Gastroesophageal Junction Patients Research Articles

Abstract 2523: Predictive biomarkers for neoadjuvant FLOT4 chemotherapy response in gastroesophageal cancer: Results of multi-omics approach

Abstract Background: The FLOT4 chemotherapy regimen is a standard preoperative treatment for gastroesophageal junction (GEJ) and gastric cancer (GC), yet the response to this treatment is variable. Identification of predictive biomarkers is crucial for optimizing therapeutic strategies. This study aims to identify predictive biomarkers for FLOT4 treatment efficacy using a multi-omics approach. Methods: We conducted a preliminary differential gene expression analysis in diagnostic tissue pre-treatment and surgical resection post-treatment in six patients (two GEJ and four GC) who all exhibited a partial pathological response (G2) to neoadjuvant FLOT4 chemotherapy. Utilizing DESeq2 for differential gene expression and David pathway analysis for functional insights, we have begun to unravel the complex molecular response to treatment. Upcoming assays include blood gDNA and tumor tissue whole exome sequencing (WES), comprehensive methylation profiling, miRNA characterization, and proteomics via LC-MSMS. Results: Our preliminary data suggest alterations in gene expression associated with cell adhesion, extracellular matrix interaction, and immune response pathways. Three common genes (CXCL2, CXCL3, CXCL1) were identified among upregulated pathways in GEJ patients, while one common gene (IL1A) was observed in GC patients. These findings suggest a complex network of biological processes influenced by FLOT4. In-depth results, including whole-exome sequencing, methylation patterns, and miRNA profiles, will be completed and presented at the conference. Conclusion: These initial findings propose that changes in gene expression related to cellular architecture and immune response are indicative of a partial response to FLOT4 in both GEJ and GC patients. The identified genes and pathways may serve as potential biomarkers for predicting treatment outcomes. Future Directions: By the time of the conference, we anticipate including a more extensive patient cohort with complete response or no response to FLOT4, and comparative analyses with a FOLFOX treatment group. The integration of forthcoming WES, methylation, miRNA, and proteomics data will provide a more comprehensive molecular predictive model. Keywords: FLOT4 chemotherapy, gastroesophageal junction cancer, gastric cancer, predictive biomarkers, differential gene expression. Citation Format: Amira Al-Fahdi, Shoaib Al Zadjali, Ibrahim Al Haddabi, Anoopa Pullanhi, Muna Al Jabri, Aida Al Yayahee, Nada Al Shuaili, Nahad Al Mahrouqi, Mansour Al Moundhri. Predictive biomarkers for neoadjuvant FLOT4 chemotherapy response in gastroesophageal cancer: Results of multi-omics approach [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 2523.

Tislelizumab plus chemotherapy is an optimal option for second-line treatment for advanced gastroesophageal junction adenocarcinoma.

The development of programmed cell death receptor-1 and its ligand (PD-L1) have offered new treatment options for several cancers, but the clinical benefit of tislelizumab in the gastroesophageal junction (GEJ) adenocarcinoma is still murky. Thus, we aim to investigate the efficacy and safety of tislelizumab combined with chemotherapy in patients with GEJ cancer. In this study, 90 GEJ patients were retrospectively enrolled including 45 patients who received chemotherapy plus tislelizumab while 45 underwent chemotherapy only. Overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) were estimated and safety was assessed by treatment-related adverse events between two arms. The ORR was significantly higher in the tislelizumab group than in patients with chemotherapy alone (71.1 vs. 44.4%). The PFS [54.7% (47.2-62.2) vs. 33.3% (26.3-40.3), P = 0.047] and OS [62.1% (54.5-69.7) vs. 40.0% (32.5-47.5), P = 0.031] were also significantly improved in patients with concomitant use of tislelizumab. When stratified by PD-L1 combined positive score (CPS), patients with PD-L1 CPS ≥ 1 also with significantly higher PFS and OS when taking tislelizumab (P = 0.015 and P = 0.038). The incidence of hematologic toxicity was similar in the combination arm compared to the chemotherapy alone arm and the number of adverse events was not significantly increased by adding tislelizumab (all P > 0.05). Concomitant use of tislelizumab and chemotherapy in GEJ patients may be with optimal therapeutic effect and similar incidence of adverse events than chemotherapy alone. Further studies with larger number of patients are warranted to confirm it.

The impact of nutrition support in advanced gastric adenocarcinoma patients treated with chemotherapy.

208 Background: Numerous studies have demonstrated how malnutrition and cachexia are associated with poor survival in advanced gastric cancer (AGC). The impact of nutrition support involving multidisciplinary specialists is unclear, particularly among patients with AGC being treated with chemotherapy. This study aimed to clarify the differences in patient characteristics and survival outcomes between patients receiving nutrition support (NS) and routine care (RC). Methods: We retrospectively analyzed 212 consecutive patients with AGC at a single institution between January 2015 and June 2020. Inclusion criteria were: histologically confirmed metastatic or recurrent gastric and adenocarcinoma and gastroesophageal junction patients treated with chemotherapy, ECOG performance status (PS) 0-2, and adequate organ function. Time to treatment failure (TTF) in the entire cohort, patients with a positive Glasgow prognostic score (GPS) (graded as 1 and 2), and hypoalbuminemia (cutoff was 3.5 g/dl) were evaluated. Univariate and multivariate analyses were conducted to identify whether NS was an independent prognostic factor of time to treatment failure (TTF). Multivariate analysis included variables with p-values ≤0.1 in univariate analyses. Results: A total of 97 patients met the inclusion criteria with 67 (69%) and 30 (31%) patients classified into the RC or NS group, respectively. The median age was 71 years (range, 26-92). The median follow-up time was 8.4 months (range, 0.5-66). Patient characteristics revealed that NS was offered to patients with poorer prognostic nutritional index (PNI) (cutoff was 45, p=0.02), GPS positivity (p=0.01), and high neutrophil-lymphocyte ratio (NLR) (cutoff was 3, p=0.01). In the entire cohort, TTF in the RC and NS groups was 4.3 and 5.3 months (p=0.15), respectively. Among the patients with GPS positivity (graded as 1 and 2) and hypoalbuminemia, TTF in the RC and NS group were 2.3 and 5.0 months (p=0.05), and 2.3 and 5.3 months (p=0.02), respectively (Table). Variables with p-values ≤0.1 in univariate analyses for TTF were PS, NS, and prior gastrectomy. As per multivariate analyses, PS and NS were significant positive prognostic factors for TTF. Conclusions: NS was provided to patients with unfavorable clinical features. Among the AGC patients treated with chemotherapy, having GPS positivity or hypoalbuminemia seems to be a good indication for NS. [Table: see text]

The relationship between gastroesophageal junction integrity and symptomatic fundoplication outcomes

The majority of patients who undergo a laparoscopic fundoplication for gastroesophageal reflux disease (GERD) have a structural (hiatal hernia, shortened lower esophageal sphincter [LES]) or functional (weak LES) defect of the gastroesophageal junction (GEJ). We hypothesized that the symptomatic outcomes of fundoplication in patients with a competent GEJ prior to surgery are inferior to those with an incompetent GEJ. This is a retrospective review of prospectively maintained data on subjects who underwent primary laparoscopic fundoplication (Nissen or Toupet) for medically refractory and confirmed GERD. Three esophageal manometry variables were used to determine GEJ competency: (1) hiatal hernia (normal = no hernia), (2) total lower esophageal sphincter length (normal ≥ 2.43cm), and (3) lower esophageal sphincter pressure (normal = 15.0-43.7mmHg). Patients in the competent group had normal values for all 3 variables. Symptomatic outcomes were assessed with the GERD Health-Related Quality of Life (HRQL) survey administered pre- and postoperatively, and then compared both intragroup, intergroup, and by procedure. A total of 78 patients met inclusion criteria-17 competent GEJ and 61 incompetent GEJ patients. GERD-HRQL scores improved in the incompetent cohort at all intervals out to 2years postoperatively. GERD-HRQL improved in the competent cohort at 2months, with no difference at 6months or 2years postoperatively compared to preoperative scores. Competent GEJ patients receiving a Nissen fundoplication had a higher rate of additional procedures (endoscopy with or without dilation, pH studies) following surgery to address recurrent or persistent GERD symptoms compared to Toupet. GERD patients with a competent GEJ report a lower GERD-HRQL with more frequent and severe reflux symptoms up to 2 years post-fundoplication. Competent GEJ patients receiving a Nissen fundoplication are more likely to have additional procedures to address symptoms following surgery. Surgeons should approach patients with a competent GEJ and medically refractory GERD with caution.

A real-world comparison of multi-modality therapies in locally advanced gastro-esophageal junction (GEJ) cancers.

96 Background: Trials show that addition of systemic therapy and/or radiation to surgery improves survival in GEJ cancers. However, the different regimens have not been directly compared. We examined population-based outcomes of 3 treatments: 1) neoadjuvant carboplatin and paclitaxel plus radiation (CROSS); 2) perioperative epirubicin, cisplatin, and fluoropyrimidine (MAGIC); and 3) cisplatin and fluoropyrimidine with radiation (CisFP). Methods: We reviewed patients diagnosed with GEJ cancer from 2005 to 2015 who received CROSS, MAGIC, or CisFP at 2 tertiary, 4 regional, and 11 community cancer centers in Alberta, Canada. Survival was assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox proportional hazards model was constructed to evaluate the impact of treatment on overall survival (OS). Results: 331 patients were identified. Median age was 63 (IQR 56-69) years and 86% were men. CROSS was used in 217 (65%) cases followed by CisFP in 72 (22%) and MAGIC in 42 (13%). Age, sex, and stage were not associated with treatment selection (all p > 0.05), but a higher proportion of CROSS and CisFP patients had adenocarcinoma (86% and 85%, respectively) compared to MAGIC patients (41%) ( p < 0.01). CROSS and MAGIC correlated with higher surgical resection rates when compared to CisFP (82% vs. 79% vs. 50%, respectively, p < 0.01). Median OS favored CROSS and MAGIC rather than CisFP, but this was not statistically significant (29 vs. 34 vs. 20 months, respectively, p= 0.17). Adjusting for confounders, OS remained similar for MAGIC (HR 0.8, 95%CI 0.5-1.3, p= 0.36) and CisFP (HR 0.7, 95%CI 0.5-1.1, p= 0.10) when compared to CROSS. In addition, age > 65, advanced stage, and lack of surgical resection were associated with increased risk of death (HR 1.5, 95%CI 1.1-2.0, p= 0.02, HR 2.2, 95%CI 1.2-3.9, p< 0.01 and HR 4.1, 95%CI 2.8-5.9, p< 0.01, respectively). Conclusions: OS was similar across all 3 regimens, but outcomes were inferior to those seen in original trials. This observation suggests that GEJ patients in routine practice are different from study participants or that treatment selection may be driven by factors other than trial eligibility criteria.

Evaluation of respiratory motion-corrected cone-beam CT at end expiration in abdominal radiotherapy sites: a prospective study

Background: Cone beam computed tomography (CBCT) for radiotherapy image guidance suffers from respiratory motion artifacts. This limits soft tissue visualization and localization accuracy, particularly in abdominal sites. We report on a prospective study of respiratory motion-corrected (RMC)-CBCT to evaluate its efficacy in localizing abdominal organs and improving soft tissue visibility at end expiration.Material and methods: In an IRB approved study, 11 patients with gastroesophageal junction (GEJ) cancer and five with pancreatic cancer underwent a respiration-correlated CT (4DCT), a respiration-gated CBCT (G-CBCT) near end expiration and a one-minute free-breathing CBCT scan on a single treatment day. Respiration was recorded with an external monitor. An RMC-CBCT and an uncorrected CBCT (NC-CBCT) were computed from the free-breathing scan, based on a respiratory model of deformations derived from the 4DCT. Localization discrepancy was computed as the 3D displacement of the GEJ region (GEJ patients), or gross tumor volume (GTV) and kidneys (pancreas patients) in the NC-CBCT and RMC-CBCT relative to their positions in the G-CBCT. Similarity of soft-tissue features was measured using a normalized cross correlation (NCC) function.Results: Localization discrepancy from the end-expiration G-CBCT was reduced for RMC-CBCT compared to NC-CBCT in eight of eleven GEJ cases (mean ± standard deviation, respectively, 0.21 ± 0.11 and 0.43 ± 0.28 cm), in all five pancreatic GTVs (0.26 ± 0.21 and 0.42 ± 0.29 cm) and all ten kidneys (0.19 ± 0.13 and 0.51 ± 0.25 cm). Soft-tissue feature similarity around GEJ was higher with RMC-CBCT in nine of eleven cases (NCC =0.48 ± 0.20 and 0.43 ± 0.21), and eight of ten kidneys (0.44 ± 0.16 and 0.40 ± 0.17).Conclusions: In a prospective study of motion-corrected CBCT in GEJ and pancreas, RMC-CBCT yielded improved organ visibility and localization accuracy for gated treatment at end expiration in the majority of cases.

TH-CD-202-11: Implications for Online Adaptive and Non-Adaptive Radiotherapy of Gastic and Gastroesophageal Junction Cancers Using MRI-Guided Radiotherapy

Purpose: Radiotherapy for gastric and gastroesophageal junction (GEJ) tumors commonly requires large margins due to deformation, motion and variable changes of the stomach anatomy, at the risk of increased normal tissue toxicities. This work quantifies the interfraction variation of stomach deformation from daily MRI-guided radiotherapy to allow for a more targeted determination of margin expansion in the treatment of gastric and GEJ tumors. Methods: Five patients treated for gastric (n=3) and gastroesophageal junction (n=2) cancers with conventionally fractionated radiotherapy underwent daily MR imaging on a clinical MR-IGRT system. Treatment planning and contours were performed based on the MR simulation. The stomach was re-contoured on each daily volumetric setup MR. Dice similarity coefficients (DSC) of the daily stomach were computed to evaluate the stomach interfraction deformation. To evaluate the stomach margin, the maximum Hausdorff distance (HD) between the initial and fractional stomach surface was measured for each fraction. The margin expansion, needed to encompass all fractions, was evaluated from the union of all fractional stomachs. Results: In total, 94 fractions with daily stomach contours were evaluated. For the interfraction stomach differences, the average DSC was 0.67±0.1 for gastric and 0.62±0.1 for GEJ cases. The maximum HD of each fraction was 3.5±2.0cm (n=94) with mean HD of 0.8±0.4cm (across all surface voxels for all fractions). The margin expansion required to encompass all individual fractions (averaged across 5 patients) was 1.4 cm(superior), 2.3 cm(inferior), 2.5 cm(right), 3.2 cm(left), 3.7 cm(anterior), 3.4 cm(posterior). Maximum observed difference for margin expansion was 8.7cm(posterior) among one patient. Conclusion: We observed a notable interfractional change in daily stomach shape (i.e., mean DSC of 0.67, p<0.0001) in both gastric and GEJ patients, for which adaptive radiotherapy is indicated. A minimum PTV margin of 3 cm is indicated to account for interfraction stomach changes when adaptive radiotherapy is not available. M. Bassetti: Travel funding from ViewRay, Inc.

Are fiducial markers useful surrogates when using respiratory gating to reduce motion of gastroesophageal junction tumors?

Background: Radiation therapy (RT) is an integral component of the management of gastroesophageal junction (GEJ) tumors. We evaluated the use of implanted radiopaque fiducials as tumor surrogates to allow for more focal delivery of RT to these mobile tumors when using respiratory gating (RG) to reduce motion.Material and methods: We analyzed four-dimensional computed tomography scans of 20 GEJ patients treated with RG and assessed correlation between tumor and implanted fiducial motion over the whole respiratory cycle and within a clinically realistic gate around end-exhalation. We evaluated fiducial motion concordance in 11 patients with multiple fiducials.Results: Gating reduced anterior-posterior (AP) and superior-inferior (SI) mean tumor and fiducial motions by over 50%. Fiducials and primary tumor motions were moderately correlated: R2 for AP and SI linear fits to the entire group were 0.54 and 0.68, respectively, but the correlation had strong inter-patient variation. For all patients with multiple fiducials, relative in-gate displacements were below 3 mm; results were similar for eight of 11 patients over the whole cycle.Conclusion: Implanted fiducial and gross tumor volume (GTV) motions correlate well but the correlation is patient-specific and may be dependent on the location of the fiducials with respect to the GTV.

The incidence and prognostic value of HER2 overexpression and cyclin D1 expression in patients with gastric or gastroesophageal junction adenocarcinoma in Israel

Human epidermal growth factor 2 (HER2) positivity rates for gastric or gastroesophageal junction (GEJ) adenocarcinoma have been reported at 15–25%. Cyclin D1 (BCL1) is a non-specific proliferative marker. The prognostic significance of HER2 and cyclin D1 is inconclusive, with contradictory data. The aim of this study was to evaluate the incidence of HER2 overexpression in gastric or GEJ patients. The presence of a possible correlation between HER2 status and cyclin D1 staining was assessed; both were evaluated as prognostic markers for survival. The clinical data and histological specimens of 150 consecutive patients diagnosed with gastric or GEJ adenocarcinoma, and treated at our hospital from June 2005 to March 2009, were analyzed. Pathological specimens were immunohistochemically stained for HER2. Immunoreactivity was determined according to the scoring system for gastric carcinoma. Cyclin D1 immunoreactivity was also tested. The results demonstrated that HER2 was positive in 14/150 (9.3%) patients. HER2-positive (HER2+) and HER2-negative (HER2−) patients did not differ significantly with regard to other clinicopathological parameters. In a multivariate analysis, HER2 positivity was revealed to be a poor prognosis variable (P=0.046; 95% CI, 1.03–3.58). In patients with non-metastatic disease, median survival was 59 months for HER2− and 42 months for HER2+ patients, but this difference was not significant. In patients with metastatic disease, median survival was 9.5 months and 2.5 months for HER2− and HER2+ patients, respectively (P=0.041). Cyclin D1 was not idemonstrated to be a prognostic factor and was not associated with HER2 overexpression. The rate of positive HER2 status in the current group of unselected patients with gastric and GEJ adenocarcinoma was relatively low compared with that observed in the literature. Nevertheless, HER2 positivity was associated with a poor prognosis.

A comparison of surgical resection for distal esophageal, gastroesophageal junction, and proximal gastric cancers in the Memphis metropolitan area (MMA).

147 Background: The incidence of distal esophageal (DE) and gastroesophageal junction (GEJ) tumors has increased rapidly in recent decades. They are often included in gastric cancer trials. The 7th AJCC staging has reclassified tumors of the DE, GEJ, and proximal stomach (PS) as esophageal cancers. We compared the historical management of these tumors in our community. Methods: Review of all curative-intent DE, GEJ, and PS cancer resections at two healthcare institutions in the MMA from 1999-2008. Results: Seventy patients were identified (Table). Males predominated. The histology was adenocarcinoma in 48% of DE, 91% of GEJ, and 100% of PS cancers. Preoperative endoscopic ultrasound (EUS) was performed in 10% of DE, 6% of GEJ, and 7% of PS patients. Neoadjuvant therapy was given to 29% of DE, 35% of GEJ and 0% of PS patients. R0 resection rates were similiar. Fewer DE and GEJ patients had up to 15 lymph nodes removed, yet lymph node metastasis was identified in 52% and 35% respectively, compared to 20% of PS patients (Table). Five-year survival rates were numerically higher in the DE and GEJ patients. Conclusions: We identified differences in DE, GEJ, and PS tumors in a community setting with respect to preoperative management and lymph node sampling. Reclassification of DE, GEJ, and PS tumors by the AJCC suggests these groups now be treated uniformly as esophageal cancers, a shift from previous management as gastric cancers. Further, prospective evaluation is needed to assess the patterns of management and outcomes in tumors of the DE, GEJ and PS. [Table: see text] No significant financial relationships to disclose.