Comparison of PD-L1 immunohistochemistry assays and response to PD-1/L1 inhibitors in advanced non-small-cell lung cancer in clinical practice.

AIMS: Several studies have demonstrated analytical comparability between different PD-L1 assays, but their clinical validity in non-small-cell lung cancer in terms of response to treatment outside clinical trials has not been established. The aim of our study is to assess the analytical performance of laboratory-developed tests for Ventana SP263 and Agilent/Dako 22C3, and to investigate the association between PD-L1 assays and response to PD-1/L1 inhibitors. METHODS AND RESULTS: PD-L1 SP263 and 22C3 assays were performed on 302 consecutive non-small-cell lung carcinoma samples Both assays were optimised for use on the automated Ventana BenchMark Ultra platform. Scoring algorithms for staining of the tumour cells using the established cut-offs were applied to all samples. Best overall response (BOR) for 44 patients treated with either nivolumab, pembrolizumab or atezolizumab were assessed using recist version 1.1 and correlated with PD-L1 assay results. Assays showed good agreement, with a concordance correlation coefficient of 0.86 [95% confidence interval (CI) = 0.82-0.90)]. Comparing the assays using cut-offs of 1%, 5%, 10%, 1-49% and ≥50% showed an association between the two assays (P < 0.0001). The SP263 10% cut-off (P = 0.032) was associated with BOR, whereas the 1% (P = 0.087) and 5% (P = 0.051) cut-offs were not. In contrast 22C3, cut-offs of 1% (P = 0.019), 5% (P = 0.025) and 10% (P = 0.014) were all associated with BOR. CONCLUSIONS: The SP263 and 22C3 LDTs demonstrated good analytical concordance, and correlation with response to PD-1/L1 inhibitors.

Oligometastatic status as predictor of survival in metastatic human papillomavirus-positive oropharyngeal carcinoma.

BACKGROUND: Oligometastasis is a good prognostic indicator when compared to widely metastatic disease in malignancies of other organ systems. We hypothesized that oligometastasis in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) would be associated with better overall survival. METHODS: This is a retrospective review of all HPV-positive oropharyngeal SCC treated at one center with at least 1-year of follow-up. Patients were stratified into 2 cohorts: oligometastasis (1-2 metastases, confined to 1 organ system) or polymetastasis (>2 metastases or multiple organ involvement) with cohorts compared for time to distant metastasis and overall survival after metastasis. RESULTS: Thirty-eight of 506 patients (7.5%) developed metachronous distant metastasis; 12 developed oligometastasis and 26 developed polymetastasis. Median overall survival after oligometastasis was significantly longer than polymetastasis at 45 months (95% confidence interval [CI] 19 months - not reached) and 10 months (95% CI 5-24 months; P = .00028). CONCLUSION: Oligometastasis in metastatic HPV-positive oropharyngeal SCC portends a better prognosis than polymetastasis.

Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence.

Oncogene-induced senescence (OIS) is considered a powerful tumor suppressor mechanism. Caveolin-1 acts as a scaffolding protein to functionally regulate signaling molecules. We demonstrate that a lack of caveolin-1 expression inhibits oncogenic K-Ras (K-RasG12V)-induced premature senescence in mouse embryonic fibroblasts and normal human bronchial epithelial cells. Oncogenic K-Ras induces senescence by limiting the detoxification function of MTH1. We found that K-RasG12V promotes the interaction of caveolin-1 with MTH1, which results in inhibition of MTH1 activity. Lung cancer cells expressing oncogenic K-Ras have bypassed the senescence barrier. Interestingly, overexpression of caveolin-1 restores cellular senescence in both A549 and H460 lung cancer cells and inhibits their transformed phenotype. In support of these findings, our in vivo data demonstrate that overexpression of oncogenic K-Ras (K-RasG12D) induces cellular senescence in the lung of wildtype but not caveolin-1-null mice. A lack of K-RasG12D-induced premature senescence in caveolin-1-null mice results in the formation of more abundant lung tumors. Consistent with these data, caveolin-1-null mice overexpressing K-RasG12D display accelerated mortality. Finally, our animal data were supported by human sample analysis in which we show that caveolin-1 expression is dramatically down-regulated in lung adenocarcinomas from lung cancer patients, both at the mRNA and protein levels, and that low caveolin-1 expression is associated with poor survival. Together, our data suggest that lung cancer cells escape oncogene-induced premature senescence through down-regulation of caveolin-1 expression to progress from premalignant lesions to cancer.

Preclinical Evidence for Combined Use of Aromatase Inhibitors and NSAIDs as Preventive Agents of Tobacco-Induced Lung Cancer.

INTRODUCTION: A hormonal role in NSCLC development is well documented. We previously showed that the aromatase inhibitor (AI) anastrozole decreased development of tobacco carcinogen-induced lung tumors in a murine lung cancer prevention model and that aromatase and estrogen receptor were expressed in pulmonary inflammatory cells. METHODS: We utilized a tobacco carcinogen-induced lung tumor mouse model by treatment with 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), to determine whether an AI combined with nonsteroidal anti-inflammatory drugs results in greater lung tumor prevention effects compared to single-agent treatment. RESULTS: Combination of anastrozole (0.1 mg/kg/d) with aspirin (25 mg/kg/d) after NNK exposure resulted in significantly fewer and smaller lung tumors than did single-agent treatments and was accompanied by maximum decreases in circulating ß-estradiol (E2) and interleukin-6, tumor-infiltrating macrophages, and tumoral Ki67, phospho-mitogen-activated protein kinase, phospho-signal transducer and activator of transcription 3, and interleukin-17A expression. Preneoplasia arising after combination treatment showed the lowest Sox-2 expression, suggesting an inhibitory effect on proliferative capacity in the airways by blocking both E2 and inflammation. Anastrozole combined with ibuprofen instead of aspirin also showed enhanced antitumor effects. Moreover, male mice treated with NNK that received E2 in their drinking water showed greater levels of pulmonary macrophages and inflammatory markers than did the control, confirming an E2 effect on inflammation in the microenvironment. CONCLUSIONS: Our results suggest a benefit to joint targeting of the estrogen and inflammatory pathways for NSCLC prevention. Combining AIs with nonsteroidal anti-inflammatory drugs reduces circulating E2, proinflammatory cytokines, and macrophage recruitment in the lung microenvironment after tobacco exposure. This strategy could be particularly effective in women who have underlying pulmonary inflammatory diseases.

Positive Margins by Oropharyngeal Subsite in Transoral Robotic Surgery for T1/T2 Squamous Cell Carcinoma.

Objective To compare positive margin rates between the 2 most common subsites of oropharyngeal transoral robotic surgery (TORS), the base of tongue (BOT) and the tonsil, as well as identify preoperative imaging characteristics that predispose toward positive margins. Study Design Case series with chart review. Setting Tertiary care referral center. Subjects and Methods We compared the final and intraoperative positive margin rate between TORS resections for tonsil and BOT oropharyngeal squamous cell carcinoma (OPSCC), as well as the effect of margins on treatment. A blinded neuroradiologist examined the preoperative imaging of BOT tumors to measure their dimensions and patterns of spread and provided a prediction of final margin results. Results Between January 2010 and May 2016, a total of 254 patients underwent TORS for OPSCC. A total of 140 patients who underwent TORS for T1/T2 OPSCC met inclusion criteria. A final positive margin is significantly more likely for BOT tumors than tonsil tumors (19.6% vs 4.5%, respectively, P = .004) and likewise for intraoperative margins of BOT and tonsil tumors (35.3% vs 12.4%, respectively; P = .002). A positive final margin is 10 times more likely to receive chemoradiation compared to a negative margin, controlling for extracapsular spread and nodal status (odds ratio, 9.6; 95% confidence interval, 1.6-59.6; P = .02). Preoperative imaging characteristics and subjective radiologic examination of BOT tumors did not correlate with final margin status. Conclusion Positive margins are significantly more likely during TORS BOT resections compared to tonsil resections. More research is needed to help surgeons predict which T1/T2 tumors will be difficult to completely extirpate.

Prevalence and determinants of end-of-life chemotherapy use in patients with metastatic breast cancer.

Cessation of chemotherapy in the last few weeks of life could be an important quality-of-care benchmark. Proportion of metastatic breast cancer patients who receive end-of-life chemotherapy is not well described. We aimed to determine the prevalence and determinants of end-of-life chemotherapy use in patients with metastatic breast cancer. A retrospective cohort study using a prospectively collated database of patients with metastatic breast cancer who died between January 1, 2010, and September 30, 2014, was conducted. End-of-life chemotherapy (EOLC) use was defined as receipt of chemotherapy within 2 weeks of death (EOLC2) and receipt of chemotherapy within 4 weeks of death (EOLC4). Patients who did not receive any chemotherapy in the last 4 weeks before death were categorized as non-EOLC. We identified 274 patients with metastatic breast cancer, of whom 28 received EOLC2 (10.2%) and 62 received EOLC4 (22.6%). In comparison with non-EOLC, patients receiving EOLC4 were younger and had greater disease burden. Patients in EOLC4 group received more number of lines of chemotherapy. In a multivariable analysis, younger age at metastatic disease and greater number of metastatic organ systems involved were predictors of end-of-life chemotherapy use. Prevalence of the use of end-of-life chemotherapy in our cohort was higher than previously described. More end-of-life chemotherapy was used in younger women, and those with greater disease burden. Earlier initiation of end-of-life discussions may be targeted to such patients.

A prospective evaluation of short-term dysphagia after transoral robotic surgery for squamous cell carcinoma of the oropharynx.

BACKGROUND: Transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC) has been associated with improved long-term dysphagia symptomatology compared with chemoradiation. Dysphagia in the perioperative period has been inadequately characterized. The objective of this study was to characterize short-term swallowing outcomes after TORS for OPSCC. METHODS: Patients undergoing TORS for OPSCC were enrolled prospectively. The Eating Assessment Tool 10 (EAT-10) was used as a measure of swallowing dysfunction (score >2) and was administered on postoperative day (POD) 1, 7, and 30. Patient demographics, weight, pain level, and clinical outcomes were recorded prospectively and focused on time to oral diet, feeding tube placement, and dysphagia-related readmissions. RESULTS: A total of 51 patients were included with pathologic T stages of T1 (n = 24), T2 (n = 20), T3 (n = 3), and Tx (n = 4). Self-reported preoperative dysphagia was unusual (13.7%). The mean EAT-10 score on POD 1 was lower than on POD 7 (21.5 vs 26.6; P = .005) but decreased by POD 30 (26.1 to 12.2; P < .001). Forty-seven (92.1%) patients were discharged on an oral diet, but 57.4% required compensatory strategies or modification of liquid consistency. Ninety-eight percent of patients were taking an oral diet by POD 30. There were no dysphagia-related readmissions. CONCLUSION: This prospective study shows that most patients who undergo TORS experience dysphagia for at least the first month postoperatively, 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. Cancer 2017;123:3132-40. © 2017 American Cancer Society.

Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation.

We show that ATM kinase inhibition using AZ31 prior to 9 or 9.25 Gy total body irradiation (TBI) reduced median time to moribund in mice to 8 days. ATR kinase inhibition using AZD6738 prior to TBI did not reduce median time to moribund. The striking finding associated with ATM inhibition prior to TBI was increased crypt loss within the intestine epithelium. ATM inhibition reduced upregulation of p21, an inhibitor of cyclin-dependent kinases, and blocked G1 arrest after TBI thereby increasing the number of S phase cells in crypts in wild-type but not Cdkn1a(p21CIP/WAF1)-/- mice. In contrast, ATR inhibition increased upregulation of p21 after TBI. Thus, ATM activity is essential for p21-dependent arrest while ATR inhibition may potentiate arrest in crypt cells after TBI. Nevertheless, ATM inhibition reduced median time to moribund in Cdkn1a(p21CIP/WAF1)-/- mice after TBI. ATM inhibition also increased cell death in crypts at 4 h in Cdkn1a(p21CIP/WAF1)-/-, earlier than at 24 h in wild-type mice after TBI. In contrast, ATR inhibition decreased cell death in crypts in Cdkn1a(p21CIP/WAF1)-/- mice at 4 h after TBI. We conclude that ATM activity is essential for p21-dependent and p21-independent mechanisms that radioprotect intestinal crypts and that ATM inhibition promotes GI syndrome after TBI.

ALK FISH patterns and the detection of ALK fusions by next generation sequencing in lung adenocarcinoma.

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.

Association of pretreatment body mass index and survival in human papillomavirus positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Pretreatment body mass index (BMI) >25kg/m(2) is a positive prognostic factor in patients with head and neck cancer. Previous studies have not been adequately stratified by human papilloma virus (HPV) status or subsite. Our objective is to determine prognostic significance of pretreatment BMI on overall survival in HPV+ oropharyngeal squamous cell carcinoma (OPSCC). METHODS: This is a retrospective review of patients with HPV+ OPSCC treated between 8/1/2006 and 8/31/2014. Patients were stratified by BMI status (>/<25kg/m(2)). Univariate and multivariate analyses of survival were performed. RESULTS: 300 patients met our inclusion/exclusion criteria. Patients with a BMI >25kg/m(2) had a longer overall survival (HR=0.49, P=0.01) as well as a longer disease-specific survival (HR=0.43, P=0.02). Overall survival remained significantly associated with high BMI on multivariate analysis (HR=0.54, P=0.04). CONCLUSIONS: Pre-treatment normal or underweight BMI status is associated with worse overall survival in HPV+ OPSCC.

Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma.

Insulin receptor substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many pathways activated in lung cancer. It has been assumed that IRS-1 promotes tumor growth through its ability to activate PI3K signaling downstream of the insulin-like growth factor receptor. Surprisingly, tumors with reduced IRS-1 staining in a human lung adenocarcinoma tissue microarray displayed a significant survival disadvantage, especially within the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant subgroup. Accordingly, adenoviral Cre recombinase (AdCre)-treated LSL-Kras/Irs-1(fl/fl) (Kras/Irs-1(-/-)) mice displayed increased tumor burden and mortality compared with controls. Mechanistically, IRS-1 deficiency promotes Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling via the IL-22 receptor, resulting in enhanced tumor-promoting inflammation. Treatment of Kras/Irs-1(+/+) and Kras/Irs-1(-/-) mice with JAK inhibitors significantly reduced tumor burden, most notably in the IRS-1-deficient group.

ATM protein is deficient in over 40% of lung adenocarcinomas.

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.

A pancreatic cancer multidisciplinary clinic: insights and outcomes.

BACKGROUND: The purpose of this study was to evaluate the impact of a multidisciplinary clinic (MDC) on the treatment of pancreatic ductal adenocarcinoma. We hypothesized that an MDC would improve trial participation, multimodality therapy, neoadjuvant therapy, time to treatment, and survival. MATERIALS AND METHODS: Pancreatic ductal adenocarcinoma cancer registry patients from 2008-2012 were analyzed. Outcomes of patients evaluated at the MDC were compared with patients not evaluated at the MDC (non-MDC). RESULTS: A total of 1408 patients were identified, 557 (40%) MDC and 851 (60%) non-MDC. MDC were more likely to be an earlier stage than non-MDC (P = 0.0005): I - 4% versus 4%, II - 54% versus 43%, III - 11% versus 9%, and IV - 32% versus 44%. MDC were younger than non-MDC (68 versus 70; P = 0.005); however, younger (<75) and older (≥75) patients were more likely to receive treatment in MDC than non-MDC. MDC were more likely to participate in trials than non-MDC (28% versus 14%; P < 0.0001). MDC were more likely to receive treatment than non-MDC (90% versus 71%; P < 0.0001). MDC were more likely to receive two (38% versus 24%; P < 0.0001) or three (12% versus 9%; P = 0.02) therapies than non-MDC. No difference in time to first treatment in MDC than non-MDC (0.95 versus 0.92 mo; P = 0.69). After adjusting for age, stage, and therapy, there was a trend; however, no statistical difference in disease-free survival (hazard ratio [HR] of non-MDC versus MDC 0.80; 95% confidence interval [95% CI] 0.61-1.05; P = 0.11), time to recurrence (HR of non-MDC versus MDC 0.69; 95% CI 0.45-1.04; P = 0.07), or overall survival (HR of non-MDC versus MDC 0.81; 95% CI, 0.62-1.07; P = 0.13). CONCLUSIONS: Patients evaluated in an MDC were more likely to receive any treatment, receive multimodality therapy, neoadjuvant therapy, and participate in a clinical trial.

Utility of up-front transoral robotic surgery in tailoring adjuvant therapy.

BACKGROUND: The purpose of this study was to describe how the up-front transoral robotic surgery (TORS) approach could be used to individually tailor adjuvant therapy based on surgical pathology. METHODS: Between January 2009 and December 2013, 76 patients received TORS for oropharyngeal squamous cell carcinoma (OPSCC). Clinical predictors of adjuvant therapy were analyzed and comparisons were made between recommended treatment guidelines for up-front surgery versus definitive nonsurgical approaches. RESULTS: Advanced N classification, human papillomavirus (HPV)-positive tumor, extracapsular spread (ECS; 26 of 76), perineural invasion (PNI; 14 of 76), and positive margins (7 of 76) were significant predictors of adjuvant chemoradiotherapy (CRT) (p < .05). Up-front TORS deintensified adjuvant therapy; 76% of stage I/II and 46% of stage III/IV patients avoided CRT. Conversely, pathologic staging resulted in 33% of patients who would have received radiotherapy (RT) alone based on clinical staging, to be intensified to receive adjuvant CRT. CONCLUSION: The TORS approach deintensifies adjuvant therapy and provides valuable pathologic information to intensify treatment in select patients. TORS may be less effective in deintensification of adjuvant therapy in patients with clinically advanced N classification disease. © 2016 Wiley Periodicals, Inc. Head Neck 38:1201-1207, 2016.

Selection of Ideal Candidates for Surgical Salvage of Head and Neck Squamous Cell Carcinoma: Effect of the Charlson-Age Comorbidity Index and Oncologic Characteristics on 1-Year Survival and Hospital Course.

IMPORTANCE: Salvage surgery for recurrent head and neck squamous cell carcinoma (HNSCC) carries substantial risks of morbidity and mortality. Risk factors for death within 1 year should be better defined. OBJECTIVES: To report preoperative oncologic prognostic factors predictive of short-term (<1 year) survival after salvage surgery in patients with HNSCC, to assess whether preoperative age and comorbidity predicts 1-year mortality, and to report hospital courses after salvage surgery within 1 year. DESIGN, SETTING, AND PARTICIPANTS: A retrospective medical record review of 191 patients with recurrent HNSCC treated with salvage surgery from January 1, 2003, through December 31, 2013, at a tertiary academic center. INTERVENTIONS: Surgical salvage of HNSCC (larynx, oral cavity, oropharynx, or hypopharynx) with curative intent. MAIN OUTCOMES AND MEASURES: Primary outcome was survival 1 year after salvage surgery. Secondary outcomes were length of inpatient hospital stay, days of admissions, and skilled nursing facility disposition within 1 year stratified by survival status. Presalvage Charlson-Age Comorbidity Index (CACI) was calculated. Associations among CACI, oncologic risk factors, and risk of death within 1 year after salvage surgery are investigated using multivariable analysis. RESULTS: Of 191 patients studied, 53 (27.7%) died within 1 year after salvage surgery. Patients who died within 1 year had more total inpatient admissions (P < .001), longer total length of stay (P < .001), and higher risk of discharge to a skilled nursing facility (P < .001) and spent 17.3% (interquartile range, 5.2-36.3) of their remaining days in the hospital. Independent risk factors for death within 1 year are CACI (relative risk [RR], 1.43; 95% CI, 1.16-1.76), primary T3 or T4 stage (RR, 2.34; 95% CI, 1.27-4.31), and disease-free interval of less than 6 months (RR, 5.61; 95% CI, 1.78-16.7). CONCLUSIONS AND RELEVANCE: Medical comorbidity and age as measured by the CACI, primary T3 or T4 stage, and short disease-free interval must be considered in selecting patients ideal for surgical salvage surgery for recurrent HNSCC. Patients with these risk factors should be more strongly considered for palliative measures.

Adenosquamous carcinoma of the head and neck: Molecular analysis using CRTC-MAML FISH and survival comparison with paired conventional squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Adenosquamous carcinoma (ASC) is a rare variant of head-and-neck squamous cell carcinoma (HNSCC) generally thought to be uniformly aggressive with poor prognosis. However, it remains unknown how overall survival compare with conventional HNSCC. Here we report for the first time that ASC does not necessarily indicate a worse prognosis than conventional HNSCC. STUDY DESIGN: Case-control retrospective study. METHODS: Forty-two primary tumors of the head and neck, treated with curative intent, were identified. Next, 2:1 matching of HNSCC was performed using the following matching criteria: gender, site, pathologic tumor stage, and pathologic node stage. Successful matching was performed for 32 of 42 tumors. Additionally, 20 samples were sent for break-apart FISH testing to evaluate for the presence of the CRTC1-MAML2 translocation. RESULTS: There was a 1.8:1 male to female ratio, with a mean age of 62 years (range 38-84). The layrnx was the most common site (26%), followed by oropharynx (24%), oral cavity (19%), and sinonasal (17%). Kaplan-Meier analysis of adenosquamous and matched HNSCC showed similar survival curves. Median survival times for ASC and HNSCC were 4 and 6 years, respectively. A random-effects Cox model with Gamma frailty revealed no statistical difference between the two groups (P=0.25). All cases of ASC were negative for the CRTC1-MAML2 translocation. CONCLUSION: This study directly compares primary ASC with HNSCC. No difference in overall survival was detected in contradistinction to the previously thought uniformly poor prognosis. We also highlight the importance of the CRTC1-MAML2 translocation in distinguishing ASC from mucoepidermoid carcinoma. LEVEL OF EVIDENCE: 3b.

Transoral robotic surgery alone for oropharyngeal cancer: quality-of-life outcomes.

IMPORTANCE: Few studies have examined quality-of-life (QOL) outcomes in patients who undergo transoral robotic surgery (TORS) alone (ie, without adjuvant radiotherapy or chemoradiotherapy). OBJECTIVE: To report QOL outcomes of patients with oropharyngeal squamous cell carcinoma who receive only TORS. DESIGN, SETTING, AND PARTICIPANTS: Medical records for all patients undergoing TORS for treatment of primary oropharyngeal squamous cell carcinoma from May 1, 2010, to March 31, 2014, at a tertiary care academic cancer center were examined from June through September 2014. Thirty-four patients who did not receive adjuvant therapy after TORS were included in the study. INTERVENTION: Primary surgical resection via TORS. MAIN OUTCOMES AND MEASURES: The University of Washington Quality of Life, version 4, questionnaire was completed by patients preoperatively and at 1-, 6-, 12-, and 24-month intervals after TORS. Demographic, clinicopathologic, and follow-up data were collected. RESULTS: Mean follow-up time was 14 months (May 1, 2010, to April 30, 2014). Most patients had T1 (20 [59%]) or T2 (13 [38%]) and N0 (13 [38%]) or N1 (16 [47%]) disease. Statistically significant improvement in QOL outcomes was noted in the following postoperative domains: chewing from 1 month (median, 50 [IQR, 50-100]) to 12 months (100 [IQR, 100-100]; P = .048), swallowing from 1 month (70 [IQR, 30-85]) to 6 months (100 [IQR, 70-100]; P = .047) and 1 to 24 months (100 [IQR, 70-100]; P = .048), pain from 1 month (38 [IQR, 25-75]) to 6 months (88 [IQR, 75-100]; P = .006) and 1 to 12 months after surgery (100 [IQR, 75-100]; P = .01), and activity from 1 month (63 [IQR, 50-88]) to 24 months (100 [IQR, 75-100]; P = .03). Two participants (6%) died during the follow-up period: 1 because of disease and 1 because of a myocardial infarction. Two patients (6%) required temporary gastrostomy tube placement, but none required tracheostomy. CONCLUSIONS AND RELEVANCE: Appropriately selected patients who undergo TORS alone for oropharyngeal squamous cell carcinoma experience acceptable short- and long-term QOL outcomes.

Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium.

BACKGROUND: The advent of effective targeted therapy for BRAF(V600E) -mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced-stage BRAF-mutant lung adenocarcinomas. METHODS: Data were reviewed for patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), human epidermal growth factor receptor 2 (HER2), AKT1, BRAF, dual-specificity mitogen-activated protein kinase kinase 1 (MEK1), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA); for anaplastic lymphoma kinase (ALK) translocations; and for MET amplification. RESULTS: Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%; 95% confidence interval [CI], 1.4%-3.4%): 17 (81%; 95% CI, 60%-92%) were BRAF(V600E) mutations, and 4 were non-BRAF(V600E) mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur than most other genotypic abnormalities in current or former smokers (BRAF vs sensitizing EGFR, 82% vs 36%, mid-P < .001; BRAF vs ALK, 39%, mid-P = .003; BRAF vs other mutations, 49%, mid-P = .02; BRAF vs patients with more than 1 oncogenic driver [doubleton], 46%, mid-P = .04.) The double-mutation rate was 16% among patients with BRAF mutations but 5% among patients with other genomic abnormalities (mid-P = .045). Differences were not found in survival between patients with BRAF mutations and those with other genomic abnormalities (P > .20). CONCLUSIONS: BRAF mutations occurred in 2.2% of advanced-stage lung adenocarcinomas, were most commonly V600E, and were associated with distinct clinicopathologic features in comparison with other genomic subtypes and with a high mutation rate in more than 1 gene. These findings underscore the importance of comprehensive genomic profiling in assessing patients with advanced lung adenocarcinomas.