Primary Gastric Adenocarcinoma Research Articles

Safety and feasibility of single-incision laparoscopic distal gastrectomy in overweight and obese gastric cancer patients: a propensity score-matched analysis

BackgroundThe technical challenges and safety concerns of single-incision laparoscopic gastrectomy for overweight and obese gastric cancer patients remain unclear. This study aimed to evaluate the safety and feasibility of single-incision laparoscopic distal gastrectomy (SIDG) compared to multiport laparoscopic distal gastrectomy (MLDG) in overweight and obese gastric cancer patients.MethodsThis study retrospectively analyzed overweight and obese patients (body mass index ≥ 25 kg/m2) and pathologic stage T1 primary gastric adenocarcinoma treated with either SIDG or MLDG. The SIDG and MLDG groups were propensity score matched at a 1:2 ratio using age, sex, height, body weight, American Society of Anesthesiologists classification, year of surgery, pathologic N stage, and anastomosis method as covariates.ResultsAfter 1:2 matching, the study included patients who underwent SIDG (n = 179) and MLDG (n = 358). No significant difference in the number of retrieved lymph nodes was found between the SIDG and MLDG groups (52.8 ± 19.3 vs. 53.9 ± 21.0, P = 0.56). Operation times were significantly shorter in the SIDG group (170.8 ± 60.0 min vs. 186.1 ± 52.6 min, P = 0.004). The postoperative hospital length of stay was comparable between the 2 groups (SIDG: 5.9 ± 3.4 days vs. MLDG: 6.3 ± 5.1 days, P = 0.23), as was postoperative complication rate (SIDG: 13.4% vs. MLDG: 12.8%, P = 0.89).ConclusionsSIDG was shown to be as safe and feasible as MLDG for overweight and obese gastric cancer patients, with comparable early postoperative complication rates without compromising operation time compared to MLDG.

ERBB2 amplification in gastric cancer: a genomic insight into ethnic disparities.

Overall, gastric adenocarcinoma (GC) incidence rates have declined in recent years, but racial/ethnic disparities persist. Individuals who identify as Hispanic/Spanish/Latino are diagnosed with GC at younger ages and have poorer outcomes than non-Hispanic individuals. However, our understanding of GC biology across racial/ethnic groups remains limited. We assessed tumor genomic patterns by race/ethnicity among 1019 patients with primary GC in the AACR Project GENIE Consortium. Hispanic individuals presented with significantly higher rates of ERBB2/HER2 amplification vs other racial/ethnic groups (Hispanic: 13.9% vs 9.8% non-Hispanic White, 8.1% non-Hispanic Asian, and 11.0% non-Hispanic Black; p < .001, FDR adjusted q < 0.001). Hispanic patients also had higher odds of an ERBB2 amplification vs non-Hispanic whites in adjusted models (OR = 2.52, 95%CI = 1.20-5.33, p = .015). These findings underscore the important role of genomic factors in GC disparities. Ensuring equitable access to genomic profiling and targeted therapies, such as trastuzumab for HER2-overexpressing GC, is a promising avenue to mitigate GC disparities and improve outcomes.

Effect of anti-claudin 18.2 monoclonal antibody zolbetuximab alone or combined with chemotherapy or programmed cell death-1 blockade in syngeneic and xenograft gastric cancer models

The development of targeted cancer therapies based on monoclonal antibodies against tumor-associated antigens has progressed markedly over recent decades. This approach is dependent on the identification of tumor-specific, normal tissue-sparing antigenic targets. The transmembrane protein claudin-18 splice variant 2 (CLDN18.2) is frequently and preferentially displayed on the surface of primary gastric adenocarcinomas, making it a promising monoclonal antibody target. Phase 3 studies of zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody targeting CLDN18.2, combined with 5-fluorouracil/leucovorin plus oxaliplatin (modified FOLFOX6) or capecitabine plus oxaliplatin (CAPOX) in advanced or metastatic first-line gastric or gastroesophageal junction (G/GEJ) adenocarcinoma have demonstrated favorable clinical results with zolbetuximab. In studies using xenograft or syngeneic models with gastric cancer cell lines, zolbetuximab mediated death of CLDN18.2-positive human cancer cell lines via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro and demonstrated anti-tumor efficacy as monotherapy and combined with chemotherapy in vivo. Mice treated with zolbetuximab plus chemotherapy displayed a significantly higher frequency of tumor-infiltrating CD8+ T cells versus vehicle/isotype control-treated mice. Furthermore, zolbetuximab combined with an anti-mouse programmed cell death-1 antibody more potently inhibited tumor growth compared with either agent alone. These results support the potential of zolbetuximab as a novel treatment option for G/GEJ adenocarcinoma.

Metastatic gastric cancer in a 23- year-old female Zambian diagnosed posthumously: A case report

Introduction: Gastric cancer is one of the leading causes of cancer mortality globally and in Zambia, its exact burden is unknown. Here, we present a case of gastric cancer in a young adult that was diagnosed posthumously.&#x0D; Clinical details: A 23-year-old female patient was referred to the largest tertiary care institution in Zambia, the University Teaching Hospital (UTH). She had been followed up at a district hospital. The patient had a three months’ history of ill-health with symptoms of anaemia, abdominal pain and distension. Upon arrival at UTH, she was noted to be very frail, with pallor, tachycardia and gross abdominal distension and a nodular irregular liver, measuring 10cm below the costal margin. A digital rectal examination revealed the presence of melena. She had no jaundice, lymphadenopathy or finger clubbing but had bilateral pedal oedema. A provisional diagnosis of hepatocellular carcinoma complicated by upper gastrointestinal bleeding was made. Subsequent investigations revealed normal alpha fetoprotein, a Transient Elastography value of 75kPa and negative hepatitis B and C serology. Computerised tomography scan showed multiple liver masses with ascites. The patient continued to deteriorate despite supportive management and died on day 10 of admission. A post mortem was done which revealed a primary gastric adenocarcinoma with metastasis to the liver, lungs and pancreas.&#x0D; Conclusion: This is an example of a case of gastric cancer that was not detected while the patient was alive. It illustrates how cases of gastric cancer would be missed by the Zambia National Cancer Registry recording system.

Abstract 5939: Enhancing nab-paclitaxel chemotherapy response in gastric cancer preclinical models through Inhibition of the HGF/c-Met pathway with merestinib

Abstract Background: Current treatments for primary metastatic or recurrent gastric adenocarcinoma (GAC) primarily involve combination chemotherapy, but the median survival time remains under a year. Nab-paclitaxel has displayed significant antitumor activity in preclinical GAC studies. GAC often exhibits overexpression of various growth factors and their receptors, which play a critical role in its pathophysiology. Aberrant activation of the HGF/c-Met pathway has been reported in up to 50% of GAC patients. We investigated the therapeutic potential of merestinib, a novel inhibitor targeting c-Met, along with Axl and DDR1/2 pathways, in combination with nab-paclitaxel in GAC preclinical models. Methods: Animal survival studies were conducted using peritoneal dissemination xenografts in NOD/SCID mice implanted with MKN-45 cells. Tumor growth was assessed in subcutaneous xenografts using MKN-45 and SNU-1 cells in NOD/SCID mice. IHC analyses were performed to evaluate tumor cell proliferation and microvessel density. In vitro cell proliferation and protein expression were assessed using the WST-1 assay and Western blot analysis, respectively. Results: Animal survival significantly improved with nab-paclitaxel (118%) and merestinib (41%) individually. The combination of merestinib with nab-paclitaxel (153%) resulted in further increased animal survival. In MKN-45 xenografts with high c-Met expression, a substantial reduction in tumor growth was observed with nab-paclitaxel and merestinib, showing a synergistic response. The net change in tumor size in the control, nab-paclitaxel, merestinib, and combination groups was 503 mm3, 115 mm3, 91 mm3, and -9.7 mm3 (tumor regression). In low c-Met expressing SNU-1 xenografts, the effect of merestinib and nab-paclitaxel was less pronounced compared to MKN-45 xenografts. The net change in tumor size in the control, nab-paclitaxel, merestinib, and combination groups was 219 mm3, 105 mm3, 131 mm3, and 57 mm3. Tumor cell proliferation and microvessel density corroborated the tumor growth study results. Nab-paclitaxel and merestinib reduced in vitro cell proliferation, with an additive effect in combination. The reduction in cell proliferation by nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% in MKN-45, 59%, 50%, and 82% in SNU-1, and 53%, 19%, and 66% in gastric fibroblasts. In MKN-45 cells, merestinib increased the expression of pro-apoptotic proteins and decreased the expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. Conclusion:Merestinib has strong antitumor activity in GAC, especially when administered with nab-paclitaxel, demonstrating a synergistic effect. These results provide compelling evidence for the potential clinical relevance of this combination therapy in improving the survival of GAC patients. Citation Format: Quinn Kaurich, Jennifer Huang, Sazzad Hassan, Urs von Holzen, Niranjan Awasthi. Enhancing nab-paclitaxel chemotherapy response in gastric cancer preclinical models through Inhibition of the HGF/c-Met pathway with merestinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5939.

A160 A CASE OF BREAST CANCER METASTASIS MASQUERADING AS SIGNET RING CELL ADENOCARCINOMA OF THE STOMACH

Abstract Background Gastric cancer has a poor prognosis, particularly at advanced stages. Endoscopic submucosal dissection (ESD) can be used to treat selected early-stage gastric cancers. This case study explores the challenge of diagnosing and managing patients when metastatic lesions mimic primary gastric cancer, as seen in this case of breast cancer metastasis resembling signet ring cell adenocarcinoma of the stomach. Aims The aim of this case report is to describe an unusual case of breast cancer metastasis to the stomach identified unexpectedly on random gastric biopsies, initially diagnosed as a primary gastric signet ring cell adenocarcinoma. Methods Clinical and pathological records of the described patient were reviewed retrospectively. Furthermore, a review of the relevant literature was also performed. Results A 68 year-old-woman underwent gastroscopy for nausea and vomiting. Her past medical history was remarkable for bilateral mastectomies ten years ago for invasive lobular carcinoma, with metastatic bone disease diagnosed by imaging five years prior. She had been well controlled on letrozole taken intermittently due to side effects. At endoscopy, while the stomach appeared grossly normal, random biopsies done for Helicobacter pylori identified a single focus of signet ring cell adenocarcinoma. Subsequent chromoendoscopy identified an area of subtle mucosal abnormality for which the patient declined surgery and was instead managed by ESD which surprisingly yielded no dysplasia. A follow up gastroscopy with random biopsies also failed to identify any areas of dysplasia, but random biopsies on a subsequent gastroscopy again identified a minute focus of adenocarcinoma with signet ring cell morphology. Given the unusual presentation of apparent signet ring cell adenocarcinoma in two distinct areas in the stomach without any visible endoscopic abnormality an in-depth pathological analysis was conducted. By immunohistochemistry the tumor cells stained positive for Estrogen Receptor, GATA3, and CK7 and negative for antibodies targeting CK20 and CDX2, which supported an interpretation of minute multifocal breast cancer metastases to the stomach from hematogenous spread. Conclusions In this case, repeated endoscopic investigations and immunohistochemical staining revealed minute multifocal breast cancer metastases to the stomach. Conventional tumor staging methods often cannot identify microscopic metastases, potentially impacting disease progression and patient care. A high level of suspicion for metastatic breast cancer and a detailed pathological analysis allowed for the correct diagnosis in this patient. Funding Agencies None

Multidisciplinary treatment of synchronous primary advanced gastric adenocarcinoma and esophageal squamous cell carcinoma–a retrospective single-institution study

Multidisciplinary treatment of synchronous primary advanced gastric adenocarcinoma and esophageal squamous cell carcinoma–a retrospective single-institution study

Effect of Preoperative Body Mass Index on Postoperative and Long-Term Outcomes in an East Indian Gastric Cancer Cohort.

Gastric cancer is a global health concern with varying clinical outcomes. This study aims to investigate the influence of preoperative Body Mass Index (BMI) on survival in patients who underwent curative resection for gastric cancer in Eastern India. Data from a prospectively maintained Surgical Oncology database were analysed for patients who underwent curative resection for primary gastric adenocarcinoma between May 2016 and March 2022. Patients with incomplete data were excluded. Preoperative BMI was categorised into three groups: Underweight (< 18.5kg/m2), Normal (18.5-22.9kg/m2), and Overweight/Obese (=23kg/m2). Clinicopathological details, short-term outcomes, and long-term oncological outcomes were assessed. Statistical analysis included survival estimates, Cox proportional hazard models, and subgroup analysis. Of 162 patients, 145 met the inclusion criteria. Patients were predominantly male (68%) with middle or lower socioeconomic status. No significant differences amongst BMI groups were observed in performance score, tumour grade, clinical stage, or short-term outcomes. Postoperative complications and 30-day mortality were similar. However, underweight patients had poorer 4-year disease-free survival (DFS) compared to overweight/obese patients (14.3% vs. 39.7%, p = 0.03). Overweight/obese patients showed significantly better 4-year overall survival (OS) than underweight patients (47.8% vs. 20.4%, p = 0.03). In Eastern Indian gastric cancer patients undergoing curative resection, preoperative higher BMI (overweight/obese) was associated with better long-term survival. Understanding these findings could guide tailored interventions to improve outcomes in this population.

Gastric collision tumor with diffuse large B-cell lymphoma and adenocarcinoma: A rare case report and literature review.

Gastric adenocarcinoma is a common malignant tumor of the digestive system. Primary diffuse large B-cell lymphoma (DLBCL) of the stomach is a common lymphoma originating from gastric submucosal lymphoid tissue, and the coexistence of DLBCL and adenocarcinoma is exceedingly rare. A 58-year-old woman came to our hospital for treatment because of a choking feeling after eating. During endoscopy, it was confirmed that multiple irregular ulcers were seen in the fundus and body of the stomach, and the surrounding mucosa was raised. The biopsy pathology showed poorly differentiated cancer, and the patient did not undergo immunohistochemical detection. A distal gastrectomy was performed. Pathological evaluation of resected specimens is as follows: gastric tubular adenocarcinoma and germinal center-type (GC)-DLBCL. No migration was found at the junction of the two tumors, forming a collision tumor. The patient received two cycles of Rituximab - Cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) chemotherapy, and there is no recurrence at present. We report a case of primary gastric adenocarcinoma colliding with the GC-DLBCL. Clinicians and pathologists should pay attention to it to avoid missed diagnosis.

Heterogeneous Cellular Response of Primary and Metastatic Human Gastric Adenocarcinoma Cell Lines to Magnoflorine and Its Additive Interaction with Docetaxel

Gastric cancer is the most common cancer and remains the leading cause of cancer death worldwide. In this study, the anticancer action of magnoflorine isolated via counter-current chromatography from the methanolic extract of Berberis vulgaris root against gastric cancer in models of primary ACC-201 and AGS and metastatic MKN-74 and NCI-N87 cell lines was analyzed. Cell viability and proliferation were tested through the use of MTT and BrdU tests, respectively. Cell cycle progression and apoptosis were evaluated using flow cytometry. The interaction of magnoflorine and docetaxel has been examined through isobolographic analysis. Moreover, potential toxicity was verified in zebrafish in an in vivo model. Gastric cancer cell lines revealed different responses to magnoflorine treatment with regard to viability/proliferation, apoptosis induction and cell cycle inhibition without any undesirable changes in the development of larval zebrafish at the tested concentrations. What is more, magnoflorine in combination with docetaxel produced an additive pharmacological interaction in all studied gastric cancer cell lines, which may suggest a complementary mechanism of action of both compounds. Taken together, these findings provide a foundation for the possibility of magnoflorine as a potential therapeutic approach for gastric cancer and merits further investigation, which may pave the way for clinical uses of magnoflorine.

A pH-Sensitive Fluorescent Chemosensor Turn-On Based in a Salen Iron (III) Complex: Synthesis, Photophysical Properties, and Live-Cell Imaging Application.

pH regulation is essential to allow normal cell function, and their imbalance is associated with different pathologic situations, including cancer. In this study, we present the synthesis of 2-(((2-aminoethyl)imino)methyl)phenol (HL1) and the iron (III) complex (Fe(L1)2Br, (C1)), confirmed by X-ray diffraction analysis. The absorption and emission properties of complex C1 were assessed in the presence and absence of different physiologically relevant analytes, finding a fluorescent turn-on when OH- was added. So, we determined the limit of detection (LOD = 3.97 × 10-9 M), stoichiometry (1:1), and association constant (Kas = 5.86 × 103 M-1). Using DFT calculations, we proposed a spontaneous decomposition mechanism for C1. After characterization, complex C1 was evaluated as an intracellular pH chemosensor on the human primary gastric adenocarcinoma (AGS) and non-tumoral gastric epithelia (GES-1) cell lines, finding fluorescent signal activation in the latter when compared to AGS cells due to the lower intracellular pH of AGS cells caused by the increased metabolic rate. However, when complex C1 was used on metastatic cancer cell lines (MKN-45 and MKN-74), a fluorescent turn-on was observed in both cell lines because the intracellular lactate amount increased. Our results could provide insights about the application of complex C1 as a metabolic probe to be used in cancer cell imaging.

ASSOCIATION OF HER2/NEU EXPRESSION WITH PATIENT PROGNOSIS IN PRIMARY GASTRIC ADENOCARCINOMA

Introduction: Gastric carcinoma is the second leading cause of cancer related deaths in the world. Aim of the present study was to determine the association of HER2 overexpression with prognostic factors in gastric adenocarcinoma affected Pakistani patients.&#x0D; Methods: For this purpose, immunohistochemical staining of gastric cancer patients (n=200) was performed. HER2 was found to be overexpressed in 70% of cases included in the study. Association of HER2 expression with age greater than 40 years at the time of diagnosis, histological types and moderately differentiated grades of primary gastric adenocarcinoma was observed.&#x0D; Results: HER2 was found to be overexpressed in 20% of cases. No association of HER2 was identified with the gender of the patients. Interestingly, HER2, overexpression was present in 75% of intestinal and 37% of diffuse type gastric adenocarcinoma. Based on tumor differentiation, well-differentiated (grade I) and moderately differentiated type (grade II) adenocarcinoma showed overexpression of HER2 in 90 and 80% patients respectively. Moreover, 60% patients having poorly differentiated adenocarcinoma (grade III) also exhibited HER2 overexpression.&#x0D; Conclusion: Due to presence of HER2 overexpression in diffuse type gastric carcinoma as well, it is suggested that every case of gastric adenocarcinoma should be tested for HER2 overexpression so that they can be offered targeted molecular therapy for better survival.

Expression of Her2-Neu in Primary Gastric and Gastroesophageal Adenocarcinoma: An Experience from a Tertiary Center in South India

Gastric cancer is one of the most commonly occurring cancers worldwide, often presenting at an advanced stage. Combining targeted therapy with chemotherapeutic agents can enhance and extend the survival of these patients. This 4-year retrospective study aims to assess the prognostic role of Her2-Neu expression in gastric and gastroesophageal (GE) cancer. Clinicopathological features, histological type (Lauren classification) of adenocarcinoma, and Her2 immunohistochemical expression were correlated with disease-free and overall survival in 114 patients. A Her2 score of 0 and 1+ indicated negativity, while 3+ marked positivity. For cases with a 2+ score, fluorescent in situ hybridization (FISH) was conducted for definitive categorization. Statistical analysis employed IBM SPSS version 20.0 software. Among 114 patients, 13 displayed strong Her2-Neu immunopositivity (3 + ), 9 scored 2 + , and 92 were negative (0 [89] and 1+ [3]). FISH classified 4 and 5 cases as positive and negative, respectively. Most (64.7%) Her2-Neu-positive tumors occurred in the proximal stomach/GE junction (GEJ) and exhibited intestinal morphology (94.1%) with moderate differentiation (p-value &lt; 0.05). Notably, 76.5% of Her2-Neu-positive patients exhibited advanced-stage disease with nodal/distant metastasis. The average disease-free survival was 15.4 months (standard error: 3.55) for positive Her2-Neu expression and 22.07 months (standard error: 1.364) for negative expression. The mean overall survival was 21.14 months (standard error: 3.702) for positive expression and 23.91 months (standard error: 1.474) for negative expression. Her2-Neu expression in gastric/GEJ adenocarcinomas correlates with reduced survival. Evaluating Her2-Neu in proximal gastric/GEJ cancers displaying low-grade intestinal morphology serves as both a predictive and prognostic indicator.

Feasibility study fulfilling expanded endoscopic resection criteria in mucosal undifferentiated gastric cancer.

The indication of endoscopic submucosal dissection (ESD) for mucosal undifferentiated early gastric cancer (EGC) remains controversial because of risk of lymph node metastasis (LNM). The aim of this study was to identify risk factors for lymph node metastasis (LNM) in mucosal undifferentiated EGC, and further to confirm feasibility of the ESD for the treatment of mucosal undifferentiated EGC. We retrospectively reviewed data of patients who underwent surgical resection with lymph node dissection of T1a stage primary gastric adenocarcinoma at three medical centers between 2012 and 2022. We evaluated the frequency of lymph node metastasis and the associated risk factors, as well as the lymph node metastasis rate in the expanded indication of mucosal undifferentiated EGC. A total of 100 surgically treated patients with mucosal undifferentiated EGC were enrolled. LNM was irrelevant to the age, tumor size, location, and macroscopic type (all P>0.05), while it was significantly associated with lymphovascular invasion (LVI, P ＜0.001). And logistic regression analysis showed that the LVI was the only significant risk factors for LNM (OR: 0.34, 95%CI: 0.06-0.204; P ＜0.001). Of 44 mucosal undifferentiated EGC patients satisfying the expanded indication of ESD, 3 patients (6.8%) showed LN metastasis, all of them with undifferentiated cancer without ulceration, less than 2.0cm in size. Because LNM is present in mucosal undifferentiated EGC patients who satisfied the expanded indication of ESD, ESD cannot be considered a better choice than surgery for all undifferentiated EGC patients. LVI was significant risk factors for LNM in patients with mucosal undifferentiated EGC.

Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression.

Understanding tumor microenvironment (TME) reprogramming in gastric adenocarcinoma (GAC) progression may uncover novel therapeutic targets. Here, we performed single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and compositions as GAC progresses. Abundant IgA+ plasma cells exist in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominate late-stage GACs. We identified six TME ecotypes (EC1-6). EC1 is exclusive to blood, while EC4, EC5, and EC2 are highly enriched in uninvolved tissues, premalignant lesions, and metastases, respectively. EC3 and EC6, two distinct ecotypes in primary GACs, associate with histopathological and genomic characteristics, and survival outcomes. Extensive stromal remodeling occurs in GAC progression. High SDC2 expression in cancer-associated fibroblasts (CAFs) is linked to aggressive phenotypes and poor survival, and SDC2 overexpression in CAFs contributes to tumor growth. Our study provides a high-resolution GAC TME atlas and underscores potential targets for further investigation.

Neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant S-1 for resectable advanced gastric cancer: Final survival outcomes of the randomized phase 3 PRODIGY trial.

30 Background: The phase 3 PRODIGY study compared neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy followed by surgery followed by adjuvant S-1 with surgery followed by adjuvant S-1 for Korean patients with resectable locally advanced gastric cancer (LAGC) (Kang et al. J Clin Oncol. 2021). The planned analysis of the primary endpoint of PRODIGY showed that the addition of neoadjuvant DOS to surgery and adjuvant S-1 improved progression-free survival (PFS). We herein report the long-term follow-up outcomes, including overall survival (OS), from this trial. Methods: Patients with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma with clinical T2-3N+ or T4Nany disease were enrolled from 18 Korean study sites. Patients were randomly assigned to D2 surgery followed by adjuvant S-1 (40–60 mg orally twice a day, days 1–28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1–14 q3w for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary endpoint was PFS. OS was the secondary endpoint. This analysis presents the final assessment of the outcomes after 5 years. Results: A total of 266 and 264 patients were randomly assigned to the CSC and SC arms, respectively, among which 238 and 246 patients were treated and included in the full analysis set. As of the data cut-off date (SEP-2022), the median follow-up duration of the surviving patients was 99.5 months (range, 68.6–127.7 months). As compared to SC, CSC significantly increased the OS (adjusted hazard ratio, 0.72; 95% CI, 0.54 to 0.97; stratified log-rank P=0.028) with a 5-year OS rate of 66.8% and 63.0% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (adjusted hazard ratio, 0.71; 95% CI, 0.53 to 0.94; stratified log-rank P=0.019) with a 5-year PFS rate of 60.6% and 56.9% for the CSC and SC arms, respectively. Among the patient subgroups determined based on different clinical T/N categories, a patient subgroup with cT4Nany disease showed the greatest relative risk reduction in OS with neoadjuvant chemotherapy (HR 0.69, 95% CI 0.51–0.95). Conclusions: The addition of neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, to surgery and adjuvant S-1 prolonged the OS and PFS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1 alone. Neoadjuvant DOS chemotherapy should be considered one of the standard treatment options for patients with LAGC in Asia. Unlike in the Western setting, neoadjuvant chemotherapy may be preferentially considered for patients with cT4 disease in Asia. Clinical trial information: NCT01515748 .

Programmed death-ligand 1 (PD-L1) expression in primary gastric adenocarcinoma and matched metastases

BackgroundCombination of immunotherapy and chemotherapy is recommended for first line treatment of gastric adenocarcinoma (GC) patients with locally advanced unresectable disease or metastatic disease. However, data regarding the concordance rate between PD-L1 combined positive score (CPS) in primary GC and matched regional lymph node metastasis (LNmet) or matched distant metastasis (Dmet) is limited.MethodsTissue microarray sections from primary resected GC, LNmet and Dmet were immunohistochemically stained with anti-PD-L1 (clone SP263). PD-L1 expression was scored separately in tumour cells and immune cells and compared between matched primary GC, LNmet and/or Dmet. CPS was calculated and results for CPS cut-offs 1 and 5 were compared between matched samples.Results275 PD-L1 stained GC were analysed. 189 primary GC had matched LNmet. CPS cut-off 1 concordance rate between primary GC and LNmet was 77%. 23 primary GC had matched Dmet but no matched LNmet, CPS cut-off 1 concordance rate was 70%. 63 primary GC had both matched LNmet and matched Dmet, CPS cut-off 1 concordance rate of 67%. CPS cut-off 5 results were similar. The proportion of PD-L1 positive tumour cells increased from primary GC (26%) to LNmet (42%) and was highest in Dmet (75%).ConclusionOur study showed up to 33% discordance of PD-L1 CPS between primary GC and LNmet and/or Dmet suggesting that multiple biopsies of primary GC and metastatic sites might need to be tested before considering treatment options. Moreover, this is the first study that seems to suggest that tumour cells acquire PD-L1 expression during disease progression.

Neoadjuvant docetaxel, oxaliplatin, and s-1 plus surgery and adjuvant s-1 for resectable advanced gastric cancer: Final survival outcomes of the randomized phase 3 PRODIGY trial.

4067 Background: The phase 3 PRODIGY study compared neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy followed by surgery followed by adjuvant S-1 with surgery followed by adjuvant S-1 for Korean patients with resectable locally advanced gastric cancer (LAGC) (Kang et al. J Clin Oncol. 2021). The planned analysis of the primary endpoint of PRODIGY showed that the addition of neoadjuvant DOS to surgery and adjuvant S-1 improved progression-free survival (PFS). We herein report the long-term follow-up outcomes, including overall survival (OS), from this trial. Methods: Patients with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma with clinical T2-3N+ or T4Nany disease were enrolled from 18 Korean study sites. Patients were randomly assigned to D2 surgery followed by adjuvant S-1 (40–60 mg orally twice a day, days 1–28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1–14 q3w for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary endpoint was PFS. OS was the secondary endpoint. This analysis presents the final assessment of the outcomes after 5 years. Results: A total of 266 and 264 patients were randomly assigned to the CSC and SC arms, respectively, among which 238 and 246 patients were treated and included in the full analysis set. As of the data cut-off date (SEP-2022), the median follow-up duration of the surviving patients was 99.5 months (range, 68.6–127.7 months). As compared to SC, CSC significantly increased the OS (adjusted hazard ratio, 0.72; 95% CI, 0.54 to 0.97; stratified log-rank P=0.028) with a 5-year OS rate of 66.8% and 63.0% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (adjusted hazard ratio, 0.71; 95% CI, 0.53 to 0.94; stratified log-rank P=0.019) with a 5-year PFS rate of 60.6% and 56.9% for the CSC and SC arms, respectively. Conclusions: The addition of neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, to surgery and adjuvant S-1 prolonged the OS and PFS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1 alone. Neoadjuvant DOS chemotherapy should be considered one of the standard treatment options for patients with LAGC in Asia. Clinical trial information: NCT01515748 .

Abstract 1194: Evolution of immune and stromal cell states during the gastric cancer continuum

Abstract Introduction: Gastric adenocarcinoma (GAC), a global health burden, lacks detail understanding of the evolution-driven cellular/molecular programs that lead to GAC tumorigenesis followed by progression/metastases. How the TME is orchestrated by precancerous lesions, primary GAC, and in metastatic niches, when well understood, may propel us into an entirely new dimension with the hopes of novel therapeutics. However, only a few studies have investigated the immune/stromal subtypes of GAC with the limitation of scope, cohort size, and/or depth or mainly focused on the primary GACs. Here, we present an atlas of transcriptionally diverse TME across the full continuum of GAC by including peripheral blood, normal gastric tissues, premalignant lesions, localized, and metastatic GACs. Methods: We performed a comprehensive single-cell profiling of 68 specimens collected from 43 subjects including a total of 77,392 high-quality cells which revealed 62 unique cell states uncovering varying profiles. We defined alterations in TMEs that underscore initiation of tumorigenesis to eventual progression. Results: We found a striking preponderance of B lineage cells, primarily the IgA+ plasma cells, in TMEs of the precancerous lesions, whereas 3 immunosuppressive myeloid subsets dominated in advanced GACs. Fractions of GZMK+ effector CD8 T cells and progenitor exhausted CD8 T cells gradually increased as GACs progressed to advanced stages. In addition, our analysis revealed extensive stromal remodeling along the GAC continuum, which may have contributed to enhanced angiogenesis and immune suppressive signaling. The observations in the primary tumors could be validated in an independent scRNA-seq dataset. Notably, we uncovered 3 unique TME interactomes and defined 6 cellular environtypes inhabited by 62 TME cell subsets giving GAC to a novel landscape not yet defined. The two distinct environtypes in GAC primaries are validated in three independent large-scale GAC cohorts, giving credence and definition to previously established histopathological variables, genomic/molecular subtypes and clinical outcomes. The analysis of tumor associated stromal cells discovered SDC2 as an exploitable target to pursue. SDC2 was abundant in cancer associated fibroblasts (CAFs), and the abundance is validated in 3 independent single-cell GAC cohorts as well as at the protein level. SDC2 expression was significantly higher in advanced (vs. early) stages and diffuse (vs. intestinal) type of GAC, and SDC2 overexpression was associated with shorter survival in all 5 large-scale GAC cohorts. Lastly, we assessed the functional effects of SDC2 expression in CAFs on tumor growth in vivo in xenograft models and found SDC2 overexpression in CAFs contributes to tumor growth. Conclusion: This study provides an atlas of GAC TMEs from tumorigenesis to advanced GAC that could be further developed for novel therapeutics but also serves as a community resource. Citation Format: Ruiping Wang, Shumei Song, Jiangjiang Qin, Katsuhiro Yoshimura, Fuduan Peng, Yanshuo Chu, Yuan Li, Yibo Fan, Jiankang Jin, Minghao Dang, Enyu Dai, Guangsheng Pei, Guangchun Han, Yating Li, Deyali Chatterjee, Melissa P. Pizzi, Ailing W. Scott, Ghia Tatlonghari, Xinmiao Yan, Matheus Da Silva Sewastjanow, Ahmed Adel Fouad Abdelhakeem, Pawel K. Mazur, Xiangdong Cheng, Jaffer A. Ajani, Linghua Wang. Evolution of immune and stromal cell states during the gastric cancer continuum [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1194.

Abstract 1305: Cellular and molecular landscape of metastatic gastric cancer

Abstract Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality in the clinic. However, to date, the study of primary tumors with matched metastases from GAC patients has not been conducted, mainly because the collection of such samples in clinics is extremely challenging. To understand the evolution of metastatic cells and their interactions with the tumor microenvironment (TME), we performed paired single-cell transcriptome and immune profiling of primary tumors, matched liver metastases (LM) and/or peritoneal carcinomatosis (PC), adjacent normal, and blood specimens, a total of 68 samples collected from 20 treatment-naïve metastatic GAC patients. Our analysis revealed differentially remodeled TMEs across primary and metastatic sites, in particular, the B, T, and myeloid cells. Relative to normal tissues, the fractions of B lineage cells decreased significantly in primary GACs and were nearly depleted in LMs and PC samples. Consistently, T and B cell clonality decreased significantly in metastatic tumors, and the majority of the top expanded T cell clones were likely non-tumor specific. We discovered divergent evolutionary paths leading to diminished anti-tumor immune responses in the liver and peritoneal TMEs. For example, the Marco_c3 (highly expressed INHBA, SDC2, and CCL20) was highly enriched in LMs, whereas Marco_c1 (highly expressed APOE, APOC1, and C1QC) and proliferative macrophages were uniquely enriched in the peritoneal TME. In addition to TME cells, we defined normal epithelial cell states, quantified, and validated cancer cell state plasticity in paired primaries/metastases, and linked it to site-specific TME architectures. Notably, unlike PC cancer cells that displayed a greater degree of chromosomal instability, most LM cancer cells lost their lineage identity, embracing markedly increased epithelial-to-mesenchymal transition and “mixed” lineage states. Significant correlations between the fractions of TME cell subsets and the abundance of tumor cells in different lineage states were observed, suggesting potential crosstalk between tumor and TME cells. Lastly, we found differential activation of cancer meta-programs and gene co-expression modules (GMs) unique to metastatic tumors. Among them, high expression of GM2 in primary GACs predicts an increased risk of distant metastasis. In summary, this study provides a much needed and detailed understanding of the cellular and molecular basis of the phenotypic diversity of matched primary-metastases from GACs that have clinical implications. The single-cell multi-omics data generated by this study can serve as a valuable resource to the community to advance scientific discoveries. Citation Format: Enyu Dai, Jiang-Jiang Qin, Jibo Wu, Natasha M. Flores, Yanshuo Chu, Ruiping Wang, Minghao Dang, Zhiyuan Xu, Guangchun Han, Xuanye Cao, Can Hu, Jieer Ying, Yian Du, Litao Yang, Xiaoqing Guan, Shaowei Mo, Xiaoyin Lu, Ana Morales Benitez, Rebecca E. Waters, Melissa Pool Pizzi, Namita Shanbhag, Yibo Fan, Fuduan Peng, Andrew Futreal, Shumei Song, Cassian Yee, Pawel K. Mazur, Xiangdong Cheng, Jaffer A. Ajani, Linghua Wang. Cellular and molecular landscape of metastatic gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1305.