BACKGROUND: Extracapsular spread (ECS) in cervical lymph node metastases from head and neck squamous cell carcinoma (SCC) is regarded as an adverse prognostic factor and is often used to select patients who may benefit from adjuvant therapy. The prognostic value of ECS was evaluated for patients with oropharyngeal SCC (OPC; with known p16/human papillomavirus [HPV] status) and for patients with SCC of the oral cavity (OCC). METHODS: Disease-specific survival (DSS) was assessed among SCC patients with cervical lymph node metastases (n 5 347, including 133 patients with OPC and 214 patients with OCC). All patients were treated surgically between 1983 and 2009. ECS status was determined by pathologists at the time of initial pathologic evaluation and confirmed for this study. HPV status of patients with OPC was determined via immunohistochemistry for p16 and in situ hybridization. RESULTS: Among OCC patients, ECS was a significant, independent factor influencing DSS. For OCC patients with ECS, 3-year DSS was 45% (95% confidence interval [CI], 36%-56%); for those without ECS, 3-year DSS was 71% (95% CI, 62%-81%; P 5.0018). The effect of ECS was independent of the number of positive lymph nodes as well as other clinical, pathologic, and treatment variables. Of the 133 OPC patients, 76 (57%) were p16-positive and 57 (43%) were p16-negative. ECS status did not correlate with DSS among p16-positive or p16-negative OPC patients. CONCLUSION: ECS was not associated with worse DSS in p16-positive or p16-negative OPC patients.

Increasing evidence shows that estrogens are involved in lung cancer proliferation and progression, and most human lung tumors express estrogen receptor β (ERβ) as well as aromatase. To determine if the aromatase inhibitor anastrozole prevents development of lung tumors induced by a tobacco carcinogen, alone or in combination with the ER antagonist fulvestrant, ovariectomized female mice received treatments with the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) along with daily supplements of androstenedione, the substrate for aromatase. Placebo, anastrozole and/or fulvestrant were administered in both an initiation and a promotion protocol of lung tumorigenesis. The combination of fulvestrant and anastrozole given during NNK exposure resulted in significantly fewer NNK-induced lung tumors (mean = 0.5) compared with placebo (mean = 4.6, P < 0.001), fulvestrant alone (mean = 3.4, P < 0.001) or anastrozole alone (mean = 2.8, P = 0.002). A significantly lower Ki67 cell proliferation index was also observed compared with single agent and control treatment groups. Beginning antiestrogen treatment after NNK exposure, when preneoplastic lesions had already formed, also yielded maximum antitumor effects with the combination. Aromatase expression was found mainly in macrophages infiltrating preneoplastic and tumorous areas of the lungs, whereas ERβ was found in both macrophages and tumor cells. Antiestrogens, especially in combination, effectively inhibited tobacco carcinogen-induced murine lung tumorigenesis and may have application for lung cancer prevention. An important source of estrogen synthesis may be inflammatory cells that infiltrate the lungs in response to carcinogens, beginning early in the carcinogenesis process. ERβ expressed by inflammatory and neoplastic epithelial cells in the lung may signal in response to local estrogen production.

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Background The prognostic and therapeutic implications of the spectrum of KRAS oncogene substitutions in lung cancer remain poorly understood. The objective of this study was to determine if KRAS oncogene substitutions differed with regard to prognosis or predictive value in lung adenocarcinoma. Methods KRAS oncogene substitutions and mutant-allele specific imbalance (MASI) were determined in patients with lung adenocarcinoma and associations with overall survival (OS) and recurrence free survival (RFS), and chemotherapy interactions were assessed. Results KRAS mutational analysis was performed on 988 lung adenocarcinomas, and 318 KRAS mutations were identified. In this predominantly early stage cohort (78.6% stage I–III), OS and RFS did not differ by the type of KRAS substitution (OS, p=0.612; RFS P=0.089). There was a trend toward better OS in the subset of patients with KRAS codon 13 mutations (p=0.052), which was not significant in multivariate analysis (p=0.076). RFS did not differ by codon type in univariate analysis (p=0.322). There was a marked difference in RFS based on the presence of MASI in univariate (p=0.004) and multivariate analysis (p=0.009). A test for interaction was performed in order to determine if the effect of chemotherapy on OS and RFS differed based on the type of KRAS substitution, codon type or the presence of MASI. There were no differences in the effects of chemotherapy for any of variables examined. Conclusions KRAS codon 13 mutations and MASI are candidate biomarkers for prognosis that may be useful to incorporate in prospective studies evaluating novel therapies in KRAS mutant lung adenocarcinoma.

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