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
5437 - Salivary cytokines and oral mucosa cells apoptosis in patients during hematopoietic cell transplantation: possible relationship with oral mucositis
Presenter: Luciana Corrêa
Session: Poster Display session 1
Resources:
Abstract
1483 - A randomized trial of sodium alginate prevention of radiation-induced esophagitis in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy: OLCSG1401
Presenter: Toshihide Yokoyama
Session: Poster Display session 1
Resources:
Abstract
2047 - Taste and smell alterations (TSAs) in patients (pts) with stage II-III colon cancer (CC): a pilot within the PROTECT study
Presenter: Jeroen Derksen
Session: Poster Display session 1
Resources:
Abstract
5984 - Clinical characteristics are associated with acupuncture treatment response for xerostomia in cancer patients
Presenter: Wenli Liu
Session: Poster Display session 1
Resources:
Abstract
2845 - Psychosocial Distress of Adolescent and Young Adults with Cancer at Diagnosis: A Case-Matched Retrospective Cohort of 2045 Patients in British Columbia.
Presenter: Alannah Smrke
Session: Poster Display session 1
Resources:
Abstract
724 - Accuracy of distress thermometer to measure cancer-related mood disorders in Chinese patients with cancer
Presenter: Sudip Thapa
Session: Poster Display session 1
Resources:
Abstract
2357 - Modalities of biosimilar filgrastim use in clinical practice in >1000 patients receiving chemotherapy regimens with a rest period of ≤14 days: the TOPAZE study
Presenter: Jean Marc Phelip
Session: Poster Display session 1
Resources:
Abstract
1426 - The Effect of Increasing Doses of Pegfilgrastim (Peg) on Thrombocytopenia (T) in Breast Cancer (BC) Patients (pts) Receiving Taxotere (Doc), Doxorubicin, Cyclophosphamide (TAC) and Plinabulin (Plin)
Presenter: Douglas Blayney
Session: Poster Display session 1
Resources:
Abstract
712 - The use of intravenous ferric carboxymaltose without erythropoiesis-stimulating agents in the treatment of anemia in cancer patients undergoing chemotherapy with or without radiotherapy
Presenter: Hikmat Abdel-Razeq
Session: Poster Display session 1
Resources:
Abstract
1496 - Randomized, double-blind, cross-over Phase I study comparing pharmacokinetics, pharmacodynamics, safety and immunogenicity of a biosimilar pegfilgrastim with EU and US references
Presenter: Maria Velinova
Session: Poster Display session 1
Resources:
Abstract