Junction Adenocarcinoma Research Articles

Pre-Surgical Endoscopic Biopsies Are Representative of Esophageal and Esophago-Gastric Junction Adenocarcinoma Histologic Classes and Survival Risk

Background and Objectives: The Esophageal Adenocarcinoma Study Group Europe (EACSGE) recently proposed a granular histologic classification of esophageal–esophago-gastric junctional adenocarcinomas (EA-EGJAs) based on the study of naïve surgically resected specimens that, when combined with the pTNM stage, is an efficient indicator of prognosis, molecular events, and response to treatment. In this study, we compared histologic classes of endoscopic biopsies taken before surgical resection with those of the surgical specimen, to evaluate the potential of the EACSGE classification at the initial diagnostic workup. Methods: A total of 106 EA-EGJA cases with available endoscopic biopsies and matched surgical resection specimens were retrieved from five Italian institutions. Histologic classification was performed on all specimens to identify well-differentiated glandular adenocarcinoma (WD-GAC), poorly differentiated glandular adenocarcinoma (PD-GAC), mucinous muconodular carcinoma (MMC), infiltrative mucinous carcinoma (IMC), diffuse desmoplastic carcinoma, diffuse anaplastic carcinoma (DAC), and mixed subtypes. Related risk subgroups (low-risk versus high-risk) were also assessed. The correlations of histologic classes and risk subgroups between diagnostic biopsies and surgical resection specimens were explored with Spearman’s correlation test. Sensitivity, specificity, accuracy, positive predictive value, negative predictive value, true positives, true negatives, false positives, and false negatives were also calculated. Results: A strong positive correlation between biopsies and surgical specimens occurred for both histologic classes (coefficient: 0.75, p < 0.001) and risk subgroups (coefficient: 0.65, p < 0.001). The highest sensitivities and specificities were observed for MMC, IMC, and DAC (100% and 99% for all), followed by WD-GAC (sensitivity 91%, specificity 79%) and PD-GAC (sensitivity 722%, specificity 86%). The low-risk and high-risk groups presented a sensitivity and specificity of 89% and 76% (low-risk) and 76% and 89% (high-risk). Conclusions: The EACSGE histologic classification of EA-EGJAs and associated prognostic subgroups can be reliably assessed on pre-operative diagnostic biopsies. Further studies on larger and more representative cohorts of EA-EGJAs will allow us to validate our findings and confirm if the EA-EGJA biopsy histomorphology and clinical TNM staging will be as efficient as the surgical specimen histomorphology and pTNM in predicting patient prognoses and tailoring personalized therapeutic approaches.

Tremelimumab and durvalumab as neoadjuvant or non-operative management strategy of patients with microsatellite instability-high resectable gastric or gastroesophageal junction adenocarcinoma: the INFINITY study by GONO

BackgroundIn resectable gastric/gastroesophageal junction adenocarcinoma (GAC/GEJAC), microsatellite instability (MSI-H) confers improved survival, but limited benefit from chemotherapy. Immunotherapy may eliminate the need of chemotherapy or surgery. Patients and methodsINFINITY is a multicentre, multicohort phase II trial (NCT04817826) investigating in Cohort 1 the activity and safety of tremelimumab+durvalumab (T300/D) as neoadjuvant treatment for dMMR/MSI-H, resectable GAC/GEJAC. Primary endpoint was pathologic complete response (pCR) rate; Secondary endpoints: progression-free survival (PFS), overall survival (OS), quality of life (QoL), and translational analyses. In Cohort 2, the activity and safety of T300/D was explored as definitive treatment in patients achieving clinical complete response (cCR). Primary endpoint was 2-year cCR rate, Secondary endpoints: PFS, OS, QoL, gastrectomy-free survival (GFS) and translational analyses. ResultsIn Cohort 1, 18 patients were recruited and 15 evaluable. pCR and major-complete pathological response were 60% and 80%. Since pCR rate in T4 tumors was 17%, this subgroup of patients was excluded from enrollment in Cohort 2. At 28.1 months median follow-up, 24-month GC-specific PFS and OS rates were 85% and 92%. In Cohort 2, 18 patients were enrolled and 17 evaluable, 13 had cCR and started non-operative management (NOM). At 11.5 months median follow up, 1 patient had local regrowth and underwent salvage surgery, 12-month GFS was 64.2%. ConclusionsThe INFINITY study provided promising activity results of a chemo-free T300/D combination regimen as pre-operative treatment in dMMR/MSI GAC/GEJAC and the first available feasibility results of a NOM strategy in this disease setting, worth of further validation in larger cohorts.

Comparison Between AJCC 8th Edition Gastric and Esophageal ypTNM Classification System in Siewert II Esophagogastric Junction Adenocarcinomas: A Retrospective Study Based on Eastern and Western Data

Multimodal therapy has become the standard treatment for curable upper gastrointestinal cancers. However, it remains unclear which 8th edition AJCC post-neoadjuvant therapy pathological classification system, esophageal (ypTNM-EC) or gastric (ypTNM-GC), can predict the overall survival (OS) of patients with Siewert II adenocarcinomas better. Patients diagnosed with Siewert II adenocarcinomas receiving neoadjuvant therapy plus curative resection at the University Medical Center Utrecht (UMC Utrecht) and the Peking University Cancer Hospital (PUCH) between the 2001 and 2022 were included in this study. The patients from two institutions were analyzed separately. Predictive univariable and multivariable Cox models based on ypTNM-EC and ypTNM-GC were constructed. The C-index and calibration curves were used to compare the predictive abilities of ypTNM-EC and ypTNM-GC Cox models. A total of 125 patients from UMCU and 145 from PUCH were included. There was no significant difference in the C-index between the ypTNM-EC and the ypTNM-GC univariable and multivariable Cox models in the UMC Utrecht (p-value=0.883; p-value=0.681) and PUCH (p-value=0.808; p-value=0.548) cohorts, and no significant difference was observed between their calibration curves in the two cohorts. The AJCC 8th edition ypTNM prognostic classification systems for esophageal and gastric cancer demonstrated no difference in predicting OS for patients with Siewert II adenocarcinomas both in the Western and Eastern data. The ypTNM-GC, with fewer stage groups, may offer greater convenience for clinical application.

Cost-effectiveness analysis of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced gastric or gastroesophageal junction adenocarcinoma: perspectives from the United States and China.

The efficacy of tislelizumab plus chemotherapy in improving progression-free survival (PFS) and overall survival (OS) in unresectable gastric or gastroesophageal junction cancer (GC/GEJC) has recently been emphasized. This study compared the cost-effectiveness of tislelizumab plus chemotherapy versus placebo plus chemotherapy for the United States (US) and Chinese populations. Using data from the RATIONALE-305 phase 3 trial, a Markov model was developed to analyze quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), incremental net health benefits (INHBs), and incremental net monetary benefits (INMBs). The health state utilities and direct medical costs were obtained from the relevant literature and local cost databases. The model uncertainty was evaluated using sensitivity analyses. In the base-case analysis, the addition of tislelizumab to chemotherapy yielded an ICER of $37,768.48 per QALY in China, slightly below the willingness-to-pay (WTP) threshold of $38,042.49 per QALY, showing marginal cost-effectiveness with an INHB of 0.05 QALYs and an INMB of $1,852.49. Subgroup analyses revealed ICERs of $23,853.52 for patients with a PD-L1 TAP score ≥ 5% (TAP ≥ 5%). In the US, the ICER was $502,786.22 per QALY in the intent-to-treat (ITT) and $321,395.28 per QALY in the TAP ≥ 5% subgroup, exceeding the US WTP threshold of $150,000.00. In China, tislelizumab plus chemotherapy is a cost-effective first-line therapy for unresectable GC/GEJC in both ITT and TAP ≥ 5% subgroups. In the US, tislelizumab plus chemotherapy is not cost-effective.

Adjuvant chemoradiotherapy plus PD-1 inhibitor for pN3 gastric cancer: a randomized, multicenter, Phase III trial.

D2 surgery followed by adjuvant chemotherapy has been established as the standard of care for patients with locally advanced gastric cancer in Asian countries. However, its efficacy is still unsatisfactory, especially for pathological N3 disease. The RACING trial is a randomized, multicenter, Phase III trial designed to compare the efficacy and safety of chemotherapy alone versus chemotherapy in combination with PD-1 inhibitor and radiotherapy in patients with pN3 gastric or gastroesophageal junction adenocarcinoma. A total of 433 patients will be assigned at a 1:1 ratio to the two arms. The primary end point is the 3-year disease-free survival rate. The secondary end points include the 3-year overall survival rate, 3-year local recurrence-free survival rate, treatment-related adverse events and quality of life.Clinical Trial Registration: NCT04997837 (ClinicalTrials.gov).

OGC SO13 - Recurrence Patterns after Minimally Invasive vs. Left Thoracoabdominal Oesophagectomy for distal oesophageal and junctional adenocarcinomas

Abstract Background Oesophageal cancer is a leading cause of cancer-related death worldwide, with oesophagec-tomy being the primary treatment for curable disease. This study compares loco-regional and distal disease recurrence patterns between minimally invasive oesophagectomy (MIO) and left thoracoabdominal oesophagectomy (LTAO) using a matched dataset. The definition of loco-regional recurrence remains unclear in the literature. In this study, loco-regional recur-rence is categorised as recurrence in the oesophageal bed, anastomosis, or local nodes in the mediastinum and upper abdomen. Method Patients from 2014 to 2021 were identified and followed until 31/12/2023. Data on MIOs and LTAO were collected from a prospectively maintained database. Gastroesophageal junction and distal oesophagus adenocarcinomas were included, and all received neoadjuvant chemotherapy. Out of 302 eligible patients, 104 were successfully matched. The primary outcome was overall cancer recurrence. Categorical variables were compared using chi-square tests, and non-parametric contin-uous variables with Mann-Whitney U tests. Propensity score matching, accounted for baseline differences. Logistic regression generated propensity scores for age, gender, and tumour stage. Operative approach was the dependant variable. The groups were then selected using ‘nearest neighbour’ matching. Results The study compared 52 cases each of LTAO and MIO. Postoperative complications were similar, LTAO (58%) and MIO (52%) P=0.554. The R0 resection rate was higher in LTAO (90%) compared to MIO (81%) P=0.163. Recurrence was significantly higher in LTAO (42%) than MIO (23%) P=0.037. Local recurrence rates were 15% for LTAO and 8% for MIO P=0.22. Distant recurrence was 35% for LTAO and 21% for MIO P=0.111. Notably, peritoneal recurrence was significantly higher in LTAO (12%) P=0.012. There was no difference in median time to recurrence. Mortality rate was similar: 38% for LTAO and 35% for MIO P=0.684. Conclusion The study found that while postoperative complications and mortality rates were similar between LTAO and MIO, LTAO had a significantly higher overall recurrence rate and notably higher peritoneal recurrence. There was no significant difference in median time to recurrence between the two groups. These findings suggest that MIO may be associated with better long-term outcomes in terms of recurrence.

OGC SO43 - Management of oesophageal adenocarcinoma in the Covid-19 Pandemic – What have we learnt?

Abstract Background The management of oesophageal adenocarcinoma in the UK has been standardised to neoadjuvant chemotherapy followed by surgery. However, during the early phase of the Covid-19 pandemic, oesophagectomy was considered to be too high risk, and alternative treatment options were explored . In our unit, patients were offered definitive chemoradiotherapy with a view to performing salvage oesophagectomy if there was residual disease or disease recurrence. Method We retrospectively screened all patients referred to the UGI MDT between March 2020 to February 2021. Patients included were those with first diagnosis of oesophageal carcinoma, on the curative pathway, planned neoadjuvant FLOT chemotherapy and oesophagectomy then converted to definitive CRT (dCRT). Data collected were patient demographics, cancer staging and cancer outcomes including progression to salvage surgery, disease free survival and overall survival at 1 year and 3 years post treatment. Results Ten patients with distal or junctional adenocarcinoma were included. Median age at diagnosis was 70.5 years. Five patients had T3 or T4 disease. All patients had N0 disease. After one year, one patient had undergone salvage surgery for residual disease and two for recurrent disease. One other patient was unfit for surgery and not offered salvage surgery. At three years, only two patients had no disease recurrence. Nine of 10 patients were alive at one year and seven alive at three years. Conclusion The Covid-19 pandemic was an unusual event in our most recent history that influenced the way we managed patients with oesophageal adenocarcinoma. Little data exists as to what alternative treatments were effective. Our limited data indicates that dCRT may be used as an alternative to surgery in a subgroup of patients – although disease recurrence was common, 3-year survival was high (70%). Our data appears to be comparable to 3-year survival in our own unit and that reported in NOCGA 2024 (63%). Nevertheless, these numbers are small and thus require further study.

OGC SO21 - Role of Staging Laparoscopy on oesophageal and junctional cancer management

Abstract Background Staging laparoscopy and peritoneal cytology is currently recommended as a staging tool required for oesophageal and gastro-oesophageal junction (OGJ) adenocarcinomas. However, evidence is variable regarding the utility of this investigation, leading to heterogenous practice in the UK. With improved staging sensitivity of CT and PET imaging and inclusion of routine MDT discussion for upper GI cancer patients, staging laparoscopy may not be necessary for all patients with oesophago-gastric cancer, and in fact may delay their treatment. We thus aimed to assess the impact of staging laparoscopy on the treatment algorithm of patients with oesophago-gastric cancer. Method All staging laparoscopies undertaken between January 2022 and March 2024 were identified from our surgical database. Patients were included if they had oesophago-gastric adenocarcinoma, with a plan for curative treatment. Data collected included age, gender, location of primary tumour, CT/PET staging, laparoscopy findings, impact on treatment intention, neoadjuvant treatment, and final histology. Primary outcome was incidence of positive microscopic or macroscopic peritoneal disease for oesophageal and OGJ malignancy. Results 127 patients were identified - 69 (55%) oesophageal, 25 (20%) GOJ, and 32 (24.4%) gastric cancer. 1/70 (1.4%) patient diagnosed endoscopically with oesophageal cancer had positive peritoneal disease, which was suspected due to pre-operative imaging findings of ascites and suspicions of linitis plastica. Of patients diagnosed with GOJ cancer, 4/25 patients (16%) had peritoneal disease present. None of the 39 patients with oesophageal/junctional tumours with clinical T1-2 disease were found to have peritoneal disease on staging laparoscopy. 6/32 (19%) patients with gastric cancer were found to have unexpected peritoneal disease present. Conclusion This study found minimal impact staging laparoscopy has on the management of primary oesophageal cancers. Consideration can be made of limiting staging in oesophageal cancer to patients with suspicious findings on CT/PET imaging. For GOJ tumours, there may be a role for limiting staging laparoscopy for Siewert 1 tumours to T3/4 tumours based on CT/PET findings. Importantly, accurate identification on primary endoscopy of the location of the tumour in relation to the gastro-oesophageal junction is necessary to help guide ongoing management.

Abstract 4134417: Cardiotoxicity Conundrum: Distinguishing Immune Checkpoint Inhibitor Myocarditis from Fluorouracil Cardiotoxicity in Concurrent Therapy

Case Description: The patient is a 37-year-old male with metastatic gastroesophageal junction adenocarcinoma presenting with chest pain and dyspnea two days after initiation of leucovorin, fluorouracil, oxaliplatin (FOLFOX), and nivolumab therapy. He was tachycardic and hypotensive with elevated cardiac biomarkers and globally reduced left ventricular systolic function. Suspecting immune checkpoint inhibitor (ICI) myocarditis versus fluorouracil (5-FU) cardiotoxicity, he was treated simultaneously for both. After starting high-dose steroids and before uridine triacetate, he had improved symptoms, cardiac function, biomarkers, and invasive hemodynamics. Though his endomyocardial biopsy did not show inflammatory cell infiltrates, his CMR demonstrated increased T1 and T2 relaxation times consistent with myocarditis. Testing revealed normal dihydropyrimidine dehydrogenase (DPD) activity. He completed uridine triacetate and was discharged on a steroid taper. At follow-up, he remained clinically stable, tolerating oxaliplatin and docetaxel (FLOT) initiation and nivolumab rechallenge without 5-FU. Discussion: This case is challenging as the presentation does not conclusively identify a causative agent. The patient’s symptom severity suggests ICI myocarditis, while the early onset points to 5-FU cardiotoxicity. His quick recovery of cardiac function after medication cessation suggests 5-FU-associated Takotsubo cardiomyopathy. His improvement after steroids raises concern for an adverse immunologic response as in ICI myocarditis or idiosyncratic reactions to oxaliplatin with 5-FU. This patient received ICI therapy and chemotherapy, increasing his risk for cardiac immune-related adverse events. His protracted 5-FU infusion increased his risk for 5-FU cardiotoxicity, but his normal DPD activity mitigates this risk. Although his biopsy was negative, it cannot exclude ICI myocarditis. By the IC-OS 2021 consensus, he meets the criteria for ICI myocarditis presenting 48 hours after nivolumab exposure with cardiogenic shock, elevated cardiac biomarkers, decline in cardiac function, and CMR with elevated T1 and T2 relaxation times. Yet, his biomarkers remained normal with nivolumab rechallenge, arguing against ICI myocarditis and suggesting 5-FU as the culprit. Early recognition and differentiation of the culprit in concurrent therapies impact management and future treatment options. Rechallenge carries risk and requires interdisciplinary collaboration to ensure patient safety.

Pembrolizumab (Keytruda)

Reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform nonbinding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses pembrolizumab (Keytruda), 100 mg/4 mL vial, solution for infusion. Indication: Pembrolizumab, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma, whose tumours express PD-L1 (combined positive score [CPS] ≥ 1), as determined by a validated test.

Current Standards and Controversies in Multidisciplinary Management of Locoregional Gastroesophageal Junction Tumors.

There has been controversy in the management of gastroesophageal (GE) junction cancers with pre-operative chemoradiation and peri-operative chemotherapy as accepted practices. We aim to assess and compare the defining trials establishing current standards of care and discuss future directions seeking to further improve patient-centered outcomes in GE junction cancers. Over the last two decades, several large Phase III randomized trials have been conducted including GE junction cancers, showing superiority of 1) pre-operative chemoradiation over surgery (CROSS) and 2) peri-operative chemotherapy with FLOT over CROSS without radiotherapy (FLOT 4). While NEO-Aegis suggested equipoise between the CROSS vs. peri-operative chemotherapy, the recently presented ESOPEC trial demonstrated superiority of peri-operative FLOT versus CROSS in esophagus and GE junction adenocarcinomas. Based on the ESOPEC trial, peri-operative chemotherapy with FLOT appears to be a preferred regimen for patients with resectable GE junction adenocarcinomas in patients able to receive FLOT. There is evidence in support of other practices, such as induction chemotherapy, pre-operative chemoradiation, definitive chemoradiation for those not fitting ESOPEC criteria. Chemoradiation ± chemotherapy with non-operative intent represents a promising strategy for patients seeking organ preservation, and ongoing studies will better define its feasibility and long-term outcomes.

More May Not Be Better: Comparison of Oncologic Outcomes Following Induction Chemotherapy Plus Chemoradiation and Chemoradiation Alone for Esophageal Adenocarcinoma.

The oncologic benefit of induction chemotherapy (IC) before chemoradiation (CRT) compared to CRT alone for locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma is not well defined. We hypothesized that IC with CRT would improve survival and pathologic complete response rate compared to CRT alone. A retrospective review of patients with biopsy proven esophageal or GEJ adenocarcinoma treated with preoperative CRT and IC + CRT and surgical resection from 2007 to 2023 at a single institution was performed. First order outcomes were overall survival and pathologic complete response rate; secondary outcomes included disease-free survival and distant metastasis failure. Subgroup analyses were conducted based on baseline characteristics and tumor-specific features. Survival analysis was performed with Kaplan-Meier curves with log-rank tests and Cox regression analysis. Of 205 patients that met inclusion criteria, 76 (38%) patients underwent IC + CRT. There were no significant differences in demographic or tumor-specific characteristics between the two cohorts. There were no differences in the median overall survival between CRT and IC + CRT groups (47 months vs. not reached, p = 0.194). The rate of pathologic complete response in the overall cohort was 22%; IC + CRT was not associated with higher complete tumor response than CRT alone (20% vs. 23%, p = 0.557). There were no significant differences in any of the secondary outcomes between the two treatment paradigms. We could not detect added oncologic benefit in survival or pathologic complete response with IC over CRT alone for resectable esophageal and GEJ cancer. Biomarker driven prospective studies exploring the optimal perioperative treatment regimens are warranted.

Accuracy of the preoperative estimation of esophageal invasion length of adenocarcinoma of the esophagogastric junction and its discrepancy with the pathological measurement.

The incidence of esophagogastric junction (EGJ) adenocarcinoma has increased worldwide. As the EGJ is located at the boundary between the thoracic and abdominal cavities, the optimal surgical approach is a subject of debate and estimation of the esophageal invasion length (EIL) is an important factor in its selection. Data from our in-house database were extracted for consecutive patients with Siewert type I, II and III EGJ adenocarcinoma (EIL ≤ 4cm), who underwent transhiatal or transthoracic surgical resection between 2010 and 2016. The clinical records of these patients were reviewed and the accuracy of EIL estimation and its discrepancy with the pathological measurement were analyzed. A total of 82 patients were included in the final analysis. We established that EIL was underestimated in 49 of these patients (59.8%). The mean-distance discrepancy between the preoperative and pathological diagnosis of EIL in the underestimation group was 7.0mm. Multivariate analysis revealed that submucosal cancer spread was an independent risk factor for underestimation (P < 0.01). The mean length of submucosal cancer spread was longer for undifferentiated histologic type EGJ adenocarcinomas. (P < 0.01). The EIL was underestimated in approximately 60% of EGJ adenocarcinomas requiring surgical treatment. Thus, careful management is necessary, especially for EGJ adenocarcinoma of the undifferentiated histologic type.

Neoadjuvant cadonilimab plus FLOT chemotherapy in locally advanced gastric/gastroesophageal junction adenocarcinoma: A multicenter, phase 2 study.

Treatment with cadonilimab and chemotherapy has shown promise as a first-line treatment for gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, its application in neoadjuvant settings has not yet been documented. This multicenter, phase 2 trial (ChiCTR2200066893) was conducted at four hospitals across China. Treatment-naive patients with locally advanced G/GEJ adenocarcinoma (cT3/4, N+, M0) and who were human epidermal growth factor receptor 2 negative received 3-cycle or 4-cycle neoadjuvant treatment of cadonilimab plus FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy, followed by gastrectomy and 4-cycle adjuvant FLOT chemotherapy. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included major pathological response (MPR), overall response rate (ORR), disease control rate (DCR), R0 resection rate, downstaging rate, and safety. Between December 23, 2022, and December 15, 2023, 32 of 38 patients completed the scheduled treatment, achieving an R0 resection rate of 100% (32/32). The pCR rate was 21.1% (8/38, 90% confidence interval [CI]: 9.7-32.4), and the MPR rate was 44.7% (17/38, 90% CI: 30.9-58.5). Radiological evaluations wereavailable for 28 of 38 patients by blinded independent central review. The ORR was 60.7% (17/28, 90% CI: 44.7-76.7), and the DCR was 100.0% (28/28, 90% CI: 100.0-100.0). Tumor downstaging occurred in 71.9% of patients (23/32), with consistent efficacy across all populations observed in the subgroup analysis. Grade 3 adverse events occurred in 31.6% of patients without severe safety issues. Neoadjuvant cadonilimab plus FLOT chemotherapy treatment exhibits promising efficacy with manageable toxicities in locally advanced G/GEJ adenocarcinoma, providing preliminary evidence for further investigation. This study was funded by Akeso Biopharma.

Two-Year Outcomes and Biomarker Analysis of Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma After Neoadjuvant Chemotherapy and Immunotherapy from the Phase II WuhanUHGI001 Trial.

This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial. Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response. Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability. Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning.

ASO Author Reflections: Neoadjuvant Chemotherapy Combined with Immunotherapy is a Promising Strategy for Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma.

ASO Author Reflections: Neoadjuvant Chemotherapy Combined with Immunotherapy is a Promising Strategy for Locally Advanced Gastric and Gastroesophageal Junction Adenocarcinoma.

A Gene Expression Signature that Predicts Gastric Cancer Sensitivity to PARP Inhibitor Therapy.

Biomarkers indicating sensitivity to poly ADP-ribose polymerase (PARP) inhibitors have not yet been identified in gastric cancer. PARP inhibitors target homologous recombination deficiency (HRD); however, homologous recombination (HR) induces complex changes in gene expression, which makes it difficult to identify reliable biomarkers. In this study, we identified a multi-gene expression signature as a marker of PARP inhibitor sensitivity in gastric cancer. Seven gastric cancer cell lines were evaluated for susceptibility to PARP inhibitors using a growth inhibition assay. Gene expression profiling (GEP) was used to identify differentially expressed genes between PARP inhibitor-sensitive and -resistant cell lines. The resulting gene set was subjected to cluster analysis using tumor samples from 250 patients who underwent gastrectomy for primary gastroesophageal junction and gastric adenocarcinoma. HRD was defined as a truncating mutation in one or more of 22 HR-related genes and HRD scores were calculated using whole-exome sequencing data. In the growth inhibition assays, the HGC27 and HSC39 cell lines were sensitive to the PARP inhibitors, olaparib, and rucaparib, and were significantly correlated with the GEP results. Seven (2.8%) patients harbored truncating mutations in HR-related genes. A gene expression signature based on the top 100 high and low differentially expressed genes between sensitive and resistant cell lines revealed a patient cluster with a high prevalence of HR-related gene mutations and high HRD scores. The 100-gene expression signature identified in this study may serve as a valuable predictive biomarker for PARP inhibitor sensitivity in gastric cancer.

Two-center experience comparing the use of the FLOT4 and CROSS schemes for patients with gastric, esophageal, and gastroesophageal junction adenocarcinoma

Two-center experience comparing the use of the FLOT4 and CROSS schemes for patients with gastric, esophageal, and gastroesophageal junction adenocarcinoma

Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer

BACKGROUND Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer have poor outcomes. Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer. Inetetamab is a novel anti-HER2 drug, and its efficacy and safety in gastric cancer have not yet been reported. AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer. METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma were randomly divided into two groups: One group received inetetamab combined with the SOX regimen, and the other group received trastuzumab combined with the SOX regimen. After 4-6 cycles, patients with stable disease received maintenance therapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were the objective response rate, disease control rate, and adverse events (AEs). RESULTS Thirty-seven patients completed the trial, with 18 patients in the inetetamab group and 19 patients in the trastuzumab group. In the inetetamab group, the median PFS was 8.5 months, whereas it was 7.3 months in the trastuzumab group (P = 0.046); this difference was significant. The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months (P = 0. 33), and the objective response rate was 50% vs 42% (P = 0.63), respectively; these differences were not significant. Common AEs included leukopenia, thrombocytopenia, nausea, and vomiting. The incidence rates of grade ≥ 3 AEs were 56% in the inetetamab group and 47% in the trastuzumab group (P = 0.63), with no significant difference. CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer, inetetamab and trastuzumab showed comparable efficacy. The inetetamab group showed superior PFS, and both groups had good safety.

Pembrolizumab (Keytruda)

Canada’s Drug Agency recommends that Keytruda should be reimbursed by public drug plans for the treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) negative gastric or gastroesophageal junction (GEJ) adenocarcinoma if certain conditions are met. Keytruda should only be covered to treat patients who have not received previous treatment for HER2-negative advanced or metastatic gastric or GEJ cancer and who have good performance status. Keytruda should only be reimbursed if prescribed in combination with fluoropyrimidine- and platinum-containing chemotherapy by a clinician with expertise and experience in treating gastric and GEJ cancer, and the cost of Keytruda in combination with chemotherapy is reduced so that it does not exceed the drug program cost of treatment with nivolumab in combination with chemotherapy.