Whether to treat LCNEC with non-small cell lung carcinoma type chemotherapy (NSCLC, i.e. platinum-gemcitabine/taxanes or pemetrexed) or small cell lung carcinoma type (SCLC, i.e. platinum-etoposide) is subject of debate. Recent molecular studies have identified two mutually exclusive genomic LCNEC subtypes, the co-mutated TP53 and RB1 (i.e. SCLC like) and the STK11/KEAP1 (predominantly RB1 wild-type, i.e. NSCLC like) subtype. We determined if genomic LCNEC subtypes are clinically relevant for chemotherapy (CT) outcome.
Clinical data and tumour specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry (PALGA, 2003-2012). All first-line CT treated patients with panel-consensus diagnosed LCNEC were included for next-generation sequencing (NGS) analysis for TP53, RB1, STK11, and KEAP1 genes. Furthermore, immunohistochemistry for RB1 (pRB1, 13A10) was analysed (H-score, ≥50 considered as positive). NGS and pRB1 results were correlated with overall survival (OS) and progression free survival (PFS) by Kaplan Meier plots and Log-rank test.
LCNEC was panel-consensus diagnosed in 148/232 patients; 79 passed quality control for NGS and 109 for pRB1. RB1 mutations were found in 47% (n = 37) and loss of pRB1 expression in 72% (n = 78) of the cases. Mutations in RB1 were mutually exclusive with mutations in STK11 (n = 8; P = 0.006). Due to reported resistance in neuroendocrine carcinomas, we analysed NSCLC-CT without pemetrexed-CT; OS was significantly longer for NSCLC-CT (n = 15, 9.6 [7.7-11.6] months) compared to SCLC-CT (n = 13, 5.8 [5.5-6.1] months, P = 0.026). LCNEC tumours expressing pRB1 also had longer OS when treated with NSCLC-CT (n = 14, 9.6 [7.4-11.8] vs. n = 9, 1.9 [1.7-2.1] months, P = 0.001). PFS of RB1 wild-type NSCLC-CT treated patients was significantly longer than SCLC-CT (P = 0.018) also for pRB1 (P = 0.023). In patients with a RB1 mutation OS and PFS were not significantly different for NSCLC-CT vs. SCLC-CT.
In LCNEC with RB1 wild-type, NSCLC-CT correlates with a more favourable outcome compared to SCLC-CT. However, RB1 mutated LCNEC treated with NSCLC-CT have similar clinical outcomes as compared to SCLC-CT. Prospective studies should be initiated.
Clinical trial identification
Legal entity responsible for the study
Maastricht University Medical Center
This study was supported by grants from the Dutch Cancer Society (UM-2014-7110) granted to Prof. Dr. A-M. C. Dingemans. Mr. J.L. Derks is the recipient of an ERS/EMBO Joint Research Fellowship – Nr. STRTF 2016 – 7178. The research leading to these results has received funding from the European Respiratory Society (ERS) and European Molecular Biology Organization (EMBO).
H.J.M. Groen: Other from Lilly, GSK, Merck, Pfizer, Roche, BMS, outside the submitted work. E-J. Speel: Other from Pfizer, Roche, Amgen, outside the submitted work. A-M. Dingemans: Personal fees from Roche, BMS, Boehringer Ingelheim, AstraZeneca, Eli Lilly, MSD, Pfizer and Amgen, outside the submitted work. All other authors have declared no conflicts of interest.