter, and institution. The co-primary endpoints were RFS and OS. As per the protocol, RFS was reported previously at 3 years after the last accrual of patients. OS was planned at 5 years after the last accrual. This trial is registered in UMIN000001795. Results: During 2009–2015, 308 patients were enrolled. After excluding ineligible patients, the surgery and RFA groups included 150 and 152 patients, respectively. Baseline factors did not differ significantly between the groups. In both groups, 90% of patients had solitary HCC. The median largest HCC diameter was 1.8 cm (interquartile range, 1.5–2.2 cm) in the surgery group and 1.8 cm (interquartile range, 1.5–2.3 cm) in the RFA group. The median (range) follow-up period was 6.4 (0.4–10.8) years in the surgery group and 6.6 (0–10.7) years in the RFA group. OS did not differ significantly between the surgery and RFA groups as the 5-year OS (95% confidence interval [CI]) was 74.6% (66.5%–81.0%) in the surgery group and 70.4% (62.2%–77.3%) in the RFA group (hazard ratio (HR), 0.96; 95% CI, 0.64–1.43; P= 0.828). The analysis after long-term follow-up in the current report showed that RFS was not significantly different between the surgery and RFA groups: the 5-year RFS (95% CI), 54.7% (46.0%–62.5%) vs. 50.5% (42.1%–58.3%); HR 0.90; 95% CI 0.67–1.22; P= 0.498. Conclusions: SURF trial revealed that OS and RFS were not significantly different between patients undergoing surgery and RFA for small HCC (≤ 3 cm and 3 nodules). Clinical trial information: 000001795.
Prognostic impact of pSTAT3 on overall survival (OS) in gastrointestinal (GI) cancers: Data from 3 phase 3, randomized controlled trials (RCTs).
Authors: Brooks Emily , Lebedinsky Claudia , Bekaii-Saab Tanios S. , Shah Manish A. , Jonker Derek J. , Kuchimanchi Kamesh , Wybieralska Ewa , Fontaine Marilyn , Oh Cindy , Sari Suha , Foos Emma , Xu Bo , Hitron Matthew 
Published: June 2021

4147 Background: Retrospective studies of phosphorylated STAT3 (pSTAT3, a regulator of gene expression) in cancer-lineage cells have suggested it is a biomarker of poor prognosis. We analyzed data from 3 phase 3 RCTs (BRIGHTER [T1; NCT02178956], CO.23 [T2; NCT01830621], CanStem111P [T3; NCT02993731]) to evaluate the prognostic impact of pSTAT3 on OS in GI cancer patients (pts). Methods: pSTAT3 was evaluated in archival tumor tissue from pts with gastric or gastroesophageal junction adenocarcinoma (T1), colorectal cancer (T2), or pancreatic cancer (T3) who received standard of care in the control arms (CTL) of their respective trials. pSTAT3 positive (+) or negative (−) status was determined by detecting pSTAT3 in both tumor and tumor microenvironment (TME) cells in a laboratory-developed immunohistochemistry (IHC) assay (T1; T2), later developed into the investigational pSTAT3 IHC D3A7 assay (Agilent Technologies, Inc.) (T3). The positivity cutoff requires a sample have both a TME score of 2 and ≥5% of tumor cells staining positively for pSTAT3. Pre-analytical variables (eg, specimen collection, handling, and processing), tumor indication, and slight differences in the assays used for each study may contribute to relative differences in evaluable rates between studies. In an exploratory analysis, OS was compared in pSTAT3+ vs pSTAT3− pts via an unstratified log-rank test. Results: In each study, intent-to-treat pts with evaluable pSTAT3 results were considered pSTAT3-evaluable. This abstract includes pSTAT3-evaluable pts randomized to the CTL arms (T1: n/N=248/357, 69.5%; T2: n/N=110/144, 76.4%; T3: n/N=243/569, 42.7%). Baseline characteristics are presented in the table. Median (m) OS was shorter in pts with pSTAT3+ tumors across all studies (T1 hazard ratio [HR]=1.32 [95% confidence interval (CI): 1.00, 1.74]; T2 HR=2.40 [1.50, 3.83]; T3 HR=1.08 [0.77, 1.50]). Conclusions: In pSTAT3-evaluable populations from 3 RCTs across GI cancers, CTL pts with pSTAT3+ (vs pSTAT3−) tumors had shorter mOS. These results suggest that pSTAT3 positivity may be a biomarker of poor clinical outcome. Clinical trial information: NCT02178956; NCT01830621; NCT02993731. [Table: see text]
Large cell neuroendocrine carcinoma of the urothelial tract (LNEC): The MSKCC experience.
Authors: Guercio Brendan John , Gandhi Jatin , Teo Min Yuen , Lattanzi Michael , Funt Samuel Aaron , Aggen David Henry , Chen Ying-Bei , Fine Samson , Pietzak Eugene J. , Bochner Bernard H. , Dalbagni Guido , Berger Michael F. , Solit David B. , Tickoo Satish , Reuter Victor E. , Bajorin Dean F. , Rosenberg Jonathan E. , Al-Ahmadie Hikmat A. , Iyer Gopa 
Published: June 2021

4526 Background: LNEC is a rare, poorly characterized entity morphologically resembling small cell NEC of the urothelial tract (SNEC). Methods: Pure and partial LNEC and SNEC cases were identified by histopathologic re-review; clinical outcomes were compared. A subset was sequenced with MSK-IMPACT (279-505 genes). Results: Between 1992-2020, 43 patients (pts) with LNEC were identified (42 bladder, 1 upper tract); 19 (44%) had concomitant SNEC. LNEC cases were compared to 192 SNEC without LNEC (SNEC-only) (Table 1). Compared to SNEC-only pts, LNEC pts experienced longer overall survival (OS), adjusting for age and M0 vs M1 (median OS not reached vs 22.4 months [mos]; HR 0.34, 95% CI 0.16-0.74, p =.006). Neoadjuvant chemo (NAC) use increased over time. Pathologic response rate (<ypT2N0) after NAC was 25% for LNEC and 50% for SNEC-only (p =.13); the ypT0N0 rate was 25% for LNEC and 40% for SNEC-only (p =.52). Perioperative chemo did not improve OS compared to surgery alone in LNEC, adjusting for age and concurrent SNEC (HR 1.46, 95% CI 0.12-17.5, p =.76), but was associated with longer OS among SNEC-only pts (n = 98; HR 0.39, 95% CI 0.22-0.69, p =.001). Two M1 LNEC pts received immunotherapy (IO) in the first-line: 1 atezolizumab, 1 atezolizumab + chemo. Both remained free of progression on IO at a follow-up of 20 and 12 mos, respectively. Of 18 sequenced LNEC tumors, 89% had TERT promoter alterations (alts), similar to 85% seen in 52 SNEC tumors. All LNEC tumors had alts of TP53 or RB1, and 10 (56%) had both. Median tumor mutational burden (TMB) was 14 (IQR 8-38) in LNEC and 30 (IQR 15-55) in SNEC. Epigenetic modifiers were altered in 78% LNEC and 79% SNEC. Two LNEC pts had ERCC2 alts and received platinum chemo; both were alive at last follow-up from NEC diagnosis of 30.7-39.1 mos. Conclusions: LNEC pts experienced longer OS compared to pts with SNEC-only in this cohort, but did not appear more chemo-sensitive. Genomic profiles of LNEC and SNEC-only tumors were similar; TERT promoter mutations suggest a potential urothelial precursor. Further investigation of IO for LNEC is warranted.[Table: see text]
Temporal characteristics of treatment-emergent adverse events and dose modifications with tivozanib and sorafenib in the phase 3 TIVO-3 study of relapsed or refractory mRCC.
Authors: Pal Sumanta K. , McDermott David F. , Escudier Bernard , Hutson Thomas E. , Porta Camillo , Verzoni Elena , Atkins Michael B. , Needle Michael N. , Rini Brian I. 
Published: June 2021

4567 Background: The randomized phase 3 TIVO-3 study met the primary endpoint of improved PFS with tivozanib (TIVO) vs sorafenib (SOR) in patients with relapsed/refractory mRCC with fewer dose reductions, interruptions and discontinuations despite a longer time on therapy. Greater insight into temporal characteristics of treatment-emergent adverse events (TEAEs) may enable proactive supportive care strategies and improve patient experience. Methods: Updated safety from the previously reported TIVO-3 study with a data cutoff August 15, 2019, was analyzed by treatment arm for time-to-onset (TTO, days [d]) of the most commonly reported TEAEs, and TTO of first dose reduction, interruption, and discontinuation occurring with TIVO and SOR. Duration of TEAE (median d and IQ range), and rate of dose reduction, interruption, or discontinuation due to the TEAE was calculated for each arm. Results: Patients in the safety analysis randomly assigned to TIVO (n = 173) or SOR (n = 170) received 11.9 and 6.7 cycles, or 336 and 192 mean days of treatment exposure, respectively. Incidence of any Gr, Gr >3, and TTO of any Gr TEAE of special interest occurring with >20% frequency in either arm is shown in Table 1. While TIVO was associated with less Gr>3 diarrhea, rash and PPE and more HTN than SOR, there were few differences in the TTO or duration of these TEAEs. Overall, dose reductions, interruptions, and discontinuations due to TEAEs were less frequent with TIVO than SOR, and TTO of first dose reduction (85 vs 45 d), interruption (81 vs 50 d), and discontinuation (114 vs 49 d) was longer for TIVO than SOR. Among those experiencing the same TEAE in either arm, resulting dose modifications were less frequent with TIVO than SOR. Conclusions: TIVO-3 demonstrated improved PFS with TIVO compared to SOR in mRCC, with longer duration of TIVO exposure, but fewer all Gr and Gr >3 TEAEs. Temporal characteristics of TEAEs were similar, but time to dose modifications was longer with TIVO than SOR. Among those with the same TEAEs, unmodified treatment was continued more often with TIVO than SOR. Clinical trial information: NCT02627963. [Table: see text]
Immune checkpoint inhibitors (ICI) in advanced sarcomatoid renal cell carcinoma (sRCC): A multicenter study.
Authors: Gopalakrishnan Dharmesh , Collier Katharine , Park Joseph J , Zaemes Jacob P , Lam Elaine Tat , Alaklabi Sabah , Jaeger Ellen , Parikh Rahul Atul , Barata Pedro C. , Kauffman Eric , Atkins Michael B. , Alva Ajjai Shivaram , Yang Yuanquan , George Saby 
Published: June 2021

4568 Background: Advanced sRCC is an aggressive disease with limited responsiveness to chemotherapy and VEGF-targeted therapies. Subgroup analyses from randomized trials showed improved outcomes with ICI, though sample sizes were relatively small. Methods: We conducted a multi-institutional retrospective analysis of consecutive patients (pts) who had RCC with any sarcomatoid component and received systemic therapy for advanced disease. The pts were classified into ICI+ and ICI- groups (gp) based on whether they had received ICI in any treatment line. Overall survival (OS) was measured from the initiation of first systemic therapy. Time to ICI failure (TIF) was defined as the interval from initiation of ICI to subsequent therapy or death. Survival distributions were estimated using the Kaplan-Meier method. Association between covariates and survival was analyzed using multivariate Cox regression. Two-tailed P < 0.05 was considered statistically significant. Results: 203 pts from 6 US academic cancer centers met the inclusion criteria – 155 in ICI+ gp and 48 in ICI- gp. Overall, 137 (67%) pts were male and 181 (89%) were white; median age at mRCC diagnosis was 59.7 (IQR 52.4-67.7) years; 129 (63%) pts presented de novo with distant metastases, 154 (76%) had clear cell (CC) histology, and 182 (90%) had intermediate/poor risk by IMDC criteria. ICI+ had a higher proportion of purely CC tumors (81% vs 64%, P =.02); other demographic and clinical features were similar between the two gps. After a median follow-up of 48.1 (95% CI 40.7-55.5) months (mos), median OS and response rates were significantly higher in the ICI+ gp (Table). OS benefit, compared to ICI-, was maintained in pts who received ICI in ≥ second line (39.6 vs 7.6 mos, HR 0.33, 95% CI 0.22-0.51, log-rank P <.001). TIF was comparable between pts treated with ICI upfront vs in ≥ second line (6.0 vs 5.3 mos, HR 1.27, 95% CI 0.87-1.85, P =.21). On multivariate analysis, ICI- (HR 2.50, 95% CI 1.61-3.88, P <.001), non-CC histology (HR 3.14, 95% CI 1.98-5.00, P <.001) and sarcomatoid component ≥20% (HR 1.92, 95% CI 1.28-2.90, P =.002) were predictive of all-cause mortality. Among pts with non-CC or mixed histology (n=45), ICI+ had higher OS (18.0 vs 5.5 mos, HR 0.20, 95% CI 0.09-0.44, P <.001) and ORR (44% vs 12%, P =.03), compared to ICI-. Conclusions: Treatment with ICI led to markedly higher survival and response rates in advanced sRCC. OS benefit was maintained with ICI in the second line and beyond. Significant benefit was also noted among pts with non-CC or mixed histology sRCC.[Table: see text]
Characterization of the tumor immune microenvironment in clear cell renal cell carcinoma (ccRCC): Prognostic value and therapeutic implications of an M0-macrophage enriched subtype.
Authors: Farha Mark , Vince Randy , Nallandhighal Srinivas , Stangl-Kremser Judith , Goldenthal Steven , Triner Daniel , Morgan Todd Matthew , Palapattu Ganesh S. , Udager Aaron M. , Salami Simpa Samuel 
Published: June 2021

4572 Background: Metastatic clear cell renal cell carcinoma (ccRCC) has a 5-year survival of 12%, but the number of approved immune checkpoint blockade (ICB) agents is growing, necessitating the need to better identify responders. The composition and role of the tumor immune microenvironment (TIME) has yet to be comprehensively characterized in ccRCC. Here, we leveraged a genomic data driven approach to characterize TIME subtypes in ccRCC. Methods: Whole transcriptome data from patients with local and metastatic disease in the Cancer Genome Atlas KIRC (TCGA-KIRC) project was utilized (n = 537). CIBERSORT was used for immune cell deconvolution, and unsupervised hierarchical clustering divided the cohort based on similar immune profiles. Progression free (PFS) and overall (OS) survival of each cluster was analyzed, and Gene Set Enrichment analysis was performed among clusters. The tumor immune dysfunction and exclusion (TIDE) tool, which uses a genomic signature validated on immunotherapy treated melanoma patients to model tumor immune evasion, was then used to predict response to ICB in the TCGA-KIRC clusters. Results: There was a distinct M0hi cluster identified which demonstrated a higher proportion of patients with stage III/IV disease, decreased PFS and OS (Table). Additionally, the M0hi cluster was characterized by lower PD-L1 expression (ANOVA, p = 0.0045) and an enrichment of epithelial to mesenchymal transition (EMT) hallmark genes [Enrichment Score = 0.64, p = 0.001]. The M0hi cluster also showed a higher degree of T-Cell Exclusion (ANOVA, p = 2.2x10-16), predominance of Cancer Associated Fibroblasts (CAFs; ANOVA, p = 2.2x10-16) and Myeloid Derived Suppressor Cells (MDSCs; ANOVA, p = 4.1x10-10). The M0hi cluster had the lowest predicted response to immunotherapy using the TIDE tool (Table). Conclusions: Comprehensive characterization of the TCGA-KIRC cohort led to identification of a distinct cluster of ccRCC defined molecularly by decreased PD-L1 and increased EMT gene expression and cellularly by enrichment of M0 macrophages, CAFs, MDSCs, and an exclusion of T Cells. Patients within this cluster exhibited aggressive disease and poor predicted response to ICB. These findings warrant further validation to identify appropriate therapeutic approaches for this ccRCC subgroup.[Table: see text]
TROP-2 co-expression with androgen receptor splice variants as a new therapeutic target in prostate cancer.
Authors: Stahlfeld Charlotte , Sperger Jamie , Slovin Susan F. , Tagawa Scott T. , Kyriakopoulos Christos , Kohli Manish , Wang Liguo , Wang Liewei , Dehm Scott , Lang Joshua Michael 
Published: June 2021

5060 Background: Tumor-associated calcium signal transducer 2 (TROP-2, TACSTD2) is a transmembrane glycoprotein that is highly expressed in many epithelial cancers. Overexpression of TROP-2 is postulated to mediate cancer cell growth, invasion, and is associated with more aggressive disease. TROP-2 has emerged as a therapeutic target for antibody-drug conjugates in clinical trials including sacituzumab govitecan and DS-1062. Here, we evaluated the expression of TROP-2 in tumor biopsies and circulating tumor cells (CTCs) in men with metastatic castration resistant prostate cancer (mCRPC) to evaluate TROP-2 as a clinically relevant target. Methods: RNA-seq data from the SU2C-PCF database and PROMOTE clinical trial (NCT#01953640) was assessed for TACSTD2 and androgen receptor (AR) splice variant ( AR_V7/AR_V9) expression. Prostate cancer ChIP-seq data was analyzed to identify binding of the AR to the TROP-2 promoter. EpCAM and TROP-2 captured CTCs were isolated from patients with mCRPC using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform and assessed for splice variant, neuroendocrine (NE), and AR-regulated gene signatures, in addition to CTC enumeration and TROP-2 protein expression. Results: TROP-2 expression was detectable in 90% of patients, in both bone and visceral metastatic biopsies (SUC2-PCF). Although TROP-2 low biopsies were infrequent (10%), 58% of these samples showed high levels of NE markers, as compared with 5% in all other patients. In the PROMOTE study, elevated TROP-2 gene expression was significantly higher in biopsies with high AR_V7 expression than in those with low (p = 0.04) or negative (p <.01) AR_V7 expression. ChIP-seq data demonstrated binding of AR at the TROP-2 promoter as well as at a potential enhancer site upstream, suggesting that TROP-2 expression can be regulated by AR activity. Splice variants and NE gene signatures were expressed in CTCs captured with both EpCAM and TROP-2, although markedly different gene expression profiles between EpCAM and TROP-2 CTCs were observed in a subset of patients with neuroendocrine prostate cancer. Detection of AR_V7 from TROP-2 CTCs corresponded to shorter overall survival in 20 patients with mCRPC. TROP-2 protein expression was identified on EpCAM captured CTCs, although patients exhibited a wide degree of both intra- and inter-patient heterogeneity. Conclusions: Our findings demonstrate that TROP-2 is highly expressed in mCRPC, and is reduced in a subset of patient tumors expressing neuroendocrine markers. In the PROMOTE clinical trial with abiraterone acetate, TROP-2 AR variant expression correlated with increased TROP-2 expression. Binding of the AR to the TROP-2 promoter and potential enhancer was observed in prostate cancer cell lines and biopsies. These results indicate TROP-2 is a high value a biomarker and therapeutic target mCRPC.