Purpose To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC). Methods Using the National Cancer Data Base (NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds. Results A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio [HR], 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P ≤ .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days. Conclusion TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival.

BACKGROUND The objective of this study was to identify trends and predictors of the time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC). METHODS The National Cancer Database (NCDB) was reviewed for the following head and neck cancer sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was defined as the number of days from diagnosis to the initiation of definitive treatment and was measured according to covariates. Significant differences in the median TTI across each covariate were measured using the Kruskal‐Wallis test, and the Spearman test was used to measure trends within covariates. For multivariate analysis, a zero‐inflated, negative, binomial regression model was used to estimate the expected TTI, which was expressed in the predicted number of days; and the Vuong test was used to identify the predictors of TTI. RESULTS In total, 274,630 patients were included. Between 1998 and 2011, the median TTI for all patients was 26 days, and it increased from 19 days to 30 days (P < .0001). Treatment with chemoradiation (CRT) (P < .0001), treatment at academic facilities (P < .0001), and stage IV disease (P < .0001) were associated with increased TTI. TTI significantly increased for each disease stage (P < .0001), treatment modality (P < .0001), and facility type (P < .0001) over time. In addition, patients became more likely to transition care between facilities after diagnosis for treatment initiation (P < .0001) over time. On multivariate analysis, treatment at academic facilities (33 days), transitioning care (37 days), and receipt of CRT (39 days) predicted for a longer TTI. CONCLUSIONS TTI is rising for patients with HNSCC. Those who have advanced‐stage disease, receive treatment with CRT, are treated at academic facilities, and who have a transition in care realized the greatest increases in TTI. Cancer 2015;121:1204–1213. © 2014 American Cancer Society.

Purpose Multiple-gene, next-generation sequencing panels are increasingly used to assess hereditary cancer risks of patients with diverse personal and family cancer histories. The magnitude of breast and ovarian cancer risk associated with many clinically tested genes, and independent of family cancer history, remains to be quantified. Methods We queried a commercial laboratory database of 95,561 women tested clinically for hereditary cancer risk with a 25-gene ( APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CHEK2, MLH2, MSH2, MSH6, MUTYH, NBN, P14ARF, P16, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53) next-generation sequencing panel. Multivariable logistic regression models accounting for family history were used to examine the association between pathogenic mutations and breast or ovarian cancer. As a confirmatory approach, a matched case-control analysis was conducted, defining cases as patients with breast or ovarian cancer and controls as women without cancer. Results One or more pathogenic mutations were detected in 6,775 (7%) of 95,561 women. Eight genes ( ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, PTEN, and TP53) were associated with breast cancer, with odds ratios (ORs) ranging from two-fold ( ATM: OR, 1.74; 95% CI, 1.46 to 2.07) to six-fold ( BRCA1: OR, 5.91; 95% CI, 5.25 to 6.67). Eleven genes ( ATM, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, NBN, STK11, RAD51C, and RAD51D) were associated with ovarian cancer, with OR ranging from two-fold ( ATM: OR, 1.69; 95% CI, 1.19 to 2.40) to 40-fold ( STK11: OR, 41.9; 95% CI, 5.55 to 315). Multivariable models and matched case-control analyses yielded similar results. Conclusion Among nearly 100,000 clinically tested women, 7% carried a pathogenic mutation in one or more cancer-associated genes. Associated breast and ovarian cancer risks ranged from two- to 40-fold after controlling for family history. These results may inform cancer risk counseling.

Colorectal cancer (CRC) is increasingly appreciated as a heterogeneous disease, with factors such as microsatellite instability (MSI), cancer subsite within the colon versus rectum, and age of diagnosis associated with specific disease course and therapeutic response. Activating oncogenic mutations in KRAS and NRAS are common in CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. The RAS mutational spectrum differs substantially between tumors arising from distinct tissues. Structure-function analysis of relatively common somatic RAS mutations in G12, Q61, and other codons is characterized by differing potency and modes of action. Here we show the mutational profile of KRAS , NRAS , and the less common HRAS in 13,336 CRC tumors, comparing the frequency of specific mutations based on age of diagnosis, MSI status, and colon versus rectum subsite. We identify mutation hotspots, and unexpected differences in mutation spectrum, based on these clinical parameters.

PURPOSE To assess the impact of radiation treatment time (RTT) in head and neck cancers on overall survival (OS) in the era of chemoradiation. MATERIALS & METHODS Patients diagnosed with tongue, hypopharynx, larynx, oropharynx, or tonsil cancer were identified using the National Cancer Database. RTT was defined as date of first radiation treatment to date of last radiation treatment. In the definitive setting, prolonged RTT was defined as >56 days, accelerated RTT was defined as ≤47 days, and standard RTT was defined as 48–56 days. In the post-operative setting, prolonged RTT was defined as >49 days, accelerated RTT was defined as ≤40 days, and standard RTT was defined as 41–49 days. Chi-squared tests were used to identify predictors of RTT. The Kaplan-Meier method was used to compare OS amongst groups. Cox proportional hazards model was used for OS analysis in patients with known comorbidity status. RESULTS 19,531 patients were included; 12,987 (67%) had a standard RTT, 4,369 (34%) had an accelerated RTT, and 2,165 (11%) had a prolonged RTT. On multivariable analysis, accelerated RTT (HR 0.84 95% CI 0.73–0.97) was associated with an improved OS while prolonged RTT (HR 1.25 95% CI 1.14–1.37) was associated with a worse OS relative to standard RTT. When examining the 9,200 (47%) patients receiving definitive concurrent chemoradiation, prolonged RTT (HR 1.29 95% CI 1.11–1.50) was associated with a worse OS relative to standard RTT while there was no significant association between accelerated RTT and OS (HR 0.76 95% CI 0.57–1.01). CONCLUSION Prolonged RTT is associated with worse OS in patients receiving radiotherapy for head and neck cancer, even in the setting of chemoradiation. Expeditious completion of radiation should continue to be a quality metric for the management of head and neck malignancies.

Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by Kras G12D expression and homozygous Trp53 loss. Consistently, PDACs in

Background:The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical.Methods:Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%).Results:A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003).Conclusions:Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation.

Complete resection is the standard of care for treatment of thymic malignancies. The use of minimally invasive surgery remains controversial. We searched online databases and identified studies from 1995 to 2014 that compared minimally invasive to open thymectomy for thymic malignancies. Study end points included operative blood loss, operative time, respiratory complications, cardiac complications, length of hospital stay, R0 resection, and recurrence. We summarized outcomes across studies using random-effects meta-analysis to account for study heterogeneity. We calculated ORs for binary outcomes and standardized mean differences for continuous outcomes. We calculated incidence rate ratios for the number of recurrences, accounting for total person-time observed in each study. Of 516 potential reference studies, 30 with a total of 2038 patients met the inclusion criteria. Patients with Masaoka stage I or II thymic malignancy constituted 94.89% of those in the minimally invasive surgery (MIS) group and 78.62% of those in open thymectomy (open) group. Mean tumor size was 4.09 cm (MIS) versus 4.80 (open). Of the 1355 MIS cases, 32 were converted to open cases. Patients in the MIS group had significantly less blood loss; however, no significant differences in operating time, respiratory complications, cardiac complications, or overall complications were identified. Length of stay was shorter for patients in the MIS group. When patients with Masaoka stage I and II thymic malignancy only were analyzed, there was no difference in rate of R0 resection or overall recurrence rate. One postoperative death occurred in the open group. The results of this unadjusted meta-analysis of published reports comparing minimally invasive with open thymectomy suggest that in selected patients with thymic malignancy, minimally invasive thymectomy is safe and can achieve oncologic outcomes similar to those of open thymectomy.