bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 18 isoform 2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.
Authors: Shitara Kohei , Van Cutsem Eric , Lordick Florian , Enzinger Peter C. , Ilson David H. , Shah Manish A. , Xu Rui-Hua , Lonardi Sara , Yamaguchi Kensei , Hung Yi-Ping , Kukielka-Budny Bozena , Bhattacharya Pranob P. , Matsangou Maria , Li Ran , Moran Diarmuid Martin , Ranganath Radhika , Pophale Rupesh , Ajani Jaffer A. 
Published: June 2024

4036 Background: The phase 3 SPOTLIGHT study showed statistically significant improvements in progression-free survival (PFS) and overall survival (OS) with 1L zolbetuximab + modified folinic acid, 5-FU, and oxaliplatin regimen (mFOLFOX6) vs placebo (PBO) + mFOLFOX6 in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma at prespecified interim and later updated analyses. We present the prespecified final OS analysis. Methods: Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (every 3 weeks) + mFOLFOX6 IV (D1, D15, D29) for four 42-day cycles or to PBO + mFOLFOX6; pts without PD continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator’s discretion, until PD or discontinuation criteria were met. The primary endpoint was PFS per RECIST v1.1 by IRC. OS was a key secondary endpoint; additional secondary endpoints were objective response rate (ORR) and safety. Ad hoc analyses examined PFS and OS in per-protocol set population (PPS; pts adherent to protocol) and time to progression (TTP) by best overall response (BOR). Results: At data cutoff (September 8, 2023), 565 pts were assigned to zolbetuximab arm (n = 283) or PBO arm (n = 282). In zolbetuximab vs PBO arms, median follow-up was 18.04 vs 17.91 mo for PFS and 33.28 vs 31.38 mo for OS, respectively. Efficacy results are summarized in Table. Median PFS and OS were significantly longer in zolbetuximab vs PBO arms. Separation of PFS and OS curves occurred earlier in the PPS population analysis (excluded majority of early withdrawals) compared with the ITT population. ORR was similar between treatment arms in ITT and pts with measurable lesions – despite this, TTP for patients with BOR of CR/PR was numerically longer in zolbetuximab vs PBO arms. Safety and tolerability were maintained with no new findings. Conclusions: Zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant and clinically meaningful improvement in PFS and OS vs PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a new standard of care option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma. Clinical trial information: NCT03504397 . [Table: see text]
Real-world data in Japan for the variants in homologous recombination gene on the etiology of gastric cancer in younger and older patients.
Authors: Kono Yoshiyasu , Ozato Toshiki , Horiguchi Shigeru , Tsutsumi Koichiro , Yamamoto Hideki , Hirasawa Akira , Ennishi Daisuke , Tomida Shuta , Toyooka Shinichi , Otsuka Motoyuki 
Published: June 2024

4053 Background: A recent study has reported the roles of Helicobacter pylori infection and germline variants in homologous-recombination (HR) gene as early onset of gastric cancer. However, the prognostic factors and genetic characteristics, especially about the variants in HR gene on the etiology of gastric cancer in younger and older patients, have not been clarified. Methods: We retrospectively analyzed the data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) utilization portal following its policy. Between June 2019 and August 2023, gastric cancer patients who conducted comprehensive cancer profile tests (Foundation One CDx, Foundation One Liquid, and OncoGuide NCC Oncopanel) were divided into patients aged ≤ 40 years (YGC) group and patients aged ≥ 70 years (EGC) group. The frequency of variants in HR gene ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C, RAD51D, RAD51, ATRX, ARID1A, BAP1, CDK12, MRE11, NBN, PTEN, FANCA, and FANCC), the incidence of microsatellite instability-high (MSI-H), the value of tumor mutation burden (TMB), and prognosis were compared between the two groups. Results: There were 81 patients in YGC group and 394 patients in EGC group. The proportion of female patients (63% vs. 25%, P< 0.01) and undifferentiated type cancer (60% vs. 27%, P< 0.01) were significantly higher in YGC group compared with those in EGC group. The frequency of variants in HR gene was higher in EGC group compared with that in YGC group (68% vs. 52%, P< 0.01). The incidence of MSI-H in YGC group was lower than that in EGC group (0% vs. 4.8%, P= 0.055), and the mean value of TMB in YGC group was significantly lower than that in EGC group as well (2.4mut/Mb vs. 7.0mut/Mb, P< 0.01). The median overall survival (OS) in YGC group was significantly shorter than that in EGC group (943 days vs. 1597 days, P < 0.01). Among EGC group, the median OS of patients with positivity of variants in HR gene was significantly longer than that of those without (1728 days vs. 1281 days, P < 0.05). On the other hand, the median OS was not significantly different between patients with positivity of variants in HR gene and those without in YGC group. Conclusions: In the present study, the YGC group had lower incidence of variants in HR gene and MSI-H, and lower value of TMB, compared with those in the EGC group. We estimate that the incidence of MSI-H and the value of TMB caused by the HR-deficiency, which may be linked with prognosis, differs according to the frequencies of the variants in HR gene or according to other factors, such as aging and lifestyle.
Neoadjuvant therapy using PD-1 inhibitor plus chemotherapy with different intervals between chemotherapy cycles for locally advanced gastric or gastroesophageal junction cancer: A randomized phase 2 study.
Authors: Gao Quanli , Zhao Lingdi , Zhao Weijie , Wang Zibing , Qin Peng , Jiang Zhiqiang , Huang Jinxi , Zhang Bin , Li Zhimeng , Fu Qiang , Zhao Yuzhou , Ren Yingkun , Shang Chuang , Wan Xiangbin , Gao Yang , Xu Yongchao , Yuan Long , Lu Chaomin , Li Zhi 
Published: June 2024

4064 Background: To explore the influence of reducing dose-intensity of chemotherapeutic agents by prolonging the interval of chemotherapeutic cycles on clinical efficacy, especially when combined with immune checkpoint inhibitors, we conducted a single-center, prospective, randomized, phase II exploratory study in patients with locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. Methods: Patients were randomly assigned to receive either toripalimab plus FLOT regimen for four biweekly cycles or three triweekly cycles before the operation. The primary endpoint was pathological complete response (pCR) rate, the secondary endpoints were major pathological response (MPR) rate, event-free survival (EFS), and safety. Results: 70 patients were enrolled; of these, 69 were eligible for inclusion. The overall pCR rate was 26.1% and the MPR rate was 55.1%. There were no statistical differences in pCR rates and MPR rates between the two groups. Although no statistical differences were found among the subgroups, the pCR rate for patients with PD-L1 CPS ≥1 was 42.1% (8/19) while 6.7% (1/15) for PD-L1 CPS<1 in the triweekly group ( P=0.047). Analysis of lymphocyte subsets in peripheral blood showed that CD3+CD8+PD-1+Ki-67+ T lymphocyte absolute counts were elevated in triweekly group and reduced in biweekly group before the second and third cycle of therapy. The incidence rates of pyrexia and myelosuppression in the biweekly group were higher than those in the triweekly group. Conclusions: These data support the idea that the efficacy of toripalimab plus FLOT, given triweekly for three cycles, was not inferior to its administration biweekly for four cycles in locally advanced G/GEJ cancer. The finding is particularly significant for those with PD-L1 CPS ≥1 and warrants further validation. Clinical trial information: NCT04891016 .
Safety and feasibility of esophagectomy following neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: Analysis of two phase 2 clinical trials.
Authors: shen dijian , Chen Runzhe , Ji Yongling , Chen Qixun , Chen Ming 
Published: June 2024

4070 Background: Despite the survival benefit of preoperative chemotherapy (CT) or chemoradiotherapy (CRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC), the prognosis remains dismal. With the potential benefit of combining immune checkpoint inhibitors (ICIs) neoadjuvantly, we initiated two phase II single-armed clinical trials to explore the efficacy, feasibility, and safety of esophagectomy following the combination of preoperative PD-1 inhibitor with CT or CRT in ESCC. Methods: A total of 55 patients with histologically confirmed ESCC (clinical stage II-IVA according to the American Joint Committee on Cancer 8th staging system) from two phase 2, single-arm trials underwent neoadjuvant ICIs combined with chemotherapy (nICT) (n=38) (NCT04506138) or chemoradiotherapy (nICRT) (n=17) (NCT03940001) between May 2019 and June 2022 were enrolled. Patients received 2 doses of intravenous PD-1 inhibitor every 3 weeks, combined with 2 cycles of CT or CRT. Data on the pathological complete response (pCR) rates, operative time, blood loss volume, 30-day complications, hospital stay, and 30-day mortality were collected and assessed between these two groups using a multivariable log-binomial regression model to obtain adjusted relative risk ratios. The primary endpoints of the studies were the safety and feasibility of esophagectomy after the combination of preoperative CT or CRT and PD-1 inhibitor. We also evaluated pCR, primary tumor pCR, operation time, postoperative stay, and 30-day mortality. Results: All the included patients successfully completed neoadjuvant therapy. Age, sex, performance status, clinical stage, histologic subtype, procedure type, operative time, and blood loss volume were similar between the two groups. The primary tumor pCR rates were 52.9% in the nICRT group and 21.6% in the nICT group, respectively (p=0.03), while the postoperative pCR rates were 41.2% in the nICRT group and 21.6% in the nICT group, respectively (p=0.19). Minimally invasive surgery was performed in 89.2% (33/37) of the nICT group and 94.1% (16/17) of the nICRT group. The risk of developing pulmonary, anastomotic, or other complications was similar in the two groups. Conclusions: Esophagectomy was safe after the addition of PD-1 inhibitor to preoperative CT or CRT in ESCC neoadjuvant therapies. Follow-up and exploratory endpoints, including biomarker analyses are ongoing. Clinical trial information: NCT03940001 ; NCT04506138 .
Whole transcriptome analysis to reveal epithelial-mesenchymal transition after neoadjuvant therapy with or without additional anti-EGFR treatment: Subgroup analysis of esophageal squamous cell carcinomas of the SAKK 75/08 and the EORTC AIO POWER study.
Authors: Siebenhuener Alexander Rheinhard , Ruhstaller Thomas , Planas-Paz Lara , Mühlberger Katharina , Hayoz Stefanie , Vassella Erik , Van Laarhoven Hanneke W.M. , Thuss-Patience Peter C. , Stahl Michael , Maderer Annett , Moehler Markus H. , Langer Rupert 
Published: June 2024

4071 Background: In localized disease of esophageal squamous cell cancer (ESCC), a trend in higher pathological response rates and longer time to treatment failure was seen by addition of anti-EGFR treatment to radio-chemotherapy (RCTX) compared to RCTX alone (SAKK 75/08 trial and others). On the contrary, the effect of anti-EGFR treatment to chemotherapy (CTX) remains unclear as no survival benefit was detected within advanced patients (EORTC-AIO-POWER study). Since perfect discrimination and selection of subgroups with highest benefit for anti-EGFR treatment (AB) is missing, we investigated the predictive values of whole transcriptomic gene expression analysis (WTGE) applied on biopsy tissue. Methods: 50 pretherapeutic formalin fixed paraffin embedded specimens of ESCC patients from SAKK 75/08 study were analyzed for the effect of RCTX with and without anti-EGFR AB. As well as 26 historic controls of primary resected tumor stage equally distributed ESCC were analyzed. For the advanced setting, we analyzed 28 additional pretherapeutic biopsies and compared groups from CTX to CTX plus AB. The HTG EdgeSeq method was used for NGS-based WTGE. Response to treatment was assessed by histopathological tumor regression in localized disease and clinical courses. Response to treatment in the advanced tumor setting was assessed to the clinical course of stable disease and partial response versus non-responders. Results: Firstly, NGS-based WTGE failed to show significant differences in expression patterns between responding and non-responding ESCC patients, irrespective of treatment protocols and EGFR AB in the localized as well in advanced disease setting. Secondly however, comparison between pre-treatment biopsies and posttreatment residual tumor tissues detected 781 genes that were upregulated and 623 that were downregulated with gene sets associated with muscle processes and epithelial-mesenchymal transition (EMT) in the localized disease. EMT genes were also enriched in residual tumors after neoadjuvant RCTX compared to primary resection in an independent control cohort. Additionally performed immunohistochemical studies showed lower numbers of ZEB-1 positive ESCC in an independent collection of tumors treated by neoadjuvant RCTX compared to primary resection. Conclusions: Our Whole transcriptomic gene expression analyses suggest that EMT is involved in responses to neoadjuvant protocols including EGFR targeting therapies. Targeting EMT may be a molecular pathway to increase complete responses after neoadjuvant RCTX in ESCC.
Multi-region exome sequencing to determine the origin of esophageal spindle-cell squamous cell carcinoma.
Authors: Wang Yulu , Han Li , Li Boyi , Han Yuchen 
Published: June 2024

4072 Background: Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of carcinomatous and sarcomatous components. However, the genomic origin and gene signature of ESS remain unclear. Methods: A total of 24 patients diagnosed with ESS were enrolled from Shanghai Chest Hospital and underwent either radical resection (23/24) or endoscopic submucosal dissection (1/24). Laser-capture microdissection was employed to isolate cancerous and sarcomatous components from tumor and lymph node metastatic tissues. The cancerous components were subsequently microdissected based on morphology. Whole exome sequencing (WES) was conducted on both tumor tissues and paired white cell samples to analyze genomic profiles. Results: The tumor tissue samples of carcinomatous and sarcomatous components showed high mutational commonality. With the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden, paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK-RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. It showed a significant association of CDC27, LRP2, APC, and SNAPC4 mutations with poor prognosis in ESS patients. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. Conclusions: In conclusion, our results regarding to the mutation characteristics of microdissected samples substantiate the monoclonal origin of both the carcinomatous and sarcomatous components of ESS.
Somatic mismatch repair deficiency in pancreas cancer (PC): Immune checkpoint blockade (ICB) outcomes and exploratory genomic analyses.
Authors: O'Connor Catherine A , Harrold Emily , Lin Yun-Te , Walch Henry S. , Gazzo Andrea , Kane Sarah R. , Keane Fergus , Schoenfeld Joshua David , Moss Drew , Suehnholz Sarah Phillips , Chakravarty Debyani , Balogun Fiyinfolu , Varghese Anna M. , Yu Kenneth H. , Kelsen David Paul , Latham Alicia , Weigelt Britta , Park Wungki , Stadler Zsofia Kinga , O'Reilly Eileen M. 
Published: June 2024

4144 Background: Microsatellite instability (MSI-H) occurs in the setting of Lynch syndrome (LS), which is caused by germline pathogenic variants (gPV) in mismatch repair (MMR) genes. The incidence and implications of somatic MMR variants without LS gPV in PC is unknown. We present a large cohort of patients (pts) with somatic only MMR variants and PC, and outline clinico-genomic descriptors, MSI-H prevalence, MMR methylation status, and response to ICB, comparing these features with a LS PC cohort. We also present microsatellite status (MS) orthogonal testing strategies. Methods: Institutional databases queried to identify pts with somatic MMR variants or LS gPVs and PC consented to matched tumor-normal NGS from 2012-2023. Clinico-genomic data abstracted from medical record. MiMSI used to assess MS stable (MSS) and indeterminate (MSI-I) PC. MMR status determined by immunohistochemistry (IHC). Composite MSI-H adjudicated as loss of MMR protein expression by IHC or MSI-H interpretation by MSISensor or MiMSI. Zygosity status assessed with FACETs. Exploratory mutational signature analysis performed on tumor mutation burden-high (TMB-H > 10) tumors with deconstructSigs. MMR methylation analyses underway. Results: N=55/4,626 (1.2%) pts with PC and MMR variant: N=23 somatic MMR variant only (Somatic Cohort) and N=32 LS Cohort. In Somatic Cohort, 10 (43%) MSI-H cases; 6 reclassified as MSI-H by MiMSI (N=2 MSI-I; N=4 MSS). Zygosity status: 11 (48%) biallelic, 11 (48%) monoallelic, 1 (4%) indeterminate. Of 11 monoallelic cases, 3 MSI-H. N=7/14 (50%) evaluable pts had dominant MSI-H mutational signatures. In LS Cohort, 17 (59%) MSI-H cases; 5 reclassified as MSI-H by MiMSI (N=4 MSI-I; N=1 MSS). Zygosity status (N=27 evaluable): 9 (33%) biallelic, 15 (56%) monoallelic, 3 (11%) indeterminate. Of 15 monoallelic cases, 4 MSI-H. N=7/15 (44%) evaluable pts had dominant MSI-H signatures. N=20 pts received ICB (N= 14 LS; N= 6 Somatic Cohort). Median ICB duration: 27.7 months (95% confidence interval (CI) 11.5, -). Overall response rate: 50% in both cohorts; similar duration of response. Conclusions: MSI-H arises due to somatic and germline oncogenesis at similar rates in ~1% of PC. MMR methylation analyses may provide further insight into the mechanisms of MSI-H. Orthogonal MS testing key to inform accurate MS status. MiMSI valuable in classifying low-cellularity specimens. Pts with MSI-H PC treated with ICB derive durable benefit, irrespective of germline or somatic etiology. [Table: see text]
Early-onset appendiceal adenocarcinoma (EOAA): 10-year experience from a single center.
Authors: Gujarathi Rushabh , Belmont Erika , Rodman Christopher , Bansal Varun Vivek , Setia Namrata , Alpert Lindsay , Hart John , Moller Mecker , Eng Oliver S. , Lee Grace , Chin Janet , Amin Manik A. , Polite Blase N. , Liao Chih-Yi , Turaga Kiran , Shergill Ardaman 
Published: June 2024

4178 Background: The incidence of early-onset (age <50) gastrointestinal cancers, including early onset Appendiceal Adenocarcinoma (EOAA) is on the rise, however reported data on etiology, treatment, and outcomes is scarce. Here we present outcomes for EOAA patients treated at a single high-volume center. Methods: Records of patients (pts) with EOAA were reviewed. Clinicopathological and genomic data were abstracted. Pts aged 18 - 49 years at diagnosis with Appendiceal Adenocarcinoma (AA) seen at UCMC between 2013 - 2023 were included. The primary outcome of Overall survival (OS) was analyzed using univariable Cox proportional hazards regression analysis. Results: 116/492 (23.6%) appendix cancer pts seen at UCMC had early-onset disease. 45 pts met eligibility (Table). 10/20 (50%) pts with localized disease had recurrence after hemicolectomy (median recurrence free survival = 41.6 months; 95% CI, 34.3 – NR; follow-up = 46.42 months). 22/44 (50%) pts had mucinous AA, 21 (47.7%) goblet cell AA, and 1 (2.33%) had poorly differentiated AA. In 35 pts with metastatic/recurrent disease, mOS was 35.93 months (95% CI, 28.4 – NR). Lymphovascular (LVI) or perineural invasion (PNI) (HR, 6.41; 95% CI, 2.10 – 19.59, p = 0.001), lymph nodes metastasis (HR, 13.11; 95% CI, 3.53 – 48.68; p < 0.001), and grade 3 disease (vs. grade 1; HR, 5.28; 95% CI, 1.43 – 19.51, p = 0.01) were prognostic for worse OS in univariable analysis. Cytoreductive surgery (CRS), irrespective of completeness, was associated with improved OS (HR = 0.21; 95% CI, 0.09 – 0.53; p < 0.001). Next Generation Sequencing results were available in 20 cases: KRAS (n = 10, 50%), TP53(n = 7, 35%), GNAS (n = 6, 30%), SMAD4 (n = 4, 20%), and MYC (n = 3, 15%) were frequently altered. Alterations with potential therapeutic targets were seen in 12/20 (60%) cases. 10 pts had germline testing with 2 (20%) pathogenic alterations detected: SDHA(H447Mfs*23) and CHEK2 (T367Mfs*15). The pt with CHEK2 mutation had AA as the only malignancy, was the youngest (age 26.17) and passed away 17.26 months after diagnosis. Conclusions: A considerable number of patients with AA may have early-onset disease. A median OS of about 3 years in this young and vulnerable patient population is alarming. As in late-onset disease, EOAA is often incidentally diagnosed. LVI or PNI may be associated with poorer outcomes and deserve additional consideration for risk stratification. Many patients have targetable genomic alterations and should be included in clinical trials where current enrollment is often unsatisfactory for AA. Germline mutation testing in patients with EOAA should be widely implemented. [Table: see text]