SLFN11 as a Biomarker in Lung Neuroendocrine Tumors: Analysis of Carcinoids, LCNEC, and SCLC

Background SLFN11 is a key determinant of sensitivity to DNA-damaging agents, enforcing replication arrest and tumor cell death under conditions of replicative stress, and has therefore emerged as a biomarker of therapeutic vulnerability. In small-cell lung cancer (SCLC), SLFN11 is frequently highly expressed and has demonstrated strong predictive value for response to cytotoxic therapies. In contrast, its role in other lung neuroendocrine neoplasms (NENs)—including typical and atypical carcinoids (TC, AC) and large-cell neuroendocrine carcinoma (LCNEC)—remains largely unexplored. These entities display profound differences in proliferative activity, transcriptomic landscapes, and genomic alterations. Moreover, biologically distinct molecular subtypes have been identified across lung NENs: TC/AC can be stratified into A1, A2, and B subtypes based on OTP, ASCL1, and HNF1A expression, while LCNEC and SCLC can be classified according to NEUROD1, ASCL1, POU2F3, and YAP1 (NAPY) programs. This multicenter study assessed SLFN11 across lung NENs and explored its molecular and clinical associations. Methods SLFN11 immunohistochemistry (H-score 0–300) was assessed in 361 tumors (127 TC, 35 AC, 152 LCNEC, 47 SCLC) from two institutions Erasmus Medical Center in Rotterdam (The Netherlands) and the Istituto Oncologico Veneto in Padua (Italy). Ki67, RB1, cMYC, DLL3, ASCL1, HNF1a, OTP and NAPY (H-score>50 as dominant subtype) staining were integrated with clinicopathologic data and survival. Results Stage at diagnosis was mainly I-III in TC/AC and LCNEC (97.1%), and IV in SCLC (87.2%). SLFN11 expression varied across histologies (p<0.001), with median values of 0 in TC (range 0-20) and AC (0-40), 2.49 (0-250) in LCNEC, 35 (0-240) in SCLC. SLFN11 showed a positive correlation with Ki67 (R²=0.187). In TC/AC, SLFN11 expression was enriched in A1 subtype tumours (known for ASCL1 expression) (p=0.035) and not correlated with HNF1A, CD44 and SSTR2A expression. A trend toward correlation with OTP was observed (p=0.091). In LCNEC, SLFN11 expression was higher in ASCL1high tumors (median 17.2; 0-162.5, p=0.003) and correlated with cMYC expression (p=0.024), but not with pRB and DLL3 status. In SCLC, a trend toward higher SLFN11 expression in ASCL1high tumours was observed. Median follow-up was 120, 85, 89 and 25 months respectively in TC, AC, LCNEC and SCLC. SLFN11 expression was not prognostic in TC/AC or LCNEC; however, in RB1-negative/SLFN11>1 LCNEC a worse overall survival (OS) (p=0.050) was observed. In SCLC, SLFN11 expression ≥ median value was associated with improved OS (13.9 vs 6.8 months; HR=0.48, 95%CI 0.26-0.90, p=0.020). Among different SLFN11 cut-offs, the median best stratified patients’ survival. Conclusion SLFN11 shows distinct, histology-dependent expression across pulmonary NENs and integrates with key molecular features such as Ki67, RB1 and MYC. Its strong predictive signal in SCLC and biological associations in LCNEC support its further investigation as a biomarker for diagnosis, molecular stratification and therapeutic vulnerability in high-grade lung NENs.