Abstract 213: Exome sequencing of paired primary and relapsed small cell lung cancers reveals increased copy number aberration complexity to be associated with disease relapse
Authors: Negrao Marcelo V. , Tang Ming , Jin Ying , Chen Yamei , Hu Xiao , Tang Huarong , Xu Haimiao , Quek Kelly , Zhang Jianhua , Mao Xizeng , Song Xingzhi , Heymach John V. , Wistuba Ignacio , Byers Lauren A. , Glisson Bonnie S. , Futreal Andrew , Chen Ming , Zhang Jianjun 
Published: August 2018

Abstract
Introduction: Although small-cell lung cancer (SCLC) is sensitive to first-line radiation and chemotherapy, nearly all patients recur often with treatment-resistant disease. Therefore, delineating subclonal architecture and molecular evolution of SCLC after treatment by comparing genomic profiles of recurrent and paired treatment-naïve tumors may provide new insights into mechanisms underlying recurrence and susceptibility to further treatment.
Methods: Treatment-naïve and paired recurrent tumor samples from 9 patients with limited-stage SCLC treated with concurrent chemoradiation (CCRT) underwent whole exome sequencing (WES) and data is currently available for 6 pairs. All 6 patients had disease recurrence more than 3 months after finishing treatment. Genomic landscape including somatic mutations, somatic copy number aberrations (SCNA), subclonal architecture and transversion rate (percentage of base changes from pyrimidine to purine and vice-versa) were compared between treatment-naïve and paired recurrent tumor samples. Circulating cell-free DNA (cfDNA) collected at the time of recurrence was also subject to deep sequencing of 461 cancer genes.
Results: SCNA analyses revealed significantly more complex chromosomal gains in relapsed SCLCs compared to pre-treatment primary tumors (7.7% vs 13.2% genes with copy number gain in primary and relapsed SCLC respectively, p=0.034). As expected, TP53 and RB1 were the most commonly mutated genes (83% and 67% respectively) and tobacco exposure related signatures were predominant in all samples. Primary and relapsed tumor pairs showed very similar genomic landscape including tumor mutational burden (11.8/MB in primary SCLC vs 9.7/MB in relapsed tumors), intra-tumor heterogeneity complexity (MATH score 38.2 in primary vs 39.2 in relapse) and transversion rates, that have been reported to be associated with alkylating-agent treatment (62% in primary vs 65% in relapse). An average of 72.25% (range: 53-86%) somatic mutations, including all canonical cancer gene mutations, were shared between primary SCLC and relapsed tumors. In addition, the subclonal architecture was also very similar between treatment-naïve primary SCLC and paired relapsed tumors. Of note, 5 out of 6 patients achieved disease control on retreatment with chemotherapy.
Conclusion: Copy number gains may play a role in post-CCRT relapse of SCLC. Paired pre-treatment and relapse samples show genomic similarities which could account for benefit to subsequent treatment. Additional sample analysis and ctDNA assessment is ongoing to better address these findings, especially in patients with chemoresistant relapse. These findings also suggest that other molecular changes involving gene expression (eg. methylation) may play a role in SCLC relapse and resistance.
Citation Format: Marcelo V. Negrao, Ming Tang, Ying Jin, Yamei Chen, Xiao Hu, Huarong Tang, Haimiao Xu, Kelly Quek, Jianhua Zhang, Xizeng Mao, Xingzhi Song, John V. Heymach, Ignacio Wistuba, Lauren A. Byers, Bonnie S. Glisson, Andrew Futreal, Ming Chen, Jianjun Zhang. Exome sequencing of paired primary and relapsed small cell lung cancers reveals increased copy number aberration complexity to be associated with disease relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 213.