DLL3 expression is a predictive marker of sensitivity to adjuvant chemotherapy for pulmonary LCNEC

Abstract

Background The mammalian Notch family ligands delta‐like 3 (DLL3) is reported to be a potential therapeutic target for large cell neuroendocrine carcinomas (LCNEC). The effect of DLL3 expression on LCNEC prognosis has not yet been elucidated. Methods We reviewed the medical records of 70 LCNEC patients undergoing surgical resection between 2001 and 2015 using a prospectively maintained database. We performed immunohistochemistry for DLL3 and investigated the correlation between the sensitivity of LCNEC to platinum‐based adjuvant chemotherapy. Results DLL3 expression was positive in 26 (37.1%) LCNEC patients. A total of 23 patients (32.9%) received platinum‐based adjuvant chemotherapy. Among patients with DLL3 expression‐positive tumors, no difference was found in the five‐year overall survival (OS) or recurrence‐free survival (RFS) between patients with and without adjuvant chemotherapy (surgery + chemotherapy vs. surgery alone, five‐year OS: 58.3% vs. 35.7% P = 0.36, five‐year RFS: 41.7% vs. 35.7% P = 0.74). In contrast, among patients with DLL3‐negative tumors, significantly greater five‐year OS and RFS rates were observed for patients with adjuvant chemotherapy than for those without it (surgery + chemotherapy vs. surgery alone: five‐year OS: 90.0% vs. 26.9% P<0.01, five‐year RFS: 80.0% vs. 21.7% P < 0.01). A multivariate analysis for the RFS revealed that adjuvant chemotherapy was a significant independent prognostic factor among patients with DLL3‐negative tumors (hazard ratio [HR]: 0.05, 95% confidence interval [CI]: 0.01–0.41, P < 0.01), although it was not a factor among patients with DLL3‐positive tumors (HR: 0.73, 95% CI: 0.23–2.27, P = 0.58). Conclusions Our results revealed that DLL3 is a predictive marker of sensitivity to platinum‐based adjuvant chemotherapy for LCNEC. Key points Significant findings of the study DLL3 was a predictive marker of sensitivity to platinum‐based adjuvant chemotherapy for LCNEC. Among patients with DLL3 expression‐negative LCNEC, platinum‐based adjuvant chemotherapy significantly improved the OS and RFS, although it did not do so among patients with DLL3 expression‐positive LCNEC. What this study adds Our results suggest that DLL3 expression‐positive LCNEC may be better treated with other types of adjuvant chemotherapy, such as the anti‐DLL3 therapies if these effects are confirmed by ongoing clinical research.

Prevalence of Delta-Like Protein 3 in a Consecutive Series of Surgically Resected Lung Neuroendocrine Neoplasms

“…However, we did not observe this association in high-grade tumors, which confirms previous results from the literature ( 29 ). In accordance with previous reports ( 29 , 37 ), we observed a significant correlation between higher DLL3 expression and increased staining intensity of chromogranin A in high-grade tumors, which supported the hypothesis that the DLL3 expression is related to NE differentiation and could promote NE tumorigenesis in high-grade lung NETs.…”

“…The association between high DLL3 expression and lower OS and DFS suggests that this marker might be associated with more aggressive tumors, even if this association has not been confirmed for high-grade tumors. The high proportion of patients with positive DLL3 tumor expression, despite the absence of prognostic implications, confirms previous results in SCLC and LCNEC patients ( 28 , 37 – 39 ). A study by Huang et al.…”

“…We also demonstrated a high DLL3 expression in 48.8% of LCNECs by using H-score and 53.7% of LCNECs by using percentages of positive tumor cells, comparable with previous studies in LCNECs ( 29 , 35 ). Only Ogawa and colleagues found lower rates of DLL3 expression (37.1% of LCNECs) by immunohistochemistry, but the results of their data could be due to the non-homogeneous study cohort, which included pure and combined LCNECs as well as different antibody clones ( 37 ).…”

“…In the last few years, DLL3 has been identified as a novel therapeutic target gene mostly in SCLCs, but also in LCNECs ( 23 , 36 ). Moreover, the literature data have demonstrated a relationship between DLL3 expression and sensitivity of platinum-based adjuvant chemotherapy, suggesting a predictive role of the DLL3 expression ( 37 ).…”

Management of Large Cell Neuroendocrine Carcinoma

“…DLL3 expression is a potential therapeutic target for DLL3 targeting agent. One such agent is Rovalpituzumab-tesirine (Rova-T) a DLL3 targeting antibody drug conjugate (139,141,142). Rova-T was evaluated in a phase 1 study and then a phase 2 study which confirmed antitumor activity but was notable for a high percentage of a patients with adverse events (141,143).…”