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. 2021 Oct;12(20):2666-2679.
doi: 10.1111/1759-7714.14102. Epub 2021 Aug 28.

Comprehensive expressional analysis of chemosensitivity-related markers in large cell neuroendocrine carcinoma of the lung

Yoichi Ohtaki  1 , Kyoichi Kaira  2 , Toshiki Yajima  1   3 , Bilguun Erkhem-Ochir  1 , Osamu Kawashima  4 , Mitsuhiro Kamiyoshihara  5 , Hitoshi Igai  5 , Ryoichi Onozato  6 , Takashi Ibe  7 , Takayuki Kosaka  7 , Seshiru Nakazawa  1 , Toshiteru Nagashima  1   6 , Tetsunari Oyama  8 , Ken Shirabe  1
Affiliations

Comprehensive expressional analysis of chemosensitivity-related markers in large cell neuroendocrine carcinoma of the lung

Yoichi Ohtaki et al. Thorac Cancer. 2021 Oct.

Abstract

Objectives: Various drug-sensitivity markers have been reported to be associated with tumor progression and chemotherapy resistance. Detailed expression profiles of sensitivity markers for cytotoxic chemotherapy in pulmonary large cell neuroendocrine carcinoma (LCNEC) remain unclear. Herein, we aimed to clarify the correlation between the expression of drug-sensitivity markers and clinicopathological features, prognostic impact, and status of tumor immunity in patients with LCNEC.

Methods: We retrospectively analyzed the correlation between clinicopathological features and the expression of drug-sensitivity-related markers, including vascular endothelial growth factor 2 (VEGFR2), thymidylate synthase (TS), tubulin beta 3 class III (TUBB3), topoisomerase I (Topo-I), and Topo-II in 92 surgically resected LCNEC samples. Furthermore, we examined the prognostic significance of expression of these and their correlation with the immune cell status.

Results: Overall, high expression of TS, TUBB3, VEGFR2, Topo-I, and Topo-II was detected in 50 (54%), 31 (34%), 23 (25%), 65 (71%), and 36 (39%) samples, respectively. Univariate and multivariate analyses revealed that advanced pathological T and N factors, positive lymphatic permeation, and Topo-II expression were independent unfavorable prognosticators for recurrence-free survival, and advanced pathological T and N factors, Topo-II positive expression, and TS positive expression were independent unfavorable prognosticators for overall survival. In terms of correlation with immune cell status, higher expression of VEGFR2 was closely linked to negative PD-L1 expression.

Conclusions: These findings suggest that elevated Topo-II and TS expression may contribute to poor outcomes through protumoral biology in patients with LCNEC, and elevated VEGFR2 expression might negatively impact tumor immune reactions in LCNEC.

Keywords: chemosensitivity; large cell neuroendocrine carcinoma; lung cancer; thymidylate synthase; topoisomerase II.

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Conflict of interest statement

All authors participated in this study and agreed with the content of this paper. K.K. has received research grants and honoraria for lectures from Ono Pharmaceutical Co., Ltd. and Bristol‐Myers Squibb. The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Representative immunohistochemical findings of LCNEC. Topo‐I low (a) and topo‐I high (b). Topo‐II low (c), topo‐II high (d), VEGFR2 low (e), VEGFR2 high (f), TUBB3 low (g), TUBB3 high (h), TS low (i), TS high (j), Ki67 low (k), and Ki67 high (l). LCNEC, large cell neuroendocrine carcinoma; Topo‐I, topoisomerase I; Topo‐II, topoisomerase II; TS, thymidylate synthase; VEGFR2, vascular endothelial growth factor 2; TUBB3, tubulin beta 3 class III
FIGURE 2
FIGURE 2
Recurrence‐free survival (RFS) and overall survival (OS) curves according to expression levels of topo‐I (a, b), topo‐II (c, d), VEGFR2 (e, f), TUBB3 (g, h), TS (i, j), and Ki67 (k, l). Topo‐I, topoisomerase I; topo‐II, topoisomerase II; TS, thymidylate synthase; VEGFR2, vascular endothelial growth factor 2; TUBB3, tubulin beta 3 class III
FIGURE 3
FIGURE 3
Survival differences according to the combination of significant prognostic markers. RFS according to the combination of topo‐II and VEGFR2 (a). OS according to the combination of topo‐II and VEGFR2 (b) or topo‐II and TS (c). OS according to the combination of topo‐II and TUBB (d). Topo‐II, topoisomerase II; TS, thymidylate synthase; VEGFR2, vascular endothelial growth factor 2; TUBB3, tubulin beta 3 class III; RFS, recurrence‐free survival; OS, overall survival
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