P1.01-82 The Different Frequencies and Genetic Profiles of Histologic Transformation After Different EGFR-TKIs in EGFR-Mutant Adenocarcinomas

Abstract

Histologic transformation is a mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor(TKIs) in EGFR-mutant non-small cell lung cancers (NSCLCs). Those adenocarcinomas with histologic transformation usually underwent poor prognosis. However, few studies have focused on the different occurrence rates and genetic profiles between EGFR-mutant adenocarcinomas treated with different generations of EGFR-TKIs. Pathology was confirmed in 345 EGFR-mutant patients at baseline and recurrence. Among these patients, 235 patients were treated with gefitinib or erlotinib, 54 with afatinib and 56 with osimertinib. But only 11 patients with sufficient tumor specimens could be evaluated for the genetic profiles by next-generation sequencing (NGS). Demographics, disease features, and outcomes of these patients were analyzed. The frequency of these EGFR-mutant adenocarcinomas with histologic transformation after the treatment of different generation TKIs were quite different. The frequency of gefitinib/erlotinib group was 7.2% (17/235), while the others were 5.6% (3/54, afatinib group) and 17.9% (10/56, osimertinib group). The median progression free survival （PFS）to EGFR-TKIs of those patients were 12.2 months (gefitinib/erlotinib group), 5.3 months (afatinib group) and 7.7 months (osimertinib group) respectively. Four adenocarcinomas treated with gefitinib/erlotinib all harbored TP53 mutations at baseline. One adenocarcinoma treated with afatinib was founded to have acquired MET amplification and transformed to small-cell lung cancer meanwhile. Moreover, the PFS of one patient to afatinib was just 3 months and her genetic profile at baseline was characterized by Rb1, TP53, and PIK3CA mutations. There were 3 patients treated with osimertinib underwent histologic transformation from adenocarcinomas to squamous carcinoma. One patient after progressive disease of osimertinib did not have enough tissue to detect NG, and her blood NGS result just showed EGFR L858R and T790M mutation. The tissue NGS result of the second patient showed EGFR p.Glu746-Ala750 deletion, EGFR T790M and C797S mutations, CDK4/CCND1/EGFR/KRAS amplifications. The second patient received the chemotherapy of pemetrexed+ carboplatin + bevacizumab and the best response was partial response. The third patient take palbociclib and osimertinib meanwhile and his symptoms improved with the tissue NGS of EGFR T790M mutation and CDK4/MDM2/EGFR amplifications. They were characterized by EGFR amplification and CDK4 amplification. The others transform from adenocarcinomas to small cell cancers or neuroendocrine tumors were seem to harbor with TP53, Rb1 and PIK3CA mutations. It seems more common in some subtypes that the EGFR-mutant adenocarcinomas treated with osimertinib undergo histologic transformation. The genetic profiles vary greatly between transformation to squamous carcinomas and transformation to small-cell cancers/neuroendocrine tumors in EGFR-mutant adenocarcinomas treated with osimertinib. Further verification is needed.