Immunophenotyping of the molecular subtypes of small-cell lung cancer and its correlation with prognostic and therapeutic implications
Sunil Pasricha, Himanshi Diwan, Ullas Batra, Manoj Gupta, Rupal Tripathi, Gurudutt Gupta, Anila Sharma, Garima Durga, Meenakshi Kamboj, Mansi Sharma, B. P. Amrith, Pankaj Goyal, Munish Gairola, Anurag MehtaABSTRACT
Background:
Small-cell lung cancer is a relatively homogeneous disease with a worse prognosis. Unlike non-small-cell lung carcinoma, targeted or personalized therapies are not available, which has led to the molecular stratification of small-cell lung carcinoma based on mRNA expression of Achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), yes-associated protein (YAP1), and POU Class 2 homeobox 3 (POU2F3), in the hope of gaining some insight into the molecular heterogeneity, and to explore therapeutic vulnerabilities. However, there is scant literature regarding the expression of these markers at protein level/immunohistochemistry and their prognostic and therapeutic relevance.
Methods:
Formalin-fixed paraffin-embedded tissue samples of 120 consecutively diagnosed unresectable small-cell lung cancer patients during 2016–2022 were classified molecularly based on the immunoexpression of ASCL1, NEUROD1, POU2F3, and YAP1. The subtypes were correlated with insulinoma ssociated protein 1 (INSM1) expression and the response after six cycles of platinum-based chemotherapy.
Results:
The expression of ASCL1, NEUROD1, POU2F3, and YAP1 was seen in 63.3%, 30%, 7.5%, and 6.5% of cases, respectively. The cases were categorized as ASCL1 dominant (58.5%), NEUROD1 dominant (12.1%), POU2F3+/ASCL1-/NEUROD1-(7.8%), and ASCL1-/NEUROD1-NOS type (21.6%) based on the relative expression of these immunohistochemistry (IHC) markers. All nine POU2F3 positive cases were associated with absent or reduced INSM1 expression. NEUROD1-dominant and POU2F3+/ASCL1-/NEUROD1-subtypes were significantly associated with a poor response to chemotherapy (
Conclusion:
This is the first study from South-Asian tertiary cancer care center for molecular classification of small-cell lung cancer based on IHC markers. NEUROD1 and POU2F3-dominant subtypes were mostly non-responders to chemotherapy. YAP1 expression was associated with poor overall survival. POU2F3 expression was associated with downregulation of neuroendocrine markers (INSM1 expression).