Adenocarcinoma Patients Research Articles

Skin microbiome differences in pancreatic adenocarcinoma, other cancers, and healthy controls: a pilot study

IntroductionMany studies have reported the importance of the human microbiome in relationship to the overall health of its host. While recent studies have explored the microbiome’s role in various types of cancer compared to healthy patients, this pilot study is the first to investigate differences in the skin microbiome composition among pancreatic adenocarcinoma patients, individuals with other cancers, and cancer-free controls.MethodsThe study characterizes the skin microbiome’s potential associations with cancer status by analyzing skin swabs from the forehead and cheek of 58 participants using Next Generation Sequencing (NGS), differential abundance analysis, and machine learning techniques.ResultsThe study results indicated that the cancer group displayed a significantly higher mean alpha diversity compared to the control group. Additionally, a machine learning classification model achieved a mean F1 Score of 0.943 in predicting cancer status, indicating measurable differentiation in the skin microbiome between the study groups. This differentiation is supported by differential abundance methods, including ANCOM-BC and MaAsLin2.DiscussionThis pilot study suggests that skin microbiome profiling could serve as a non-invasive biomarker for cancer detection and monitoring, which warrants a larger, longitudinal study to validate these results.

Long-term survival of an ALK fusion lung adenocarcinoma patient with high mutation burden and microsatellite instability high: a case report.

Immune checkpoint blockage (ICB) therapy has shown minimal effectiveness in anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC) regardless of Programmed death-ligand 1 expression. ALK fusion accompanied by mismatch repair deficiency or microsatellite instability-high (MMRd/MSI-H) and high tumor mutation burden (TMB-H) are extremely rare in NSCLC, and the efficacy of ALK inhibitors or ICB-based therapies is unclear. Here, we report the case of a 60-year-old female patient with metastatic lung adenocarcinoma accompanied by EML4-ALK fusion, TMB-H, MMRd/MSI-H, and pathogenic mutations in TP53, MLH1, and STK11. The patient experienced progression on initial iruplinalkib and subsequent alectinib therapy within 5 months. After the failure of third-line therapy with cisplatin-pemetrexed combined with bevacizumab, she received sintilimab plus anlotinib which led to a progression-free survival of 6.5 months. She received sintilimab combined with albumin-paclitaxel plus carboplatin and achieved partial response after 6 months. She developed adverse events after one cycle of sintilimab plus albumin-paclitaxel treatment. Then she was continued with sintilimab plus anlotinib as a maintenance therapy due to intolerance to chemotherapy. After progression on ICB-based therapy, the patient was treated with lorlatinib and still under follow-up with overall survival of more than 3 years. Our findings highlight the therapeutic potential of ICB-based regimens in patients with MSI-H and ALK-rearranged NSCLC.

Identification of tumor microenvironment-based gene prognostic signature with promising predictive value for chemo‐immunotherapy outcomes in lung adenocarcinoma patients

Objectives: The tumor microenvironment (TME) plays a critical role in tumor progression and therapeutic response. We aimed to establish a TME-associated gene signature for lung adenocarcinoma (LUAD) patients. Materials and Methods: We comprehensively analyzed the gene expression data of 513 LUAD patients deriving from The Cancer Genome Atlas (TCGA) database. To estimate the composition of TME, The Estimation of Stromal and Immune cells in malignant tumor tissue using the Expression data (ESTIMATE) algorithm was used. We then utilized protein-protein interaction (PPI) analysis, LASSO, and COX regression to explore the related candidate genes with survival. Eventually, a three-gene signature was constructed for risk stratification. Furthermore, we investigated its predictive value in advanced LUAD patients who received chemotherapy alone or combined with anti-PD-1 inhibitors. Results: We identified three genes, namely CCR2, CD40LG, and CCL21, to construct a TME-associated risk stratification gene signature. This gene signature was independently linked to patients' overall survival (OS) among the TCGA dataset (HR, 1.99; 95% CI 1.36-2.93, p < 0.001) and GEO dataset (HR, 1.62; 95%CI 1.19-2.20, p < 0.001). The addition of anti-PD-1 inhibitor Siltuximab to chemotherapy resulted in significantly longer progression-free survival (PFS) in low-risk patients (HR, 0.33; 95% CI: 0.20 - 0.56, p < 0.001) but not in those with high- risk (HR, 0.56; 95% CI:0.24 - 1.31, p = 0.173). Moreover, in patients who received Sintilimab combined with chemotherapy, PFS was significantly different between the high- and low-risk group (HR,1.958; 95%CI:1.079-3.555, p = 0.024), whereas no significant difference was found in chemotherapy alone treated patients (HR, 1.303; 95%CI: 0.610-2.784, p = 0.492). Conclusions: This study generated a three-gene prognostic signature based on TME-associated core genes in patients with LUAD. This gene signature has good value for prognosis prediction. In addition, this signature correlated with treatment outcomes among patients treated with chemotherapy combined with anti-PD1 therapy.

First-line Apatinib Combined With Tislelizumab and Chemotherapy for Advanced Gastric and Gastroesophageal Junction Adenocarcinoma Patients with Poor Prognosis.

In this prospective, open-label, exploratory study (RENMIN-213), patients with previously untreated, HER2-negative, advanced G/GEJ adenocarcinoma patients with signet ring cell carcinoma or peritoneal metastasis, were enrolled to receive 8 cycles of apatinib, tislelizumab, and chemotherapy every 3 weeks, with a maintenance therapy with apatinib plus tislelizumab for a maximum of 1 year. Homogeneous patients receiving ICIs combined with chemotherapy at the same time were deemed as the control group for efficacy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), biomarkers, health-related quality of life (HRQoL), and safety. A total of 33 patients (median [range] age, 60 [32-72] years; 21 [63.6%] male; 11 [33.3%] signet ring cell carcinoma; 30 [90.9%] peritoneal metastasis) were enrolled and deemed evaluable for efficacy analysis. Of these patients, 32 (97%) were without progression disease, of whom one (3.0%) patient had complete response and 18 (54.6%) had partial response. 6 patients (18.2%) were able to undergo surgery after treatment. After propensity score matching, the median PFS was 10.17 months (95% CI: 7.13-13.21) of apatinib combined with tislelizumab and chemotherapy group, as compared with 6.0 months in ICIs combined with chemotherapy group. The median DOR increased from 4.5 months to 8.7months. ORR increased from 33.3% to 54.6% and DCR increased from 87.9% to 97.0%. Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 11 patients (33.3%), patients' HRQoL improved after treatment.

Integrated analysis of M2 macrophage-related gene prognostic model and single-cell sequence to predict immunotherapy response in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) patients have high heterogeneity. The significance and clinical value of M2 macrophage-related genes in LUAD require further exploration. We aimed to construct a prognostic signature to predict the immunotherapy efficacy and prognosis in LUAD.MethodsGSE26939 and GSE19188 chips were downloaded from the Gene Expression Omnibus (GEO). Weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) analysis were used to screen M2 macrophage-related prognostic genes. A signature based on M2 macrophage-related prognostic genes was established and used to predict the prognosis and immunotherapy efficacy in LUAD.ResultsTwenty-two M2 macrophage-related genes associated with the prognosis of LUAD were confirmed using WGCNA, and then two molecular subtypes were identified with significantly different survival, gene expressions, and clinic characteristics were classified. LASSO analysis identified nine M2 macrophage-related prognostic genes to establish a risk signature, classifying patients into low- and high-risk groups. Data indicated that low-risk patients had better survival. Moreover, the signature was an independent prognostic factor for LUAD and a potential biomarker for patients receiving immunotherapy. Single-cell transcriptome analysis may provide important information on molecular subtypes and heterogeneity.ConclusionRisk signature based on M2 macrophage-related genes is a valuable tool for predicting prognosis and immunotherapy response in patients with LUAD.

Tislelizumab (TIS) + chemotherapy (chemo) vs placebo (PBO) + chemo as first-line (1L) treatment in gastric/gastroesophageal junction adenocarcinoma (GC/GEJC) patients with/without peritoneal or liver metastases: A post hoc analysis of RATIONALE-305 study.

414 Background: Gastric cancer patients with peritoneal or liver metastases had poor prognosis, and the efficacy of immunotherapy in these patients remains unclear. The global phase 3 RATIONALE-305 study (NCT03777657) demonstrated that tislelizumab combined with chemotherapy could bring survival benefits to 1L treatment of GC/GEJC patients. Here, we assessed the efficacy of TIS + chemo vs PBO + chemo in patients with/without peritoneal or liver metastases in RATIONALE-305. Methods: Patients with systemic treatment-naïve GC/GEJC were randomly assigned (1:1) to receive either TIS + chemo or PBO + chemo. Regression analyses were conducted to explore the associations between peritoneal or liver metastases and OS. Relative treatment effect between tislelizumab and placebo was assessed in each subgroup. The Kaplan-Meier method was used to estimate the median OS, and hazard ratios (HRs) for OS were estimated using Cox proportional hazards models. Results: Among the 997 randomized patients (TIS + chemo, n=501; PBO + chemo, n=496), 434 (43.5%) had peritoneal metastases (220 in TIS arm; 214 in PBO arm) and 378 (37.9%) had liver metastases (190 in TIS arm; 188 in PBO arm) at baseline. Regression analyses showed peritoneal and liver metastases were significantly associated with shorter OS. Baseline characteristics were balanced between TIS and chemo arms within each subgroup, including PD-L1 expression levels. As of data cut-off on Feb 28, 2024, OS was longer in the TIS arm compared with the PBO arm in patients with peritoneal metastases (HR= 0.78, 95% CI 0.64-0.96) or without (HR = 0.79, 95% CI 0.65-0.95). OS improvement was also observed in patients with liver metastases (HR = 0.77, 95% CI 0.62-0.96) or without (HR = 0.80, 95% CI 0.67-0.95). Conclusions: This post hoc analysis demonstrated OS improvement with TIS + chemo vs PBO + chemo in GC/GEJC patients with/without peritoneal or liver metastases. To our knowledge, RATIONALE-305 is the first global pivotal study reporting survival benefits with TIS + chemo as 1L treatment for GC/GEJC, irrespective of peritoneal or liver metastases. Clinical trial information: NCT03777657 . With metastases Without metastases TIS arm PBO arm TIS arm PBO arm Peritoneum n=220 n=214 n=281 n=282 Median OS, mo (95% CI) 12.3 (10.6-14.3) 11.8 (10.6-13.0) 17.3 (15.0-20.3) 14.0 (12.6-16.0) HR (95% CI) 0.78 (0.64-0.96) 0.79 (0.65-0.95) Liver n=190 n=188 n=311 n=308 Median OS, mo (95% CI) 13.9 (11.4-15.6) 12.9 (10.9-14.5) 16.0 (13.6-18.0) 12.9 (11.9-14.4) HR (95% CI) 0.77 (0.62-0.96) 0.80 (0.67-0.95)

Spatial profiling of endoplasmic reticulum stress markers in tumor associated cells predicts patient outcomes in pancreatic cancer.

The impact of endoplasmic reticulum (ER) stress in tumor-associated cells, such as cancer associated fibroblasts (CAFs), immune cells and endothelial cells, on patient outcomes in clinical specimens have not been examined. For the first time, we characterized the expression and spatial locations of ER stress markers, BiP and CHOP, in tumor-associated cells and assessed their prognostic significance in a panel of pancreatic ductal adenocarcinoma (PDAC) patient samples. Multiplex immunofluorescence was performed on tumor microarrays and images were analyzed using HALO AI software. BiP and CHOP were upregulated in CAFs and endothelial cells in PDAC sections relative to non-neoplastic pancreas sections. High BiP expression in CAFs and endothelial cells was associated with greater vascular invasion and in immune cells was correlated with increased tumor size. High CHOP expression in immune cells correlated with poor patient survival. CAFs and immune cells were more likely to express BiP or CHOP when located close (< 20 μm) to tumor cells. High expression of CHOP in CAFs close to tumor cells correlated with improved patient survival. For the first time, this study demonstrated that ER stress occurs in CAFs and immune cells predominantly in proximity to tumor cells in PDAC patient tissue. The correlation of high ER stress in immune cells with poor patient survival highlights the importance of the TME and the use of spatial analysis for the identification of novel biomarkers.

More isn't always better: Expanding and refining prognostic methylation signatures for pancreatic ductal adenocarcinoma.

769 Background: In our previous study, we developed protein-informed methylation signatures from a chemoresistance gene panel (RGp, n=122) curated from the literature, identifying 28 signatures with strong prognostic value in The Cancer Genome Atlas (TCGA) pancreatic ductal adenocarcinoma (PDA) database. To enhance the clinical utility of this panel, we incorporated methylation changes from genes with known prognostic (PGp) and diagnostic (DGp) significance in PDA to form a composite gene panel (CGp-PDA) and repeated our analysis. We hypothesized that epigenetic changes in these genes reflect protein expression and that deriving signatures from them could help identify patients at risk of treatment failure. Methods: We assembled a composite gene panel (CGp-PDA) of 206 genes (122 RGp + 26 PGp + 82 DGp) through a literature review spanning from January 1970 to April 2024. These PGp and DGp genes are unique, as cell-free DNA methylation changes in them have established prognostic and diagnostic value, respectively in PDA. The same cohort of pancreatic ductal adenocarcinoma (PDA) patients (n=184) from our previous study was analyzed. We applied elastic net multivariate analysis to calculate survival outcomes and generated Kaplan-Meier plots using our gene panel, optimizing values for 𝛼 and λ over 100 iterations. Results: Our analysis identified 20 signatures with cytosines followed by a guanine residue (CpG) site in genes from our panel. The number of CpG sites in these signatures ranged from 3 to 4248. The most effective signature featured 17 CpG sites (22 months [m] vs. 67m, p=0.03), followed by signatures with 3 (16m vs. 49m, p=0.009) and 12 (17m vs. 36m, p=0.02) CpG sites. The 4248 CpG site signature demonstrated the poorest prognostic value among the signatures (17m vs. 21m, p=0.01). Some signatures included multiple CpG sites within a single gene. Notably, KCNH2 reappeared in several signatures, as in the prior study. Expanding our RGp to CGp-PDA did not produce more (20 vs. 28) signatures or improved prognostic value. Conclusions: Targeted methylation signatures, supported by robust preclinical or translational evidence of their impact on treatment resistance, can be clinically valuable for informing treatment selection and prognosis. We may need to shift our focus from machine learning-based broad methylation or transcriptomic analyses to more targeted investigations.

XPO1 inhibition as a clinically viable strategy to enhance durability of response to KRAS G12D inhibitor in pancreatic ductal adenocarcinoma.

736 Background: The OFF State (GDP bound) KRASG 12D inhibitor MRTX1133 is currently being evaluated in pancreatic ductal adenocarcinoma (PDAC) patients. Nevertheless, as with other OFF state KRAS G12C inhibitors sotorasib and adagrasib, the KRAS G12D inhibitor may yield only a modest increase in disease-free survival due to emergence of drug resistance. This underscores the need to identify strategies that can enhance the efficacy of KRAS inhibitors in PDAC. Nuclear protein transport plays an important role in several pro-tumorigenic pathways and has been shown to be a therapeutic vulnerability in KRAS mutant cancers. XPO1 is the major nuclear exporter and plays a pivotal role in shuttling various critical tumor suppressors, genome surveillance proteins, and transcription factors out of the nucleus and is frequently overexpressed in various cancers, including PDAC. In this study, we employed a KRAS G12D inhibitor resistant model and evaluated its sensitivity to nuclear exporter protein inhibitor. Methods: We examined the cytotoxic and molecular effects of KRAS G12D inhibitor MRTX1133 in combination with nuclear transport inhibitor eltanexor in KRAS G12D inhibitor resistant models. The preclinical antitumor efficacy of the combination was evaluated in KRAS G12D mutant PDAC cell derived xenograft (CDX) subcutaneous and orthotopic models. Results: Eltanexor treatment reversed MRTX1133 resistance in vitro yielding suppressed proliferation of KRAS G12D mutant 2D and 3D cultures of PDAC cell lines and patient derived primary tumors cells. High throughput P-kinome analysis showed suppression of a larger repertoire of MAPK substrates in combination treatment compared to single agent group. Eltanexor and MRTX1133 combination led to reduction in protein expression of KRAS downstream effectors and cell cycle markers. Furthermore, a combined administration of eltanexor and MRTX1133 at sub-optimal doses resulted in remarkable tumor growth inhibition in multiple subcutaneous and orthotopic KRAS G12D mutant mice models. Moreover, eltanexor as a maintenance therapy also prevented tumor relapse indicating durability of response in PDAC. Conclusions: This is the first study demonstrating that nuclear transport inhibitors can overcome KRAS G12D inhibitor MRTX1133 resistance in PDAC cells. This study provides a rationale for combining MRTX1133 with eltanexor for the treatment of PDAC patients with KRAS G12D mutant tumors.

GOBLET study: Results of the safety run-in for first-line metastatic pancreatic ductal adenocarcinoma (PDAC) patients treated with pelareorep + modified FOLFIRINOX +/- atezolizumab.

730 Background: Immunotherapies are effective in only the small subset of metastatic PDAC patients with MSI-H or dMMR tumors. Pelareorep (pela) is a non-genetically modified, intravenously administered reovirus that selectively infects cancer cells. It stimulates the expansion of pre-existing tumor-infiltrating lymphocyte (TIL) clones, and it makes tumors visible to the immune system by upregulating interferon-induced gene expression including PD-L1, CXCL9, CXCL10, and CXCL11. PD-L1 upregulation also provides a basis for potential synergy between pela and immune checkpoint inhibitors. Pela combined with gemcitabine/nab-paclitaxel/atezolizumab showed promising tumor responses in mPDAC. Here, we are assessing the safety and preliminary efficacy of pela + mFOLFIRINOX +/- atezolizumab in a new cohort in the ongoing GOBLET study. Methods: GOBLET is a phase 1/2, open-label, Simon two-stage study in patients with advanced or metastatic GI cancers. In this new GOBLET cohort (Cohort 5), patients with newly diagnosed mPDAC are randomized to receive either pela + mFOLFIRINOX or pela + mFOLFIRINOX + atezolizumab. The primary endpoints are safety and objective response rate (ORR). In Stage 1, 15 evaluable patients will be enrolled in each arm. Both arms include a 3-6 patient safety run-in that must be successfully completed prior to opening the study to full enrollment. If pre-specified ORR success criteria are met, one or both arms may be advanced to Stage 2 during which 17 additional evaluable patients/per arm will be enrolled. Results: The 3-patient safety run-in for both arms of Cohorts 5 (6 patients total) have been enrolled, and all patients have completed the required 1-month evaluation period. Cohort 5 safety data have been reviewed by the independent Data Safety Monitoring Board (DSMB). The DSMB identified no safety signals attributable to the combination of pela and mFOLFIRINOX +/- atezolizumab and recommended that enrollment into these arms of Cohort 5 continue without modification. Reported adverse events are consistent with the known toxicities of the components of the treatment regimen. Tumor response results are pending. Conclusions: The results of the GOBLET Cohort 5 safety run-in indicate that pela can be given safely in combination with mFOLFIRINOX +/- atezolizumab to newly diagnosed mPDAC patients. Safety and efficacy of these combination therapies will continue to be monitored (Eudra-CT: 2020-003996-16). Clinical trial information: 2020-003996-16 .

Clinical Characteristics and Risk Factors of Patients with Lung Cancer Complicated with Pulmonary Embolism: A Case Control Study.

The purpose of this study was to investigate the clinical characteristics and risk factors for patients with lung cancer complicated by pulmonary embolism and to provide a reference for the early clinical identification of these patients. Eighty patients with lung cancer complicated with pulmonary embolism who were treated at Bethune Hospital of Shanxi from October 2018 to October 2025 were compared with 80 patients with lung cancer without pulmonary embolism. The clinical data of the two groups of patients were collected and analysed. Compared with that in patients in the LC group, the proportion of patients with pulmonary interstitial fibrosis in the LP group was significantly greater (p < 0.05). The incidence of dyspnoea in the LP group was significantly greater than that in the LC group (p < 0.05). Compared with that in the LC group, the proportion of pulmonary artery compression in the LP group was significantly greater, and the difference was statistically significant (p < 0.05). In terms of pathological type, the proportion of adenocarcinoma patients in the LP group was significantly greater than that in the LC group (p < 0.05). In terms of tumor stage, the proportion of patients with stage III/IV disease in the LP group was significantly greater than that in the LC group, while the proportion of patients with stage I/II disease was significantly lower than that in the LC group, and the difference was statistically significant (p < 0.05). The neutrophil [NEUT (%)], prothrombin time (PT), white blood cell (WBC), carcinoma embryonic antigen (CEA) and D-dimer (DD) levels were significantly greater in the LP group than in the LC group (p < 0.05). In terms of treatment, the proportion of patients receiving systemic chemotherapy in the LP group was significantly greater than that in the LC group (p < 0.05). Logistic regression analysis revealed that adenocarcinoma, systemic chemotherapy and tumor stage III-IV were independent risk factors for lung cancer complicated with pulmonary embolism. (1) Tumor stage (III/IV), systemic chemotherapy, and adenocarcinoma were independent risk factors for pulmonary thromboembolism in patients with lung cancer. (2) In addition, patients with LP were more likely to have pulmonary interstitial fibrosis, dyspnoea, compression of the pulmonary artery by the tumor location, biological targeted therapy, and abnormal increases in D-dimer, WBC, NEUT (%), CEA and PT levels as laboratory indicators. (3) Pulmonary thromboembolism should be considered in lung cancer patients with a combination of the factors described above.

Prognostic Significance of C-reactive protein or Prealbumin in Pancreatic Ductal Adenocarcinoma.

To clarify the prognostic significance of the C-reactive protein to prealbumin ratio (CRP or PALB) in patients with pancreatic cancer after radical resection. A total of 432 patients with pathologically confirmed pancreatic ductal adenocarcinoma were enrolled in this retrospective study. The predictive capacity of various inflammatory indices was analyzed and compared using the area under the time-dependent receiver operating characteristic curve, including CRP or PALB, CRP-to-albumin ratio, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio. The univariate and multivariate Cox hazard models were employed to analyze the effects of CRP or PALB on overall survival (OS) and recurrence-free survival (RFS). The optimal cut-off value for preoperative CRP or PALB was 5.94, which was derived from the receiver operating characteristic curve. In comparison with traditional inflammatory indices, CRP or PALB had the highest area under the time-dependent receiver operating characteristic curve (0.693 for 3-y OS, 0.664 for 3-y RFS, 0.662 for 5-y OS, and 0.670 for 5-y RFS), all with P<0.05. However, when compared with neutrophil-to-lymphocyte ratio, the predictive power of CRP or PALB was not significant for 3-y RFS (P=0.085). Based on the results of the univariate and multivariate survival analyses, patients in the high CRP or PALB group (HCP: CRP or PALB >5.94) exhibited significantly poorer OS and RFS (median OS: 20.0 versus. 38.0mo, P=0.003; median RFS: 10.0 versus. 22.0mo, P<0.001) than those in the low CRP or PALB group (CRP or PALB ≤5.94). The multivariate analysis indicated that the HCP was independently associated with poor OS (hazard ratio (HR): 1.556, 95% confidence interval (CI) [1.089-2.222], P=0.015) and RFS (HR: 1.551, 95% CI [1.135-2.119], P=0.006). The predictive capacity of preoperative CRP or PALB in pancreatic ductal adenocarcinoma patients exceeds that of traditional inflammatory indices. HCP levels are significantly correlated with a poor prognosis.

Elevated SAMD3 expression in T cells predicts improved survival in pancreatic ductal adenocarcinoma patients

ObjectivePancreatic ductal adenocarcinoma (PDAC) has an immune-suppressive tumor microenvironment that contributes to resistance to immunotherapy. This study aimed to demonstrate that elevated sterile alpha motif domain-containing protein 3 (SAMD3) expression in effector CD8+ T cells was associated with improved survival in PDAC patients.DesignWe investigated the heterogeneity and gene expression profiles of T cells using a single-cell RNA sequencing (sc-RNA-seq) dataset comprised of human PDAC samples. SAMD3 mRNA expression was further evaluated in a tumor-specific OT-I/ovalbumin (OVA) mouse model. SAMD3 levels and their clinical significance were evaluated via immunohistochemistry (IHC) analysis.ResultsSAMD3 was highly expressed in cytotoxic CD8+ T cells, with expression significantly downregulated during T cell exhaustion. SAMD3 levels were positively correlated with CD8+ T cell function. In PDAC patients, high SAMD3 levels in T cells were associated with improved overall survival (OS), disease-free survival (DFS), and T cell infiltration. A patient exhibiting partial response to combination immunotherapy also showed high SAMD3 levels in T cells.ConclusionSAMD3 is a biomarker of T cell function, with elevated expression in T cells predicting improved survival. These findings highlight the potential of precision immunotherapy approaches for treating PDAC.

Real-world biomarker testing and first-line treatment patterns among locally advanced, unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma patients in the US.

348 Background: Advanced-stage gastric cancer and gastroesophageal junction adenocarcinoma (advG/GEJC) are leading causes of cancer-related morbidity and mortality. Chemotherapy is the traditional first-line (1L) therapy for patients in the advanced setting, with targeted and immunotherapy considered based on biomarker expression. This study aimed to describe real-world HER2 and PD-L1 testing practices and 1L treatment patterns among advG/GEJC patients. Methods: A retrospective cohort study was conducted among adult patients diagnosed with advG/GEJC between 01 Jan 2017 and 30 Jun 2023 usingthe US-based Flatiron Health electronic health record-derived de-identified database. HER2 and PD-L1 testing practices were evaluated prior to and up to 1-month post-1L treatment initiation or 6 months post-advG/GEJC diagnosis date in untreated patients. 1L treatment regimens were described overall and stratified by HER2 and PD-L1 expression. Results: Among 4,256 advG/GEJC patients, the average age was 67 years with the majority male (68%), non-Hispanic white (44%), and with metastatic disease (64%). Nearly three quarters (72%) of patients included received a HER2 test and 55% had a HER2 test with a valid result within the timeframe mentioned above. More than a quarter of patients (27%) received a PD-L1 test and 25% had a PD-L1 test with a valid result. PD-L1 testing before the approval of nivolumab in 1L (i.e. before 2021) showed testing at 19% (490/2,629; 17% with a valid result) and from 2021 onward at 40% (643/1,627; 37% with a valid result). Across the full cohort, half of the patients received chemotherapy alone (52%) and one quarter received no treatment (25%). Similar treatment patterns were observed in the subset of 1,117 patients who did not receive a HER2 or PD-L1 test; 54% received chemotherapy alone and 36% no treatment. Of the 340 patients who were tested for HER2 and were HER2 positive, half (52%) received trastuzumab combination therapy, 23% received chemotherapy alone, and 18% had no treatment. Of the 301 patients who received a PD-L1 test with a combined positive score (CPS) ≥5 from 2021 onward, 41% received immunotherapy, 34% received chemotherapy alone and 18% had no treatment. Prior to 2021, most patients with a PD-L1 test and CPS &gt;5 used chemotherapy alone (57%; 132/233), 13% (31/233) received PD-L1 targeted therapies and 19% (43/233) received no treatment. Conclusions: This study describes a potential subset of US advG/GEJC patients who do not receive a HER2 or PD-L1 test and/or do not receive eligible targeted or immunotherapy as part of routine clinical practice. As precision medicine options continue to evolve, these data suggest an opportunity to further understand the drivers for biomarker testing as well as the factors impacting the use of biomarker-informed treatment options.

Clinical outcomes of adjuvant chemoradiotherapy in pancreatic adenocarcinoma with R1 resection.

731 Background: The benefit of chemoradiotherapy (CRT) following adjuvant chemotherapy in pancreatic cancer is unclear, though recent findings suggest some disease-free survival benefit over chemotherapy alone. We aimed to assess overall (OS) and progression-free survival (PFS) and patterns of disease recurrence following adjuvant chemoradiotherapy (CRT) in pancreatic adenocarcinoma patients with R1 resection (defined as &lt;1mm). Methods: We retrospectively collected data of patients with pancreatic adenocarcinoma who underwent adjuvant CRT (50.4-54Gy) following surgery with R1 resection between 2007-2023 in a single centre in the UK. Clinical data was collected from electronic medical records and information on radiotherapy was collected from treatment planning systems (TPS). Toxicity during and after CRT was graded with Common Terminology Criteria for Adverse Events (CTCAE). OS and PFS were measured with Kaplan-Meier curves from the time of surgery to death or disease progression or last follow up. In-field and locoregional recurrence were determined from restaging scans compared against radiotherapy field in TPS. Results: Among 33 patients included, 27 (81.8%) died within median follow-up 39 (14.8-111.4) months. All patients received adjuvant chemotherapy prior to CRT. Median OS was 42 (21.6-52.7) months and median PFS was 18.2 (15.5-28.4) months. In all but one patient, the R1 involved the posterior resection margin. Most patients (84.8%) had documented disease progression. In the majority the site of first progression was distant metastatic disease (51.5%), whilst six (18.2%) had local recurrence within the radiotherapy field. Four (12.1%) relapsed locoregionally. No statistically significance difference in OS or PFS was seen with presence of perineural or lymphovascular invasion, though analysis was limited by low number of patients. The majority of patients (72%) were node positive on pathology. Two (6.1%) patients had grade 3-4 toxicity during CRT (neutropenic and non-neutropenic sepsis). Conclusions: Our study supported acceptable safety following CRT as an adjuvant treatment in pancreatic cancer patients with R1 resection on surgery. Despite R1 resection, we observed survival outcomes with adjuvant chemotherapy and CRT somewhat above previously reported data. However the benefit of CRT after adjuvant chemotherapy remains unclear. Further evaluation is warranted to clarify which subgroups of patients benefit.

Phase II preoperative pembrolizumab for MSI high or MSS/PD-L1 gastric cancer followed by surgery and adjuvant therapy with pembrolizumab (NCT03257163): Results of a multicenter study.

441 Background: Data suggest that patients with tumors with microsatellite instability (MSI-H), EBV expression, or positive PD-L1 expression can benefit from immunotherapy. This trial evaluated PD-1 immunotherapy in this subset of patients with operable gastric cancer. Methods: We present results of a phase 2 multi-institutional clinical trial (NCT03257163). Patients with cT2-T4, N0-N3, M0 gastric adenocarcinoma with MSI-H, PDL1 CPS &gt; 1%, or EBV+ were included. Patients received 2 cycles preop pembrolizumab 200 mg IV q3 weeks followed by surgery. Pembrolizumab was given for 16 additional cycles postoperatively, concurrently with adjuvant chemoradiation (45 Gy) and 5 cycles of capecitabine (825 mg/m2 days 1-14 during cycles 3, 6 and 7; 625 mg/m2 BID days 1-14 during cycles 4 and 5 with radiation). Patients were defined as evaluable if they received &gt; one cycle of postop pembrolizumab. Primary endpoint is DFS, powered to detect 3-yr DFS of 70% with 89% power. Results: All enrolled patients received two cycles of pembrolizumab preoperatively (n=45). Eight patients did not undergo surgery (1 due to frailty, 2 with distant progression on preoperative imaging, 2 with peritoneal disease on surgical exploration and 3 with locally advanced, unresectable tumors). Six patients did not receive adjuvant therapy (2 due to surgical complications, 2 for failure to thrive, 1 refusal and 1 pending adjuvant therapy). 31 patients received adjuvant therapy and are included in the predetermined, evaluable analytic cohort. These 31 patients had a median age of 67 years (range 44 – 85) with 22.6% Hispanic, 29.0% Asian, 25.8% Black and 25.8% White. Median follow-up was 31.1 months (range 3.45-63.8). In these patients, 14 (45.2%) had MSI-H, 2 (6.5%) EBV+, and 29 (93.5%) had PDL1 expression &gt;1% tumors. Most tumors were advanced stage with 81% ≥ cT3 and 58% cN+. In the 31 evaluable patients, the 3-year DFS was 79.4%; 3-year OS was 78.9%. For MSI-H patients, 3-year DFS was 81.8%. For patients with MSS/PD-L1+ tumors, 3-year DFS was 77.8%. For the 45-patient cohort, 3-year DFS was 70%; 3-year OS was 65%. Three patients had pCR, two with MSI-H tumors and one with PD-L1 CPS of 4%. Downstaging occurred in 62.2% of patients, and 40% of surgical specimens had pT0/T1 tumors consistent with significant pathologic responses. Conclusions: A biomarker-driven preoperative treatment strategy for MSI-H, EBV+, and MSS/PDL1+ operable gastric adenocarcinoma patients is promising and warrants additional evaluation. This treatment strategy is novel and effective, and it incorporates immune checkpoint immunotherapy, low dose chemotherapy, and radiation thus avoiding more intensive combination chemotherapy regimens for patients with these biomarkers. Clinical trial information: NCT03257163 .

Developing a novel model for predicting overall survival in late-onset colon adenocarcinoma patients based on LODDS: a study based on the SEER database and external validation

AimTo construct a predictive model based on the LODDS stage established for patients with late-onset colon adenocarcinoma to enhance survival stratification.MethodsLate-onset colon adenocarcinoma data were obtained from the public database. After determining the optimal LODDS truncation value for the training set via X-tile software, we created a new staging system by integrating the T stage and M stage. Nomograms of the prognostic model were created after Cox analyses identified independent risk factors for overall survival (OS) and cause-specific survival (CSS) and were validated internally and externally. The efficacy of the nomograms was assessed by calibration, time-dependent area under the curve (AUC) and decision curve analysis (DCA). Finally, the prognoses of the patients were compared by plotting survival curves on the basis of risk scores.ResultsA total of 103,291 and 100 patients with late-onset colon adenocarcinoma (50–80 years old) were screened from the Surveillance, Epidemiology, and End Results (SEER) and The Cancer Genome Atlas (TCGA) databases, respectively. Cox regression analysis revealed independent risk factors for OS and CSS, including age, gender, race, size, LODDS stage, PLN stage, LNR stage, and TNM stage. A comparison of the four models constructed on the basis of different stages revealed that the model constructed with the LODDS stage had the minimum AIC (Akaike information criterion), maximum C-index (concordance index) and time-dependent AUC. Nomograms based on the LODDS stage were constructed and successfully validated for accuracy and clinical utility.ConclusionFor patients with late-onset colon adenocarcinoma, LODDS may achieve optimal predictive performance. Furthermore, compared to the 8th edition of the AJCC classification system, the nomogram based on LODDS stage may demonstrate superior survival prediction capabilities.

Whole slide image based deep learning refines prognosis and therapeutic response evaluation in lung adenocarcinoma

Existing prognostic models are useful for estimating the prognosis of lung adenocarcinoma patients, but there remains room for improvement. In the current study, we developed a deep learning model based on histopathological images to predict the recurrence risk of lung adenocarcinoma patients. The efficiency of the model was then evaluated in independent multicenter cohorts. The model defined high- and low-risk groups successfully stratified prognosis of the entire cohort. Moreover, multivariable Cox analysis identified the model defined risk groups as an independent predictor for disease-free survival. Importantly, combining TNM stage with the established model helped to distinguish subgroups of patients with high-risk stage II and stage III disease who are highly likely to benefit from adjuvant chemotherapy. Overall, our study highlights the significant value of the constructed model to serve as a complementary biomarker for survival stratification and adjuvant therapy selection for lung adenocarcinoma patients after resection.

Gene mutation in diabetic patients with lung adenocarcinoma: a real-world retrospective cohort study

PurposeThe incidence of lung cancer is closely associated with diabetes; however, it remains unclear whether diabetes influences the genetic mutations present in lung cancer. Therefore, we will compare the genetic mutations in patients with lung adenocarcinoma (ADC) who have diabetes against those who do not.MethodsWe included 279 patients diagnosed with lung adenocarcinoma (143 with diabetes and 136 without diabetes) at the Second Affiliated Hospital of Chongqing Medical University between 2016 and 2023, and analyzed the clinical characteristics and genetic mutation profiles of all participants.ResultsIn comparison to ADC patients without diabetes, those with diabetes exhibited a lower overall gene mutation rate (49.7% vs. 65.4%, P = 0.008). Female ADC patients demonstrated a higher total gene mutation rate and EGFR gene mutation rate than their male counterparts (49.3% vs. 66.9%, P = 0.003; 27.6% vs. 58.3%, P &amp;lt; 0.001, respectively), although their TP53 gene mutation rate was lower (8.6% vs. 2.4%, P = 0.027). ADC patients without a smoking history had a higher gene mutation rate and EGFR gene mutation rate than those with a smoking history (62.6% vs. 47.4%, P = 0.014; 51.6% vs. 22.7%, P &amp;lt; 0.001, respectively), but a lower KRAS gene mutation rate (4.4% vs. 14.4%, P = 0.003). Conversely, ADC patients with a drinking history had a lower EGFR gene mutation rate than those without (48% vs. 62.6%, P = 0.018; 31.0% vs. 47.5%, P = 0.007), yet a higher KRAS gene mutation rate (14.0% vs. 4.5%, P = 0.005). Univariate and multivariate linear regression analyses revealed that being female, having no smoking history, and being in phase II or IV of tumor stage were associated with gene mutation. Subgroup analysis indicated that the rate of gene mutation in male smoking lung adenocarcinoma patients with diabetes was significantly lower than in those without diabetes.ConclusionThis retrospective study of real-world data suggests that patients with lung adenocarcinoma and diabetes may have a reduced likelihood of developing genetic mutations, particularly among male smokers. Furthermore, gender, smoking history, and tumor stage may be correlated with the presence of gene mutations.

Tracing Metastatic Evolutionary Patterns in Lung Adenocarcinoma: Prognostic Dissection Based on a Multi-state Model.

After surgery for lung adenocarcinoma, a patient may experience various states of recurrence, with multiple factors potentially influencing the transitions between these states. Our purpose was to investigate the effects of clinical and pathological factors on tumor recurrence, death, and prognosis across various metastasizing pathways. Our study group included 335 patients with all demographic and pathologic data available who underwent surgical resection for lung adenocarcinoma for more than 10 years. The following states of disease were defined: initial state, operation (OP); three intermediate states of local recurrence (LR), metastasis (Meta), and concurrent LR with metastasis (LR+Meta); and a terminal state, death. We identified 8 transitions representing various pathways of tumor progression. We employed a multi-state model (MSM) to separate the impacts of multiple prognostic factors on the transitions following surgery. After surgery, approximately half of patients experienced recurrence. Specifically, 142 (42.4%), 54 (16.1%), and 7 (2.1%) patients developed Meta, LR+Meta, and LR, respectively. Clinical and pathological factors associated with the transitions were different. Impact of pathological lymph node remained a risk factor for both OP to Meta (λ02, p-value=0.001) and OP to LR+Meta (λ03, p-value = 0.001). Lung adenocarcinoma displays a broad spectrum of clinical scenarios even after curative surgery. Incidence, risk factors, and prognosis varied across different pathways of recurrence in lung adenocarcinoma patients. The greatest implication of this MSM is its ability to predict the timing and type of clinical intervention that will have the greatest impact on survival.