Esophagogastric Research Articles

Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (DEP CTX) in patients with advanced solid cancers in a phase 1/2 trial (P1/2).

3004 Background: DEP CTX is a highly optimized dendrimer nanoparticle formulation of cabazitaxel that achieves sustained cytotoxic drug delivery to tumors via enhanced permeability & retention effects. Unlike standard cabazitaxel (s-CTX), DEP CTX is highly water soluble, does not contain toxic excipients associated with anaphylaxis & does not require steroid/antihistamine premedication. We report the final P2 efficacy and safety results in patients (pts) with advanced/metastatic solid tumors. Methods: Pts were treated with DEP CTX at 20 mg/m2 cabazitaxel, IV 3-weekly. Efficacy was assessed by RECIST v1.1, Prostate Cancer Working Group 3 (PCWG3) guidelines or serum tumor markers; evaluable pts had relevant criteria at baseline and a follow-up assessment per protocol window. Safety was assessed by CTCAE v4.03. (EudraCT 2017-003424-76). Results: In P2, 75 pts were enrolled, prioritizing metastatic castration-resistant prostate cancer (mCRPC, s-CTX’s only approved indication), esophagogastric (EG) & ovarian (OV) cancers. For all pts, median progression free survival (mPFS) and overall survival (mOS) were 3.8 and 9.0 mths, respectively. Objective response rate (ORR) was 20% in 45 evaluable pts. All 25mCRPC pts were heavily pre-treated with a median of 4 prior lines of anticancer treatment. mPFS was 4.4 mths (radiographic or prostate specific antigen [PSA]); mOS was 14.7 mths. The disease control rate (DCR) was 70.6%; ORR was 16.7%. PSA reduced in 90% pts (by > 50% in 52.4%); 87% with bone metastases had no progression or improved. Of 15 EG pts, 9 were adenocarcinoma (ADENO) (3 gastric, 2 esophageal & 4 EG junction) & 6 were esophageal squamous cell carcinoma (SCC). For all EG pts, mPFS was 4.0 mths, mOS was 8.6 mths. mPFS was 4.0/1.9 mths for ADENO/SCC, respectively. Overall, DCR was 80%; ORR 30%. DCR was 100%/50% and the ORR was 33%/25% for ADENO/SCC, respectively. Of 22 OV pts, 96% were platinum resistant (Pt-R), with a median of 4 prior lines of anticancer treatment, including 59% with ≥ 3 platinum lines. mPFS/mOS were 3.1 mths & not reached, respectively. DCR was 66.7%; ORR 17.6%. Treatment related adverse events (TRAEs) were mostly mild/moderate (grade (G) 1/2; 64%/25%). Only 21% of pts had G 3/4 non-hematological TRAEs, while G3/4 lab detected neutropenia was seen in only 23% of pts despite no routine G-CSF. TRAEs observed in ≥10% of pts included fatigue, neutropenia, anemia, thrombocytopenia, diarrhea, nausea, vomiting, peripheral neuropathy and decreased appetite. Conclusions: DEP CTX exhibited clinically meaningful, durable antitumor activity in multiple advanced solid cancers, including mCRPC, Pt-R OV and EG cancers without the need for steroid premedication. The antitumor activity & safety results compare favorably to s-CTX, or standard of care chemotherapy in non-prostate cancers, and highlight the promising potential of dendrimer-enhanced delivery of cabazitaxel. Clinical trial information: 2017-003424-76 .

RNA-based fusion testing in gastrointestinal (GI) carcinomas: A single-institution experience.

3061 Background: Molecular profiling with next-generation sequencing is critical to provide appropriate clinical care in most GI cancers. However, outside of biliary tract cancers (BTCs), the utility of routine comprehensive fusion testing in GI carcinomas is not well established. We evaluated fusion testing of GI carcinomas in routine clinical care at Massachusetts General Hospital Cancer Center (MGHCC). Methods: Patients with confirmed GI carcinomas who underwent RNA-based tissue fusion testing at MGHCC between Jan 2016 and April 2023 were included. Samples with tumor cellularity <20% or not meeting quality controls were excluded. Fusions of known clinical relevance were evaluated for molecular and histopathologic associations. Results: 2300 GI cancers with at least 1 fusion assay were included (see Table). As expected, BTCs had the highest incidence of fusions (13.7%), 80% of which were FGFR2. Fusions were detected in 3.9-7.7% of colorectal (CRC), pancreatic ductal (PDAC), esophagogastric (EGC), and small bowel (SBC) carcinomas. Fusions of BRAF, FGFR1-3, NTRK1/3, RSPO2/3, and NRG1 were rare (excepting FGFR2 in BTCs) but observed in 3 or more cancer types. Consistent with prior studies, the 3 NTRK1 fusions observed in CRC were associated with MLH1 loss and 15 of 21 (71%) PDAC tumors with fusions were KRAS wild-type (WT). RSPO2/3fusions were the second most frequent after FGFR1-3. RSPO3fusions were predominantly seen in CRC and SBC and were associated with poorly differentiated histology (43%), microsatellite stability (100%), APC WT (92.6%), and KRAS (44.4%), BRAF V600E (40%), and BRCA1/2 mutations (29.6%). Of 5 RSPO2fusions, 4 were in EGC and 100% had poorly differentiated histology and TP53 mutations. No fusions were detected in 47 GI neuroendocrine tumors. Conclusions: Although individually rare, in aggregate RNA-based testing identifies clinically relevant fusions in a small but significant fraction of BTC, CRC, PDAC, EGC, and SBC. Molecular selection may identify subpopulations in which fusion testing is higher yield. CRC and SBC harboring RSPO3 fusions have a distinct molecular and pathologic phenotype, including a potentially novel association with BRCA1/2 mutations. Several detected fusions had novel partners that were nonetheless predicted actionable, highlighting the utility of partner-agnostic fusion testing in this population. [Table: see text]

Analysis of ctDNA assay as a strategy for watchful waiting in locally advanced esophageal cancer.

e16126 Background: Standard treatment for locally advanced esophagogastric (EG) cancer is neoadjuvant chemoradiotherapy (CRT) followed by surgery. The treatment goal is curative in order to control the tumor in the thorax, prevent regional recurrence, and to help prevent or delay metastatic progression. Despite achieving pathologic complete response (pCR) after surgery, patients with supposed local control may have recurrence up to a third of the time. Circulating tumor DNA (ctDNA) is an evolving tool in the field of oncology used as an informative biomarker. We provide longitudinal, real world observation of ctDNA minimal residual disease (MRD) to predict pCR and risk of recurrence. Methods: 22 participants with newly diagnosed locoregional EG cancer were enrolled under single institution approved protocol [IRB#1864127-7]. CtDNA-based MRD levels were obtained by Natera SignateraTM bespoke mPCR-NGS assay. Additionally, Natera Altera TM was used as a non-invasive biopsy to provide the comprehensive tumor-specific genomic profile. We evaluated thirteen participants who underwent definitive surgery and those who did not. Non-invasive plasma samples were surveilled at various timepoints which included the time of diagnosis, during neoadjuvant CRT, after definitive surgery. The primary outcome is a comparison of assay recurrence (AR) to disease recurrence (DR) defined as radiologic or clinical disease recurrence in participants with locoregional disease. Exploratory endpoints examine the profile of tumor. Results: Baseline levels were detected (n = 22) at new diagnoses. Longitudinal results demonstrated ctDNA clearance in eight participants while undergoing neoadjuvant chemoradiaton. Residual ctDNA were found in five participants for which two had clinical disease recurrence. Esophagectomy was done in three participants achieving pCR. Post procedural ctDNA were detected in one participant. Conclusions: The clearance of ctDNA favors less clinical disease recurrence in this study. This may indicate that ctDNA clearance confers lower risk of relapase. However, a larger cohort prospective study will be needed to validate the application of ctDNA as an early biomarker. The future application of ctDNA can be used to identify patients who may benefit from a watchful waiting adjuvant strategy instead of proceeding with invasive esophagectomy.

Endoscopic Treatment of Postoperative Esophageal Anastomotic Strictures: A Single Center Experience

Background
 To evaluate the analysis, treatment methods and results of endoscopic treatments of esophagojejunostomy (EJ) and esophagogastric (EG) anastomotic strictures. 
 Methods:
 Data from patients treated between 2009 and 2019 was collected and analyzed. The primary endpoint was defined as the absence of dysphagia for at least 6 months after the final endoscopic treatment session. The improvement in dysphagia scores at 1 and 6 months was accepted as the secondary endpoint.
 Results
 Of 18 patients (10 male), there were 11 patients with EG anastomotic stricture and 7 patients with EJ anastomotic stricture. Only balloon or bougie dilatation was applied to 13 patients, while 5 patients received a full-covered metal stent (FCMS) in addition to balloon or bougie dilatation due to persistent dysphagia symptoms. The primary endpoint was reached in 10 of the 13 patients (76.9%) who received only balloon or bougie dilatation. The secondary endpoint was reached in 3 patients. The primary endpoint was reached in 4 of the 5 patients (80%) who received a FCMS in addition to balloon or bougie dilatation. 6 patients (33.3%) had a recurrence. Major complications occurred in 4 (22.2%) patients, including perforation in 2 and stent migration in 2 patients.
 Conclusion
 The study demonstrated that endoscopic treatment of esophageal anastomotic strictures is a reliable and effective treatment option with a high success rate. The use of FCMS, either as a primary treatment option or in the treatment of perforation as a complication of endoscopic treatment, showed good effectiveness in our study.

Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab

Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3 as a mechanism potentially involved in trastuzumab-acquired resistance. FGFR inhibition could be a potential mechanism as a second-line treatment. In this Simon's two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. The primary end point was the 12-week progression-free survival rate. Translational analyses were performed on tissue and plasma samples. Eight patients were enrolled in the first stage. Although the 6-week disease control rate was 25%, only one patient achieved a stable disease after 12 weeks of treatment. The trial was discontinued before the second stage. Two out of six evaluable tumor samples expressed FGFR3. No FGFRs amplification was detected. HER2 amplification was lost in three out of eight patients. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies.

Clinical Importance of Clonal Hematopoiesis in Metastatic Gastrointestinal Tract Cancers

Clonal hematopoiesis (CH) has been associated with development of atherosclerosis and leukemia and worse survival among patients with cancer; however, the association with cancer therapy efficacy, in particular immune checkpoint blockade (ICB), and toxicity has not yet been established. Given the widespread use of ICB and the critical role hematopoietic stem cell-derived lymphocytes play in mediating antitumor responses, CH may be associated with therapeutic efficacy and hematologic toxicity. To determine the association between CH and outcomes, hematologic toxicity, and therapeutic efficacy in patients with metastatic gastrointestinal tract cancers being treated with systemic therapy, both in the first-line metastatic treatment setting and in ICB. This retrospective cohort study included 633 patients with stage IV colorectal (CRC) and esophagogastric (EGC) cancer who were treated with first-line chemotherapy and/or ICB at Memorial Sloan Kettering Cancer Center. Patients underwent matched tumor and peripheral blood DNA sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing assay between January 1, 2006, and December 31, 2020. Clonal hematopoiesis-related genetic alterations were identified by next-generation sequencing of patients' tumor and normal blood buffy coat samples, with a subset of these CH alterations annotated as likely putative drivers (CH-PD) based upon previously established criteria. Patients with CH and CH-PD in peripheral blood samples were identified, and these findings were correlated with survival outcomes (progression-free survival [PFS] and overall survival [OS]) during first-line chemotherapy and ICB, as well as baseline white blood cell levels and the need for granulocyte colony-stimulating factor (G-CSF) support. Among the 633 patients included in the study (390 men [61.6%]; median age, 58 [IQR, 48-66] years), the median age was 52 (IQR, 45-63) years in the CRC group and 61 (IQR, 53-69) years in the EGC group. In the CRC group, 161 of 301 patients (53.5%) were men, compared with 229 of 332 patients (69.0%) in the EGC group. Overall, 62 patients (9.8%) were Asian, 45 (7.1%) were Black or African American, 482 (76.1%) were White, and 44 (7.0%) were of unknown race or ethnicity. Presence of CH was identified in 115 patients with EGC (34.6%) and 83 with CRC (27.6%), with approximately half of these patients harboring CH-PD (CRC group, 44 of 83 [53.0%]; EGC group, 55 of 115 [47.8%]). Patients with EGC and CH-PD exhibited a significantly worse median OS of 16.0 (95% CI, 11.6-22.3) months compared with 21.6 (95% CI, 19.6-24.3) months for those without CH-PD (P = .01). For patients with CRC and EGC, CH and CH-PD were not associated with PFS differences in patients undergoing ICB or first-line chemotherapy. Neither CH nor CH-PD were correlated with baseline leukocyte levels or increased need for G-CSF support. These findings suggest CH and CH-PD are not directly associated with the treatment course of patients with metastatic gastrointestinal tract cancer receiving cancer-directed therapy.

Abstract 3988: Identification of HER4 mutations with potential as biomarkers of response to neratinib

Abstract Background: HER4 is a member of the human epidermal growth factor receptor (HER/ErbB) family of receptor tyrosine kinases. HER4 is activated through ligand binding, transmitting intracellular signals by homodimerizing, or by heterodimerizing with other family members (EGFR, HER2, HER3). The role of HER4 in cancer or normal tissue has not been studied as comprehensively as EGFR and HER2, potentially due to a more complex biology that includes four different isoforms and different stability/tissue-specific expression patterns, and oncogenic or oncosuppressor roles. The oral, irreversible pan-HER (EGFR, HER2, HER4) tyrosine kinase inhibitor (TKI) neratinib (NER) is clinically active against HER2-mutant and HER2-amplified cancers. Using publicly available datasets including cBioPortal and COSMIC and predicted structural and functional impacts, this study aimed to identify HER4 mutations with the greatest oncogenic potential that may have value as potential biomarkers of response to NER. Methods: The frequency of HER4 mutations across 33 cancer types was determined by using the clinical database cBioPortal and TCGA PanCancer Atlas datasets (n=10967). A shortlist of potentially oncogenic HER4 mutations was created based on the occurrence in cBioPortal and COSMIC databases, annotation as putative driver and cancer hotspot, structural and functional impacts according to OncoKB, Mutation Assessor, SIFT and Polyphen-2 software, and HER4 protein folding studies. Analysis was carried out using the R-studio statistical environment. Results: HER4 amplification is rare in cancer, with the majority of genetic changes reported as point mutations; particularly missense (31.93%), synonymous (6.43%) and nonsense (3%) substitutions. Melanoma and esophagogastric (EG) cancers showed the highest HER4 alteration frequency, 17.34% and 13.42%, respectively, across different cancer types in the cBioPortal database. Melanoma and EG cancers showed the second and third highest absolute count of HER4 genomic alterations (n=77 and n=69, respectively). Based on the criteria outlined in methods, a priority list of HER4 mutations with greatest oncogenic potential was curated for melanoma (HER4 R106C, R306C, R711C, G936E, F1003I), stomach (HER4 C217R, S774N, K1002R, Y1150C) and esophageal (HER4 R488W, S449Y) adenocarcinomas. Mutations at these sites, located across ligand-binding, dimerization and intracellular signaling domains, have the potential to impact HER4 activity and thus possibly act as biomarkers of response to an irreversible pan-HER TKI like NER. Conclusions: These data suggest that melanoma and EG cancers are the cancer types with the highest rate of HER4 mutations. In vitro functional characterization of the identified HER4 mutations is now required to further explore their value as biomarkers of response to NER. Citation Format: Marta Valenti, Neil T. Conlon, Lisa D. Eli, Irmina Diala, John Crown, Denis M. Collins. Identification of HER4 mutations with potential as biomarkers of response to neratinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3988.

P-244 Feasibility, safety, and biodistribution of 18F-BMS-986229 PET in patients with esophagogastric (EG) cancer

The addition of programmed cell death protein 1 (PD-1) blockade to combination cytotoxic chemotherapy improves overall survival among patients with EG cancer in the frontline metastatic setting. However, due to tumor heterogeneity, PD-L1 expression based on single site biopsies is inadequate to identify those who will derive benefit from the addition of checkpoint blockade, and better biomarkers are needed. We developed PD-L1 specific positron emission tomography (PET) imaging using 18F-BMS-986229 in patients with EG cancer for non-invasive assessment of tumor PD-L1 status.

P-296 - Cholesterol-depleting drugs for HER2-targeted radioimmunotherapy of patient-derived esophagogastric (EG) cancer

P-296 - Cholesterol-depleting drugs for HER2-targeted radioimmunotherapy of patient-derived esophagogastric (EG) cancer

189: THE EFFECT OF COVID -19 ON THE NEW DIAGNOSIS OF ESOPHAGOGASTRIC CANCER IN THE UK: A SINGLE-CENTRE EXPERIENCE

Abstract Background and aim Covid-19 has had a devastating global impact and resulted in over 4.4 million directly attributed deaths. The UK entered lockdown in March 2020, redistributing its medical workforce and resources. Early estimations suggested at least 4700 extra cancer deaths at 5 years if there was a 3-month delay to surgery. Delays to diagnosis and treatment for esophagogastric (EG) cancers can be particularly detrimental to survival. The aim of this study is to assess the impact of Covid-19 on new cancer referrals to a centralised UK EG cancer centre, including presentation, decision making and treatment. Methods Patients with EG cancer referred to a tertiary, high-volume centre between March 2019 and March 2021 were reviewed. Patients were stratified into Pre-covid (March 2019–March 2020) and Covid (March 2020–2021) cohorts. Number of new referrals, clinical stage, treatment decision, and time to treatment were compared for gastric adenocarcinoma (GA), esophagogastric-junction adenocarcinoma (EGJA), esophageal adenocarcinoma (EA) and esophageal SCC (ESCC). Results There was an 11% reduction in new cancer referrals (485 vs 431). GA, EGJA and EA did not have significant change in treatment intent, although there was a significant increase in the decision for definitive non-surgical treatment of EA (P = 0.046). GA and EA patients had a small, but significant increase in average clinical stage at presentation (P < 0.05). There was no increase in time to treatment for GA, EGJA and EA. A significantly higher proportion of ESCC patients were given curative intent treatment in the Covid-19 cohort (P = 0.0006) however, this was accompanied with an increased time to treatment (35.8 days vs 27.9 days P = 0.0198). Conclusion This high-volume centre has seen a reduction in new cancer referrals since the first UK lockdown. This was associated with a small, but significant, increase in clinical stage of GA and EA at presentation. This may represent an early indication of excess esophagogastric cancer deaths due to the impact of Covid-19. This data also confirms initial results showing that oncological decisions were not compromised, although Covid-19 remains a dynamic challenge.

Esophageal and gastric malignancies after bariatric surgery: a retrospective global study.

Bariatric surgery can influence the presentation, diagnosis, and management of gastrointestinal cancers. Esophagogastric (EG) malignancies in patients who have had a prior bariatric procedure have not been fully characterized. To characterize EG malignancies after bariatric procedures. University Hospital, United Kingdom. We performed a retrospective, multicenter observational study of patients with EG malignancies after bariatric surgery to characterize this condition. This study includes 170 patients from 75 centers in 25 countries who underwent bariatric procedures between 1985 and 2020. At the time of the bariatric procedure, the mean age was 50.2 ± 10 years, and the mean weight 128.8 ± 28.9 kg. Women composed 57.3% (n = 98) of the population. Most (n = 64) patients underwent a Roux-en-Y gastric bypass (RYGB) followed by adjustable gastric band (AGB; n = 46) and sleeve gastrectomy (SG; n = 43). Time to cancer diagnosis after bariatric surgery was 9.5 ± 7.4 years, and mean weight at diagnosis was 87.4 ± 21.9 kg. The time lag was 5.9 ± 4.1 years after SG compared to 9.4 ± 7.1 years after RYGB and 10.5 ± 5.7 years after AGB. One third of patients presented with metastatic disease. The majority of tumors were adenocarcinoma (82.9%). Approximately 1 in 5 patients underwent palliative treatment from the outset. Time from diagnosis to mortality was under 1 year for most patients who died over the intervening period. The Oesophago-Gastric Malignancies After Obesity/Bariatric Surgery study presents the largest series to date of patients developing EG malignancies after bariatric surgery and attempts to characterize this condition.

Leak After Sleeve Gastrectomy: A Videoscopic Documentation on Occurrence, Diagnosis, and Treatment

Introduction: Leak after a sleeve gastrectomy varies between 1.1% and 4.7% with a 7% mortality rate.1,2 This video of the primary operation shows a staple line failure coupled with problematic stitching, suggesting an overlooked micro-leak. Methods: In 1163 consecutive sleeve gastrectomies, two leaks (0.17%) occurred, and both were associated with technical failures. Our protocols/technique and changes during the Covid-19 pandemic were reported.3,4 In brief, the protocol includes staple-line reinforcement with full-thickness-continuous-suturing without imbrication, drainage, discharge on postoperative day three, and a selective leak test. The first leak occurred in a patient with a body mass index of 67 kg/m2 with an obstructed distal sleeve at the incisura. This was diagnosed on postoperative day nine and managed by emergency conversion to a gastric bypass. This approach avoided a stent.5 The second patient developed fever on postoperative day three which was attributed to pneumonia. An upper gastrointestinal (UGI) study and computed tomogram (CT) failed to identify a leak. There was no stenosis. A leak was diagnosed ultimately on postoperative day 12 on a repeat UGI study and confirmed with a CT scan. Results: Re-laparoscopy was performed for debridement, stenting, and drainage. A central catheter was inserted for total parenteral nutrition. Subsequent management required repeat hospital admissions, aspirations of abscesses/collections under radiologic guidance, and administration of antibiotics/antifungal agents. Subsequently, the stent was removed on day 54 with resolution of the metabolic syndrome and a 20 kg weight loss. Conclusions: Esophagogastric (EG)-junction encompasses the lower esophageal sphincter and the small “B” formations were unable to provide sufficient closure in this area. Moving the stapler off the EG-junction or using cartridges with larger/deeper “B” formations may have prevented this leak. Full-thickness-continuous-stitching might also have prevented the leak but failed because of technical reasons in this case. A leak test, if performed, may have identified the leak intraoperatively. Overall, leak presentation may be variable and management must be individualized. Leaks that are diagnosed a week after surgery are generally attributed to “non-technical” issues (i.e., ischemia). Our decade-long experience in 1163 consecutive patients contradicts this view and suggests that leaks occur because of technical errors and, therefore, may be preventable. If required, double cuffed stents which can be placed under laparo-endoscopic guidance seems to be a reasonable option provided that the distal cuff is neatly deployed in the duodenal bulb. Since the distal cuff is also fully covered, this must not occlude the pancreatic duct. Migration even a few cm distally will not be tolerable and requires stent re-positioning. No competing financial interests exist. Runtime of video: 9 mins 24 secsPatient Consent: Authors have received and archived patient consent for the video. All individuals appearing in the video also gave written consent to use their footage.

Digital histological markers based on routine H&E slides to predict benefit from maintenance immunotherapy in esophagogastric adenocarcinoma.

e16074 Background: Immune checkpoint inhibition (ICI) is an effective treatment for a subset of patients with inoperable esophagogastric (EG) adenocarcinoma. Robust predictive biomarkers are required to identify these patients and a variety of strategies including immunohistochemical staining of PD-L1 and tumor mutational burden (TMB) assessment have been employed. Here, we explore digital histological (dHis) markers based on routine hematoxylin and eosin (H&E) slides alone or in combination with molecular markers (PD-L1 and TMB) as predictive biomarkers of benefit from maintenance immunotherapy in patients with inoperable EG adenocarcinoma. Methods: We developed a deep learning based algorithm to construct novel digital histological (dHis) markers by summarizing the statistics of all different types of nuclei present in the tumor tissue sections, their morphological features and their colocalization across each of the whole slide image. The dHis markers were then input into a decision-tree based approach to test for prognostic and predictive power alone or in combination with molecular markers. We assessed two cohorts of patients randomized to surveillance (n=38) or maintenance durvalumab (n=35) after 18 weeks of first-line platinum-based chemotherapy in the PLATFORM trial (NCT02678182) according to the 12-week progression-free rate. We measured the accuracy as the area under the receiver operating characteristics curve (AUROC) to determine the prognostic and predictive power of each marker set. We conducted a stratified 3-fold cross-validation, repeated 5 times and report the overall AUROC results. Results: Molecular markers alone yielded an AUROC of 0.5581±0.0939 on the surveillance arm, 0.6671±0.1479 on the treatment arm, and 0.6376±0.0958 for both the arms. Digital histological markers alone yielded an AUROC of 0.8952±0.0638, 0.8995±0.0719 and 0.8488±0.0700 on surveillance, immunotherapy and both arms, respectively. When using these two sets of markers together for both arms, molecular markers offered a limited improvement (around 0.02). Patients with TMB in the highest tertile were associated with lower likelihood of having progressive disease 12 weeks after randomization. Interestingly, dHis markers from morphology of connective and inflammatory nuclei were highly predictive for treatment benefit. Conclusions: Preliminary results suggest digital histological markers offer significant improvement over PD-L1 and TMB markers alone for predicting benefit from immunotherapy in EG adenocarcinoma with the added advantages of scalable, rapid, low-cost and objective quantification on routine histology sections. We are further validating their effectiveness on a larger cohort. Clinical trial information: NCT02678182.

Abstract S02-03: The impact of the COVID-19 pandemic on Barrett’s esophagus and esophago-gastric cancer

Abstract Objective The COVID-19 pandemic has placed an inexorable strain on endoscopy services worldwide, affecting the diagnosis of esophago-gastric (EG) cancer and Barrett’s esophagus (BE). As coronavirus infection rates rose many professional bodies advised that all endoscopy, except emergency and essential procedures, be stopped immediately. We sought to quantify the decline in EG cancer and BE diagnoses following implementation of British Society of Gastroenterology (BSG) guidance related to COVID-19 and the psychosocial effects on BE patients. Methods We examined EG cancer and BE diagnoses in Northern Ireland from March-September 2020 and compared them with the three-year average number of patients during the same time period between 2017-2019 by utilizing Northern Ireland Cancer Registry (NICR) data. The psychosocial impact of COVID-19 was assessed using an online survey, which included validated WHOQOL-BREF and EQ-5D-5L quality of life measures, and was completed by 24 BE patients from April-May 2020. Results During the first six months of the pandemic the proportion of EG cancer and BE diagnoses declined by 26.6% and 59.3%, respectively, compared to expected levels. In April, BE diagnoses fell by 95.5% but by September, whilst EG cancer rates had returned to baseline, BE cases remained suppressed by approximately 20%. We estimate that these declines in diagnosis represent 53 ‘missed’ EG cancer and 236 ‘missed’ BE diagnoses. In the online survey sample, BE patients reported consistently lower quality of life scores than population norms, and highlighted a number of concerns with regard to their health and care. Conclusion The COVID-19 pandemic has resulted in an abrupt decline in EG cancer and BE diagnoses and has profoundly impacted the wellbeing of BE patients. Our study represents the first report of the impact of COVID-19 on the diagnosis of BE. Strategies to mitigate the ongoing effects of the pandemic are urgently required to preserve the ability to rapidly detect and diagnose cancer and pre-malignant conditions. Citation Format: Richard C. Turkington, Anita Lavery, David Donnelly, Anna T. Gavin, Damian T. McManus, Victoria Cairnduff, Charlene M. McShane, Brian T. Johnston, Lesley A. Anderson, Helen G. Coleman. The impact of the COVID-19 pandemic on Barrett’s esophagus and esophago-gastric cancer [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S02-03.

The Impact of the COVID-19 Pandemic on Barrett’s Esophagus and Esophagogastric Cancer

The Impact of the COVID-19 Pandemic on Barrett’s Esophagus and Esophagogastric Cancer

Clinical and molecular characteristics of early-onset versus average-onset esophagogastric cancer.

250 Background: While the rate of esophagogastric (EG) cancer is declining, early onset (EO) gastric cancer prior to age 50 is rising. It is unknown whether EO-EG cancer represents a distinct entity. This study investigates the clinical and molecular characteristics of EO compared with average onset (AO)-EG cancers. Methods: We reviewed clinical and molecular features of gastric (G), esophageal (E) and gastroesophageal junction (GEJ) cancer in patients treated at MSKCC between 2005 and 2018. We defined early onset as age < 49, based on the age cutoff for urgent endoscopy referral. Clinical symptoms at diagnosis, primary tumor location, histology, HER2 and MSI status and molecular alterations were compared using Fisher’s exact test. Benjamini-Hochberg method was used to decrease the false discovery rate. Results: We analyzed 738 pts with EG cancer (age < 49 n=151; age >50 n=587). Race and sex were different with more Asian (19% vs. 9%), fewer Caucasian (62% vs. 81%) ( P<0.001) and more female patients (40% vs. 29%, P=0.014) in the EO group. Time from symptom onset to diagnosis was longer in the EO group (median (IQR) 144 d (66-276) vs. 75 d (34-136), P=0.009), though stage did not differ ( P=0.49). Patients with EO-EG cancer had less weight loss ( P<0.001), but no other distinct presenting symptoms. Primary disease site was different with more gastric in the EO group (66% vs. 55%, P=0.04). Signet-ring histology was more common in the EO group (11% vs. 3%; P=0.0009). ERBB2 amp and MSI-H were similar, with a trend toward more MSI-H in the AO group (ERBB2 amp P=0.88, Q=0.830; MSI-H P=0.0157, Q=0.056). The most frequent somatic alterations were similar in EO vs. AO pts, including TP53 (68% vs. 70%, P=0.370, Q=0.825), CDH1 (15% vs. 11%, P=0.139, Q=0.825), RHOA (6% vs. 5%, P=0.395, Q=0.825). There was a trend toward more ARID1A (19% vs. 7%, P<0.01, Q=0.250) and FBWX7 (5% vs. 2%, P=139, Q=0.825) mutations in the AO group. Conclusions: Presenting symptoms, stage, histology, HER2 and MSI status are similar in patients with EO vs. AO-EG cancer. There is a trend in EO toward longer time to diagnosis, gastric primary site of disease, signet-ring histology and fewer ARID1A and FBWX7 mutations. Expanded clinical and molecular data will be presented. [Table: see text]

Abstract 1773: Targeting HER2 and Src in HER2-driven ovarian and esophagogastric cancers

Abstract Background: Neratinib, an oral, irreversible pan-HER tyrosine kinase inhibitor, has exhibited clinical activity against HER2-mutant and HER2 over-expressing cancers. Our previous pre-clinical studies have shown that combining the multi-kinase inhibitor dasatinib with neratinib is highly synergistic in HER2-positive breast cancer. Therefore, the aim of this study was to examine the potential of combining neratinib and dasatinib in HER2 over-expressing/mutant esophagogastric (EG) and ovarian cancer. Methods: The prevalence of HER2 mutation and amplification levels in ovarian and EG cancers was determined using the AACR Project GENIE database. The anti-proliferative effects of neratinib and dasatinib were assessed by acid phosphatase assay in a panel of HER2-altered ovarian (Caov3, OVCAR8, IGROV-1) and EG (NCI-N87, OE19) cancers. Synergy was assessed using Combenefit software with the Loewe additivity model, with additivity and synergy > 0 and antagonism < 0. Western blotting was used to examine the basal expression of HER2 and downstream signalling activity and to investigate the signalling effects of drug treatment in HER2-mutant OVCAR8 cells. Results: HER2 was the most commonly amplified gene in EG cancers (14.1%) and was also amplified in 2.4% of ovarian cancers. HER2 mutations occurred in 6.1% of EG and 1.5% ovarian cancers. All five cell lines tested displayed nanomolar sensitivity to single agent neratinib or dasatinib (Table). The combination of neratinib and dasatinib was synergistic in all cell lines. The greatest synergy was observed with low concentrations of neratinib in EG cell lines. Synergistic interactions occurred across a range of concentrations with both drugs in ovarian cancer cell lines. Antagonism was not observed at any concentration tested. Neratinib plus dasatinib inhibited Src and MAPK activity in OVCAR8 cells. Neratinib and dasatinib in ovarian and EG cancersCell linesCancertypeNeratinib EC50 value (nM)Dasatinib EC50 value (nM)Combination effectNCI-N87Esophagogastric0.188979SynergismOE19Esophagogastric0.432284SynergismOVCAR8Ovarian16281SynergismIGROV-1Ovarian1706SynergismCaov3Ovarian13730Synergism Conclusions: These data suggest that the addition of dasatinib may enhance the anti-cancer effect of neratinib in HER2-driven ovarian and EG cancers and warrants further investigation. Citation Format: Neil T. Conlon, Keshia Kroh, John Crown, Denis M. Collins. Targeting HER2 and Src in HER2-driven ovarian and esophagogastric cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1773.

PD-L1 positive esophagogastric (EG) cancer is associated with distinct bacteria.

4568 Background: Pembrolizumab is approved for chemotherapy-refractory PD-L1 CPS >1 mEG cancer. In clinical trials, pts with MSI-H, EBV+ and PD-L1 CPS >10 EG cancers derive the greatest benefit with immune checkpoint blockade (ICB). Pre-clinical data suggest that the gut microbiome modulates response to ICB; however, the EG cancer microbiome has not been characterized in EG cancer with respect to PD-L1 and MSI-H status. Therefore, we evaluated the EG tumor microbiome in the context of PD-L1 expression in order to define biologically unique EG tumor phenotypes for future therapeutic development. Methods: Clinical and pathologic characteristics, including age, stage at diagnosis, tumor PD-L1 CPS, HER2 IHC, EBV ISH, genomic analysis, treatment history and survival status were reviewed. CPS was stratified a priori using cutoffs of >1/>10/>20 due to biologic differences. MSK-IMPACT, a capture-based next-generation sequencing platform that detects mutations, copy-number alterations, and select fusions was used to detect non-human bacterial reads identified in the NCBI NT database. Bacterial species found in >2 pts were analyzed and stratified by highest PD-L1 CPS score for each individual patient (Vanderbilt, AMP 2018) and Bonferroni correction was used for odds ratio (OR) confidence intervals where each unique species was considered an independent hypothesis. Results: Molecular data from 311 pts was clinically annotated. PD-L1 results (Table) correlated with bacterial species identified on tumor sequencing. PD-L1 CPS >1 was associated with Selenomonas sputigena (OR: 8.2, 95% CI:1.2-53.6), and PD-L1 CPS >20 was associated with presence of Bifidobacterium dentium (OR: 7.4, 95% CI:1.1-48.5) and Prevotella denticola (OR: 4.2, 95% CI: 1.1-16.6) after multiple comparison correction for the 166 bacterial species identified in the cohort. No differences were seen between PD-L1 < 10 vs >10. Four patients were also found to have EBV+ tumors using this approach, including the 1/54 patients identified by EBER ISH. Conclusions: PD-L1 > 20 EG cancer represents a biologically unique subset, enriched for Bifidobacterium dentium and Prevotella denticola. Correlation between PD-L1 expression, microbial and immune environment, and survival on ICB is underway. [Table: see text]

Irinotecan with or without capecitabine as a beyond 2nd line regime for esophago-gastric adenocarcinomas.

e16545 Background: Purpose: The aim of this retrospective study was to assess the efficacy and toxicity of irinotecan +/- capecitabine for patients with metastatic esophago-gastric (EG) adenocarcinomas previously treated with at least two chemotherapy regimens including platinum-based, fluoropyramidines and taxanes. Introduction: Treatment for metastatic EG cancer beyond 2nd line remains controversial. Recently, the TAGS phase III trial (Shitara et al., 2018) showed overall survival benefit with Trifluridine/tipiracil of 2.1 months compared to placebo as a third line. Apatinib is also approved for use as third line in China (Li et al., 2013). Based on minimal evidence (Kang et al., 2013), irinotecan in combination with capecitabine is used in the UK. We performed a retrospective study to assess the efficacy and toxicity of irinotecan as a beyond 2nd line regime in metastatic EG adenocarcinomas in one of Europe’s largest cancer centres, The Christie. Methods: Data was collected retrospectively from all metastatic EG adenocarcinoma patients who were treated with irinotecan +/- capecitabine as a beyond 2nd line palliative treatment at the Christie Hospital from January 2014 to December 2019. Irinotecan was either given 2 or 3 weekly at dose of 180 mg/m² with or without capecitabine 800 mg/m². Response rate (RR) was calculated according to RECIST version 1.1, overall survival measured and toxicity data collected. Results: Fifty-six patients received irinotecan as beyond 2nd line palliative chemotherapy. Out of the thirty-seven patients with measurable disease on their scans, the overall response rate was 8.1% and the disease control rate was 51.4% as per RECIST 1.1. Median overall survival was 5 months (95% CI 4.2-5.8). The presence of grade 3-4 toxicities was 16% (9 patients) and included neutropenia, fatigue, nausea and diarrhea. On average, 3.7 cycles were administered, 32% (18 patients) required dose reductions, mainly secondary to grade 2 diarrhea and fatigue. Conclusions: Irinotecan in combination with capecitabine is efficacious as a beyond 2nd line regime in metastatic EG with an acceptable toxicity profile with a limited role in patients with resistant disease to first line platinum-based chemotherapies with fluoropyramidines.

Hiatal repair in Ivor Lewis minimally invasive esophagectomy: a case report

Hiatal hernia after minimally invasive esophagectomy (MIE) is an important postoperative complication that can cause severe morbidity or even mortality among patients with esophageal cancer. Usually repair of the hiatus immediately after esophageal reconstruction is suggested to prevent such complication. However, during the Ivor Lewis MIE procedure, hiatal repair is difficult to perform due to the deep-seated location of the hiatus after the final step of esophageal reconstruction in the right chest. The current study demonstrates a method of repairing the hiatus in the Ivor Lewis MIE. This is especially useful in the resection of a massive tumor near the esophagogastric (E-G) junction, which harbors a high risk of hiatal hernia when the hiatus is left unrepaired after extensive hiatal dissection.