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      Expression of p63 and CK5/6 in early-stage lung squamous cell carcinoma is not only an early diagnostic indicator but also correlates with a good prognosis

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          Abstract

          Background

          Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers, and lung squamous cell carcinoma (SQCC) is one of the main types. Advances in the treatment of lung SQCC are lacking when compared to lung adenocarcinoma. The main treatment for early-stage SQCC is surgery. However, factors affecting the efficacy of surgical treatments for early-stage lung SQCC remain unclear. In this study, we examined the significance of commonly used lung SQCC diagnostic markers p63, p40, and cytokeratin (CK)5/6 in prognosis.

          Methods

          Seventy-six cases of early-stage lung SQCC (N 0) were obtained from our lung cancer database (January 2000 to December 2009). Tissue microarray and immunohistochemical (IHC) staining were used to detect the expression of p63, p40, and CK5/6. The effect of the expression level of each marker on patients' survival was examined.

          Results

          Sensitivity and specificity of each marker for detecting lung SQCC was 87.0% and 81.0% for p63, 75.9% and 97.9% for p40, and 78.9% and 97.7% for CK5/6. Survival rates of patients with high expression levels of p63 or CK5/6 or both were higher than in patients with low expression levels ( P < 0.05). Expression levels of p40 had no effect on survival ( P > 0.05). Multivariate analysis showed that high levels of p63 expression p63+CK5/6 co-expression were independent prognostic factors for good survival.

          Conclusion

          IHC staining detection of p63 and CK5/6 in specimens should be routinely performed in postoperative early-stage lung SQCC patients. Its significance lies not only in differential diagnosis, but also in determining prognosis.

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          Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer.

          Helena Linardou, Issa Dahabreh, Dimitra Kanaloupiti … (2008)
          Somatic mutations of the k-RAS oncogene have been assessed as a mechanism of de-novo resistance to epidermal growth factor receptor (EGFR) tyrosine-kinase inhibition in patients with non-small-cell lung cancer (NSCLC), and to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (mCRC). The aim of this systematic review and meta-analysis was to assess if k-RAS mutations represent a candidate predictive biomarker for anti-EGFR-targeted therapeutic strategies in mCRC and NSCLC. We systematically identified articles pertaining to k-RAS mutational status in patients with NSCLC treated with tyrosine-kinase inhibitors (TKI), and patients with mCRC treated with any anti-EGFR-based regimens. Eligible studies had to report complete responses (CR) and partial responses (PR), stratified by k-RAS mutational status. Potential between-study heterogeneity was accommodated by use of random-effects models for bivariable meta-analysis of sensitivity and specificity (the primary endpoints). The positive and negative likelihood ratios (+LR and -LR, respectively) of k-RAS mutations for predicting an absence of response were considered as secondary endpoints and were calculated by use of pooled estimates for sensitivity and specificity. Of 252 retrieved manuscripts, 17 were deemed eligible for the NSCLC meta-analysis (165 of 1008 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to TKIs (sensitivity=0.21 [95% CI 0.16-0.28], specificity=0.94 [0.89-0.97]; +LR=3.52; -LR=0.84). Of 68 retrieved manuscripts reporting on anti-EGFR monoclonal-antibody-based treatment of mCRC, eight studies were deemed eligible for the final analysis (306 of 817 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments (sensitivity=0.47 [0.43-0.52]; specificity=0.93 [0.83-0.97]; +LR=6.82; -LR=0.57). This analysis provides empirical evidence that k-RAS mutations are highly specific negative predictors of response (de-novo resistance) to single-agent EGFR TKIs in advanced NSCLC; and similarly to anti-EGFR monoclonal antibodies alone or in combination with chemotherapy in patients with mCRC. The low sensitivity and relatively high -LR of k-RAS mutations for determining non-responsiveness clearly shows that additional mechanisms of resistance to EGFR inhibitors exist.
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            Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer.

            Tetsuya Mitsudomi, Yasushi Yatabe (2007)
            Recent discovery of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma greatly stimulated biomarker research on predictive factors for EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. Although patients with activating mutations of the EGFR generally respond to EGFR TKIs very well, it is natural to assume that there is no sole determinant, considering great complexity and redundancy of the EGFR pathway. Subsequently, roles of different types of EGFR mutations or mutations of genes that are members of the EGFR pathway such as KRAS and HER2 have been evaluated. In this review, we summarize the recent findings about how mutations of the EGFR and related genes affect sensitivity to EFGR-TKIs. We also discuss molecular mechanisms of acquired resistance to EGFR-TKIs that is almost inevitable in EGFR-TKI therapy. The door for genotype-based treatment of lung cancer is beginning to open, and through these efforts, it will be possible to slow the progression of lung cancer and eventually, to decrease mortality from lung cancer.
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              Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features.

              Ignacio Wistuba, Wenli Dong, Shyam Biswal … (2010)
              To understand the role of nuclear factor erythroid-2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in non-small cell lung cancer (NSCLC), we studied their expression in a large series of tumors with annotated clinicopathologic data, including response to platinum-based adjuvant chemotherapy. We determined the immunohistochemical expression of nuclear Nrf2 and cytoplasmic Keap1 in 304 NSCLCs and its association with patients' clinicopathologic characteristics, and in 89 tumors from patients who received neoadjuvant (n = 26) or adjuvant platinum-based chemotherapy (n = 63). We evaluated NFE2L2 and KEAP1 mutations in 31 tumor specimens. We detected nuclear Nrf2 expression in 26% of NSCLCs; it was significantly more common in squamous cell carcinomas (38%) than in adenocarcinomas (18%; P < 0.0001). Low or absent Keap1 expression was detected in 56% of NSCLCs; it was significantly more common in adenocarcinomas (62%) than in squamous cell carcinomas (46%; P = 0.0057). In NSCLC, mutations of NFE2L2 and KEAP1 were very uncommon (2 of 29 and 1 of 31 cases, respectively). In multivariate analysis, Nrf2 expression was associated with worse overall survival [P = 0.0139; hazard ratio (HR), 1.75] in NSCLC patients, and low or absent Keap1 expression was associated with worse overall survival (P = 0.0181; HR, 2.09) in squamous cell carcinoma. In univariate analysis, nuclear Nrf2 expression was associated with worse recurrence-free survival in squamous cell carcinoma patients who received adjuvant treatment (P = 0.0410; HR, 3.37). Increased expression of Nrf2 and decreased expression of Keap1 are common abnormalities in NSCLC and are associated with a poor outcome. Nuclear expression of Nrf2 in malignant lung cancer cells may play a role in resistance to platinum-based treatment in squamous cell carcinoma. Copyright 2010 AACR.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Thorac Cancer
                Journal ID (iso-abbrev): Thorac Cancer
                Journal ID (publisher-id): tca
                Title: Thoracic Cancer
                Publisher: BlackWell Publishing Ltd (Oxford, UK )
                ISSN (Print): 1759-7706
                ISSN (Electronic): 1759-7714
                Publication date (Print): May 2015
                Publication date (Electronic): 24 April 2015
                Volume: 6
                Issue: 3
                Pages: 288-295
                Affiliations
                [1 ]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), The First Department of Thoracic Surgery, Peking University Cancer Hospital & Institute Beijing, China
                [2 ]Department of Pathology, Peking University Cancer Hospital & Institute Beijing, China
                Author notes
                Correspondence, Keneng Chen, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), The First Department of Thoracic Surgery, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100036, China., Tel: +86 10 88196105, Fax: +86 10 88196526, Email: chenkeneng@ 123456bjmu.edu.cn
                Article
                DOI: 10.1111/1759-7714.12181
                PMC ID: 4448377
                PubMed ID: 26273374
                SO-VID: 56f6723d-9f34-4cec-875a-a1273c5a3c19
                Copyright © © 2014 The Authors. Thoracic Cancer published by Tianjin Lung Cancer Institute and Wiley Publishing Asia Pty Ltd.
                License:

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 04 August 2014
                Date accepted : 15 September 2014
                Categories
                Subject: Original Articles

                Keywords: immunohistochemistry,lung squamous cell carcinoma,non-small cell lung cancer,prognosis
                Data availability:
                Keywords: immunohistochemistry, lung squamous cell carcinoma, non-small cell lung cancer, prognosis

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