Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster Display session 1

1408 - DNA damage repair deficiency is associated with early resistance to crizotinib: whole-genome analysis in non-small cell lung cancer patients with ALK-fusion


28 Sep 2019


Poster Display session 1


Tumour Site

Non-Small Cell Lung Cancer


Dongyun He


Annals of Oncology (2019) 30 (suppl_5): v602-v660. 10.1093/annonc/mdz260


D. He, H. Yang, Q. Deng, Z. Xie, D. Xiao

Author affiliations

  • Thoracic Oncology, First Affiliated Hospital of Guangzhou Medical University, 510405 - Guangzhou/CN


Login to access the resources on OncologyPRO.

If you do not have an ESMO account, please create one for free.

Abstract 1408


ALK-tyrosine kinase inhibitor (TKI) is associated with a favarable survival benefit in ALK-fusion patients in advanced non-small cell lung cancer (NSCLC). However, almost 20% patients with TKI early resistance (progression-free survival is shorter than six months while treated by either crizotinib or second-line TKIs), show a poor survival with no more than one year. The mechanisms of early resistance to TKIs are unknown. Reliable biomarkers are required to predict the response to ALK-TKIs, especially in the early resistance. So we investigated genomic variations associated with responses to crizotinib in advanced NSCLC patients with ALK-fusion.


Advanced NSCLC primary tumor samples with ALK-fusion from 5 extreme poor and 5 extreme strong responders to crizotinib were subjected to whole-genome analysis. And we found 44 genomic variant sites with poor response through gene based pathway enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then we randomly assigned 17 advanced NSCLC patients’ sample with ALK-fusion to validate the candidate variant sites using small sequence capture panel. Genomic data of > 0.2 gigabases/sample was generated at average of 828 sequencing depth which covering 44 relative genes.


In total, 774 genomic variations were matched to crizotinib responses in clinical data; which were located within regions for DNA repaired, mitochondrial apoptosis and tumor angiogenesis-target genes. From them, 4 DNA damage repair (DDR)-related gene variations (TP53, MLH1, XPA, and MSH2) were associated with early resistance to crizotinib in ALK-fusion NSCLC patients, from which 5 variants were within the coding regions and 4 identified as non-synonymous single-nucleotide variants. Validation genotyping confirmed sequencing results and revealed patients genotype for rs28934575 in TP53 showed extreme shorter PFS (P < 0.002) to crizotinib and poor survival, while the median PFS was 3 months (range, 2-5 months, 95% CI:2.2-3.8 months). And these patients survived no more than 12 months.


Thus, DDR deficiency may contribute to the early resistance to crizotinib in ALK-fusion patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.


Has not received any funding.


All authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.