Role of Biomarkers to Assess the Use of Alcohol.

Alcohol-associated liver disease has seen a significant rise in the last 2 decades, with an associated rise in the need for accurate alcohol use assessment. Alcohol use has been associated with poor outcomes in both the pre-liver transplant and post-liver transplant patients. Patients with alcohol use disorder often under-report their alcohol consumption because of varying factors, highlighting the need for objective assessment of alcohol use. Aside from the available self-report questionnaires, multiple serologic biomarkers are currently available to assist clinicians to assess recent alcohol consumption among patients with chronic liver disease, liver transplant candidates, and recipients. In this review, we will assess some of these alcohol biomarkers, discuss their strengths and weakness, and review-available data to discuss their role in pre-liver transplant and post-liver transplant population.

Survival After Trimodality Therapy in Patients With Locally Advanced Esophagogastric Adenocarcinoma: Does Only a Complete Pathologic Response Matter?

OBJECTIVE: To evaluate whether pCR exclusively defines major pathologic response to treatment with improved survival. SUMMARY BACKGROUND DATA: pCR after trimodality therapy for EAC is infrequent but associated with improved prognosis. Yet most clinical trials and correlative studies designate pCR as the primary endpoint. METHODS: We analyzed our prospectively maintained database for patients who underwent trimodality therapy for locally advanced esophageal adeno-carcinoma between 1995 and 2017. Overall survival (OS) was examined by percentage TR in the primary tumor bed and pathologic nodal stage (ypN0) using Kaplan-Meier plots. Optimal thresholds of TR for differentiating patients in terms of OS were investigated with descriptive plots using restricted cubic spline functions; associations were quantified using Cox multivariable analysis. RESULTS: Among 788 patients, median follow-up was 37.5 months (range, 0.4210.6); median OS was 48.3 months (95% CI, 42.2-58.8). Absence of residual nodal disease was independently associated with improved survival ( P < 0.001). Survival curves for 90% to 99% TR and 100% TR were similar, and a change in probability of improved OS was observed at 90% TR. On multivariable analysis, combining 90% to 99% and 100% TR was independently associated with improved OS, compared with 50% to 89% and <50% TR. CONCLUSIONS: ypN0 status is the strongest indicator of major pathologic response to trimodality therapy, in addition to >90% TR in the primary tumor bed. These findings may allow the definition of major pathologic response to be expanded, from pCR to > 90% TR and ypN0. This has meaningful implications for future clinical trials and correlative studies.

The Role of the TP53 Pathway in Predicting Response to Neoadjuvant Therapy in Esophageal Adenocarcinoma.

PURPOSE: In patients with locally advanced esophageal adenocarcinoma, response to neoadjuvant therapy strongly predicts survival, but robust molecular predictors of response have been lacking. We therefore sought to discover meaningful predictors of response in these patients. EXPERIMENTAL DESIGN: We retrospectively identified all patients with adenocarcinoma of the lower esophagus or gastroesophageal junction who (i) were treated with multimodality therapy with curative intent at our institution from 2014 through 2020 and (ii) underwent prospective sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Clinicopathologic and genomic data were analyzed to identify potential genomic features, somatic alterations, and oncogenic pathways associated with treatment response. RESULTS: In total, 237 patients were included. MDM2 amplification was independently associated with poor response to neoadjuvant therapy [OR, 0.10 (95% confidence interval, 0.01-0.55); P = 0.032], when accounting for significant clinicopathologic variables, including clinical stage, tumor grade, and chemotherapy regimen. Moreover, TP53 pathway alterations, grouped according to inferred severity of TP53 dysfunction, were significantly associated with response to neoadjuvant therapy (P = 0.004, q = 0.07). Patients with MDM2 amplifications or truncating biallelic TP53 mutations had similar outcomes in terms of poor responses to neoadjuvant therapy and, consequently, shorter progression-free survival, compared with patients with TP53 pathway wild-type tumors. Thus, worsening TP53 dysfunction was directly correlated with worse outcomes. CONCLUSIONS: MDM2 amplification and TP53 status are associated with response to therapy in patients with esophageal adenocarcinoma. Given the dearth of actionable targets in esophageal adenocarcinoma, MDM2 inhibition, in combination with cytotoxic chemotherapy, may represent an important therapeutic strategy to overcome treatment resistance and improve outcomes in these patients.

Defining low-risk lesions in early-stage esophageal adenocarcinoma.

OBJECTIVE: As endoscopic approaches become more widely used to treat early-stage esophageal cancer, reliably identifying patients with less-aggressive tumors is paramount. We sought to identify risk factors for recurrence in patients with completely resected T1 esophageal adenocarcinoma. METHODS: We retrospectively analyzed a single-institutional database for all patients with completely resected pathologic T1 esophageal adenocarcinoma (1996-2016). Risk factors for recurrence were identified using competing-risk regression methods. Risk stratification was performed on the basis of known preoperative clinicopathologic factors; this model's discriminative power for overall survival was evaluated using a Cox proportional hazards model. RESULTS: Of 243 patients, 32 experienced recurrence. At a median follow-up among survivors of 4 years (range, 0.05-19 years), the 5-year cumulative incidence of recurrence was 15%, and median time to recurrence was 2 years (range, 0.26-6.13 years). On univariable analysis, submucosal invasion, N1 disease, poor differentiation, tumor length, lymphovascular invasion, and multicentricity were significantly associated with recurrence. On multivariable analysis, N1 disease (hazard ratio, 2.93; 95% confidence interval, 1.17-7.34; P = .022) and tumor length (hazard ratio, 1.44; 95% confidence interval, 1.12-1.86; P = .004) were independently associated with recurrence. Risk stratification showed that patients without lymphovascular invasion and a with median tumor length of 0.8 cm (range, 0.10-1.70 cm) had a <10% risk of recurrence and improved survival. CONCLUSIONS: Pathologic T1 tumors have a 5-year cumulative incidence of recurrence of 15%. Nodal involvement and tumor length were independent risk factors for recurrence, whereas tumors <2 cm in length without lymphovascular invasion were associated with a low risk of recurrence.

Next-Generation Sequencing of 487 Esophageal Adenocarcinomas Reveals Independently Prognostic Genomic Driver Alterations and Pathways.

PURPOSE: To delineate recurrent oncogenic driver alterations and dysregulated pathways in esophageal adenocarcinoma and to assess their prognostic value. EXPERIMENTAL DESIGN: We analyzed a large cohort of patients with lower esophageal and junctional adenocarcinoma, prospectively sequenced by MSK-IMPACT with high-quality clinical annotation. Patients were subdivided according to treatment intent, curative versus palliative, which closely mirrored clinical staging. Genomic features, alterations, and pathways were examined for association with overall survival using Cox proportional hazard models, adjusted for relevant clinicopathologic factors knowable at the time of diagnosis. RESULTS: Analysis of 487 patients revealed 16 oncogenic driver alterations, mostly amplifications, present in ≥5% of patients. Patients in the palliative-intent cohort, compared with those in the curative-intent cohort, were more likely to have metastatic disease, ERBB2 amplifications, Cell-cycle and RTK-RAS pathway alterations, as well as a higher fraction of genome altered and rate of whole-genome doubling. In multivariable analyses, CDKN2A alterations, SMAD4 alterations, KRAS amplifications, Cell-cycle and TGFß pathways, and overall number of oncogenic drivers were independently associated with worse overall survival. ERBB2 amplification was associated with improved survival, presumably due to trastuzumab therapy. CONCLUSIONS: Our study suggests that higher levels of genomic instability are associated with more advanced disease in esophageal adenocarcinoma. Furthermore, CDKN2A, KRAS, and SMAD4 represent prognostic biomarkers, given their strong association with poor survival.