Feasibility of proposed single-nucleotide polymorphisms as predictive markers for targeted regimens in metastatic colorectal cancer

• Published in: British journal of cancer Vol. 108; no. 9; pp. 1862 - 1869
• Main Authors: Kim, J C, Ha, Y J, Roh, S A, Choi, E Y, Yoon, Y S, Kim, K P, Hong, Y S, Kim, T W, Cho, D H, Kim, S Y, Kim, Y S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-05-2013; Nature Publishing Group
• Subjects: 692/699/67/1059/602; 692/699/67/1504/1885; 692/699/67/1857; 692/699/67/68; Adult; Aged; Angiogenesis Inhibitors - therapeutic use; Annexins - genetics; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Biological and medical sciences; Biomarkers; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Cetuximab; Chemotherapy; Cloning; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Disease-Free Survival; Drug Resistance; Epidemiology; Extracellular Signal-Regulated MAP Kinases - biosynthesis; Extracellular Signal-Regulated MAP Kinases - genetics; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genomics; Genotype; Humans; Leukemia Inhibitory Factor Receptor alpha Subunit - genetics; Male; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; Medical research; Medical sciences; Metastasis; Middle Aged; Molecular Diagnostics; Molecular Medicine; Molecular Targeted Therapy; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - genetics; Oncology; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Response rates; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tomography; Tumors; targeted chemotherapy; marker; colorectal cancer; Rectal disease; Genetic variability; Targeting; Targeted therapy; Colorectal cancer; Biological marker; Genotype; Malignant tumor; Metastasis; ANXA11 rs1049550; Colonic disease; Target; Cancerology; Treatment; Digestive diseases; Intestinal disease; Advanced stage; Feasibility; Single nucleotide polymorphism; LIFR rs3729740; Therapeutic protocol; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.163

Background:
Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy.
Methods:
A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway.
Results:
For cetuximab regimens, patients homozygous for the wild-type alleles (
GG
) of
LIFR rs3729740
exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (
GA
and
AA
;
P
=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (
TT
) of
ANXA11 rs1049550
exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (
CC
and
CT
;
P
=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type
LIFR rs3729740
patients either with wild-type
KRAS
or skin toxicity (
P
=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type
LIFR rs3729740
(
P
=0.044) and in those expressing minor-type
ANXA11 rs1049550
(
P
=0.007), respectively.
Conclusion:
LIFR rs3729740
and possibly
ANXA11 rs1049550
may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.