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

2015; Elsevier BV; Volume: 26; Issue: 4 Linguagem: Inglês

10.1093/annonc/mdv005

1569-8041

Maria Pia Morelli, Michael J. Overman, Arvind Dasari, Syed Mohammad Ali Kazmi, Thibault Mazard, Eduardo Vilar, Van K. Morris, M. S. Lee, David S. Herron, Cathy Eng, James Morris, Bryan K. Kee, Filip Janků, F.L. Deaton, Christopher R. Garrett, Dipen M. Maru, Frank Diehl, Philipp Angenendt, Scott Kopetz,

Genetic factors in colorectal cancer

Colorectal tumors become more heterogeneous after progression on EGFR-inhibitors by developing multiple independent mutations. Upon discontinuation of treatment, the mutant allele burden declines over several months, which suggests that the changes may be dynamic. Monitoring genetic changes during treatment using ctDNA may provide opportunities to optimize therapeutic strategies.IntroductionKRAS andEGFR 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 acquiredKRAS andEGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA (ctDNA).Patients and methodsSixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples fromKRASwt mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction forKRAS codon 12, 13, 61, and 146 andEGFR 492 mutations.ResultsPlasma analyses showed newly detectableEGFR andKRAS 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 multipleEGFR and/orKRAS 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).ConclusionNewly detectedKRAS and/orEGFR 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 inKRAS andEGFR 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.