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Ann Oncol. 2015 Apr;26(4):731-6. doi: 10.1093/annonc/mdv005. Epub 2015 Jan 26.

Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment.

Author information

1
Department of Gastrointestinal Medical Oncology.
2
Department of Gastrointestinal Medical Oncology Department of Clinical Cancer Prevention.
3
Department of Investigational Cancer Therapeutics.
4
Department of Biostatistics.
5
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
6
Sysmex Inostics, Hamburg, Germany.
7
Department of Gastrointestinal Medical Oncology SKopetz@mdanderson.org.

Abstract

INTRODUCTION:

KRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs). We investigated the frequency, co-occurrence, and distribution of acquired KRAS and EGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA (ctDNA).

PATIENTS AND METHODS:

Sixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples from KRAS (wt) mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction for KRAS codon 12, 13, 61, and 146 and EGFR 492 mutations.

RESULTS:

Plasma analyses showed newly detectable EGFR and KRAS mutations in 5/62 [8%; 95% confidence interval (CI) 0.02-0.18] and 27/62 (44%; 95% CI 0.3-0.56) samples, respectively. KRAS codon 61 and 146 mutations were predominant (33% and 11%, respectively), and multiple EGFR and/or KRAS mutations were detected in 11/27 (41%) cases. The percentage of mutant allele reads was inversely correlated with time since last treatment with EGFR mAbs (P = 0.038). In the matching archival tissue, these mutations were detectable as low-allele-frequency clones in 35% of patients with plasma mutations after treatment with anti-EGFR mAbs and correlated with shorter progression-free survival (PFS) compared with the cases with no new mutations (3.0 versus 8.0 months, P = 0.0004).

CONCLUSION:

Newly detected KRAS and/or EGFR mutations in plasma ctDNA from patients refractory to anti-EGFR treatment appear to derive from rare, pre-existing clones in the primary tumors. These rare clones were associated with shorter PFS in patients receiving anti-EGFR treatment. Multiple simultaneous mutations in KRAS and EGFR in the ctDNA and the decline in allele frequency after discontinuation of anti-EGFR therapy in a subset of patients suggest that several resistance mechanisms can co-exist and that relative clonal burdens may change over time. Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.

KEYWORDS:

EGFR acquired mutation; KRAS acquired mutation; anti-EGFR mAbs; ctDNA

PMID:
25628445
PMCID:
PMC4374387
DOI:
10.1093/annonc/mdv005
[Indexed for MEDLINE]
Free PMC Article

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