Analysis of SLFN11 expression in small cell lung cancer, carcinoids and large cell neuroendocrine carcinoma: insights into lung neuroendocrine neoplasms

Background: SLFN11, highly expressed in SCLC, predicts sensitivity to DNA-damaging agents. Its role in other lung neuroendocrine neoplasms (NENs) (typical/atypical carcinoids - TC/AC and large cell neuroendocrine carcinoma- LCNEC) is unknown. This multicentre study assessed SLFN11 across lung NENs exploring its clinical-molecular associations. Methods: SLFN11 immunohistochemistry (H-score 0-300) was assessed in 361 tumours (127 TC, 35 AC, 152 LCNEC, 47 SCLC). Ki67, pRb, cMYC, DLL3, ASCL1, HNF1a, OTP and NEUROD1, ASCL1, POU2F3, and YAP1 (NAPY; H-score > 50 as dominant subgroup) staining were integrated with clinicopathologic data and survival. Median SLFN11expression (exp) was used for survival analysis. Results: SLFN11exp 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) across all histologies. In TC/AC, SLFN11exp was enriched in A1 subgroup tumours (known for ASCL1exp) (p = 0.035) and not correlated with OTP, HNF1A, CD44 and SSTR2Aexp. In LCNEC, SLFN11exp was higher in ASCL1high tumors (median 17.2; 0-162.5, p = 0.003) and correlated with cMYCexp (p = 0.024), but not with pRB and DLL3 status. In SCLC, a trend toward higher SLFN11exp in ASCL1high tumours was observed. SLFN11exp was not prognostic in TC/AC or LCNEC. In SCLC, SLFN11exp ≥ 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). Conclusion: SLFN11exp in lung NENs is higher in SCLC > LCNEC > TC/AC, and correlated with Ki67. SLFN11exp was associated with ASCL1exp in all lung NENs. SLFN11 role in TC/AC and LCNEC remains to be defined.