Abstract 1408
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4883 - A New Population Model Validated Pharmacokinetic Similarity of HLX01 and Rituximab in B-Cell Lymphoma
Presenter: Yuankai Shi
Session: Poster Display session 1
Resources:
Abstract
4908 - Efficacy of salvage therapy in the treatment of Helicobacter pylori-positive gastric low-grade mucosa-associated lymphoid tissue lymphoma
Presenter: Sung-Nam Lim
Session: Poster Display session 1
Resources:
Abstract
2360 - Mutational analysis of extranodal marginal zone lymphoma using next generation sequencing
Presenter: Seok Jae Huh
Session: Poster Display session 1
Resources:
Abstract
2430 - Clinical features, treatment and outcomes of colon and rectum mucosa-associated lymphoid tissue (MALT) lymphoma: Literature reviews published in English between 1993 and 2017
Presenter: Jeong Yeon Kim
Session: Poster Display session 1
Resources:
Abstract
4654 - Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 52 patients
Presenter: Guldane Cengiz Seval
Session: Poster Display session 1
Resources:
Abstract
1732 - Safety and efficacy of Bendamustine and Rituximab (BR) regimen in Indian Chronic Lymphocytic Leukemia patients
Presenter: Ajay Gogia
Session: Poster Display session 1
Resources:
Abstract
5784 - N-terminal B-type natriuretic peptide (NT-proBNP) as an independed prognostic marker for patients with newly diagnosed multiple myeloma complicated by dialysis-dependent renal failure
Presenter: Sergey Semochkin
Session: Poster Display session 1
Resources:
Abstract
836 - The first-line effect of Bortezomib-based Therapy on Clinical Outcomes for Taiwanese Patients with multiple myeloma
Presenter: Ching-Liang Ho
Session: Poster Display session 1
Resources:
Abstract
2085 - Impact of Donor Lymphocyte Infusion in Relapsing Myeloid Neoplasms Post Allogeneic Hematopoietic Stem Cell Transplantation
Presenter: Hanafy Hafez
Session: Poster Display session 1
Resources:
Abstract
6079 - Invasive fungal diseases in patients with Hodgkin’s lymphoma before and after allogeneic hematopoietic stem cell transplantation
Presenter: Marina Popova
Session: Poster Display session 1
Resources:
Abstract