bluuebunny/crossref_metadata_2025 huggingface dataset:
PD1 and CD39 expression on tumor infiltrating lymphocytes in patients with gastric cancer.
Authors: Okayama Takafumi , Tsukamoto Nobuo , Suzuki Toshihiro , Mochizuki Kiyotaka , Sano Junichi , Nagata Hiromi , Terajima Daiki , Habu Takumi , Yoshida Mitsumasa , Sato Kazuma , Fujiwara Naoto , Yura Masahiro , Fujita Takeo , Shimomura Manami , Oonuki Kazunobu , Fukuda Kyoko , Uemura Yasushi , Nakatsura Tetsuya , Kinoshita Takahiro
Published: January 2024

377

Background: Activation and clonal expansion of tumor antigen-specific T cells in cancer patients are crucial for immunotherapies. Recent reports indicate that CD39 is a marker to distinguish tumor-reactive CD8 T cell populations from bystander populations. In gastric cancer (GC), anti-CD39 antibody, anti-PD-1 antibody, and FOLFOX combination therapy may be effective therapy at AACR 2022. Methods: We retrospectively reviewed the data of 62 GC patients who underwent gastrectomy at our hospital (2017 - 2018) and examined their rejected specimen’s immune-microenvironment using immunohistochemistry. Then we prospectively enrolled 16 GC patients. Their tumor tissue and tumor-infiltrating lymphocytes (TILs) were extracted from surgical specimens, these fractions were subjected to the RNA-seq analysis ( n = 3), CD107a degranulation assay ( n = 7) and 3H-Thymidine incorporation assay ( n = 7). Results: The densities of CD39+CD8 TILs positively correlated with the densities of CD4 T cells and B-cells in GC tissues ( P = 0.01, < 0.01, respectively). Furthermore, higher densities of CD39+CD8 TILs in GC patients were associated with better overall survival ( P < 0.01). We classified TILs into four groups based on expression levels of the PD-1 and CD39. The proportion of CD39+CD8 T cells was significantly higher in GC tissues than their PBMCs ( n = 13) and non-cancerous tissues ( n = 4). CD39+PD-1+CD8 (DP) TILs in primary tumors were elevated expression of multiple inhibitory receptors such as LAG3, TIGIT and reduced expression of IL-2 by RNA-seq analysis. T cells expanded in vitro from DP-TILs ( n = 5) efficiently recognized autologous tumor cells in CD107a assay compared with other populations, and considered to be tumor-reactive T cells fraction. However, since these DP TILs in primary tumors show exhausted phenotypes, capacities to kill tumor are expected to be reduced in the tumor-microenvironment (TME). By adding ATP to the DP-TILs in vitro at the concentration reported in the TME, we observed reduction of cell proliferation by 3H-thymidene incorporation assay and of degranulation by CD107a assay, and we observed recovery of these changes by adding anti-CD39 inhibitory antibody. Conclusions: DP-TILs may have superior T cell receptors recognizing tumor-antigens and contribute to tumor eradication, especially when administrated anti-CD39 antibody.
Dysbiosis in gastric mucosal microbiota associated with gastric carcinogenesis.
Authors: Kim Byung-Wook , Choe Younghee , Kim Joon Sung , Na Soo-Young
Published: January 2024

381

Background: Gastric microbiota, including H. pylori, may play a role in the development of gastric cancer. This study aimed to investigate the gastric microbiota throughout the stages of gastric carcinogenesis, encompassing atrophic gastritis, gastric dysplasia, and gastric adenocarcinoma. Methods: From December 2021 to August 2023, we collected gastric mucosal tissue samples from patients with atrophic gastritis, gastric dysplasia, and early gastric cancer. Subsequently, we conducted 16S rRNA gene profiling through next-generation sequencing. We compared alpha-diversity and beta-diversity within each group and analyzed the taxonomic composition. Results: This study included a total of 98 patients, comprising 16 with atrophic gastritis, 23 with low-grade dysplasia, 15 with high-grade dysplasia, and 44 with early gastric cancer. The H. pylori infection status was comparable across all groups. While there was a difference in alpha diversity between tumor lesions and normal stomach lesions, it did not reach statistical significance. Notably, Phyllobacterium was dominant in early gastric cancer, Prevotella in high-grade dysplasia, and Kocura in low-grade dysplasia. Furthermore, within the early gastric cancer group, Bacillus was widely distributed in cases of undifferentiated type adenocarcinoma. Conclusions: The analysis of microbiota collected from Korean stomach tissue revealed distinct microbial distributions across the various stages of gastric carcinogenesis.
Exploratory analysis of biomarkers of response to durvalumab in advanced HER2-negative oesophago-gastric adenocarcinoma within a phase 2 clinical trial.
Authors: Lote Hazel , Giota Eleftheria , Fong Caroline , Gordon Anderley , Begum Ruwaida , Satchwell Laura , Kidd Shannon , Cromarty Susan , Fribbens Charlotte Victoria , Starling Naureen , Rao Sheela , Chau Ian , Cunningham David , Zapata Luis
Published: January 2024

384

Background: Advanced oesophago-gastric cancers have showcased varied responses to immunotherapy based on biomarkers such as tumour mutational burden, microsatellite instability, and PD-L1 expression. However, these markers may not fully capture tumour heterogeneity and evolutionary dynamics. Hence, understanding the intricate relationship between immune selection, specifically immune dN/dS,1 and tumour evolution is vital for devising personalized therapeutic strategies. Methods: In our phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182), patients received maintenance durvalumab post first-line chemotherapy. A survival advantage was not seen with maintenance durvalumab compared to surveillance and exploratory analysis of PD-L1 expression was not associated with improved survival outcomes.2 However, a subset of patients treated with durvalumab experienced durable responses and some experienced incremental radiological responses. A pilot substudy on a selected cohort (n=24) of these patients was designed to explore the potential of immunogenomics evolutionary-based metrics, notably dN/dS, as predictive biomarkers. DNA and RNA from FFPE baseline tumour samples underwent analysis, examining genomic factors including tumour mutational burden, indel signatures, PDL1 status, and immune evasion mechanisms. Furthermore, the evolutionary metric, immune dN/dS, which has implications in tumour immunoediting and its response to immunotherapies, was scrutinized. Results: A dominant indel mutational signature emerged from the analysis. The majority of patients displayed a significantly higher number of indel variants, compared to non-synonymous and synonymous single-nucleotide variants. A recurring observation was dN/dS values consistently above 1, indicating positive selection for non-synonymous somatic variants. Additionally, hypermutation in driver genes, notably TP53 and XIRP2, was detected. One patient, with a unique dN/dS < 1, showcased survival beyond four years without liver metastases. Immune dN/dS > 1 and no evidence of liver metastases displayed the best prognosis after treatment in contrast with those that have immune dN/dS < 1 with or without liver metastases. Conclusions: Immune dN/dS emerges as a promising tool to decode tumour evolutionary mechanisms, providing profound insights into the dynamics of tumour evolution in advanced HER2 negative oesophago-gastric cancer patients receiving durvalumab immunotherapy. This pilot study underscores the potential of this novel immunogenomic approach in improving patient stratification and tailoring therapeutic strategies in cancer immunotherapy. 1. Zapata et al, Nature Genetics, 2023. 2. Fong et al, J Clin Oncol, 2021. Clinical trial information: NCT02678182 .
The expanded indications of HER2-targeted therapies by monitoring of circulating tumor cells.
Authors: Kimura Yasuaki , Suzuki Koichi , Tamaki Sawako , Abe Iku , Endo Yuhei , Ichida Kosuke , Muto Yuta , Saito Masaaki , Rikiyama Toshiki
Published: January 2024

385

Background: Despite success in the HER2 targeted therapies for metastatic gastric cancer patients, the conventional assessment of HER2 status in tumor tissue specimens is still under debate. Methods: Twenty-seven patients with metastatic gastric cancer were treated according to histological HER2 status. On-chip sorting system was used for the isolation of circulating tumor cells (CTCs) before treatments. Epithelial mesenchymal transition (EMT) was assessed by the vimentin and cytokeratin. DNA was extracted from CTCs and applied to the gene panel with 409 cancer related genes. The fluorescence signal intensity > 50 is set to be a threshold value for distinguishing between positive and negative HER2 on CTCs. Results: Thirteen patients (48%) with HER2 positive in tumor tissues (Group A) were treated with cytotoxic agents and trastuzumab (anti HER2 antibody) while 14 patients (52%) were negative and treated with cytotoxic agents. In these 14 patients, 8 patients (30%) showed HER2 positive (Group B) and 6 patients (22%) displayed HER2 negative (Group C) on CTCs. Increased expression of EMT was seen in Group A and B, indicating they are likely to have metastasis. Group B showed worse PFS than others (13.8 M in A, 7.0 M in B and not reached in C, p=0.012), suggesting Group B could be a candidate for expand indication of Trastuzumab. Genomic analysis showed some mutated genes involved in the PI3K signaling pathway which associated with drug resistance. Conclusions: Monitoring of circulating tumor cells leads to the expand indication of the HER2 targeted therapies in patients with metastatic gastric cancer.
Relationship between the number of positive MSI markers and the efficacy of NIVO+IPI therapy in MSI-H gastric cancer: A subgroup analysis of NO LIMIT study (WJOG13320G/CA209-7W7).
Authors: Hirata Kenro , Kawakami Hisato , Kadowaki Shigenori , Makiyama Akitaka , Tsuda Masahiro , Sugimoto Naotoshi , Machida Nozomu , Hara Hiroki , Hirano Hidekazu , Esaki Taito , Komatsu Yoshito , Hironaka Shuichi , Chiba Yasutaka , Muro Kei
Published: January 2024

386

Background: Although high instability of microsatellite lesion (MSI-H) is an established biomarker for response to immune checkpoint inhibitors, the relationship between the number of MSI markers and the efficacy of immune checkpoint inhibitors in MSI-H tumors has not been well elucidated. NO LIMIT (WJOG13320G/CA209-7W7) is a phase II trial of nivolumab plus low-dose ipilimumab (NIVO+IPI) for MSI-H advanced gastric or esophagogastric junction cancer (GC) in the first-line setting.1 Here, we investigated the relationship between the number of positive MSI markers and the efficacy of NIVO+IPI in NO LIMIT study. Methods: Eligible patients were unresectable advanced, recurrent, or metastatic GC with confirmed as MSI-H with the MSI-IVD Kit (FALCO), where two or more of the five MSI markers are defined as positive. Nivolumab (240 mg) biweekly and ipilimumab (1 mg/kg) every six weeks were given until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and the association between number of positive MSI markers and clinical efficacy (ORR, PFS, OS). The analysis was performed 18 weeks after the first dose in the last patient, with a median follow-up of 9 months (range, 4.0-18.0). Results: The breakdown of MSI markers in the 29 patients enrolled in NO LIMIT was as follows: BAT-26 (26/26, 100%), NR-21 (25/29, 86.2%), BAT-25 (25/29, 86.2%), MONO-27 (29/29, 100%), NR-24 (27/29, 89.4%). Since most of the cases were positive for all five of them (the number of cases with 2, 3, 4, and 5 positive markers was 2, 2, 1, and 24, respectively), we dichotomized cases into group A (all five positive) and group B (the others). Response rates in groups A vs. B were 62.5% (15/24) vs. 60.0% (3/5), respectively. There was no difference in PFS or OS between the two groups. Conclusions: The number of MSI markers is not related to the efficacy of NIVO+IPI in NO LIMIT study. Further follow-up is needed to confirm the relationship between survival. 1. Muro K, et al. ESMO Congress 2023. Clinical trial information: jRCT2080225304 . [Table: see text]
Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC): Real-world experience from a tertiary Asian cancer center.
Authors: Wang Meng , Gwee Yong Xiang , Lin Zhaoting , Yong Wei Peng , Sundar Raghav , Tan Hon Lyn , Choo Joan RE , Tan Ker Kan , Lieske Bettina , Cheong Wai Kit , Tan Teng Hwee , Tey Jeremy Chee Seong , Chee Cheng Ean , Chan Gloria Hui Jia
Published: January 2024

39

Background: Multiple studies of TNT for LARC have shown improved pathological complete response (pCR) rate and disease-free survival (DFS). However, real-world data in Asia is limited. Methods: Patients (pts) diagnosed with LARC at National University Cancer Institute, Singapore were discussed at a multidisciplinary tumor board. Patients were eligible for TNT if they had cT2/3N+ or cT4Nany, threatened circumferential resection margin (CRM) and adequate organ function. TNT protocol was systemic chemotherapy with 5-6 cycles of mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or 3-4 cycles of XELOX (capecitabine, oxaliplatin) followed by short- or long-course chemoradiation (CRT), then 3 cycles of mFOLFOX6 or 2 cycles of XELOX. Clinical outcomes included rates of clinical complete response (cCR), pCR, surgery type, R0 resection and DFS. Baseline pt demographics, laboratory results and tumor characteristics were analyzed against these outcomes. Results: 173/205 pts who were diagnosed with rectal cancer between February 2020 and November 2022 had LARC and 47 received TNT. Median age was 65 (range: 33-79), 68.1% male, 78.7% were Chinese, 19.2% had cT4 tumors, 87.2% node positive and 80.9% had CRM involvement. Median tumor distance from anal verge was 6cm (range: 1-15cm) on colonoscopy and 5cm (range: 2-12cm) on magnetic resonance imaging. 95.7% received XELOX, 87.0% had long-course CRT and 83.0% completed all cycles of systemic chemotherapy and CRT. 44.7% had dose reduction of systemic therapy and 4.3% required emergent surgery due to local complications during TNT. After TNT completion, 7 pts did not pursue surgery – 3 achieved cCR (6.4%) and adopted a watch-and-wait approach, 2 had disease progression (PD), and 2 declined. Of those who underwent surgery, 75.0% had sphincter-preserving surgery and 85.0% achieved R0 resection. 2.1% (n =1) achieved pCR. Rates of tumour regression grade (TRG) 0, 1, 2, 3 were 7.5%, 15.0%, 67.5% and 10.0%, respectively. After a median follow up of 21.7 months (range: 9.3 – 41.6 months), 21.3% (n = 10) had disease recurrence and 14.9% (n=7; 5 from PD, 1 from surgery-related complication, 1 unrelated to treatment) passed away. 1-year DFS rate was 88.7% (95% CI 75.0% - 95.2%). Conclusions: This is the first Asian study reporting real-world data of TNT for LARC since its wide-scale adoption. pCR rates appear lower than reported studies. Understanding the limitation of retrospective studies, further analysis is ongoing to determine if factors other than sequence of modality can contribute to the observed findings.
Impact of PD-L1 expression on survival in patients with unresectable/recurrent gastric cancer receiving first-line chemotherapy without immune checkpoint inhibitors.
Authors: Hirano Hidekazu , Yamada Yasuhide , Nagashima Kengo , Hiraoka Nobuyoshi , Sekine Shigeki , Takahashi Naoki , Azuma Mizutomo , Iwasa Satoru , Kanato Keisuke , Machida Nozomu , Kinoshita Takahiro , Hata Hiroaki , Kawakami Hisato , Takahari Daisuke , Ojima Toshiyasu , Kadowaki Shigenori , Boku Narikazu , Kurokawa Yukinori , Terashima Masanori , Yoshikawa Takaki
Published: January 2024

391

Background: Although high PD-L1 expression predicts a favorable response of advanced solid tumors to immune checkpoint inhibitors (ICIs), its impact on survival in patients with unresectable/recurrent gastric cancer (GC) has remained unclear. We investigated the prognostic value of PD-L1 expression for survival in unresectable/recurrent GC patients receiving first-line chemotherapy without ICIs. Methods: JCOG1013, a phase 3 randomized trial, demonstrated the addition of docetaxel to cisplatin and S-1 as first-line chemotherapy was of no benefit to patients with unresectable/recurrent GC (N=741) either for overall survival (OS) or progression-free survival (PFS). Tumor specimens prior to chemotherapy were collected for assessing PD-L1 expression for this ancillary study. PD-L1 expression was determined using immunohistochemistry (Dako, 28-8 pharmDx) and used to derive the PD-L1 combined positive score (CPS) and PD-L1 tumor proportion score (TPS). As with the CheckMate 649 study, the cutoff values for PD-L1 CPS and PD-L1 TPS were set at 5 and 1%, respectively. Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of PD-L1 CPS and PD-L1 TPS as predictors of OS and PFS. All p values were 2-sided; values <0.05 were considered statistically significant. Results: We analyzed 427 patients with unresectable/recurrent GC. The prevalence of PD-L1 CPS≥5, and PD-L1 TPS≥1% was 33% and 24%, respectively. There was no significant difference in OS and PFS between the PD-L1 CPS ≥5 group and the PD-L1 CPS <5 group (Table). The PD-L1 TPS ≥1% group had superior OS and PFS compared to the PD-L1 TPS <1% group (Table). In multivariable analyses for OS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (hazard ratio (HR) = 0.64 [95% CI: 0.50–0.83], p<0.001), but PD-L1 CPS≥5 was not (HR = 0.82 [95% CI: 0.65–1.02], p = 0.073). In multivariable analyses for PFS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (HR = 0.67 [95% CI: 0.52–0.84], p<0.001), but PD-L1 CPS≥5 was not (HR = 0.83 [95% CI: 0.67–1.03], p = 0.090). Conclusions: PD-L1 TPS≥1% is significantly correlated with longer OS and PFS in patients with unresectable/recurrent GC receiving first-line chemotherapy without ICIs. PD-L1 TPS should be considered as a stratification factor in randomized clinical trials for unresectable/recurrent GC. Clinical trial information: UMIN000007652 . [Table: see text]
Role of heat shock protein 90 in hypoxia-induced angiogenesis and epithelial-mesenchymal transition for esophageal squamous cancer cells.
Authors: Tzao Ching , Wang Jin-Kun
Published: January 2024

395

Background: Hypoxia is known as an important trigger for the development and progression of human cancers. Heat shock proteins (Hsps) may be up-regulated in response to cellular stressors including hypoxia. To date, the functional role of Hsps within hypoxic tumor microenvironment for esophageal squamous cell cancer (ESCC) remains poorly defined. Methods: CoCl2 was used to induce hypoxia that mimics a hypoxic tumor microenvironment in cultured ESCC cells. Successful induction of hypoxia was confirmed by 2’,7’ –dichlorofluorescein diacetate (DCFDA) assay by detection of cellular reactive oxygen species (ROS). 7-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a selective Hsp90 inhibitor, was used to treat 2 ESCC cell lines, KYSE-170 and -510 cells pretreated with or without CoCl2, an agent to induce a hypoxic tumor microenvironment. Cytotoxicity (MTT) and migration assays were conducted in KYSE-17 and -510 ESCC cells in response to different concentrations of CoCl2, followed by protein expression of Hsp 90, vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1a (HIF-1a), mTOR as well as markers related epithelial-mesenchymal transition (EMT) such as snail or E-cadherin, by immunoblot or ELISA. In parallel, cell proliferation and migration assays of ESCC cells were analyzed. Results: CoCl2 induced hypoxia was supported by an induction of reactive oxygen species (ROS). CoCl2 (200 mM) significantly suppressed cell viability and proliferation with a concomitant up-regulation of VEGF and HIF-1a in a dose-dependent fashion. In contrast, cell migration was significantly increased in response to CoCl2, while down-regulating E-cadherin with concomitant increase in Snail expression. 17-DMAG decreased expression of VEGF and HIF-1a. In addition, it inhibited cell migration and invasion of ESCC cells were analyzed. Conclusions: Our data have shown that CoCl2 induced hypoxia promotes EMT and angiogenesis, which are inhibited by 17-DMAG, suggesting that hypoxia induced EMT and angiogenesis is Hsp 90 dependent in ESCC.
Prognostic role of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in advanced gastric cancer treated with immunotherapy: A systematic review and meta-analysis.
Authors: Matsas Silvio , Aguiar Junior Pedro N. , Del Giglio Auro
Published: January 2024

397

Background: Recent advances in the treatment of Gastric Cancer (GC) have introduced immunotherapy as a promising approach for advanced disease. In this context, potential biomarkers such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have gained attention for their roles in predicting treatment outcomes. In this meta-analysis, we explore the clinical significance of PLR and NLR as predictors of Overall Survival (OS) and Progression-Free Survival (PFS) in advanced GC patients undergoing immunotherapy. Methods: Two independent reviewers systematically searched electronic databases, including PubMed, Embase and Scopus. The search incorporated controlled vocabulary (MeSH terms) and keywords related to Gastric Cancer, immunotherapy, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). Eligible studies were selected based on predefined criteria, including HR availability, and were assessed for quality and bias using the Newcastle-Ottawa Scale. Data extraction was independently performed by two reviewers, and discrepancies in study selection and data extraction were resolved by a third reviewer. Subgroup analyses were performed to explore potential variations in the study outcomes. All analyses were conducted with RevMan 5.4 and employed random-effects model. Results: In total, 16 studies encompassing 1176 patients for NLR and 8 studies covering 766 patients for PLR were included in this systematic review and meta-analysis. The studies spanned the years between 2018 and 2023. Our analysis revealed significant associations between high NLR and poor OS (HR: 2.11, 95% CI: 1.70-2.62, p < 0.00001) and PFS (HR: 1.76, 95% CI: 1.43-2.17, p < 0.00001). Similarly, elevated PLR was significantly associated with worse OS (HR: 1.77, 95% CI: 1.44-2.17, p < 0.00001) and PFS (HR: 1.61, 95% CI: 1.33-1.96, p < 0.00001). In all conducted subgroup analyses, high NLR and PLR were consistently associated with poor survival outcomes. Conclusions: Our analysis supports the significance of NLR and PLR as accessible and cost-effective biomarkers for predicting survival outcomes in the context of immunotherapy for advanced GC. These findings underscore their potential significance in guiding clinical decisions. Further investigation should be carried out to validate our findings.
Treatment development targeting Hippo pathway for scirrhous type gastric cancer.
Authors: Miki Yuichiro , Yoshii Mami , Kuroda Kenji , Miyamoto Hironari , Tamura Tatsuro , Toyokawa Takahiro , Lee Shigeru , Maeda Kiyoshi
Published: January 2024

398

Background: Treatment outcome of gastric cancer (GC) has been improved by minimally invasive surgery, and development of new drugs including immune checkpoint inhibitors. However, survival for patients with scirrhous type (SGC, Type4) gastric cancer is dismal. Methods: We collected miRNAs form exosomes released from cancer associated fibroblasts which is developed from resected gastric cancer tissue. Pathway enrichment analysis (PEA) of top miRNAs showed that they are significantly associated with Hippo signaling pathway (Hippo pathway). The molecules relating Hippo pathway was evaluated by Western blotting in cell line, and IHC of tissue array. Results: PEA using top miRNAs showed the significant relationship to Hippo pathway. Yap is a final effector in this pathway, and we found that YAP is not expressed in MKN45 cells (diffuse type), which is supposed to be degraded in cytoplasm. On the contrary, MKN74 cells express both YAP and pYAP. IHC showed that YAP translocation to nucleus is significantly associated with CTGF expression. CTGF low expression is significantly associated with worse prognosis especially in diffuse type GC (Log rank p = 0.022). This trend is similar in the analysis of patients with SGC. Conclusions: The role of Hippo pathway is different between intestinal type and diffuse type of GC. YAP activator could be effective for the treatment of SGC, and we are focusing on the treatment development.
International real-world study of TOTAL neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC).
Authors: Audisio Alessandro , Velenik Vaneja , Meillat Hélène , Ruiz-Garcia Erika , Riesco Martinez Maria Carmen , Dekervel Jeroen , Carvalho Carlos Torres , Suárez Francisco Javier , Kirac Iva , Hernando Jorge , Artac Mehmet , O'Connor Juan Manuel , Braam Pètra , Shamseddine Ali , Borelli Beatrice , Paez Lopez-Bravo David , Dulskas Audrius , De Felice Francesca , Vanden Bulcke Alexander , Sclafani Francesco
Published: January 2024

40

Background: TNT has recently emerged as a standard treatment for LARC. However, use and outcome of the different TNT regimens in real-world practice are largely unknown. Methods: This is an international, multicentre, retrospective study sponsored by the Institut Jules Bordet, Brussels. Eligibility was limited to newly diagnosed LARC patients treated with TNT between March 2013 and May 2023 and outside the context of a clinical trial. The primary objective was to describe real-word practice across international centres. Secondary objectives included treatment safety and efficacy. Data were collected into a central electronic database, and remotely monitored. Descriptive statistics were used, and survival outcomes were estimated with Kaplan-Meier curves. Results: 1,272 eligible patients were included from 47 centres across four continents (Europe, Asia, North America and South America). Baseline characteristics were as follows: 63% males, median age 60 years (range 21-88), 47% low rectum, 26% cT4, 47% cN2, 49% EMVI+, 59% CRM+. In the overall population, 21% of the resected patients had a pathological complete response (pCR), while 11.3% were managed according to a watch-&-wait (w&w) strategy. Median follow-up was 24.1 months (IQR 23.7). Local and distant recurrences after curative-intent surgery occurred in 5.5% and 16.2% of patients, respectively. 3-year event-free survival (EFS) was 68.3%, while 3-year overall survival (OS) was 89%. Serious adverse events were reported in 4.3% of patients during radiotherapy, and in 14.7% during chemotherapy. Patient distribution according to the TNT sequence/regimen, and respective efficacy outcomes are reported in the table. Conclusions: This is the largest real-world study of TNT for LARC. Our findings show substantial variation in the choice of TNT sequence and regimen. Efficacy and safety results are overall in line with those reported in clinical trials, and confirm feasibility of TNT in a real-world setting. Patient recruitment is ongoing, and updated results with propensity score matching analyses will be reported at the meeting. [Table: see text]
Total neoadjuvant therapy for rectal cancer in the rural community oncology setting.
Authors: McKean Heidi Ann , Nordstrom James , Gaster Sam , Whiting Emily , Guardado Jesse , Choudhry Sabina , Johnson Thomas , Casey Matthew , Murphy Charles , McKean Heidi Ann , Grow Joel , Sulaiman Raed , Quist Erin , O'Neill Elizabeth , Stoltenberg Kelci , Schultz Jill
Published: January 2024

41

Background: The treatment of localized rectal adenocarcinomas with Total Neoadjuvant Therapy (TNT) has become the national standard. Data on the efficacy of TNT in a predominantly rural community oncology setting is limited. Methods: This ongoing retrospective analysis included 94 patients with proficient MMR Stage II or III rectal adenocarcinoma treated with traditional neoadjuvant treatment of chemoradiation followed by surgical resection +/- adjuvant chemotherapy, or Consolidation (chemoradiation upfront) TNT versus Induction (chemotherapy upfront) TNT followed by surgical resection, diagnosed between 2017 and 2022 and treated at the Avera Cancer Institute in Sioux Falls, South Dakota. The primary objectives were to compare the pathologic response and treatment completion rates in patients with rectal cancer treated with TNT to patients treated with traditional neoadjuvant treatment. The secondary objective was to compare the pathologic response rate for TNT at different tumor locations. Results: Of 94 patients assessed, 54 patients received traditional neoadjuvant treatment and 40 patients received TNT. For patients treated with traditional neoadjuvant treatment, 43% (n=23) completed all recommended treatment, with 63% (n=34) achieving a partial response (PR) and 19% (n=10) a complete pathologic response (CR). For patients treated with TNT, 93% (n=37) completed all recommended treatment, and 68% (n=27) achieved a PR and 15% (n=6) achieved a CR. For patients that received Consolidation TNT (n=21), 66% (n=12) achieved a PR and 21% (n=4) achieved a CR. For patients that received Induction TNT (n=19), 68% (n=13) achieved a PR and 11% (n=2) achieved a CR. For patients with high tumor location (n=4) treated with TNT, 50% (n=2) achieved a PR and one patient achieved a CR (25%). For patients with mid tumor location (n=18) treated with TNT, 67% (n=12) achieved a PR and 22% (n=4) achieved a CR. For patients with low tumor location (n=18) treated with TNT, 72% (n=13) achieved a PR and one patient (6%) achieved a CR. Conclusions: The treatment of rectal adenocarcinoma with TNT in the rural community cancer center setting is achievable with a higher completion rate compared to traditional neoadjuvant treatment. Our results also show a trend toward a higher complete pathologic response rate in Consolidation compared to Induction approach and in high/mid rectal tumors compared to low rectal tumors. Future work will be conducted to assess for any differences in recurrence and survival.
Impact of primary prophylaxis (PP) with granulocyte colony-stimulating factor on the outcomes of patients with locally advanced gastric cancer treated with FLOT: A single-center retrospective analysis.
Authors: Gomes Pedro Henrique Benfatti , Torrez Miguel Adolfo Lopez , Souza E Silva Virgilio , Camandaroba Marcos Pedro Guedes , Cavalher Felicia Peterson , Taboada Rodrigo Gomes , Felismino Tiago Cordeiro , Brito Angelo Borsarelli Carvalho
Published: January 2024

414

Background: The role of primary prophylaxis (PP) with granulocyte colony-stimulating factor (G-CSF) for patients with locally advanced gastric cancer (LAGC) treated with FLOT is currently unknown. Although original FLOT4 study did not recommend PP, the use of G-CSF is common in clinical practice to avoid serious complications. However, its use is associated with increased financial costs. Methods: This is a retrospective, single-institution study. We included patients with pathologically confirmed LAGC who received perioperative FLOT4. Patients were categorized in two groups: PP versus no- PP. Our objectives were to compare frequency of grades 3 or 4 neutropenia (G3/4N) and febrile neutropenia (FN) between PP and non-PP patients. We also evaluate the association between pathological complete response (pCR) and disease-free survival (DFS) and overall survival (OS) according to the use of PP. Binomial variables were compared using Fisher's exact test. Kaplan-Meier method was used to calculate median DFS and OS and respective 95% confidence intervals [95%CI] and any difference assessed by the log-rank test. Results: From January 2019 until December 2022, 122 LAGC patients were treated with perioperative FLOT. Median age was 56 years, 53.2% were female and 84.4% were ECOG 0. Primary prophylaxis (PP) was used by 58 patients (47.5%); there was no difference between clinical and tumor features between both groups regarding age, sex, ECOG, T and N staging and Lauren’s subtype. PP costs raised treatment costs up to 15%. Grade 3 or 4 neutropenia occurred more frequently among patients without PP (65.6 vs. 1.7%; p < 0.001). There was no difference in the frequency of FN between groups (7.8 vs. 0%; p = 0.06). Overall patients, pCR occurred in 11.8% os patients. Regarding the influence of PP in pathological response after FLOT chemotherapy, there was no difference between PP vs non-PP patients with pCR (14.3% vs 9.5%, p = 0.57). Median follow-up was 27.4 (range 2.8 – 70.6 months). Twenty-six patients (21.3%) died during follow-up. Median OS was 52.5 months (95% CI: 47.1-57.8). Median OS for patients in PP and no PP groups were 44.5 and 56.2 months (log-rank P =0.06), respectively. Median DFS was 43.1 months (95% CI: 37.2-48.9). Median DFS for patients in PP and no PP groups were 39.6 and 43.5 months (log-rank P =0.80), respectively. Conclusions: Despite the reduction in the frequency of G3/4N, rates of FN among patients treated with FLOT with G-CSF are too low to justify its use in a routine basis. Furthermore, PP is not associated with relevant clinical endpoints such as pCR neither OS or DFS. Based on this, PP in such situations should not be routinely used due to its financial costs.
The efficacy of chemotherapy for colorectal cancer with early recurrence after adjuvant chemotherapy.
Authors: Okemoto Dai , Yamaguchi Toshifumi , Sugino Kanako , Matsuo Nanako , Sanomura Makoto , Kameishi Shin , Kadono Toru , Yukami Hiroki , Goto Masahiro , Nishikawa Hiroki
Published: January 2024

43

Background: Adjuvant chemotherapy is the standard treatment for patients with stage III colorectal cancer (CRC) underwent surgery.However, the efficacy of chemotherapy for early recurrence after adjuvant chemotherapy remains unclear. This study aimed to assess the efficacy of chemotherapy for CRC with early recurrence during or after adjuvant chemotherapy. Methods: We retrospectively reviewed CRC patients who underwent surgery at 3 institutions between 2016 and 2021. The inclusion criteria were as follows: ECOG performance status was 0 or 1, histology was adenocarcinoma, patients who received adjuvant chemotherapy following surgical resection, early recurrence during or within 12 months after adjuvant chemotherapy and no prior treatment for CRC after early recurrence. The interval from the last administration of adjuvant chemotherapy to recurrence was defined as the recurrence-free interval (RFI). Overall survival (OS), progression-free survival (PFS), objective response rates (ORR), and disease control rate (DCR) were assessed according to the RFI. Results: Of 448 patients, 32 patients were eligible. Median age was 57 years (range 26–79), 14 patients (44%) were male and ECOG performance status 0 / 1 was 29 (91%) / 3 (9%). RAS wild-type / mutant was 12 (38%) / 20 (62%) and right / left as sidedness was 21 (66%) / 11 (34%). Regarding adjuvant chemotherapy, 4 patients (12%) received single-agent therapy, while 28 patients (88%) received combination therapy with two agents. Palliative chemotherapy after early recurrence included Oxaliplatin-based regimens in 13 patients (41%), irinotecan-based regimens in another 13 patients (41%), and other regimens in 6 patients (18%). For all patients, the median PFS and OS were 10.4 months and 43.0 months, respectively. The ORR and DCR were 34.4% and 75.0%, respectively. When patients were divided into RFI < 6 months and RFI ≥ 6 months, the ORR was superior in the RFI ≥ 6 months group to RFI < 6 months group (56 % vs. 26%). The PFS (median 10.4 months vs. 17.8 months, HR 0.92; 95% Cl 0.36-2.38, p = 0.87) and OS (median 31.3 months vs. 43.0 months, HR 0.97; 95% Cl 0.31-3.08, p = 0.97) did not differ between the RFI < 6 months group and the RFI ≥ 6 months group. Multivariate analysis for OS indicated a trend toward a poor prognosis in the RFI < 6 months group compared to the RFI ≥ 6 months group (HR 1.78; 95% CI 0.35-8.98, p = 0.48). Conclusions: In patients with CRC experienced early recurrence, the RFI < 6 months group had a trend of poor efficacy compared to the RFI of ≥ 6 months group.
Impact of Hispanic ethnicity on immunotherapy outcomes in hepatocellular carcinoma: Insights from the National Cancer Database.
Authors: Gaur Sumit , Dwivedi Alok Kumar , Eiring Ana , Konstantinidis Ioannis , Rukhsan Rabia , Singh Vishwajeet
Published: January 2024

438

Background: Hepatocellular carcinoma (HCC) is the fastest-growing cancer in the US with more age-adjusted incident cases in Hispanics compared to non-Hispanics. Immunotherapies are considered integral part of treatment for most unresectable HCC. Recent multinational phase III trials suggest the benefit of immunotherapies may differ based on geographic region and underlying etiology of HCC. We hypothesized that Hispanic ethnicity might influence responses to immunotherapy in HCC. Methods: We analyzed the National Cancer Database (NCDB) to assess the impact of immunotherapy on overall survival (OS) in Hispanic patients with HCC. The database was queried for liver cancer from 2004 to 2020. Kaplan Meier method was used to assess OS and a log-rank test was used to compare survival distribution between Hispanic and non-Hispanic groups. Cox regression analysis was performed to estimate the adjusted effect of ethnicity on OS based on immunotherapy status. NCDB is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoCÕs NCDB are the source of the de-identified data used herein. Results: A total of 225079 patients were identified of whom 2036 patients (0.9%) received immunotherapy as first-line treatment. Patients with non-Hispanic ethnicity, male sex, who received treatment at academic/research institutions, and were insured were more likely to receive immunotherapy. In the entire cohort, there was no difference (p=0.94) in survival between those who did not receive immunotherapy (median OS,11.63 months; IQR: 2.79, 34.83) vs. those who did (median OS, 10.68 months, IQR: 5.19, 23.29[DA2]). There were more Hispanics in the cohort who did not receive immunotherapy (12.28% vs. 10.61%). In the adjusted Cox analysis, Hispanics had a reduced risk of death than non-Hispanics among patients who did not receive immunotherapy (HR: 0.873, 95%CI, 0.858-0.889; p<0.001). Among patients with immunotherapy, there was no OS difference between ethnicities (HR 0.904, 95% CI, 0.755-1.082; p 0.271). Conclusions: Hispanics were less likely to receive immunotherapy than non-Hispanics. Although Hispanics had a better OS than non-Hispanics among patients without immunotherapy, the differences no longer persist among patients who received immunotherapy. These findings suggest that Hispanic ethnicity may influence responses to immunotherapy. As compared to non-Hispanic whites, Hispanics with HCC have significantly more nonalcoholic fatty liver disease and alcohol-related liver disease as contributing factors. A better understanding of the impact of immunotherapies on alcoholic and nonalcoholic liver disease-related HCC is needed.
Relative and collective contribution of liver and bile duct cancer risk factors among minority groups in California.
Authors: Monge B. M. Cecilia , Arroyo Figueroa Gabriela , Greten Tim F.
Published: January 2024

439

Background: Liver and Bile Duct Cancer is a significant public health concern with higher incidence rates observed among people belonging to racial and ethnic minority groups compared to non-Hispanic White people. This study aims to understand which underlying factors contribute most to this disparity in liver and bile duct cancer. Methods: The California Health Maps database was analyzed from 2015-2019, including 58 counties: consistent with the SEER census and CDC PLACES Project. Variables examined included race, ethnicity, age, health insurance status, foreign-born status, rural residence, obesity prevalence, socioeconomic status, smoking status, and percentage of individuals receiving preventative care. Linear regression analysis was used to determine which factors significantly predict higher prevalence of liver and bile duct cancer. Results: The population consisted of 39,283,494 people, predominantly Hispanic (39%) with 38.7% being non-Hispanic White; 15.5% Asian or Pacific Islander and 6.2% non-Hispanic Black. Hispanic people accounted for 21% of the 868,882 total cancer cases and 33% of the 22,439 cases of liver and bile duct cancers reported. Race and ethnicity were the most substantial predictors of liver and bile duct cancer prevalence; counties with a higher monitory population exhibited higher incidence rates (Hispanic: R=0.39; p=0.003, Black: R=0.39; p=0.004, White: R=-0.55; p<0.0001, Asian: R=0.33; p=0.01). Being foreign-born (R=0.45; p=0.0008), residing in non-rural areas (R= -0.33; p=0.01), and lacking preventative care (women: R= -0.30; p=0.03, men: R= -0.37; p=0.006) were also significantly associated with increased liver and bile duct cancer incidence rates (Table). Conclusions: This study highlights the association of race, ethnicity, and access to healthcare services with higher incidence rates of liver and bile duct cancer among Hispanic and non-Hispanic Black people compared to non-Hispanic White people. Addressing these disparities is crucial for promoting equitable health outcomes in liver and bile duct cancer. [Table: see text]
Racial/ethnic disparities in the effectiveness of atezolizumab plus bevacizumab (A+B) vs. tyrosine kinase inhibitors (TKIs) among veterans with unresectable hepatocellular carcinoma (uHCC).
Authors: Kaplan David Edward , Tan Amie , Xiang Cheryl , Mu Fan , Hernandez Sairy , Ogale Sarika , Sundar Manasvi , Lin Yilu , Shi Lizheng , Singal Amit G.
Published: January 2024

448

Background: The etiology of liver disease and HCC often differs by race and ethnicity, which may lead to potential differential effectiveness of immunotherapy (IO) by race/ethnicity. However, clinical trials for HCC have historically had limited racial diversity. Emerging data has characterized the real-world effectiveness of A+B, the standard of care for first-line (1L) uHCC. This study assessed whether there is racial/ethnic difference in the effectiveness of A+B compared to TKIs, including sorafenib (S) or lenvatinib (L). Methods: A population-based retrospective analysis was conducted using data from the Veterans Health Administration (VHA) Data Warehouse. Non-Hispanic White, African American (AA), and Hispanic patients diagnosed with uHCC between 2017 and 2022 who initiated 1L A+B (on or after 2020), S, or L were selected. Kaplan-Meier analyses and multivariable Cox regression analysis with race/ethnicity as a treatment modifier (adjusting for age, region, extrahepatic metastases, etiology, presence of cirrhosis, comorbidity index, prior local therapies, Child-Pugh [CP] class, and Albumin-Bilirubin [ABLI] grades) were conducted to investigate the racial/ethnic differences in the effectiveness of A+B vs S or L. Results: Of 1,738 patients, 1,140 were White (20% A+B, 56% S, 24% L), 437 were AA (25% A+B, 50% S, 25% L), and 161 were Hispanic (22% A+B, 57% S, 21% L). Compared to Whites, a significantly higher proportion of AAs had underlying hepatitis C (87% vs 56%, p<0.05). There was a trend towards a lower proportion of CP B and C and less ascites in AAs compared to Whites. Table shows median OS (mOS) by race and regimen, along with hazard ratios (HRs) from the multivariate analysis. The survival benefit associated with A+B compared with S or L was numerically greater in AA patients versus White patients, although the difference did not achieve statistical significance. Conclusions: In this real-world cohort of 1L uHCC patients, A+B demonstrated a significant survival advantage over TKIs across racial/ethnic groups. Understanding the factors contributing to the effectiveness of A+B across racial/ethnic groups could provide valuable insights for guiding future trials and initiatives aimed at addressing racial disparities in HCC. [Table: see text]
Real-world survival outcomes and treatment patterns in patients (pts) with unresectable hepatocellular carcinoma (uHCC): Results from the OREIOS study.
Authors: Chan Stephen , Breder Valeriy Vladimirovich , Shao Yu Yun , Tai David , Waked Imam , Ganguly Sandip , Alolayan Ashwaq , Aboutaleb Ahmed , Farag Heba , Ryu Min-Hee
Published: January 2024

449

Background: Recent advances in systemic therapies have revolutionized the management of HCC. However, there is limited real-world data on treatment patterns and survival outcomes in pts with uHCC. OREIOS (NCT05239507) study determined the clinical characteristics, management patterns and survival outcomes in pts with uHCC from 12 countries across Asia, Latin America, and Middle East and Africa. Methods: This non-interventional, retrospective study included pts with Barcelona Clinic Liver Cancer (BCLC) stage B or C unresectable or advanced/metastatic HCC at index date (date of diagnosis), diagnosed between January 2017 and December 2019. We present the clinicodemographic characteristics, treatment patterns, median overall survival (mOS), landmark survival (12 and 24 months), and median progression-free survival (mPFS). Results: A total of 1115 pts (median [range] age: 63 [18.0-97.0] yrs) were assessed; 83.2% (928/1115) were males, 49.1% (422/859) were current or ex-smokers, 21.4% (122/571) consumed alcohol. Most common etiologies were hepatitis B (48.9% [529/1082]), hepatitis C (23.1% [250/1082]) and alcoholic liver disease (6.6% [72/1082]). At index date, 22.3% (249/1115) and 77.7% (866/1115) presented with BCLC stage B and C, respectively with main portal vein invasion in 23.5% (262/1114), >50% liver involvement in 23.1% (250/1081) and extrahepatic metastases in 48.5% (541/1115). After index date, treatment modalities included systemic therapy (88.2% [992/1112] (including sorafenib [77.5%], nivolumab [21.3%], lenvatinib [19.8%], regorafenib [15.6%]), transarterial chemoembolization (TACE) (20.8% [232/1115]), and surgery (2.6% [29/1115]). The mPFS was 6.6 (95% CI 6.0, 7.2) months and mOS was 13.1 (95% CI 11.6, 14.2) months. Conclusions: Our study provides real-world data on treatment patterns and reports poor prognosis with pts reaching a mOS of ∼13 months. With novel agents and combination therapies being approved for uHCC, integrating them in routine care is important to improve survival. Alongside, further real-world studies are warranted for evaluating the change in treatment patterns and prognosis. Clinical trial information: NCT05239507 . [Table: see text]