Immunophenotyping of the molecular subtypes of small-cell lung cancer and its correlation with prognostic and therapeutic implications
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Sunil Pasricha1, Himanshi Diwan1, Ullas Batra2
1Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, Delhi, India.
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 ( P value: 0.027).
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).