Morphologic and molecular analysis of early-onset gastric cancer.

BACKGROUND: Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed. METHODS: Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next-generation sequencing data. RESULTS: A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers. CONCLUSIONS: Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.

Epidermal Growth Factor Receptor Inhibition in Epidermal Growth Factor Receptor-Amplified Gastroesophageal Cancer: Retrospective Global Experience.

PURPOSE: Subset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR-amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to date. PATIENTS AND METHODS: A total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB). RESULTS: Sixty patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR-amplified GEA received EGFRi. CONCLUSION: Patients with EGFR-amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease.

The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided P = 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study. SIGNIFICANCE: This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial.This article is highlighted in the In This Issue feature, p. 211.

Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy.

PURPOSE: Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICI). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA. EXPERIMENTAL DESIGN: A cohort of 211 patients with stage II-IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data. PD-L1 status was defined as positive if combined positive score (CPS) ≥1 using the 22C3 pharmDx assay. TMB levels were categorized as low, intermediate, or high (≤5, 5-15, or >15 mutations/Mb), or using a single threshold (<10 or ≥10 mutation/Mb), determined by next-generation sequencing using a targeted gene panel. RESULTS: Of 407 tumors, 56% were PD-L1 negative and 44% PD-L1 positive. Of 319 tumors, 50% were TMB-low, 45% TMB-intermediate, and 5% TMB-high; 86% had <10 and 14% ≥10 mutations/Mb. TMB level was significantly associated with MSI-status. PD-L1 expression and TMB exhibited marked spatial heterogeneity between baseline primary and metastatic tumors (61% and 69% concordance), and temporal heterogeneity between tumors before and after chemotherapy (57%-63% and 73%-75% concordance). PD-L1 expression and TMB were not significantly associated with overall survival. CONCLUSIONS: PD-L1 expression and TMB exhibit marked spatial and temporal heterogeneity in GEA. This heterogeneity should be considered when obtaining tumor samples for molecular testing and when deciding whether ICI therapy is appropriate.See related commentary by Klempner et al., p. 6401.

Evaluation of the Association of Perioperative UGT1A1 Genotype-Dosed gFOLFIRINOX With Margin-Negative Resection Rates and Pathologic Response Grades Among Patients With Locally Advanced Gastroesophageal Adenocarcinoma: A Phase 2 Clinical Trial.

Importance: Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ≥T3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and UGT1A1 genotype-directed irinotecan) to optimize efficacy while limiting toxic effects may have value. Objective: To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma. Design, Setting, and Participants: This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019. Interventions: Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m2 over 46 hours; oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2 for UGT1A1 genotype 6/6, 135 mg/m2 for UGT1A1 genotype 6/7, or 90 mg/m2 for UGT1A1 genotype 7/7; and prophylactic peg-filgastrim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive for ERBB2 also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg). Main Outcomes and Measures: Margin-negative resection rate and PRG. Results: A total of 36 evaluable patients (27 [78%] men; median [range] age, 66 [27-85] years; 10 [28%] with gastric body cancer; 24 [67%] with intestinal-type tumors; 6 [17%] with ERBB2-positive tumors; 19 [53%] with UGT1A1 genotype 6/6; 16 [44%] with genotype 6/7; and 1 [3%] with genotype 7/7) were enrolled. Of these, 35 (97%) underwent surgery; 1 patient (3%) died after completing neoadjuvant chemotherapy while awaiting surgery. Overall, R0 resection was achieved in 33 of 36 patients (92%); 2 patients (6%) with linitis plastica achieved R1 resection. Pathologic response grades 1, 2, and 3 occurred in 13 patients (36%), 9 patients (25%), and 14 patients (39%), respectively, and PRG 1 was observed in 11 of 24 intestinal-type tumors (46%). Median disease-free survival was 30.1 months (95% CI, 15.0 months to not reached), and median overall survival was not reached (95% CI, 8.3 months to not reached). There were no differences in outcomes by UGT1A1 genotype group. A total of 38 patients, including 2 (5%) with antral tumors, were evaluable for toxic effects. Grade 3 or higher adverse events occurring in 5% or more of patients during the perioperative cycles included diarrhea (7 patients [18%]; 3 of 19 patients [16%] with genotype 6/6; 2 of 16 patients [13%] with genotype 6/7; 2 of 3 patients [67%] with genotype 7/7), anemia (2 patients [5%]), vomiting (2 patients [5%]), and nausea (2 patients [5%]). Conclusions and Relevance: In this study, perioperative pharmacogenomically dosed gFOLFIRINOX was feasible, providing downstaging with PRG 1 in more than one-third of patients and an R0 resection rate in 92% of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02366819.

Pancreatic ß-Cell Adaptive Plasticity in Obesity Increases Insulin Production but Adversely Affects Secretory Function.

Pancreatic ß-cells normally produce adequate insulin to control glucose homeostasis, but in obesity-related diabetes, there is a presumed deficit in insulin production and secretory capacity. In this study, insulin production was assessed directly in obese diabetic mouse models, and proinsulin biosynthesis was found to be contrastingly increased, coupled with a significant expansion of the rough endoplasmic reticulum (without endoplasmic reticulum stress) and Golgi apparatus, increased vesicular trafficking, and a depletion of mature ß-granules. As such, ß-cells have a remarkable capacity to produce substantial quantities of insulin in obesity, which are then made available for immediate secretion to meet increased metabolic demand, but this comes at the price of insulin secretory dysfunction. Notwithstanding, it can be restored. Upon exposing isolated pancreatic islets of obese mice to normal glucose concentrations, ß-cells revert back to their typical morphology with restoration of regulated insulin secretion. These data demonstrate an unrealized dynamic adaptive plasticity of pancreatic ß-cells and underscore the rationale for transient ß-cell rest as a treatment strategy for obesity-linked diabetes.

Peak coalescence, spontaneous loss of coherence, and quantification of the relative abundances of two species in the plasma regime: particle-in-cell modeling of Fourier transform ion cyclotron resonance mass spectrometry.

Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) is often limited by space-charge effects. Previously, particle-in-cell (PIC) simulations have been used to understand these effects on FTICR-MS signals. However, none have extended fully into the space-charge dominated (plasma) regime. We use a two-dimensional (2-D) electrostatic PIC code, which facilitates work at very high number densities at modest computational cost to study FTICR-MS in the plasma regime. In our simulation, we have observed peak coalescence and the rapid loss of signal coherence, two common experimental problems. This demonstrates that a 2-D model can simulate these effects. The 2-D code can handle a larger numbers of particles and finer spatial resolution than can currently be addressed by 3-D models. The PIC method naturally takes into account image charge and space charge effects in trapped-ion mass spectrometry. We found we can quantify the relative abundances of two closely spaced (such as (7)Be(+) and (7)Li(+)) species in the plasma regime even when their peaks have coalesced. We find that the frequency of the coalesced peak shifts linearly according to the relative abundances of these species. Space charge also affects more widely spaced lines. Singly-ionized (7)BeH and (7)Li have two separate peaks in the plasma regime. Both the frequency and peak area vary nonlinearly with their relative abundances. Under some conditions, the signal exhibited a rapid loss of coherence. We found that this is due to a high order diocotron instability growing in the ion cloud.

An interchangeable-cathode vacuum arc plasma source.

A simplified vacuum arc design [based on metal vapor vacuum arc (MeVVA) concepts] is employed as a plasma source for a study of a (7)Be non-neutral plasma. The design includes a mechanism for interchanging the cathode source. Testing of the plasma source showed that it is capable of producing on the order of 10(12) charges at confinable energies using a boron-carbide disk as the cathode target. The design is simplified from typical designs for lower energy and lower density applications by using only the trigger spark rather than the full vacuum arc in high current ion beam designs. The interchangeability of the cathode design gives the source the ability to replace only the source sample, simplifying use of radioactive materials in the plasma source. The sample can also be replaced with a completely different conductive material. The design can be easily modified for use in other plasma confinement or full MeVVA applications.