Clinicopathologic and molecular characteristics of EGFR-mutant lung adenocarcinomas that transform to small cell lung cancer after TKI therapy

Li Yu; Lyudmila Bazhenova; Kathryn Gold; Lisa Tran; Van Hilburn; Peter Vu; Sandip Pravin Patel

doi:10.21037/tlcr-21-665

Clinicopathologic and molecular characteristics of EGFR-mutant lung adenocarcinomas that transform to small cell lung cancer after TKI therapy

Transl Lung Cancer Res. 2022 Mar;11(3):452-461. doi: 10.21037/tlcr-21-665.

Authors

Li Yu^{1

2}, Lyudmila Bazhenova², Kathryn Gold², Lisa Tran², Van Hilburn², Peter Vu², Sandip Pravin Patel²

Affiliations

¹ Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China.
² Moores Cancer Center, University of California, San Diego, CA, USA.

Abstract

Background: Small cell lung cancer (SCLC) transformation is one of the mechanisms of drug resistance to tyrosine kinase inhibitors (TKIs) in advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) and represents an increasingly recognized clinical dilemma.

Methods: We performed a retrospective review of 964 cases at the University of California, San Diego of patients with EGFR sensitizing mutations. Nine patients had a biopsy-confirmed small cell transformation. The unique gene alterations and clinicopathologic features were collected and analyzed.

Results: Nine cases (9/964, 0.9%) were identified, all with stage IV adenocarcinoma (ADC) at diagnosis, 7 were poorly differentiated, and 7 had an EGFR exon 19 deletion. All nine patients had tumor protein p53 (TP53) mutation. Among seven cases that had next-generation sequencing (NGS), 5 harbored retinoblastoma 1 (RB1) loss. WNK lysine deficient protein kinase 1 (WNK1) mutation was found in two patients that had longer survival. The median time from the initial diagnosis to transformation was 22.7 months (IQR: 15.1-25.1). After small cell transformation on EGFR inhibition, all patients were treated with etoposide/platinum, conferring a median progression-free survival (PFS) of 3.2 months (IQR, 2.2-6.5 months) and post-chemotherapy survival of 8.6 months (IQR, 4.0-19.0 months). Six patients, as they retained the initial EGFR mutations, resumed (did so after terminating chemotherapy)/continued (did so concomitantly with chemotherapy) TKIs with a median duration of 13.8 months (IQR, 3.8-27.7 months). Two patients received immunotherapy but had no benefit.

Conclusions: In our series, most patients with small cell transformation had poorly differentiated adenocarcinomas at baseline. RB1 loss was not universal in transformed patients in this series, though TP53 mutation was present in all tumor samples. WNK1 mutation may be a new resistance mechanism to TKIs that may be associated with improved survival.

Keywords: EGFR mutation; Lung adenocarcinoma; small cell lung cancer (SCLC); transformation; tyrosine kinase inhibitor (TKI).