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Clin Cancer Res. 2014 Sep 1;20(17):4499-4510. doi: 10.1158/1078-0432.CCR-14-0348.

A let-7 microRNA-binding site polymorphism in KRAS predicts improved outcome in patients with metastatic colorectal cancer treated with salvage cetuximab/panitumumab monotherapy.

Author information

1
Laboratory of Tumor Cell Biology School of Medicine, University of Crete, Heraklion, Greece.
2
Laboratory of Molecular Digestive Oncology, Department of Oncology , Katholieke Universiteit Leuven, Leuven, Belgium.
3
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, USA.
4
Department of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
5
UMR-S775 INSERM laboratory, Descartes University Medical School, Paris, France.
6
Oncology Unit, Ziekenhuis Oost-Limburg, Genk, Belgium.
7
Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
8
Faculté de Médecine, Université Paris Descartes, Paris, France.
9
Service d'Hépato Gastroentérologie et de Cancérologie Digestive, CHU Robert Debré, Reims, Champagne Ardenne, France.
10
Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
#
Contributed equally

Abstract

PURPOSE:

An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRAS oncogene. We studied this biomarker's correlation to anti-EGFR monoclonal antibody (mAb) therapy response in patients with metastatic colorectal cancer.

EXPERIMENTAL DESIGN:

LCS6-variant and KRAS/BRAF mutational status was determined in 512 patients with metastatic colorectal cancer treated with salvage anti-EGFR mAb therapy, and findings correlated with outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-variant allele to therapy exposure.

RESULTS:

In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6-variant (TG/GG), which was found twice as frequently in the BRAF-mutated versus the wild-type (WT) group (P=0.03). LCS6-variant patients had significantly longer progression-free survival (PFS) with anti-EGFR mAb monotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; P=0.019) and in the double WT (KRAS and BRAF) patient population (18 vs. 10.4 weeks; P=0.039). Combination therapy (mAbs plus chemotherapy) led to improved PFS and overall survival (OS) for nonvariant patients, and brought their outcome to levels comparable with LCS6-variant patients receiving anti-EGFR mAb monotherapy. Combination therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy.

CONCLUSIONS:

LCS6-variant patients with metastatic colorectal cancer have an excellent response to anti-EGFR mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm the importance of this mutation as a biomarker of anti-EGFR mAb response in patients with metastatic colorectal cancer, and warrant further prospective confirmation.

PMID:
25183481
PMCID:
PMC4155520
DOI:
10.1158/1078-0432.CCR-14-0348
[Indexed for MEDLINE]
Free PMC Article

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