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P2.04-19 Correlation of Clinicopathological Characteristics with Tumor Mutation Burden in Chinese Patients with NSCLC

      Background

      Higher tumor mutation burden(TMB) has been associated with improved immune checkpoint inhibitor objective response, progression-free survival and over survival in non-small cell lung cancer(NSCLC). But the correlation of clinicopathological characteristics with tumor mutation burden(TMB) in Chinese patients with NSCLC remains unknown.

      Method

      266 lung adenocarcinoma (LUAD) and 66 lung squamous cell carcinoma (LUSC) patients from 18 hospitals across 11 provinces in China were recruited and the clinical whole exome of paired tumor/normal samples of each patient were sequenced.

      Result

      Among the 332 prospectively enrolled NSCLC patients, 81.3% patients were recommended at least one FDA approved targeted/immunotherapy drug and 88.5% were matched at least one ongoing clinical trials. The median TMB of Chinese NSCLC patients was 5.62 mutations/Mb and upper tertilewas 7.87 mutations/Mb. TMB in Chinese LUSC cohort was slightly higher than the TCGA cohort (median: 10.6 mutations/Mb vs.9.0 mutations/Mb).WhileTMB in Chinese LUAD patients was slightly lower than the Caucasian cohort (median: 5.14 mutations/Mb vs. 6.3 mutations/Mb).Chinese LUAD patients with EGFR-mutant status (122/266) had significantly lower TMB compared with patients with EGFR wild-type (median: 4.90 mutations/Mb vs. 5.53 mutations/Mb, P=0.0013). This may help to explain why in EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel in secondline setting. However LUAD patients with KRAS-mutant status (31/266) had significantly higher TMB compared with patients with KRAS wild-type (median: 9.94 mutations/Mb vs. 4.84 mutations/Mb, P=0.021).A small subset (8/266) of NSCLC patients with CDKN2A-mutant possessed high TMB, although it did not reach statistical significance (P=0.0588). Consistent with previous research, mutant POLE/POLD1 (LUAD: 15/266 and LUSC: 8/66)was significantly associated with increased TMB. For all NSCLC in our study, patients with mutant POLE/POLD1 had significantly higher TMB compared with patients with wild-type POLE/POLD1 (Median: 10.18 mutations/Mb vs. 5.59 mutations/Mb; P=5.16e-7).TP53 and PTEN mutations were not enriched in NSCLC patients with high TMB. One EGFR (p.L858R) mutant LUAD patient with CTNNB1 (p.S33F) co-mutation developed to be innate PD-1 and EGFR-TKI resistance. Increased β-catenin signaling led to poor T cells infiltration into tumors and promoted epithelial-mesenchymal transition (EMT) as well. This case represented a novel genomic predictor of de-novo resistance to immune checkpoint blockade in EGFR-mutant LUAD.

      Conclusion

      High TMB caused by DNA repair deficiency such as POLE/POLD1 mutation is common in Chinese NSCLC patient, and clinical evidence suggest that TMB status and cancer driver mutations can help to establish clinically available tool to identify patients who are most likely to benefit from immunotherapies or targeted therapies.

      Keywords

      Non-small-cell lung cancer, Immunotherapy, Tumor mutation burden