Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma.

Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven patients received ≥1 dose of treatment: three first-line FOLFOX plus ABT-806, one second-line FOLFIRI plus cetuximab, and three third/fourth-line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pretreatment and posttreatment tumor next-generation sequencing (NGS), serial plasma circulating tumor DNA (ctDNA) NGS, and tumor IHC/FISH for EGFR revealed preexisting and/or acquired genomic events, including EGFR-negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC, and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.Significance: This paper highlights the role of EGFR inhibitors in EGFR-amplified GEA-despite negative results in prior unselected phase III trials. Using serial ctDNA and tissue NGS, we identified mechanisms of primary and acquired resistance in all patients, as well as potential contribution of antibody-dependent cell-mediated cytotoxicity to their clinical benefit. Cancer Discov; 8(6); 696-713. ©2018 AACR.See related commentary by Strickler, p. 679This article is highlighted in the In This Issue feature, p. 663.

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.

The Many Faces of Medication-Related Injury in the Gastrointestinal Tract.

Every year many new medications are approved for clinical use, several of which can cause clinically significant gastrointestinal tract toxicity. This article emphasizes the histologic features and differential diagnosis of drug-induced injury to the gastrointestinal mucosa. Ultimately, clinical correlation and cessation of a drug with resolution of symptoms are needed to definitively confirm a drug as a causative factor in mucosal injury. Recognizing histologic features in gastrointestinal biopsies, however, can allow surgical pathologists to play a key role in establishing a diagnosis of drug-induced gastrointestinal toxicity.

Interobserver variability in intraductal papillary mucinous neoplasm subtypes and application of their mucin immunoprofiles.

Intraductal papillary mucinous neoplasm is considered a precursor lesion to pancreatic adenocarcinoma. These are further classified into four histologic subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. The first aim of this study was to assess the interobserver variability among five gastrointestinal pathologists in diagnosing intraductal papillary mucinous neoplasm subtypes by morphology alone. The second aim of the study was to compare intraductal papillary mucinous neoplasm subtypes, which received consensus diagnoses (≥80% agreement) with their respective mucin immunoprofiles (MUC1, MUC2, MUC5AC, MUC6, and CDX2). A consensus histologic subtype was reached in 58% of cases (29/50) among the five gastrointestinal pathologists. Overall there was moderate agreement (κ=0.41, P<0.01) in subtyping intraductal papillary mucinous neoplasms without the use of immunohistochemistry. The histologic subtype with the best interobserver agreement was intestinal type (κ=0.56, P<0.01) followed by pancreatobiliary, gastric, mixed, and oncocytic types (κ=0.43, P<0.01; κ=0.38, P<0.01; κ=0.17, P<0.01; κ=0.08, P<0.04, respectively). Both kappa values for mixed and oncocytic subtypes were likely artificially low due to the underrepresentation of these subtypes in this study and not a true indication of poor interobserver agreement. Following an intradepartmental consensus meeting between two gastrointestinal pathologists, 68% of cases (34/50) received a consensus intraductal papillary mucinous neoplasm subtype. Sixty-nine percent of cases (11/16) that did not receive a consensus intraductal papillary mucinous neoplasm subtype could be classified based on their respective immunoprofiles. Standardizing the use of immunohistochemistry with a mucin immunopanel (MUC1, MUC2, MUC5AC, and MUC6) may improve the agreement of diagnosing intraductal papillary mucinous neoplasm histologic subtypes.

Clinical Characteristics of Patients with Cryptogenic Hepatocellular Carcinoma in a Hepatitis B Virus-Endemic Area.

OBJECTIVES: Chronic hepatitis B virus (HBV) infection is the most common cause of hepatocellular carcinoma (HCC) in South Korea, but a high prevalence of metabolic diseases may result in increases in the incidence of cryptogenic HCC (cHCC). We studied characteristics of the cHCC in a single-center cohort. METHODS: A cohort of 1,784 HCC patients newly diagnosed and treated at the National Cancer Center, Korea, between 2004 and 2009 was reviewed and analyzed. RESULTS: The cause of HCC was categorized as cHCC, HBV, hepatitis C virus (HCV), or alcohol. Overall, 162 (9.1%) patients of the HCC cohort had cHCC, and their mean age was 61.9 years. The median survival of cHCC patients was 24.7 months, which was the second shortest among the four groups after HBV HCC. cHCC patients had the largest tumor size (mean 7.4 cm) and the second highest proportion of poor prognostic factors such as the proportion of poorly defined tumors and extrahepatic spread in imaging studies. cHCC patients had better survival than HBV HCC patients according to multivariate analysis. Among cHCC patients, 137 (84.6%) had anti-HBc IgG antibodies, but this sub-group had different clinical features to those of HBV HCC patients. The body mass index (BMI) and hyperglycemia and hypercholesterolemia levels in cHCC patients were similar to those in HCV and alcoholic HCC patients. CONCLUSIONS: Anti-HBc IgG antibodies were present in most cHCC patients, but cHCC patients had better survival than HBV HCC patients on multivariate analysis. However, cHCC patients had a larger mean tumor size and more aggressive tumor characteristics than HCV HCC or alcoholic HCC patients did. It is hoped that this study will contribute to a better understanding of cHCC in HBV-endemic areas.

Individual having a parent with early-onset gastric cancer may need screening at younger age.

AIM: To evaluate whether individuals with gastric cancer (GC) are diagnosed earlier if they have first-degree relatives with GC. METHODS: A total of 4282 patients diagnosed with GC at National Cancer Center Hospital from 2002 to 2012 were enrolled in this retrospective study. We classified the patients according to presence or absence of first-degree family history of GC and compared age at diagnosis and clinicopathologic characteristics. In addition, we further classified patients according to specific family member with GC (father, mother, sibling, or offspring) and compared age at GC diagnosis among these patient groups. Baseline characteristics were obtained from a prospectively collected database. Information about the family member's age at GC diagnosis was obtained by questionnaire. RESULTS: A total of 924 patients (21.6%) had a first-degree family history of GC. The mean age at GC diagnosis in patients having paternal history of GC was 54.4 ± 10.4 years and was significantly younger than in those without a first-degree family history (58.1 ± 12.0 years, P < 0.001). However, this finding was not observed in patients who had an affected mother (57.2 ± 10.0 years) or sibling (62.2 ± 9.8 years). Among patients with family member having early-onset GC (< 50 years old), mean age at diagnosis was 47.7 ± 10.3 years for those with an affected father, 48.6 ± 10.4 years for those with an affected mother, and 57.4 ± 11.5 years for those with an affected sibling. Thus, patients with a parent diagnosed before 50 years of age developed GC 10.4 or 9.5 years earlier than individuals without a family history of GC (both P < 0.001). CONCLUSION: Early-onset GC before age of 50 was associated with parental history of early-onset of GC. Individual having such family history need to start screening earlier.

Characteristics of gastric cancer according to Helicobacter pylori infection status.

BACKGROUND AND AIMS: The definition and incidence of gastric cancer (GC) without Helicobacter pylori (Hp) infection varies between studies. The aim of our study was to compare the characteristics of GC according to Hp infection status. METHODS: We evaluated the presence of Hp infection in 1833 GC patients with rapid urease tests, serology examinations, and histological evaluations. GC was classified as GC with current Hp infection (HpC-GC), GC with past Hp infection (HpP-GC), and GC not associated with Hp infection (HpN-GC). HpP-GC was defined as GC without current infection but with a positive serology test, glandular atrophy, and/or intestinal metaplasia. HpN-GC was defined as GC with negative Hp test results and no histological changes. RESULTS: The numbers of HpC-GC, HpP-GC, and HpN-GC were 1378 (75.2%), 412 (22.5%), and 43 (2.3%), respectively. Among GCs without current infection, 90.5% (412/455) were associated with HpP-GC. HpP-GCs were more common in older and male patients, had an increased incidence of synchronous cancer, and less frequently had a diffuse-type histology than HpC-GCs. HpN-GCs were more common in younger, female patients; had a higher proportion of diffuse-type cancers; and more frequently showed distant metastasis than HpP-GCs. In the 40s, the proportion of HpP-GCs with diffuse-type histology (41.9%) was lower than that of HpC-GCs (60.3%) (P = 0.016). The difference was also significant in the 50s (29.1% vs 40.1%, respectively, P = 0.004). CONCLUSIONS: Most GCs in Korea without current Hp infection showed evidence of past Hp infection. The proportion of GCs with diffuse-type histology decreased in patients with past infection.

Long-term outcomes of second treatment after initial transarterial chemoembolization in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: All outcome studies concerning the management of hepatocellular carcinoma (HCC) are based on the initial treatment. However, remaining, progressing or recurring tumours (RPRTs) after transarterial chemoembolization (TACE) are common; therefore, various second treatments are administered to HCC patients. Here, we investigated the long-term outcomes of second treatments for RPRT after initial TACE. METHODS: We enrolled 855 consecutive HCC patients who underwent TACE as the initial treatment at the National Cancer Center, Korea, from January 2004 to December 2010. RESULTS: The median follow-up was 43.4 months, and the median progression-free survival following initial TACE was 4.0 months, being 18.1 and 1.0 months for complete remission and progressive disease respectively. Second treatments were administered to 790 RPRT patients (92.4%); the most common was TACE (56.4%), followed by best supportive care (22.8%), systemic chemotherapy (9.4%), external radiotherapy (4.4%), radiation ablation (RFA; 2.9%), resection (2.0%) and liver transplantation (1.4%). Median overall survival (mOS) for initial TACE was 18.8 months [95% confidence interval (CI), 16.6-21.0 months]; after second treatments, it was 12.4 (95% CI, 10.6-14.2) months, differing significantly by mRECIST assessment, BCLC stage and RPRT type (28.0, 5.0 and 3.9 months for intrahepatic, vascular and extrahepatic RPRT, respectively; P < 0.001). Intrahepatic RPRT with a curative treatment as a second treatment showed the best OS. CONCLUSION: These novel insights into the patterns and long-term outcomes of second treatments for RPRT in HCC patients who underwent initial TACE are expected to aid in formulating treatment strategies for HCC patients.

Clinical outcomes of a cohort series of patients with hepatocellular carcinoma in a hepatitis B virus-endemic area.

BACKGROUND AND AIMS: To evaluate the clinical outcomes of patients with hepatocellular carcinoma (HCC) and compare the findings with that of a previous cohort. METHODS: Overall, 1972 HCC patients diagnosed and treated at the National Cancer Center, Korea between 2004 and 2009 were enrolled. The data of this cohort were compared with those of a previous cohort (2000-2003) from the same institution. RESULTS: In all (mean age, 56.4 years; 1642 men), 74.6% was hepatitis B virus (HBV) positive, 81.6% were Child-Pugh (CP) class A, and 64.4% was Barcelona Clinic Liver Cancer (BCLC) stage C. The modified Union for International Cancer Control (mUICC) stage I, II, III, IVa, and IVb was found in 8.9%, 29.6%, 24.8%, 23.1%, and 13.6% patients, respectively. The most common initial treatment was transarterial chemotherapy (58.3%), followed by resection (18.6%). The 5-year survival rate of BCLC stage 0, A, B, and C were 79.6%, 67.2%, 33.9%, and 17.1%, respectively. The performance status, BCLC stage, mUICC stage, CP class, model for end-stage liver disease score, tumor characteristics, portal vein tumor invasion, and serum alpha-fetoprotein level proved to be independent prognostic variables. Overall survival in the present cohort was better than that in the previous cohort (hazard ratio, 0.829; 95% confidence interval, 0.754-0.912), especially for advanced HCC patients with HBV-positive status. CONCLUSIONS: This cohort study provides valuable insights into the characteristics of HCC in Korean patients. Our findings may help develop clinical trials, treatment strategies, and prognosis systems for HCC patients in HBV-endemic areas.

Efficacy of argon plasma coagulation in the treatment of radiation-induced hemorrhagic gastroduodenal vascular ectasia.

OBJECTIVE: Radiation-induced hemorrhagic gastroduodenal vascular ectasia (GDVE) is rare but difficult to manage. Argon plasma coagulation (APC) has not yet been evaluated in the treatment of radiation-induced hemorrhagic GDVE. The efficacy of APC in patients with radiation-induced hemorrhagic GDVE has been investigated in this article. MATERIAL AND METHODS: Eighteen patients with upper gastrointestinal (GI) bleeding caused by radiation-induced GDVE, including 13 with hepatocellular carcinoma, 3 with pancreatic cancer, and 2 with cholangiocarcinoma, were treated with APC. The efficacy of APC was retrospectively evaluated, based on cessation of macroscopic GI bleeding, resolution or stabilization of anemia and transfusion dependence, endoscopic ablation of almost all vascular lesions, complications, and recurrence. RESULTS: Mean patient age was 59 years (range 42-80 years). The median time from radiation to GDVE diagnosis was 4.6 months (range 3.3-21.5 months). The median number of APC sessions per patient was 2.4 (range 1-4). All 18 patients showed an endoscopic response to APC treatment, with sustained increases in mean hemoglobin level, from 6.6 g/dL (range 2.9-9.5 g/dL) to 9.7 g/dL (range 7.1-12.7 g/dL) (p < 0.001), and decreased dependence on transfusion, from 9.1 (range 0-30) to 4.1 (range 0-15) units of packed red blood cells per patient (p = 0.038) after last endoscopic eradication by APC treatment. There were no major procedure-related adverse events or deaths. At a median follow up of 4.7 months (range 0.6-24.5 months), none of the patients experienced recurrence of GDVE. CONCLUSIONS: APC showed short-term effectiveness and safety in the treatment of radiation-induced hemorrhagic GDVE.