Prolonged Air Leak After Pulmonary Resection Increases Risk of Noncardiac Complications, Readmission, and Delayed Hospital Discharge: A Propensity Score-adjusted Analysis.

OBJECTIVE: The aim of the study was to determine whether prolonged air leak (PAL) is associated with postoperative morbidity and mortality following pulmonary resection after adjusting for differences in baseline characteristics using propensity score analysis. SUMMARY BACKGROUND DATA: Patients with PAL after lung resection have worse outcomes than those without PAL. However, adverse postoperative outcomes may also be secondary to baseline risk factors, such as poor lung function. METHODS: Patients who underwent pulmonary resection for lung cancer/nodules (1/2009-6/2014) were stratified by the presence of PAL [n = 183 with/1950 without; defined as >5 d postoperative air leak; n = 189 (8.3%)]; probability estimates for propensity for PAL from 31 pretreatment/intraoperative variables were generated. Inverse probability-of-treatment weights were applied and outcomes assessed with logistic regression. RESULTS: Standardized bias between groups was significantly reduced after propensity weighting (mean = 0.18 before vs 0.08 after, P < 0.01). After propensity weighting, PAL was associated with increased odds of empyema (OR = 8.5; P < 0.001), requirement for additional chest tubes for pneumothorax (OR = 7.5; P < 0.001), blood transfusion (OR = 2; P = 0.03), pulmonary complications (OR = 4; P < 0.001), unexpected return to operating room (OR = 4; P < 0.001), and 30-day readmission (OR = 2; P = 0.009). Among other complications, odds of cardiac complications (P = 0.493), unexpected ICU admission (P = 0.156), and 30-day mortality (P = 0.270) did not differ. Length of hospital stay was prolonged (5.04 d relative effect, 95% confidence interval, 3.77-6.30; P < 0.001). CONCLUSIONS: Pulmonary complications, readmission, and delayed hospital discharge are directly attributable to having a PAL, whereas cardiac complications, unexpected admission to the ICU, and 30-day mortality are not after propensity score adjustment.

Extreme chromosome 17 copy number instability is a prognostic factor in patients with gastroesophageal adenocarcinoma: A retrospective cohort study.

Gastric and esophageal cancers frequently show genomic instability and aneuploidy. Chromosomal copy number instability (CIN) is a form of genomic instability that exerts pleiotropic effects on cellular biology and is a source of genetic heterogeneity in a population of cells. CIN results in cell-to-cell variation in chromosome copy number which can be detected and quantified by fluorescence in situ hybridization (FISH). CIN is a biomarker associated with differential response to a number of chemotherapy compounds. We quantified chromosome 17 copy number instability (CIN-17) in 348 gastroesophageal adenocarcinomas by centromeric FISH in cases that were tested for HER2 amplification. We evaluated the association between CIN-17 and clinical outcome after surgical and nonsurgical treatment. CIN-17 was detected in 45.4% (158/348) and extreme CIN-17 in 28.4% (99/348). Extreme CIN-17 had no association with outcome in surgically treated patients. However, in patients treated with conventional radiation and/or chemotherapy, extreme CIN-17 was associated with 55% reduction in overall mortality (hazard ratio, 0.448; 95% confidence interval, 0.263-0.763) after adjusting for age and clinical stage at diagnosis. Extreme CIN-17 is detected in over a quarter of gastroesophageal adenocarcinomas and is a favorable prognostic marker in patients treated nonoperatively.

A Model Based on Pathologic Features of Superficial Esophageal Adenocarcinoma Complements Clinical Node Staging in Determining Risk of Metastasis to Lymph Nodes.

BACKGROUND & AIMS: It is important to identify superficial (T1) gastroesophageal adenocarcinomas (EAC) that are most or least likely to metastasize to lymph nodes, to select appropriate therapy. We aimed to develop a risk stratification model for metastasis of superficial EAC to lymph nodes using pathologic features of the primary tumor. METHODS: We collected pathology data from 210 patients with T1 EAC who underwent esophagectomy from 1996 through 2012 on factors associated with metastasis to lymph nodes (tumor size, grade, angiolymphatic invasion, and submucosal invasion). Using these variables, we developed a multivariable logistic model to generate 4 categories for estimated risk of metastasis (<5% risk, 5%-10% risk, 15%-20% risk, or >20% risk). The model was validated in a separate cohort of 39 patients who underwent endoscopic resection of superficial EAC and subsequent esophagectomy, with node stage analysis. RESULTS: We developed a model based on 4 pathologic factors that determined risk of metastasis to range from 2.9% to 60% for patients in the first cohort. In the endoscopic resection validation cohort, higher risk scores were associated with increased detection of lymph node metastases at esophagectomy (P = .021). Among patients in the first cohort who did not have lymph node metastases detected before surgery (cN0), those with high risk scores (>20% risk) had 11-fold greater odds for having lymph node metastases at esophagectomy compared with patients with low risk scores (95% confidence interval, 2.3-52 fold). Increasing risk scores were associated with reduced patient survival time (P < .001) and shorter time to tumor recurrence (P < .001). Patients without lymph node metastases (pT1N0) but high risk scores had reduced times of survival (P < .001) and time to tumor recurrence (P = .001) after esophagectomy than patients with pT1N0 tumors and lower risk scores. CONCLUSIONS: Pathologic features of primary superficial EACs can be used, along with the conventional node staging system, to identify patients at low risk for metastasis, who can undergo endoscopic resection, or at high risk, who may benefit from induction or adjuvant therapy.

BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett's Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia.

OBJECTIVES: Barrett's esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD). METHODS: We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations. RESULTS: In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients. CONCLUSIONS: In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.

Tumor budding is associated with an increased risk of lymph node metastasis and poor prognosis in superficial esophageal adenocarcinoma.

The treatment approach for superficial (stage T1) esophageal adenocarcinoma critically depends on the pre-operative assessment of metastatic risk. Part of that assessment involves evaluation of the primary tumor for pathologic characteristics known to predict nodal metastasis: depth of invasion (intramucosal vs submucosal), angiolymphatic invasion, tumor grade, and tumor size. Tumor budding is a histologic pattern that is associated with poor prognosis in early-stage colorectal adenocarcinoma and a predictor of nodal metastasis in T1 colorectal adenocarcinoma. In a retrospective study, we used a semi-quantitative histologic scoring system to categorize 210 surgically resected, superficial (stage T1) esophageal adenocarcinomas according to the extent of tumor budding (none, focal, and extensive) and also evaluated other known risk factors for nodal metastasis, including depth of invasion, angiolymphatic invasion, tumor grade, and tumor size. We assessed the risk of nodal metastasis associated with tumor budding in univariate analyses and controlled for other risk factors in a multivariate logistic regression model. In all, 41% (24 out of 59) of tumors with extensive tumor budding (tumor budding in ≥3 20X microscopic fields) were metastatic to regional lymph nodes, compared with 10% (12 out of 117) of tumors with no tumor budding, and 15% (5 out of 34) of tumors with focal tumor budding (P<0.001). When controlling for all pathologic risk factors in a multivariate analysis, extensive tumor budding remains an independent risk factor for lymph node metastasis in superficial esophageal adenocarcinoma associated with a 2.5-fold increase (95% CI=1.1-6.3, P=0.039) in the risk of nodal metastasis. Extensive tumor budding is also a poor prognostic factor with respect to overall survival and time to recurrence in univariate and multivariate analyses. As an independent risk factor for nodal metastasis and poor prognosis after esophagectomy, tumor budding should be evaluated in superficial (T1) esophageal adenocarcinoma as a part of a comprehensive pathologic risk assessment.

Minimally Invasive Resection of Benign Esophageal Lesions.

Benign esophageal lesions include a wide variety of rare neoplasms, polyps, and cysts. In general, these lesions are asymptomatic and have little clinical importance. However, on occasion these lesions become symptomatic due to esophageal obstruction, airway obstruction, or compression of mediastinal structures. In these cases, as well as cases when it is unclear if the lesion is malignant or benign, surgical resection is recommended. Resection is most often performed by extramucosal enucleation, a procedure that is oftentimes well-suited for a minimally invasive approach. Here we discuss the general approach and operative techniques used for minimally invasive resection of benign esophageal lesions.

A cross-sectional analysis of the prevalence of Barrett esophagus in otolaryngology patients with laryngeal symptoms.

BACKGROUND: Populations at risk for esophageal adenocarcinoma remain poorly defined. Laryngeal symptoms can be secondary to laryngopharyngeal reflux (LPR) and can occur without associated gastroesophageal reflux symptoms such as heartburn and regurgitation. GOAL: We sought to determine the prevalence of Barrett esophagus (BE) in otolaryngology patients with laryngeal symptoms±typical gastroesophageal reflux disease (GERD) symptoms. STUDY: We performed a cross-sectional study of otolaryngology clinic patients who reported laryngeal symptoms. Symptoms, medications, and exposure histories were obtained. Unsedated transnasal endoscopy was performed. Suspected BE was biopsied and confirmed histologically. Risk factors and prevalence of BE were assessed. RESULTS: Two hundred ninety-five patients were enrolled [73% male, median age 60 y (interquartile range 51 to 68 y)]. The overall prevalence of BE was 11.8% (n=33). Antisecretory medication use was present in 56% (n=156) of patients at enrollment. Compared with patients without BE, patients with BE were more likely to be male (P=0.01) and to report occupational lung injury (P=0.001). Duration, but not severity of laryngeal symptoms, significantly increased the odds of BE (odds ratio, 5.64; 95% confidence interval, 1.28-24.83; for a duration of symptoms >5 y). Of patients with BE, 58% (n=19) had coexisting LPR and GERD symptoms and 30% (n=10) had only LPR symptoms. Presence and size of hiatal hernia and length of columnar-lined esophagus were significant risk factors for BE. CONCLUSIONS: Long-standing laryngeal symptoms are associated with the presence of BE in otolaryngology patients. Patients with chronic laryngeal symptoms and no identifiable ear, nose, or throat etiology for those symptoms may benefit from endoscopic screening regardless of whether typical GERD symptoms are present.

Genomic signatures of past and present chromosomal instability in Barrett's esophagus and early esophageal adenocarcinoma.

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

Outcomes after minimally invasive esophagectomy: review of over 1000 patients.

BACKGROUND: Esophagectomy is a complex operation and is associated with significant morbidity and mortality. In an attempt to lower morbidity, we have adopted a minimally invasive approach to esophagectomy. OBJECTIVES: Our primary objective was to evaluate the outcomes of minimally invasive esophagectomy (MIE) in a large group of patients. Our secondary objective was to compare the modified McKeown minimally invasive approach (videothoracoscopic surgery, laparoscopy, neck anastomosis [MIE-neck]) with our current approach, a modified Ivor Lewis approach (laparoscopy, videothoracoscopic surgery, chest anastomosis [MIE-chest]). METHODS: We reviewed 1033 consecutive patients undergoing MIE. Elective operation was performed on 1011 patients; 22 patients with nonelective operations were excluded. Patients were stratified by surgical approach and perioperative outcomes analyzed. The primary endpoint studied was 30-day mortality. RESULTS: The MIE-neck was performed in 481 (48%) and MIE-Ivor Lewis in 530 (52%). Patients undergoing MIE-Ivor Lewis were operated in the current era. The median number of lymph nodes resected was 21. The operative mortality was 1.68%. Median length of stay (8 days) and ICU stay (2 days) were similar between the 2 approaches. Mortality rate was 0.9%, and recurrent nerve injury was less frequent in the Ivor Lewis MIE group (P < 0.001). CONCLUSIONS: MIE in our center resulted in acceptable lymph node resection, postoperative outcomes, and low mortality using either an MIE-neck or an MIE-chest approach. The MIE Ivor Lewis approach was associated with reduced recurrent laryngeal nerve injury and mortality of 0.9% and is now our preferred approach. Minimally invasive esophagectomy can be performed safely, with good results in an experienced center.

Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in stage 1A non-small-cell lung cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have been found to increase survival in many forms of cancer, including, endometrial, bile ductal, colonic, esophageal, and urothelial cancers, as well as melanoma and follicular lymphoma. The relevance of TILs in the prognosis of non-small-cell lung cancer (NSCLC), however, still remains controversial. We compared the outcomes of stage 1A NSCLC with and without tumor infiltrating lymphocytes to evaluate the effects of TILs on recurrence and survival patterns. MATERIALS AND METHODS: From 2000 to 2009, 273 anatomic segmentectomies and lobectomies were performed on stage 1A NSCLC. Patients were stratified into TIL- and TIL+ cohorts based on pathologic evaluation. Further investigation was conducted on the effects of TILs in patients with and without angiolymphatic invasion. Variables analyzed include overall survival, recurrence-free survival, and type of recurrence. RESULTS: Overall 5-y survival was not affected by TIL status (65% versus 60%, P = 0.469). Five-year recurrence-free survival (RFS) was significantly increased in the TIL+ group versus the TIL- group (87% versus 73%, P = 0.011), most significantly in women (P = 0.016). The presence of angiolymphatic invasion (ALI) was associated with decreased 5-y RFS versus patients without ALI (61% versus 85%, P < 0.001). Interestingly, in the ALI negative group, TIL+ patients experienced a significantly increased 5-y recurrence-free survival versus TIL- patients (93% versus 80%, P = 0.036). CONCLUSIONS: High levels of intratumoral TILs are associated with improved recurrence-free survival in stage 1A NSCLC patients as well as a reduced likelihood of systemic recurrence. When angiolymphatic invasion is not present, the beneficial effects of TILs become even more profound.

Anastomotic complications after esophagectomy: Influence of omentoplasty in propensity-weighted cohorts.

OBJECTIVE: A recent meta-analysis of 3 randomized controlled trials reported reduced incidence and severity of postesophagectomy anastomotic dehiscence with anastomotic omentoplasty. Unfortunately, these trials excluded neoadjuvant patients who received chemoradiation. We aimed to determine whether anastomotic omentoplasty was associated with differential postesophagectomy anastomotic complications after neoadjuvant chemoradiotherapy. METHODS: Data for patients who underwent minimally invasive esophagectomy following neoadjuvant chemoradiotherapy were abstracted (n = 245; 2001-2016; omentoplasty = 147 [60%]). Propensity for omentoplasty was estimated on 21 pretreatment variables, using augmented inverse probability of treatment weights, and used to determine the adjusted proportion of adverse anastomotic outcomes, major morbidity, and 30-day/in-hospital mortality. RESULTS: Overall, anastomotic leak rate was 15%; leak-associated mortality was 13% (n = 5 out of 37). Leak rates (omentoplasty n = 24 [16%] vs no omentoplasty n = 13 [13%]; P = .512) and incidence of any major complications (48% vs 48%; P = .958) were similar. Leaks requiring surgical intervention occurred in 12 patients (5% vs 5%; P = .904). Propensity weighting achieved excellent balance across all 21 pretreatment variables (before weighting, standardized differences ranged from -0.23 to 0.35; postweighting standardized differences ranged from -0.09 to 0.07). In propensity-weighted data, omentoplasty was not associated with differential adjusted risk of anastomotic leak (13.2% vs 14.3%; P = .83), major morbidity (27.9% vs 32.6%; P = .44), or mortality (6.7% vs 4.8%; P = .61). CONCLUSIONS: Within the limits of our sample size and statistical approach, our study failed to find evidence that anastomotic omentoplasty during esophagectomy after neoadjuvant chemoradiation reduced anastomotic leak rate or need for leak-related reoperation.

The Association of Nicotine Replacement Therapy With Outcomes Among Smokers Hospitalized for a Major Surgical Procedure.

BACKGROUND: There are concerns that starting nicotine replacement therapy (NRT) in the immediate perioperative period may negatively impact wound healing. We investigated the association of NRT with postoperative outcomes among smokers hospitalized for a surgical procedure. METHODS: This was a retrospective study in 552 hospitals of active smokers hospitalized between January 1, 2015 and December 31, 2016 for a major surgical procedure (Medicare Severity Diagnosis-Related Group expected length of stay, ≥ 2 days). We analyzed the association of receipt of NRT within 2 days of admission with a composite outcome of inpatient complications and with other outcomes. We developed a propensity score for receipt of NRT and examined differences in outcomes in a propensity-matched cohort. RESULTS: Of 147,506 active smokers, 25,651 (17.4%) were prescribed NRT within 2 days of admission. Patients treated with NRT were younger; less likely to be black or Hispanic; more likely to have Medicaid; and more likely to have a diagnosis of alcohol or other substance use disorder, or COPD, compared with those who were not treated. In the propensity-matched analysis, there was no association between receipt of NRT and in-hospital complications (OR, 0.99; 95% CI, 0.93-1.05), mortality (OR, 0.84; 95% CI, 0.68-1.04), all-cause 30-day readmissions (OR, 1.02; 95% CI, 0.97-1.07), or 30-day readmission for wound complications (OR, 0.96; 95% CI, 0.86-1.07). CONCLUSIONS: This is the first large observational study of surgical patients to demonstrate that perioperative NRT is not associated with adverse outcomes after surgery. These results strengthen the evidence that NRT should be prescribed routinely in the perioperative period.

Loss of ARID1A expression is associated with DNA mismatch repair protein deficiency and favorable prognosis in advanced stage surgically resected esophageal adenocarcinoma.

Esophageal adenocarcinoma often presents at an advanced stage and has a dismal prognosis. Current prognostic markers have limited utility. ARID1A is implicated as a tumor suppressor gene in esophageal adenocarcinoma. Loss of ARID1A expression correlates with DNA mismatch repair (MMR) protein deficiency in other tumors. We hypothesized that ARID1A loss is associated with prognosis and DNA MMR protein deficiency in esophageal adenocarcinoma. Tissue microarrays representing 316 surgically resected esophageal adenocarcinomas without neoadjuvant treatment were evaluated for ARID1A and MMR proteins by immunohistochemistry. Loss of ARID1A expression (ARID1A-loss) was detected in 41 of 316 (13%) adenocarcinomas. MMR deficiency was identified in 5% (17/316) but was detected more frequently in ARID1A-loss adenocarcinomas (13/41, 32%) than in ARID1A-retained adenocarcinomas (4/275, 1%; P < .001). Morphologically, ARID1A-loss adenocarcinomas frequently demonstrated peritumoral lymphoid aggregates (90%) and tumor infiltrating lymphocytes (51%). In patients with locally advanced or metastatic disease (stages III or IV, N = 169), patients with ARID1A-loss adenocarcinomas (N = 22) had longer overall survival than patients with ARID1A-retained adenocarcinomas (median [month]: 26 vs. 16, P = .010). In these patients, ARID1A-loss correlated with a 56% reduction in mortality independent of other prognostic factors (P = .007). In summary, loss of ARID1A expression is associated with DNA MMR protein deficiency in esophageal adenocarcinoma. Furthermore, ARID1A loss is independently associated with a more favorable prognosis for patients with locally advanced or metastatic esophageal adenocarcinomas.

Percutaneous computed tomography-guided biopsy performed by thoracic surgeons in 955 patients: A paradigm shift in image-guided thoracic procedures.

OBJECTIVES: Computed tomography-guided fine needle aspiration (CT-FNA) biopsy is a well-established diagnostic technique in the evaluation of lung nodules that is performed by radiologists in most centers. In this series, we analyzed the diagnostic and perioperative outcomes following CT-FNA performed by a dedicated group of thoracic surgeons. METHODS: We conducted a retrospective analysis of 955 patients undergoing CT-FNA by the thoracic surgery service. Primary outcome variables included diagnostic yield and accuracy, number of needle passes, complication rates, and adequacy of specimen for molecular testing. RESULTS: A satisfactory diagnostic specimen was obtained in 94.1% of cases. The average number of needle passes was 3.2 ± 1.5 (range, 1-10 passes). Diagnostic yield was significantly improved by increasing the number of passes from 1 to 2 to 3 passes (P = .0003). CT-FNA diagnostic accuracy was 88.8%. Diagnostic accuracy did not significantly improve with ≥4 passes (P = .20). Molecular testing was successful in 43.1%, and did not improve with ≥4 passes (P = .5). Molecular testing success did improve with the addition of core needle biopsy (P = .005). The pneumothorax rate for CT-FNA alone was 26.4%, and increased with ≥4 passes (P = .009). The median length of stay for CT-FNA alone was 0 days (range, 0-74 days), with same-day discharge in 67.5% of patients. CONCLUSIONS: Thoracic surgeons can perform CT-FNA with excellent diagnostic yield and accuracy. Diagnostic yield, accuracy, and success in molecular testing do not improve with ≥4 CT-FNA passes. Pneumothorax rates do increase with ≥4 passes. The addition of core needle biopsy enhances success with molecular testing.

Endoscopic therapies for the treatment of reflux disease.

Endoscopic techniques for the treatment of reflux disease were first introduced in 2000 as an alternative to laparoscopic antireflux operations. Because of reports of long-term treatment failure with laparoscopic fundoplication and the fact that surgery is increasingly being reserved for the relatively small proportion of patients with complicated reflux disease, attempts to develop safe, effective, and durable endoscopic approaches to antireflux surgery continue. Techniques include radiofrequency ablation, injection therapy, and suturing/stapling techniques. Of these, the suturing/stapling techniques are most similar to the anatomic restructuring of the gastroesophageal junction provided by fundoplication. While early attempts at endoscopic suturing have been disappointing, significant advances in endoscopic instrumentation, a more complete understanding of the gastroesophageal junction anatomy, and improvements in the technical skills of the endoscopic surgeon have been realized. As a result, techniques now being tested, such as the endoluminal fundoplication, may prove more effective and durable than previous endoscopic antireflux procedures.

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma.

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.Significance: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37-48. ©2017 AACR.See related commentary by Sundar and Tan, p. 14See related article by Janjigian et al., p. 49This article is highlighted in the In This Issue feature, p. 1.