(1) PURPOSE The advent of effective targeted therapy in BRAFV600E mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced stage BRAF mutant lung adenocarcinomas. (2) PATIENTS AND METHODS We reviewed data from patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in EGFR, KRAS, HER2, AKT1, BRAF, MEK1, NRAS, PIK3CA, ALK translocations, and MET amplification. (3) RESULTS Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%: 95% CI 1.4 to 3.4%); 17 (81%: 95% CI 60 to 92%) were BRAFV600E and 4 were non-BRAFV600E mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur in current or former smokers than most other genotypic abnormalities (BRAF versus sensitizing EGFR: 82% versus 36%, mid-P<0.001; versus ALK: 39%, mid-P=0.003; versus other mutations: 49%, mid-P=0.02; versus patients with more than one oncogenic driver (doubleton): 46%, mid-P=0.04.) The double mutation rate among patients with BRAF mutations was 16%, compared with 5% in patients with other genomic abnormalities (mid-P=0.045). Differences were not found in survival between patients with BRAF mutations and those with other genomic abnormalities (P>0.20). (4) CONCLUSIONS We demonstrate BRAF mutations occur in 2.2% of advanced stage lung adenocarcinomas, were most commonly V600E, were associated with distinct clinicopathologic features compared with other genomic subtypes and a high mutation rate in more than one gene, underscoring the importance of comprehensive genomic profiling in assessing patients with advanced lung adenocarcinomas.

Appropriately selected patients who undergo TORS alone for oropharyngeal squamous cell carcinoma experience acceptable short- and long-term QOL outcomes.

BACKGROUND Transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC) has been associated with improved long-term dysphagia symptomatology as compared to chemoradiation. Dysphagia in the perioperative period has been inadequately characterized. The objective of this study is to characterize short-term swallowing outcomes after TORS for OPSCC. METHODS Patients undergoing TORS for OPSCC were prospectively enrolled. The Eating Assessment Tool 10 (EAT-10) was used as a measure of swallowing dysfunction (score > 2) and was administered on post-operative day (POD) 1, POD7, and POD30. Patient demographics, weight, pain level and clinical outcomes were recorded prospectively focused on time to oral diet, feeding tube placement and dysphagia-related readmissions. RESULTS 51 patients were included with pathologic T-stages of T1 (24), T2 (20), T3 (3), Tx (4). Self-reported preoperative dysphagia was unusual (13.7%). The mean EAT-10 score on POD1 was lower than on POD7 (21.5 vs. 26.6, p=0.005) but decreased by POD30 (26.1 to 12.2, p<0.001). 47/51 (92.1%) were discharged on an oral diet but 57.4% required compensatory strategies or modification of liquid consistency. 98.0% of patients were taking an oral diet by POD30. There were no dysphagia-related readmissions. CONCLUSIONS This prospective study shows that most patients who undergo TORS experience dysphagia for at least the first month post-operatively but nearly all can be started on an oral diet. The dysphagia-associated complication profile is acceptable after TORS with a minority of patients requiring temporary feeding tube placement. Aggressive evaluation and management of postoperative dysphagia in TORS patients may help prevent dysphagia-associated readmissions.

Break-apart ALK FISH probe is the FDA approved approach for detection of ALK rearrangements in lung carcinoma patients who may benefit from ALK kinase inhibitors. The FISH assay can be technically challenging and difficult to interpret. ALK immunohistochemistry and next generation sequencing have been proposed as alternative approaches. In this study, we compared various ALK –FISH patterns to next –generation sequencing (NGS) for gene fusion detection, ALK immunohistochemistry (IHC) and tumor responses to crizotinib. 72 (4%) of 2116 lung adenocarcinoma were positive by ALK- FISH. Of 28 ALK-FISH positive cases selected for the study, FISH patterns included 15 (54%) cases with split signal, 10 (36%) with single orange signal and 3 (10%) with “mixed pattern”. 12 (80%) cases with split signal and 4 (40%) cases with single orange signal were positive by NGS and IHC, while mixed cases were all negative. Mutation analysis of discordant cases revealed multiple mutations including oncogenic mutations in EGFR, KRAS, BRAF and ATM genes. All discordant cases in groups with split and mixed signal showed a lower number of cells with rearrangement (mean 28.5%; range 20.5-36.9%). No statistically significant association between response to crizotinib and FISH patterns was observed (p=0.73). In contrast, NGS fusion positive cases were associated with more responses to crizotinib than NGS negative cases (p= 0.016). Our study suggests that ALK FISH alone may not be the most reliable assay for detection of ALK gene rearrangements, and probably should be used in parallel with ALK IHC and NGS for detection of gene fusions and mutations.

Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year.