An amino-terminal BRAF deletion accounting for acquired resistance to RAF/EGFR inhibition in colorectal cancer.

Although combination therapy with RAF and EGFR inhibitors has improved the survival outcomes of patients with BRAF-mutated colorectal cancer (CRC), acquired resistance invariably develops. The mechanisms of acquired resistance to RAF inhibitors have been largely attributed to activating mutations in RASgenes, MAP2K mutations, and amplifications in BRAF, RAS genes, and EGFR In this report, we describe a patient with BRAF-mutated CRC who acquired an amino-terminal BRAF deletion involving the Ras-binding domain (RBD) after treatment with RAF/EGFR inhibitor therapy. Amino-terminal BRAF deletions involving the RBD are a rare mechanism of acquired resistance to RAF inhibitors, particularly in CRC for which there is only one prior report in the literature.

BAP-1 Expression Status by Immunohistochemistry in Cellular Blue Nevus and Blue Nevus-like Melanoma.

The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti-BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.

Performance and prognostic utility of the 92-gene assay in the molecular subclassification of ampullary adenocarcinoma.

BACKGROUND: Ampullary adenocarcinoma is a rare gastrointestinal cancer associated with diverse outcomes due to clinical and pathological heterogeneity. Standardized methods to better prognosticate and inform therapeutic selection for ampullary adenocarcinoma are needed. This study explored the novel use and potential prognostic utility of a 92-gene cancer classifier in ampullary adenocarcinomas. METHODS: In this prospectively-defined, blinded study of ampullary adenocarcinoma [N =54; stage T3 or higher (57 %); Grade III (44 %); Node positive (55 %)], the performance of a 92-gene classifier was examined to predict the ampullary subtype that was derived from histomorphological examination of resected ampullary samples. Outcome data for relapse-free survival (RFS) and overall survival (OS) were plotted to compare the prognostic utility of histological subtyping, histomolecular phenotyping, and the 92-gene classifier. Multivariate analysis was used to determine clinicopathological variables that were independently associated with overall survival. RESULTS: The 92-gene classifier demonstrated sensitivities and specificities of 85 % [95 % CI, 66-94] and 68 % [95 % CI, 48-84] and 64 % [95 % CI, 46-79] and 88 % [95 % CI, 70-98] for the pancreaticobiliary and intestinal histological subtypes, respectively. For the 92-gene classifier, improved outcomes were observed for the intestine versus the pancreaticobiliary prediction (median OS 108.1 v 36.4 months; HR, 2.17; 95 % CI, 0.98 to 4.79; P = 0.05). Similar results were seen for ampullary adenocarcinoma stratification by histological subtype (P = 0.04) and histomolecular phenotype (P = 0.02). Within poorly differentiated ampullary adenocarcinomas only the 92-gene classifier demonstrated statistically significant differences in RFS and OS (P < 0.05). CONCLUSIONS: Prognostic stratification of ampullary adenocarcinoma was similar for the 92-gene classifier, histological subtype, and histomolecular phenotype. The 92-gene classifier provides an unbiased standardized molecular-based approach to stratify ampullary tumors.

Distribution of Resistant Esophageal Adenocarcinoma in the Resected Specimens of Clinical Stage III Patients after Chemoradiation: Its Clinical Implications.

BACKGROUND: We have limited knowledge of the geographic distribution of resistant esophageal adenocarcinoma (EAC) in resected specimens, but its clinical importance can be enormous. METHOD: We selected patients with baseline stage III EAC who had had chemoradiation followed by surgery and had residual EAC (resistant cases only). Outcomes were correlated with various endpoints (percentage of resistant EAC and anatomic distribution). RESULTS: A total of 100 clinical stage III patients were studied; 90% had an R0 resection, and 99% had either moderate or poorly differentiated EAC. Twelve percent had >50% residual cancer, 31% had 11-50% residual cancer, 53% had 1-10% residual cancer, and 3% had positive nodes only. Each compartment was frequently involved: mucosa/submucosa (66%), muscularis propria (76%), and serosa (62%); all compartments were involved in 35% of the cases. Lack of EAC (meaning response) was observed in the mucosa/submucosa (34%), muscularis propria (24%), serosa (38%), and nodes (42%). Although the endoscopic biopsies prior to surgery showed no EAC in 79% of the patients, in the surgical specimens, resistant EAC was frequently occurring in the mucosa/submucosa (66%). CONCLUSION: Contrary to our hypothesis that resistant EAC would be frequent in the nodes, our data show that its distribution is heterogeneous and unpredictable. Most importantly, the postchemoradiation biopsies are misleading, and a decision to delay/avoid surgery based on negative biopsies can be detrimental for the patients.