In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 3_suppl ( 2015-01-20), p. 570-570
Abstract:
570 Background: Colorectal cancer (CRC) treatment with the EGFR-inhibitory antibody Cetuximab (CTX) is known to cause skin rashes (SR) of varying degree in most patients. Severity of SR is positively associated with tumor response. The underlying molecular mechanism linking both effects is still unknown. Detangling its genetic background would allow a simultaneous understanding of SR and response. Stratification of patients based on the related polymorphisms (PMs) is of clinical relevance. Methods: A systematic literature review was performed to develop a molecular map which incorporates specific pathways related to cancer, CTX specific mechanisms of action, skin rash, and autoimmunity. Exome data was generated from blood samples of 23 KRAS wild type patients taken prior to CTX treatment. Under CTX, eleven of the 23 patients showed SR of grades 3-4, twelve reacted with a grade 1 SR. Differential somatic PMs were analyzed between both groups. A gene set enrichment analysis for the imbalanced PMs was performed against gene sets of our molecular map. Imbalance was stated if at least seven patients more in the one group compared to the other carried this specific PM. Results: A total of 591 genes containing imbalanced PMs were found. Bioinformatic validation focused on the following findings of potential clinical interest: (1) PMs in genes specifically related to cell adhesion (CDH1, LAMC1, FBN2, NCAM1) or its regulation (WNT9B), (2) to autoimmunity (CXCL16, ADAM12, OS9, DOCK2), (3) in the central regulator TP53, (4) in genes playing a role in immunity and cell adhesion (DOCK2 and THBS2). PMs in the mentioned genes enabled to discriminate patients with and without severe skin rash. Validation of these findings is needed based on new independent CTX treated patients. Conclusions: Our findings suggest that genomic predisposition may exist which interact with CTX treatment by inducing alteration of cell adhesion. Altering adhesion between tumor cells makes them more accessible to the EGFR-inhibitory effect of CTX. Altering cell adhesion between epithelial cells introduces the acne like phenotypes of skin rash, presumably via the mechanism of epithelial activation. This will be the starting point for further research.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2015.33.3_suppl.570
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2015
detail.hit.zdb_id:
2005181-5
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