Comprehensive Biomarkers for Personalized Treatment in Pulmonary Large Cell Neuroendocrine Carcinoma: A Comparative Analysis With Adenocarcinoma

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• 作者：Takashi Makino ; MD^a ; Tetuo Mikami ; MD ; PhD^b ; Yoshinobu Hata ; MD ; PhD^a ; Hajime Otsuka ; MD ; PhD^a ; Satoshi Koezuka ; MD^a ; Kazutoshi Isobe ; MD ; PhD^c ; Naobumi Tochigi ; MD ; PhD^d ; Kazutoshi Shibuya ; MD ; PhD^d ; Sakae Homma ; MD ; PhD^c ; Akira Iyoda ; MD ; PhD^a ; ^{aiyoda@med.toho-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AC ; adenocarcinoma ; EGFR ; epidermal growth factor receptor ; ERCC1 ; Excision repair cross-complementation group 1 ; LCNEC ; large cell neuroendocrine carcinoma ; NSCLC ; non-small cell lung carcinoma ; OS ; overall survival ; SCLC ; small cell lung carcinoma ; SST ; somatostatin ; SSTR ; somatostatin receptor ; TKI ; tyrosine kinase inhibitor ; TUBB3 ; class III β-tubulin ; Topo1 ; topoisomerase-I ; Topo2 ; topoisomerase-II
• 刊名：The Annals of Thoracic Surgery
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：102
• 期：5
• 页码：1694-1701
• 全文大小：1114 K

文摘

The prognosis for patients with large cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor, and optimal treatment strategies have not yet been established. To improve prognoses in patients with LCNEC, this study analyzed immunohistochemical expression and gene mutations of several known molecular targets in LCNECs and compared the expression levels of these targets with those in lung adenocarcinomas.

Methods

Twenty-six patients with primary LCNEC and 40 patients with adenocarcinoma were analyzed. Excision repair cross-complementation group 1 (ERCC1), class III β-tubulin, topoisomerase I, topoisomerase II, epidermal growth factor receptor (EGFR)–L858R, and somatostatin receptor expression were evaluated by immunohistochemistry, and EGFR mutations were evaluated using direct DNA sequencing and the Scorpion-amplified refractory mutation system.

Results

In patients with LCNEC and adenocarcinoma, positive rates of topoisomerase I, topoisomerase II, ERCC1, class III β-tubulin, EGFR-L858R, and somatostatin were 100.0% and 100.0%, 65.4% and 15.0% (p < 0.0001), 42.3% and 17.5% (p = 0.0462), 46.2% and 62.5%, 0.0% and 20.0% (p = 0.0182), and 50.0% and 5.0% (p < 0.0001), respectively. The frequencies of EGFR mutations were 0.0% and 37.5% in LCNEC and adenocarcinoma (p = 0.0002), respectively. Five-year overall survival rates were 64% in LCNEC and 91% in adenocarcinoma in stage I (p = 0.0132). Multivariate analysis showed that LCNEC histologic type was an independent prognostic factor in stage I.

Conclusions

LCNEC showed overexpression of topoisomerase II, somatostatin, and ERCC1. These findings suggested that it was possible to have good response to treatment with etoposide and octreotide and that LCNEC may be resistant to platinum-based therapy compared with adenocarcinoma. EGFR mutations were not observed in LCNEC. These results may indicate a favorable response to adjuvant treatments that are not typically prescribed for non-small cell lung cancer.