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. 2021 Nov;10(11):4209-4220.
doi: 10.21037/tlcr-21-691.

Molecular subtypes of small cell lung cancer transformed from adenocarcinoma after EGFR tyrosine kinase inhibitor treatment

Soohyun Hwang #  1 , Tae Hee Hong #  2   3 , Sehhoon Park #  4 , Hyun-Ae Jung  4 , Jong-Mu Sun  4 , Jin Seok Ahn  4 , Myung-Ju Ahn  4 , Keunchil Park  4 , Yoon-La Choi  1 , Se-Hoon Lee  4
Affiliations

Molecular subtypes of small cell lung cancer transformed from adenocarcinoma after EGFR tyrosine kinase inhibitor treatment

Soohyun Hwang et al. Transl Lung Cancer Res. 2021 Nov.

Abstract

Background: A certain proportion of non-small cell lung cancer (NSCLC) with activating EGFR mutations showed resistance to tyrosine kinase inhibitors (TKIs) by transforming their histology into small cell lung cancer (SCLC). In this study, we evaluated the molecular characteristics of transformed SCLCs.

Methods: Eighteen SCLC tissue samples transformed after EGFR TKI treatment were used for the analysis. Immunohistochemistry was conducted to evaluate the molecular subtype using antibodies representative of the major transcriptional factor-based molecular subtypes, ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1. Subtypes were categorized based on a predefined criteria.

Results: Among the study population (n=18), most of the patients were initially diagnosed with adenocarcinoma (n=17), and one patient was diagnosed with adenosquamous histology. Eight patients (44.4%) were never-smokers, and nine patients were women (50.0%). Staining of pre-transformation sample was conducted in six patients, and five of them showed no discernible expression for ASCL1, NEUROD1, or POU2F3. However, the proportion of molecular subtypes after SCLC transformation was predominantly SCLC-N (n=9, 50.0%), followed by SCLC-Triple Negative (SCLC-TN; n=5, 27.8%) and SCLC-A (n=4, 22.2%). The median overall survival from TKI initiation was longer in patients who transformed to SCLC-A (P=0.009) than in those who transformed to either SCLC-N or SCLC-TN. However, the overall survival difference since SCLC transformation was not significant (P=0.370).

Conclusions: In our series, SCLC-N subtype was prevalent in SCLC transformed after EGFR TKI treatment. In addition, overall survival and the time to SCLC transformation from the EGFR TKI treatment were longer in patients who transformed to the SCLC-A type. Large-scale data will be required to confirm our findings.

Keywords: Histologic transformation; epidermal growth factor receptor; molecular subtype; small cell lung cancer (SCLC); tyrosine kinase inhibitor (TKI).

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-691). JSA reports personal fees from Amgen, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Menarini, personal fees from Roche, personal fees from Eisai, personal fees from Boehringer Ingelheim, personal fees from BMS-Ono, personal fees from MSD, personal fees from Janssen, personal fees from Samsung Bioepis, outside the submitted work. SHL reports grants and personal fees from MSD, personal fees from Novartis, personal fees from AstraZeneca, personal fees from BMS, personal fees from Roche, outside the submitted work. KP reports personal fees from Astellas, Astra Zeneca, AMGEN, Boehringer Ingelheim, Clovis, Eli lilly, Hanmi, KHK, Merck, MSD, Novartis, ONO, Roche, BluePrint, outside the submitted work. SP reports stock holding of Lunit Inc. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Consort diagram for the study population.
Figure 2
Figure 2
Clinicopathologic characteristics of the cohort. (A) Overall baseline demographics and expression profile of ASCL1, NEUROD1, and POU2F3. (B) Swimlane plot for time to transformation and post transformed survival. EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; SCLC, small cell lung cancer.
Figure 3
Figure 3
Representative cases for SCLC-A, SCLC-N, and SCLC-TN with immunohistochemistry results and clinical outcomes (hematoxylin-eosin, RB1, ASCL1, NEUROD1, POU3F3 and YAP1 stain; scale bars =100 µm). Arrows indicate the region of disease progression. SCLC, small cell lung cancer.
Figure 4
Figure 4
Survival analysis of entire cohort and its stratification according to each molecular subtype. (A) Overall survival from the initiation of EGFR TKI treatment. (B) Transformation-free survival from the initiation of EGFR TKI to the date of histological confirmation of SCLC. (C) The overall survival from the date of histological confirmation of SCLC. EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; SCLC, small cell lung cancer.
Figure 5
Figure 5
Multivariate cox regression for (A) overall survival and (B) transformation-free survival. *P<0.05; **P<0.01.
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