bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the COVID-19 pandemic on colorectal cancer (CRC) care: Data from 22 German cancer centers (CC) and the Institute of Pathology, Ruhr-University Bochum - the AIO (Working Group for Internal Oncology of the German Cancer Society) CancerCOVID Consortium - AIO-YMO/KRK 520/ass.
Authors: Lugnier Celine , Foerster Sarah , Kraeft Anna-Lena , Feder Inke Sabine , Christmann Jens , Kourti Eleni , Overheu Oliver , Sommerlatte Sabine , Uhl Waldemar , Schoenlein Martin , Rosery Vivian , Biermann Christoph , Müller Lothar , Schoffer Olaf , Schmitt Jochen , Modest Dominik Paul , Heinemann Volker , Schildmann Jan , Reinacher-Schick Anke C. , Tannapfel Andrea
Published: June 2022

3626

Background: CRC still is one of the leading causes of cancer related death though prognosis has improved through guideline based management. The COVID-19 pandemic lead to re-allocation of resources subordinating all sections of care for CRC patients. We present data on changes of CRC care during the pandemic from 22 German AIO CC and our high volume Institute of Pathology (pathology). Methods: Data was collected retrospectively comparing the months (mo) of the first wave (fw) (4-6/2020) and second wave (sw) (11-12/2020) of the pandemic with corresponding periods (cp) in 2019 focusing on the number of precancerous (ICD-O/0+2) and malignant (ICD-O/3+6) colorectal lesions (CRL) diagnosed by our pathology, the number/stage of primary diagnoses (PD) and the number of surgeries (surg) at AIO CC. There, quality criteria of CRC care were also assessed (number of PD discussed within a multidisciplinary tumor board (tb), received social service (soc)/ psychological (psy) counseling or recruited into a clinical trial). Statistical analysis was performed using students t-test for paired data. Results: Numbers of CRL detected upon histology (row 1-3), number of cases, surg and quality criteria from AIO CC (row 4-9) are displayed in the table. We saw a dip in diagnosed CRL and number of surg (p=0.007) only during fw, whereas PD dipped significantly in both waves. A significant reduction in diagnosis of stage III CRC was detected for 2019 vs. 2020 (p=0.001), not for other stages. Quality criteria showed a significant reduction in clinical trial inclusion, a small dip in soc/psy counseling and persistently high tb presentation. Conclusions: We detected a significant decrease of premalignant lesions and primary cancers during the first year of the pandemic which may impact cancer mortality in the future. Certified German CC provided CRC care with significant reduction in clinical trial inclusion only, suggesting high stability of established certified cancer care infrastructure.[Table: see text]
The first report of K-Umbrella Gastric Cancer Study: An open label, multi-center, randomized, biomarker-integrated trial for second-line treatment of advanced gastric cancer (AGC).
Authors: Rha Sun Young , Lee Choong-kun , Kim Hyo Song , Jung Minkyu , Kim Hyunki , Woo Kyun Bae , Koo Dong-Hoe , Jeung Hei-Cheul , Park Sook Ryun , Hwang In Gyu , Zang Dae Young , Lee Hyun Woo , Park Sejung , Nam Jung Mo , Chung Hyun Cheol Cheol
Published: June 2022

4001

Background: To explore proper agents for AGC patients as 2nd-line treatment based on optimal biomarker, we conducted K-Umbrella GC study with standard of care (SOC) controlled umbrella trial design. Methods: HER2-negative AGC patients from 6 Korean cancer centers were centrally screened for druggable targets by IHC and in situ hybridization. Patients were randomized to the biomarker vs. control group with SOC as 4:1 ratio. In the biomarker group, patients were treated with specific targeted agents in combination with weekly paclitaxel; 1) EGFR 2+/3+ patients for pan-ERBB inhibitor (afatinib; EGFR cohort), 2) PTEN loss/null (H-score <100) patients for PIK3Cβ inhibitor (GSK2636771; PTEN cohort), and 3) PD-L1+, dMMR/MSI-high, or EBV-related cases for anti-PD-1 inhibitor (nivolumab; NIVO cohort). Control group and NONE cohort in biomarker group without predefined biomarkers were treated with SOC (weekly Paclitaxel±Ramucirumab). Primary endpoint was PFS between control and biomarker groups. Secondary endpoints included efficacy and safety of each cohort. Results: Between Feb 2016 and Feb 2021, total 722 patients were centrally screened. 329 patients were enrolled and randomized to control group (n=63) or biomarker group (n=266; EGFR cohort n=67; PTEN cohort n=42; NIVO cohort n=54; NONE cohort n=103). With a median follow-up of 35 months (95%CI 26.1-55.3), median PFS and OS were 3.8 (95%CI 3.2-4.3) and 8.9 (95%CI 7.8-10.1) months for biomarker group and 4.1 (95%CI 3.0-4.8) and 8.7 months (95%CI 7.2-10.2) for control group. In control group, PTEN loss/null was poor prognostic marker; patients with PTEN loss/null (n=12) showed worse survival compared to PTEN intact patients (n=51) (mPFS, 2.8 vs 4.3 months, P=0.03; mOS, 8.7 vs 9.1 months), where other biomarkers showed similar prognosis. Afatinib for EGFR cohort or GSK2636771 for PTEN cohort did not show significant survival benefit compared to control group (Table). Among patients with immune-related biomarkers, addition of nivolumab showed durable survival benefit (mOS 12.0 vs 7.6 months, P=0.08) compared to SOC. Conclusions: Considering the characteristics of umbrella design with multiple biomarkers having different biological roles, biomarker group did not show the improved survival over control arm with these 3 drugs. For optimal biomarker-driven targeted agent applications, NGS-based biomarker driven K-Umbrella GC-2 study is ongoing. Clinical trial information: NCT02951091. [Table: see text]
Distinct biosignatures associate with survival after chemoimmunotherapy in a randomized, three-arm phase II study in patients with metastatic pancreatic cancer.
Authors: Padrón Lacey J. , Maurer Deena M. , O'Hara Mark H. , O'Reilly Eileen Mary , Wolff Robert A. , Wainberg Zev A. , Ko Andrew H. , Fisher George A. , Rahma Osama E. , Lyman Jaclyn P. , Cabanski Christopher R. , Yu Jia , Pfeiffer Shannon M. , Spasic Marko , Hollmann Travis J , Chen Richard , O'Donnell-Tormey Jill , Bucktrout Samantha , LaVallee Theresa , Vonderheide Robert H.
Published: June 2022

4010

Background: Preclinical and small clinical studies of chemoimmunotherapy for metastatic pancreatic ductal adenocarcinoma (mPDAC) point to a yet unrealized potential of clinically significant immune activation. In our phase II study of the CD40 agonist antibody sotigalimab (sotiga) and/or nivolumab (nivo) with gemcitabine and nab-paclitaxel (chemo), we observed promising improvements in overall survival (OS) in 105 patients with newly diagnosed mPDAC (NCT03214250); the primary endpoint of 1-year OS rate was 57.7% (p = 0.006) in the nivo/chemo arm, 48.1% (p = 0.062) in the sotiga/chemo arm and 41.3% (p = 0.233) in the nivo/sotiga/chemo arm (O’Hara, ASCO 2021) as compared to a historical control of 35%. Here, we report results of multi-omic translational analyses designed to identify signatures predictive of OS benefit. Methods: Longitudinal blood and tumor tissue samples were collected for immune and tumor biomarker analysis. Tumor samples underwent RNA sequencing and multiplex immunofluorescence (mIF). Peripheral blood was analyzed by mass cytometry time of flight (CyTOF), high parameter flow cytometry, and proteomics. Machine learning (ML) algorithms were applied to the data to identify biosignatures related to OS in each arm. Results: Comprehensive multi-omic, multi-parameter immune and tumor biomarker analyses identified distinct pretreatment immune signatures predictive of longer OS specific to nivo/chemo or sotiga/chemo (Table, representative examples). Because patients in each arm received chemotherapy, these and other arm-unique biomarkers suggest a relationship to the immunotherapy rather than chemotherapy in this randomized study. There was evidence of immune exhaustion in the sotiga/nivo/chemo arm that may explain the lack of survival benefit. Conclusions: From in-depth translational and ML analyses of randomized phase II trial of first-line chemoimmunotherapy in mPDAC patients, we identified novel biomarkers that associated with OS distinctly in each arm. Clinical trials in first-line mPDAC exploiting these previously unappreciated biomarkers and aiming to enrich patients for response, are warranted to further advance chemoimmunotherapy in this disease. Clinical trial information: NCT03214250. [Table: see text]
A randomized phase Ib/II study of niraparib (nira) plus nivolumab (nivo) or ipilimumab (ipi) in patients (pts) with platinum-sensitive advanced pancreatic cancer (aPDAC).
Authors: Reiss Kim Anna , Mick Rosemarie , Teitelbaum Ursina R. , O'Hara Mark H. , Schneider Charles John , Massa Ryan Campbell , Karasic Thomas Benjamin , Onyiah Chioma , Gosselin Mary Kate , Donze Alyssa , Domchek Susan M. , Vonderheide Robert H.
Published: June 2022

4021

Background: Establishing alternatives to perpetual chemotherapy for pts with aPDAC has been proposed to address inevitable chemotherapy resistance and cumulative toxicity. Poly (ADP ribose) polymerase (PARP) inhibitors have shown clinical efficacy in this setting, and preclinical data suggest that the addition of immune checkpoint blockade (ICB) may offer synergistic tumor control. We performed a randomized, phase Ib/II study of nira plus anti-PD-1 (nivo) or nira plus anti-CTLA-4 (ipi) maintenance for pts with aPDAC who had not progressed after >4 mo of platinum-based therapy. Methods: After discontinuation of chemotherapy, pts were randomized 1:1 to nira 200mg PO daily plus either nivo 240mg IV q2 weeks (later amended to 480mg IV q4 weeks) or ipi 3mg/kg IV q3 weeks for four doses. Nira could be escalated to 300mg PO daily if tolerated. Pts were treated until progression or unacceptable toxicity. The primary endpoint was progression free survival at six months (PFS6) in each arm. Secondary endpoints included safety, OS, ORR, and outcomes by DNA damage repair (DDR) deficiencies. Pts were evaluable for safety if they had received > 1 dose of study treatment and for efficacy if they had also received > 1 follow-up imaging study. Based on historical data, the null hypothesis of PFS6 = 44% vs a 2-sided alternative hypothesis of PFS ≠ 44% was tested. 42 pts per arm provided 81% power for testing at a 5% significance level to detect inferior PFS6 < 27% or superior PFS6 > 61%. Results: As of Oct 2021, 91 pts were enrolled, of whom 84 were evaluable for efficacy (44 nira/nivo; 40 nira/ipi). The median potential follow-up was 23 mos. Most common treatment-related AEs were nira/nivo: thrombocytopenia (28%), arthralgia (25%), nausea (23%), and fatigue (23%) and nira/ipi: thrombocytopenia (45%), anemia (43%), fatigue (43%), nausea, (41%), AST increase (36%), rash (34%) and ALT increase (29%). 88% of AEs were grade 1-2. Efficacy results were: nira/nivo: PFS6 20.6% (95% CI 8.3-32.9, p = 0.0002), mPFS 1.9 mo and nira/ipi: PFS6 59.6% (95% CI 44.3-74.9, p = 0.045), mPFS 8.1 mo. Fifteen pts (8 nira/nivo; 7 nira/ipi) had pathogenic variants in BRCA or PALB2 . Excluding these: mPFS on nira/nivo was 1.9 mo (95% CI 1.8-1.9) and mPFS on nira/ipi was 7.6 mo (95% CI 4.0 – 11.1). Conclusions: In a randomized phase 1B/II study, nira/ipi as maintenance therapy met the primary endpoint of superior PFS6 while nira/nivo yielded inferior PFS6 for pts with aPDAC who had not progressed on first-line platinum-based chemotherapy. The benefit of nira/ipi maintenance persisted in pts without known DDR variants. Clinical trial information: NCT03404960. [Table: see text]
Tandem CAR-T cells targeting CLDN18.2 and NKG2DL for treatment of gastric cancer.
Authors: Xu Hui , Li Weiguang , Lv Huixia , Gu Dongying , Wei Xiaowei , Dai Hong-jiu
Published: June 2022

4030

Background: Gastric cancer (GC) is one of most common malignant tumor which is fifth for melanoma incidence and second for mortality rates worldwide. Novel therapeutic strategies are urgently needed. Recently people are exploring the potential of chimeric antigen receptor T (CAR-T) cell therapy in GC, yet the clinical outcome is limited. Reportedly, the bispecific CAR-T cell with tandem scFvs exhibited superior response rates or synergistic response compared with CAR-T cell with single scFv. It's reported that Claudin18.2 (CLDN18.2) is the most potential target of gastric cancer. Here, we construct a novel bispecific CAR-T cells (KD-496), which simultaneously recognize NKG2D ligands and CLDN18.2, to show superior antitumor efficacy and safety in vitro and in vivo. Methods: Gastric cancer cell lines as well as GC patient tissue samples were evaluated for NKG2DL and CLDN18.2 expression. The KD-496 CAR-T cells showed antigen-specific stimulation by cytokine secretion and tumor cell cytotoxicity assay. The patient tumor tissue fragments (8 mm3) were implanted subcutaneously into B-NDG mice to establish PDX models. When the tumor volume reached 50-100mm3, the mice received a single treatment of 5 million KD-496 CAR-T cells intravenously. The effect of KD-496 CAR-T in vivo was detected by measuring tumor volume twice a week. Results: CLDN18.2 and NKG2DL were detected on NUGC4, AGS-18.2 and MKN-28-18.2 cells and most of screened BM patient samples. The bispecific CAR-T cell KD-496 was generated with CD8 hinge region and transmembrane region, 4-1BB costimulatory region and CD3 zeta region. The KD-496 expression was > 50% on the surface of T cells confirmed by flow cytometry. Co-incubation of KD-496 CAR-T cells with NUGC4 and MKN-28-18.2 cell specifically upregulates IFN-γ cytokines and strongly lysis tumor cells even at low E:T ratio (50-60% at 4:1). Strikingly, KD-496 CAR more efficiently eliminated xenograft tumors in vivo and did not exhibit significant treatment-related toxicity in the treated mice. No obvious pathological changes were found in the tested organs. Conclusions: Our work construct a tandem CAR molecule targeting two tumor-associated antigens, NKG2DL and CLDN18.2, and found that Tan-CAR-T cells（KD-496）distinctly recognize the antigens and exhibited superior antitumor effect. KD-496 CAR-T cells potently respond to GC and more efficient tumor elimination than single CAR such as KD-025 and KD-182 CAR-T cells in PDX model with no obvious safety issue. The results support future clinical trial of KD-496 CAR in patients with GC, where the need for effective treatment is great.
Perioperative ramucirumab in combination with FLOT versus FLOT alone for resectable esophagogastric adenocarcinoma (RAMSES/FLOT7) with high rate of signet cell component: Final results of the multicenter, randomized phase II/III trial of the German AIO and Italian GOIM.
Authors: Goetze Thorsten Oliver , Hofheinz Ralf-Dieter , Schmalenberg Harald , Strumberg Dirk , Goekkurt Eray , Angermeier Stefan , Zander Thomas , Potenberg Jochem , Kopp Hans-Georg , Pink Daniel , Siegler Gabriele Margareta , Schenk Michael , De Vita Ferdinando , Maiello Evaristo , Gaiser Timo , Sookthai Disorn , Brulin Tanita , Pauligk Claudia , Homann Nils , Al-Batran Salah-Eddin
Published: June 2022

4042

Background: Periop. FLOT has become SOC for resectable, esophagogastric adenocarcinoma. However, patient’s outcome is still poor. This trial evaluates the addition of the VEGF-R2 inhibitor ramucirumab (RAM) to FLOT for resectable patients (pts). Methods: This is a prospective, international, randomized, investigator-initiated phase II/III trial. Pts with resectable, Her2-negative, adenocarcinoma of the stomach and GEJ type II and III (≥ cT2 or cN+) were enrolled. Pts were randomized to 4 pre-and post-operative cycles of FLOT (docetaxel 50 mg/m²; oxaliplatin 85 mg/m²; leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2w) alone (Arm A) or the same regimen with RAM 8mg/kg q2w, followed by 16 cycles RAM (Arm B, FLOT-RAM). Important endpoints of phase II (exploratory) were major pathological (complete and nearly complete) response, centrally assessed acc. to Becker criteria, R0-resection rate, overall survival (OS), disease-free survival (DFS) and safety. GEJ type I tumors and pts requiring trans-thoracic esophagectomy were excluded for safety reasons during the conduct of the study. Results: In total, 152 pts were analyzed within the intention to treat population. Baseline characteristics were similar between arms (male, 70%; median age, 60y; cT3/T4, 82%; cN+, 77%; GEJ, 45%). The rate of cancers with signet-ring cell component was at 45%. The FLOT-RAM arm included more unfavorable pts with T4 (8% vs. 5%), impaired ECOG PS of 1 (32% vs. 20%), and concomitant disease (86% vs. 76%). 92% of pts with FLOT as well as with FLOT-RAM completed the 4 pre- cycles. R0-resection could be achieved in 82% of pts with FLOT and 96% of pts with FLOT-RAM (p = 0.0093). The rate of major path response was similar in both arms and was 29% for FLOT and 26% for FLOT-RAM. Median DFS was slightly improved in pts with FLOT-RAM (32 months vs. 21 months), while median OS was similar in both treatment arms (FLOT 45 months, FLOT-RAM 46 months). Surgical morbidity was observed in 32% of pts with FLOT and 41% of pts with FLOT-RAM. Mortality at 60 days after surgery was 4.1% with FLOT and 2.8% with FLOT-RAM. There were bit more G≥3 adverse events with FLOT-RAM (76% vs. 92%). Conclusions: In this phase II trial, the addition of ramucirumab to perioperative FLOT significantly improved R0-resection rates and slightly prolonged DFS without an impact on path response or overall survival. FLOT-RAM is feasible and safe, when type I tumors are excluded. Clinical trial information: NCT02661971.
FOLFOX versus FOLFOX plus nivolumab and ipilimumab administered in parallel or sequentially versus FLOT plus nivolumab administered in parallel in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: A randomized phase 2 trial of the AIO.
Authors: Lorenzen Sylvie , Thuss-Patience Peter C. , Riera Knorrenschild Jorge , Goekkurt Eray , Dechow Tobias Nicolaas , Hofheinz Ralf-Dieter , Luley Kim Barbara , Ettrich Thomas Jens , Pink Daniel , Lindig Udo , Folprecht Gunnar , Schuch Gunter , Bitzer Michael , Bolling Claus , Homann Nils , Junge Sabine , Pauligk Claudia , Gaiser Timo , Goetze Thorsten Oliver , Al-Batran Salah-Eddin
Published: June 2022

4043

Background: FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. The aim of Moonlight trial is to generate signals for whether (a) dual checkpoint inhibition or (b) a triplet chemotherapy is beneficial in the context of nivolumab therapy in this setting. Methods: The AIO-STO-0417 trial (Moonlight) is a four-arm investigator-initiated trial. Pts were randomized to FOLFOX alone (Arm B) or FOLFOX plus nivo 240 mg; q2w and ipilimumab (ipi) 1 mg/kg; q6w administered in parallel (Arm A/A1) or sequentially (Arm A2) or pts were treated in a non-randomized fashion with FLOT plus nivo 240 mg; q2w (Arm C). PD-L1 expression was centrally assessed. Primary endpoint is progression-free survival (PFS). Results: The study completed enrollment with 260 pts. Arms A1/A2 and C started later and will be analyzed in Mar 2022 and presented at the meeting. The abstract, therefore, focuses on Arms A (n = 60) vs B (n = 60). Baseline characteristics were: median age 62.5y, GEJ, 55%, intestinal type, 36%. Forty-one percent had PD-L1 CPS≥1 (available in 79% of pts). Pts received a median of 10 and 9 cycles Arms A and B. Adverse events of grade 3/4 were seen in 86% for Arm A and 60% for Arm B, respectively, and serious adverse events (SAE) in 78% in Arm A and 50% in Arm B. Median follow-up was 9.7 mo. No difference in PFS (5.7 and 6.6 mo), OS (10 vs. 12 mo) or objective response rate (45% and 48%) was seen in Arms A and B, respectively. The results were similar in the PD-L1+ group. Conclusions: FOLFOX plus dual checkpoint inhibition administered in parallel is associated with an increase in toxicity but not activity. This portion of the moonlight trial does not generate a signal for further trials on FOLFOX plus nivo and ipi for adenocarcinoma of stomach and GEJ. Clinical trial information: NCT03647969.
Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer.
Authors: Kwon Minsuk , Kim Seung Tae , Hong Jung Yong , Kim Gahyun , Smith Simon , Mortimer Peter G. , LoembE Bienvenu , Dean Emma , Kang Won Ki , Lee Jeeyun
Published: June 2022

4045

Background: Alterations in DNA damage response (DDR) and repair are associated with genomic instability and increased somatic tumor mutational burden, and modulating DNA repair using specific inhibitors is a promising strategy to boost the efficacy of cancer immunotherapy. Ceralasertib is an oral inhibitor of the serine/threonine protein kinase Ataxia Telangiectasia and Rad3 Related (ATR), which is crucial to the cell’s response to replication stress. Methods: This phase 2 trial was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with advanced gastric cancer (AGC). The study drug regimen was ceralasertib 240 mg BD days 15 to 28 in a 28-day cycle in combination with durvalumab at 1500 mg day 1 every 4 weeks. The primary end point was overall response rate (ORR) by RECIST (v1.1). Exploratory biomarker analysis was performed using fresh tumor biopsies in all enrolled patients. Results: 31 patients (median no. of prior lines, 2; range, 2-5) were enrolled between Jul 2019 and Mar 2020. All enrolled patients had confirmed microsatellite stable tumors, 5 patients were EBV positive, and 24 patients were PD-L1 positive (CPS≥1). Two patients had received prior anti-PD-1 treatment. At the time of data cut-off (Dec 2020), 30 patients were evaluable for response: 7 partial responses (one patient with prior anti-PD-1 treatment), 11 stable disease, and 12 disease progression were observed. The ORR was 22.6%, DCR 58.1 %, median PFS 3.0 months (95% confidence interval (CI), 2.1-3.9), median duration of response 5.7 months (95% CI, 4.9-6.5), and median OS was 6.7 months (95% CI, 3.8-9.6). A subgroup of patients (n = 11) who with loss of ATM expression and/or high proportion of mutational signature attributable to homologous repair deficiency (sig. HRD) demonstrated significantly longer PFS than those (n = 12) who had intact ATM and low sig. HRD (5.60 vs 1.65 months, hazard ratio 0.13, 95% CI 0.045-0.39, long-rank P < 0.001). The most common adverse events of any grade were fatigue (n = 22, 71.0%), nausea (n = 20, 64.5%) and anorexia (n = 19, 61.3%), and the most common adverse events of grade 3 or more were anemia and thrombocytopenia (n = 11, 35.5% each). Conclusions: Ceralasertib in combination with durvalumab demonstrated promising anti-tumor activity with durable responses in refractory AGC. Clinical trial information: NCT03780608.
A biological network approach for mining target genes in EBV-positive gastric cancer.
Authors: Barra Williams Fernandes , Mourao Ronald Matheus da Silva , Silva Jessica Costa , Anaissi Ana Karyssa , Demachki Samia , Ishak Geraldo , Calcagno Danielle Queiroz , Moreira Fabiano Cordeiro , Assumpção Paulo Pimentel
Published: June 2022

4056

Background: Epstein–Barr virus (EBV) discriminates a molecular group of gastric cancer (GC) that seems to have peculiar treatment responses and prognosis. Nevertheless, the gene expression pattern of such tumors needs additional investigations due to the heterogeneity of the tumor microbiome and the small number of studied samples. Biological networks analysis of gene expression patterns, in this complex scenario, might lead to the discovery of putative "hubs" genes, supposed to have important roles in cancer occurrence and consequences. This study aimed to explore the biological value of hub genes in EBV-positive gastric cancer patients. Methods: Fresh tumor samples collected during gastrectomies from individuals with gastric adenocarcinoma (n = 41, 59.0±11.0 years) were included. Gene expression of tumor samples was evaluated in the Illumina sequencing platform. A weighted correlation network analysis (WGCNA) was used to find highly correlated gene patterns. The gene's correlation to EBV status was also explored, including eight EBV positive and 33 EBV negative cases. Gene Ontology (GO) term enrichment was performed to predict the involved biological functions. The expression level of the hubs gene was measured by differential expression analysis. Results: A gene cluster including 636 genes able to discriminate EBV status (ρ = 0.65, p-value = 6e-05) was identified. GO analysis (padj <0.05) showed that this cluster of genes is related to T cell activation, regulation of immune effector process, and response to the biotic stimulus. In this cluster, 54 genes were differentially expressed (log2FoldChange (FC) >1 and padj< 0.05). The top hub genes were LAPTM5, PTPN22, C1QA, CD84, CD53, ADAMDEC1, DPYD, TYROBP, RARRES3, IFI16, CYBB, CMKLR1, PHF21A, GPNMB, and C1QC, according to cluster significance and gene expression level. In positive EBV-GC, all hub genes were overexpressed (FC 1.24 - 2.49) (Table). The average area under the ROC curve (AUC) for hub genes was 0.9 (0.84-0.99). Overexpression of LAPTM5 (p-value = 0.013) and DPYD (p-value =0.0065) and low expression of ADAMDEC1 (p-value = 0.05) were strongly related to poor survival outcome. Conclusions: EBV-positive status was correlated with overexpression of hub genes. Genes found in this investigation have high sensitivity and specificity to discriminate EBV status in GC. Some of them seem to be related to patients' survival, opening an avenue for future scientific explorations in this field. The biological network's approach may be a promising tool for mining target genes for potential clinical applications. [Table: see text]
Comparison of four clinical prognostic scores in patients with advanced gastric and esophageal cancer.
Authors: Ma Lucy Xiaolu , Espin-Garcia Osvaldo , Bach Yvonne , Aoyama Hiroko , Allen Michael J , Wang Xin , Darling Gail Elizabeth , Yeung Jonathan , Swallow Carol Jane , Brar Savtaj Singh , Veit-Haibach Patrick , Kalimuthu Sangeetha , Wong Rebecca KS , Chen Eric Xueyu , O'Kane Grainne M. , Jang Raymond Woo-Jun , Elimova Elena
Published: June 2022

4057

Background: While several clinical scoring systems exist to aid prognostication and patient (pt) selection for clinical trials in oncology, none are standardly used. We compared the ability of four prognostic scores to predict overall survival (OS) in pts with advanced gastric and esophageal (GE) cancer. Methods: Pts with advanced (unresectable or metastatic) GE cancer receiving first-line palliative-intent systemic therapy at the Princess Margaret Cancer Centre from 2007 to 2020 were included. High prognostic risk pts were identified using four scoring systems: Royal Marsden Hospital (RMH), MD Anderson Cancer Centre (MDACC), Gustave Roussy Immune Score (GRIm-S) and MD Anderson Immune Checkpoint Inhibitor (MDA-ICI) score. 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 factors. Harrell’s c-index was used to evaluate predictive discrimination of the models. Time-dependent AUCs were used to measure predictive ability for early death (within 90 days). Results: In total, 451 pts with advanced GE cancer were included. The median age was 59 years, 68% were male, 51% had ECOG status 0-1, 63% presented with de novo metastatic disease. The proportion of pts categorized as high risk was: RMH 25% (N=113), MDACC 13% (N=95), GRIm-S 24% (N=109), MDA-ICI 26% (N=117). In all scoring systems, high risk pts had significantly shorter OS (median OS 7.9 versus 12.2 months for RMH high vs. low risk, p<0.001; 6.8 vs. 11.9 months p<0.001 for MDACC; 5.3 vs. 13 months p<0.001 for GRIm-S; 8.2 vs. 12.2 months p<0.001 for MDA-ICI). On multivariable analysis, each prognostic score was significantly associated with OS (Table). The GRIm-S had the highest predictive discrimination (c-index 0.645 [0.612-0.678]) and highest predictive ability for early death (AUC 0.754 [0.675-0.832]). Conclusions: All four prognostic scoring systems compared had reasonable accuracy in predicting OS for patients with advanced GE cancer. The higher accuracy for predicting early death may render the GRIm-S as preferable. These tools can aid oncologists in discussions about prognosis, therapeutic decision-making and patient selection for clinical trials.[Table: see text]
Outcomes in patients undergoing curative surgery for gastric cancer by facility type and socioeconomic factors: An analysis of the National Cancer Database (NCDB).
Authors: Alqahtani Ali , Dykes Kaitlyn , Yin Chao , Geng Xue , Wang Hongkun , Weinberg Benjamin Adam
Published: June 2022

4066

Background: Surgical and medical treatment for resectable gastric cancer is complex, and multidisciplinary team involvement is essential to provide optimal treatment outcomes. However, socioeconomic disparities influence the quality of medical care patients receive. We hypothesized that facility type, median income, insurance type, and location would impact patients' overall survival (OS). Methods: In a retrospective analysis of NCDB data, we identified patients with stage II and III gastric adenocarcinoma who underwent curative-intent surgical resection and chemotherapy between 2004-2018. Demographic and socioeconomic factors were studied, including treatment facility type, median household income, urban/rural residence, and insurance status. Multivariate Cox proportional hazard model was used to evaluate the impact of these variables on overall survival (OS). The Kaplan-Meier method was used to estimate OS. Log-rank test was used to compare the OS between groups. Results: Based on the criteria listed above, 36,318 patients were identified: 76.3% were Caucasian, 14.4% black, 7.2% Asian, and 2.0% other. 56.4% lived in large metropolitan areas (LM), 29.9% in small/medium metropolitan areas (SM), and 14.2% in rural areas (RA). Patients who were treated in academic/research programs had significantly better OS (mOS 40.5 months) compared to integrated-network cancer programs (mOS 34.0 months, HR 0.897, p < 0.0001), comprehensive community cancer programs (mOS 31.0 months, HR 0.89, p < 0.0001), and community cancer programs (mOS 29.5, HR 0.881, p < 0.0001). Patients from LM had better OS compared to those from SM and RA (mOS 39.0, 32.1, 29.9 months respectively, p < 0.0001). Privately insured patients had improved OS compared to Medicare-insured patients (mOS 40.8 vs 29.7 months, HR 0.758, p < 0.0001). Higher annual income (≥ $63,000) was positively associated with improved OS (p < 0.0001). Conclusions: Outcomes for patients with gastric cancer treated with surgery and chemotherapy are strongly influenced by socioeconomic variables, including place of residence, treatment setting, insurance, and income level. We highlight improved outcomes in patients who resided in LM and were treated at academic/research centers. A potential hypothesis for this trend is increased access to specialized, multidisciplinary care and clinical trials.
Characterization of tumor responses in patients (pts) with unresectable hepatocellular carcinoma (uHCC) treated with lenvatinib in REFLECT.
Authors: Kudo Masatoshi , Qin Shukui , Piscaglia Fabio , Vogel Arndt , Evans T.R. Jeffry , Knox Jennifer J. , López López Carlos , Ramji Zahra , Ren Min , Mody Kalgi , Finn Richard S.
Published: June 2022

4078

Background: In REFLECT, lenvatinib was noninferior to sorafenib based on overall survival in pts with uHCC (median 13.6 vs 12.3 mos; hazard ratio [HR] 0.92, 95% CI 0.79–1.06). The objective response rate (ORR) with lenvatinib was 18.8% by blinded independent imaging review (IIR) per RECIST v1.1; ORR was 40.6% by blinded IIR per mRECIST. Here we further characterize the tumor responses in pts with uHCC who were treated with lenvatinib in REFLECT. Methods: Assessments of ORR included all pts randomly assigned to lenvatinib treatment (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg). Time to first objective response (TTR) and duration of response (DOR) were calculated among pts who achieved a partial or complete tumor response. Tumors were assessed by IIR per RECIST v1.1 or mRECIST. Median DOR was estimated with the Kaplan-Meier product-limit method; 95% CI was estimated with a generalized Brookmeyer and Crowley method. Results: 478 Pts were randomly assigned to receive lenvatinib. Among the 90 pts (18.8%) who achieved an objective response by IIR per RECIST v1.1, median TTR was 2.8 mos (range 1–29) and median DOR was 7.4 mos (95% CI 5.6–9.2). Of the 194 pts who had an objective response by IIR per mRECIST, median TTR was 1.9 mos (range 1–15) and median DOR was 7.3 mos (95% CI 5.6–7.4). ORRs by selected baseline characteristics are reported in the Table. Notably, among responders by IIR per RECIST v1.1 (n=90), median overall survival (by Simon-Makuch method) was 23.4 mos (95% CI 17.6–26.3), median duration of treatment was 10.3 mos, and 65.6% of pts experienced grade ≥3 treatment-related adverse events. Conclusions: Pts with uHCC treated with lenvatinib achieved objective responses with a similar frequency to those seen with single-agent immune checkpoint inhibitors. These responses occurred irrespective of baseline characteristics. Tumor responses occurred early and were durable. Clinical trial information: NCT01761266. [Table: see text]
FGFR2 fusion detection in plasma: A new era in the clinical monitoring of iCCA.
Authors: Gonzalez-Medina Alberto , Verdaguer Helena , Vila-Casadesús Maria , Sierra Alexandre , Castillo Gloria , Fabregat-Franco Carles , Gómez-Rey Marina , Aymar Josep Maria Miquel , Macarulla Teresa , Vivancos Ana
Published: June 2022

4085

Background: Actionable genetic alterations can be identified in over 50% of intrahepatic cholangiocarcinoma (iCCA). Since EMA approved Pemigatinib, a selective Fibroblast growth factor receptor 1-3 (FGFR1-3) inhibitor for the treatment of CCA with FGFR2 fusions or rearrangements, the screening of patients who may benefit from such targeted therapies is especially relevant. In addition, novel FGFR inhibitors that are effective for treatment of resistant mutant clones are under development. In patients with no available tissue for genomic profiling or at different timepoints after targeted therapy, NGS testing of circulating cell-free DNA (ccfDNA) would be the most convenient option. Hence, two important issues must be addressed: i) technical set-up and validation of detection of FGFR2 rearrangements in plasma, and ii) patient shedding in iCCA, in order to consider liquid biopsy for routine clinical care. Methods: We conducted a retrospective study in a cohort of 18 iCCA patients with known FGFR2 fusion or rearrangement events previously identified in tumor FFPE by NGS (FoundationOne CDx test). A custom-designed capture-based NGS panel for use in plasma or tissue (VHIO-iCCA test) was developed to detect FGFR2 rearrangements and other common altered genes in iCCA. After validating our VHIO-iCCA panel with fusion positive FFPE samples, a concordance study was conducted to evaluate the detection of FGFR2 fusion and rearrangements in matched-to-tissue timepoint plasmas. Finally, additional serial plasma samples taken during FGFR inhibitor treatment were also analyzed. Results: From the 18 rearrangement events previously detected with FoundationOne CDx, we were able to identify all 18 in FFPE samples and 15 in the paired plasma using our VHIO-iCCA panel, representing a 100% and 83% concordance, respectively. In the 3 discordant cases, no additional alterations were detected in plasma, indicating a lack of circulating tumor DNA (ctDNA) shedding. Serial sampling of these patients indicated persistent non-shedding. The analysis of fusion allele fraction (FAF) in serial plasma samples revealed that detection of fusion FGFR2 changed during treatment and correlated with best response. In general, patients with a stable FAF showed a SD, while patients which reduced FAF presented a PR. Conclusions: This extremely valuable set of cases has allowed us to validate our VHIO-iCCA panel to be used in tissue and plasma, and to determine that the sensitivity in plasma is >80%, making this a feasible option to avoid tissue biopsies, whenever patients cannot undergo the procedure and even to aid in cancer monitoring. Patient shedding is high in iCCA, yet a fraction of patients may not find a useful resource in liquid biopsy. For those who shed ctDNA, monitoring through the FAF may guide clinical management of iCCA.
Discovery and clinical validation of cost-effective noninvasive early detection of hepatocellular carcinoma (HCC) through circulating tumor DNA (ctDNA) methylation signature.
Authors: Yang Xin-Rong , Liu Rui , Zhou Jian , Fan Jia , Guo De-Zhen , Huang Ao , Wang Yingchao , Cai Zhixiong , Wang Hui , Yang Qichang , Su Zhixi , Ma Chengcheng , Xu Minjie , Li Wei
Published: June 2022

4103

Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, especially in Asian counties. Patients can be treated more effectively if detected earlier, however the current screening strategies with alpha-fetoprotein (AFP) or ultrasound it is largely suboptimal. We aimed to develop non-invasive and cost-effective assay to improve HCC early detection. Methods: HCC-specific DNA methylation markers were screened from tissue and plasma samples through a modified reduce representation bisulfite sequencing assaay,and optimized by a targeted methylation sequencing assay. The most informative markers were then integrated in a multi-locus qPCR assay, HepaQ. Results: Profiling DNA methylation pattern on 61 tissue samples (31 HCC tumor and 30 normal tissues) and 663 plasma samples (276 HCC and 393 control plasma samples) achieved an AUC of 0.99, which corresponds to 91% sensitivity at 94% specificity. The best-performance markers were further screened and analytically verified in additional tissues and plasmas after several rounds of marker selection. A multi-locus qPCR assay, designated as HepaQ, was then developed to incorporate the most effective markers. A cohort of 559 plasma samples including 293 HCC (84% of them at stage 0/A), 60 liver cirrhosis (LC), 36 chronic hepatitis B (CHB) and 170 healthy controls (CTRL), were used to train a classifier for HCC early detection. HepaQ classifier enables to detect 85.3% of HCC under a specificity of 88.3%, 91.7% and 92.4% in LC, CHB and CTRL, respectively. Finally, HepaQ classifier was validated in 374 plasma samples independently collected from multiple clinical centers to confirm its performance of 87.2% sensitivity in HCC and 86.8%,90.5% and 93.4% specificities in LC, CHB and CTRL respectively. Conclusions: We have developed and demonstrated a blood-based ctDNA methylation assay, HepaQ, that can detect early-stage HCC at high sensitivity and specificity. We proposed that HepaQ assay, a cost-effective qPCR assay, has the great potential to benefit the population at-risk for HCC early detection and screening.
A pooled analysis of surufatinib safety from phase 3 trials in advanced NETs.
Authors: Li Jie , Xu Jianming , Shen Lin , Bai Chunmei , Zhou Zhiwei , Li Zhiping , Chi Yihebali , Yu Xianjun , LI Enxiao , Xu Nong , Liu Tianshu , Lou Wenhui , Bai Yuxian , Yuan Xianglin , Wang Xiuwen , Yuan Ying , Chen Jia , Zhang Tao , Xiu Dianrong , Su Weiguo
Published: June 2022

4126

Background: Surufatinib is a small-molecule inhibitor of VEGFR1, 2, & 3, FGFR1, and CSF-1R. Surufatinib demonstrated prolonged PFS and tolerable safety in two phase 3 studies in advanced neuroendocrine tumors (NETs) of pancreatic (SANET-p; NCT02589821) and extrapancreatic (SANET-ep; NCT02588170) origin (Xu, 2020 Lancet Oncology). Detailed outcomes on safety from these 2 studies are reported here as a pooled analysis. Methods: Data is pooled from SANET-p and SANET-ep studies which have similar designs including a 2:1 randomization of surufatinib to placebo in patients ≥18 years with advanced, well differentiated NETs, progressing on or after ≤2 prior therapies. Surufatinib 300 mg or placebo, was administered once daily until disease progression or unacceptable toxicity. Safety outcomes for each pooled treatment group are reported as treatment-emergent adverse events (TEAE) assessed by NCI-CTC 4.03. Patients were included if they had received study treatment during the double-blinded phase of the studies. Results: As of 30th June 2020, 396 patients were assigned to the surufatinib (n = 263) and placebo (n = 133) groups. Median treatment duration was longer with surufatinib 7.4 months (range 0.1–41.4) compared with placebo 4.6 months (range 0.1–39.9). 29% of patients reached more than 12 months of treatment with surufatinib group compared to 11% with placebo. The mean relative dose intensity was 87.56% in the surufatinib group and 97.01% in the placebo group. Most common TEAEs (surufatinib vs placebo) were proteinuria 68.8% vs 54.9%, hypertension 68.4% vs 27.1%, and diarrhea 49% vs 22.6%. Most common grade ≥3 TEAE were hypertension 38.8% vs 13.5%, proteinuria 14.8% vs 0.8% and hypertriglyceridaemia 5.3% vs 0%. Deaths due to TEAEs were comparable between groups 2.7% vs 2.3%. TEAEs led to dose reductions in 43.0% vs 6.8% of patients and dose interruptions in 47.1% vs 29.3% of patients. The majority of patients (83.3% vs 93.2%) were managed without discontinuation because of TEAE. Median onset of proteinuria and hypertension were < 1 month in both groups. Median (range) onset was 0.95 months (0.16–30.36) vs 0.95 months (0.23–16.95) for proteinuria and 0.49 months (0.03–31.18) vs 0.89 months (0.03–14.75) for hypertension. Among patients with hypertension, 59% (n = 111) vs 28% (n = 11) received antihypertensive medication. Conclusions: Surufatinib was generally well tolerated in this pooled analysis and the safety profile was consistent with its previously reported data. The monitoring and management of hypertension and proteinuria are important for patients receiving surufatinib. Clinical trial information: NCT02589821; NCT02588170. [Table: see text]
Landscape of homologous recombination reversion mutations in pancreaticobiliary malignancies.
Authors: Decker Brennan James , Domchek Susan M. , Nathanson Kate , Bailey Shannon , Danziger Natalie , Thornton James , Hartman Mark , Cui Chenming , Yang Lei , Sivakumar Smruthy , Madison Russell , Sokol Ethan , Schrock Alexa Betzig , Yilmazel Bahar , Mata Douglas A , Vietz Christine , Ross Jeffrey S. , Elvin Julia Andrea , Oxnard Geoffrey R. , Reiss Kim Anna
Published: June 2022

4156

Background: Homologous recombination (HR) pathway reversion mutations (REV) are emerging treatment resistance biomarkers for platinum and PARP inhibitor therapy. The wide diversity of REV presents a diagnostic challenge. We implemented an automated computational approach to detect REV and examined the genomic features of REV-positive pancreaticobiliary cancers. Methods: Retrospective study of tissue (n = 31,124) and liquid biopsy (n = 3,870) samples from patients undergoing hybrid-capture comprehensive genomic profiling during routine clinical care 11/2012-03/2021. A proprietary algorithm tested samples for seven distinct REV mechanisms in BRCA1, BRCA2, or PALB2. For subjects with multiple samples, the earliest REV-positive sample was used for downstream analyses. Results: 5.3% (1,866/34,994) of biliary and pancreatic primary tumors harbored one or more pathogenic variants (PV) in BRCA1 (1.4%, n = 499), BRCA2 (3.2%, n = 1,119), or PALB2 (0.81%, n = 282). Among patients with at least one PV in these genes, 2.4% (45/1,866) had REV. The majority of REV involved BRCA2 (82%, 37/45), significantly higher than the proportion of BRCA2 PV in the cohort overall (59%, 1,119/1,900; p = 0.022). The remainder of REV involved either BRCA1 (8.9%, 4/45) or PALB2 (8.9%, 4/45). A total of 63 REV pairs were identified. The most frequent REV mechanism was an exonic non-frameshift deletion completely encompassing a PV (36%, 23/63), followed by a frameshift restoring the reading frame of a pathogenic frameshift (23%, 15/63), a benign missense replacing a PV at the same codon (17%, 11/63), and deletion with intronic breakpoints causing loss of a PV (17%, 11/63). REV were approximately equally prevalent in liquid biopsy (2.8%, 5/178) and tissue samples (2.4% 40/1,688; p = 0.72). A range of 1-9 REV were found per sample (liquid biopsy = 1-9, tissue = 1-2), and liquid biopsy samples had a higher median REV per sample compared to tissue (2.0 vs. 1.0; p < 0.001), as well as a higher prevalence of multiple REV per sample (60% [3/5] vs 7.5% [3/40]; p = 0.013). These differences likely reflect stage of disease and sampling of multiple subclones. Conclusions: Although REV are uncommonly detected in pancreaticobiliary carcinomas, the presence of REV in BRCA2, BRCA1, and PALB2 in patients with pancreaticobiliary neoplasms supports HR as a therapeutic target in these cancers. Diverse REV mechanisms highlight a need for robust detection to incorporate REV in identifying treatment resistance and guiding therapy selection.
Patient-derived explant model of appendiceal cancer.
Authors: Strach Madeleine Cornelia , Yeung Nicole , Lin Hui-Ming , Ansari Nabila , Koh Cherry , Shin Joo-Shik , Kench James , Centenera Margaret , Butler Lisa , Horvath Lisa , Mahon Kate
Published: June 2022

4160

Background: Appendiceal cancers (AC) are rare with 5-year survival of 15% for high grade (HG) adenocarcinomas and 75% for low grade (LG) mucinous neoplasms. There is limited literature on the AC tumour microenvironment (TME) in disease progression and drug resistance. Ex vivo cultures, such as patient derived explants (PDEs), have been used for other solid tumours to test anticancer agents, explore the TME, and are being developed as personalised models. The aim of our study was to develop a PDE model of AC, preserve the TME, study the biological profile of AC and test novel therapies. Methods: Fresh tissue was collected during cytoreductive surgery (CRS) from consenting patients with AC with peritoneal disease, Jul 2020-Mar 2021. Tissues from 10 patients were dissected and cultured as PDEs under varying conditions of tissue size, media, matrix support and duration (Table). Uncultured Day 0 tissues and PDEs were fixed in formalin prior to paraffin embedding (FFPE). Immunohistochemical staining was performed on sections of FFPE tissue to assess viability with antibodies against the tumour marker, Cytokeratin-20 (CK20), and cell death marker, cleaved caspase 3 (CC3). Tissue architecture was rated on a 4-point scale (MS, J-SS). Cancer cells were counted in 6 Day 0 samples and PDEs from 3 patients using QuPath v0.3.2. Apoptotic index (AI) was calculated as the proportion of cells positive for CC3 divided by the number of total CK20 positive cells. Results: The mean proportion of tumour and mucin in the tissues was 3% (0-60%) and 39% (0-95%) respectively. Day 0 samples were viable with mean AI of cancer cells 7% (0-4%). Tissue architecture was maintained, as compared to Day 0 control, for varying sizes of PDE and culture durations up to 4d. More small or medium-sized PDEs had improved architecture compared to large sized PDEs (Table). PDEs at 4d had poorer architecture compared to at 1-3d. There was improved architecture in PDEs using enriched media with support factors compared to base media, and in specimens with matrix support compared to none. The mean AI of PDE cancer cells was 21% (0-92%) and 51% of PDEs had no cancer cell death. Conclusions: This is the first study demonstrating that AC tissue is amenable to ex vivo culture as PDEs. The optimal PDE model was <10mm tissue placed on a gelatine sponge in enriched media for 1-3d. PDEs had preserved tissue architecture and viability compared to uncultured tissue. Protein expression was in keeping with the original tumour. We plan to use this model to test anticancer agents and explore the TME of AC.[Table: see text]