357P - Molecular stratification of small cell lung carcinoma subtypes by immunoexpression of ASCL1, NEUROD1, POU2F3 and YAP1 with clinicopathological correlation

Background

Recently, molecular studies in small cell lung carcinoma (SCLC) have identified 4 subtypes defined by RNA expression of achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3) and yes-associated protein 1 (YAP1) transcriptional regulators. However, there is scant literature regarding expression of these markers at protein/immunohistochemistry (IHC) level along with its prognostic implications. These molecular subtypes might define distinct therapeutic implications.

Methods

Formalin-fixed paraffin embedded tissue samples of 120 consecutively diagnosed unresectable SCLC patients were subjected to IHC (ASCL1, NEUROD1, POU2F3 and YAP1) and analyzed for their immunoexpression. The subtypes identified were correlated with expression of neuroendocrine marker (NE): INSM-1 and also with the response after 6-cycles of platinum-based chemotherapy: Responder (R; complete or partial response /stable disease) vs Non responder (NR; progression).

Results

There was a male predominance (81.7%) and majority were smokers (70.8%). Extensive stage disease was seen in 70.8% of patients. The expression of ASCL1, NEUROD1, POU2F3 and YAP1 was seen in 63.3%, 30%, 7.5% and 6.6% of cases, respectively. On the basis of relative immunoexpression of these IHC markers, four distinct categories were identified: ASCL1-dominant (58.5%), NEUROD1 dominant (12.1%), POU2F3+/ASCL1-/ NEUROD1- (7.8%), and ASCL1-/ NEUROD1- NOS (21.6%). All the POU2F3 positive cases were ASCL1-/NEUROD1- and were associated with absent/reduced NE (INSM-1) expression (p< 0.0001). Overall expression of YAP1 was very low and not exclusive of other subtypes. NEUROD1 dominant and POU2F3+/ASCL1-/ NEUROD1- categories were significantly associated with NR (p= 0.027).

Conclusions

This is the first study from India showing molecular stratification of SCLC at IHC level along with clinical correlation. We found that NEUROD1 dominant and POU2F3+/ASCL1-/ NEUROD1- categories have distinct therapeutic implications and prognosis and needs further larger studies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.