550O - Molecular mechanism of transformation from adenocarcinoma to small-cell lung cancer after EGFR-TKI

Date 17 December 2016
Event ESMO Asia 2016 Congress
Session Basic science and translational research
Topics Biomarkers
Thoracic Malignancies
Translational Research
Presenter Jiefei Han
Citation Annals of Oncology (2016) 27 (suppl_9): ix179-ix180. 10.1093/annonc/mdw601
Authors Q. Zhang1, J. Han2, B. Wang3, Q. Zhou2, Z. Zhang4, S. Chuai5, J. Yang2, Y. Wu2
  • 1Guangong Lung Cancer Institute, Guangdong General Hospital, 510000 - Guangzhou/CN
  • 2Guangdong Lung Cancer Institute, Guangdong General Hospital, 510000 - Guangzhou/CN
  • 3Guangong Lung Cancer Instituted, Guangdong General Hospital, 510000 - Guangzhou/CN
  • 4Medical Oncology, Burning Rock Dx Ltd, Guangzhou 510300, China, 510000 - Changzhou/CN
  • 5Medical Oncology, Burning Rock Dx Ltd, Guangzhou 510300, China, 510000 - Guangzhou/CN



In patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, EGFR-tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment due to favorable clinical efficacy. However, acquired resistance inevitably develops after median progression-free survival (PFS) of 11 months. Among the mechanisms of acquired resistance, small-cell lung cancer (SCLC) transformation was reported to account for nearly 5%. However, the molecular details underlying this histological change remain unclear.


15 out of 233 (6.4%) patients were confirmed to develop SCLC transformation after failure to EGFR-TKI. We analyzed the clinical parameters of these patients by using chi-square test and Kaplan-Meier analysis. To explore gene alterations that might contribute to SCLC transformation, next generation sequencing (NGS) was performed on four pairs of matched pre- and post-transformation tumor tissue samples. We further performed NGS on 11 matched circulating tumor DNA (ctDNA) to explore the potential mechanism of resistance to EGFR-TKI.


93.3% (14/15) SCLC transformed patients harbored EGFR 19 deletion. The median PFS and overall survival (OS) of SCLC-transformed patients treated with EGFR-TKI compared to those without transformation were 11.7 versus 11.9 months (P = 0.473) and 29.4 versus 24.3 months (P = 0.664), respectively. All 4 patients developed loss of heterozygosity of TP53/RB1 after transformation. Besides, increased copy number of five proto-oncogenes were identified in post-transformation tissue samples. Three patients developed EGFR T790M mutation in the post-transformation ctDNA rather than their tissue samples.


SCLC transformation was commonly seen in patients harboring EGFR 19 deletion. The clinical outcomes of TKI and OS in SCLC transformed patients were similar to non-transformed patients. The loss of heterozygosity of TP53 and RB1 along with increased copy number of proto-oncogenes may lead to the SCLC transformation. The mechanisms of acquired resistance to TKI during SCLC transformation might be the emergence of classic drug resistance mutations, which was undetectable due to the intra-tumor heterogeneity.

Clinical trial indentification

Legal entity responsible for the study

Guangdong Lung Cancer Institute


This study was supported by grants from the Project of the National Natural Science Funding of China (Grant No. 81472207)


All authors have declared no conflicts of interest.