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

M. P. Morelli, M. J. Overman, A. Dasari, S. M.A. Kazmi, T. Mazard, E. Vilar, V. K. Morris, M. S. Lee, D. Herron, C. Eng, J. Morris, B. K. Kee, F. Janku, F. L. Deaton, C. Garrett, D. Maru, F. Diehl, P. Angenendt, Scott Kopetz

Research output: Contribution to journalArticlepeer-review

208 Scopus citations


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 KRASwt 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 treatmentinduced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.

Original languageEnglish (US)
Pages (from-to)731-736
Number of pages6
JournalAnnals of Oncology
Issue number4
StatePublished - Apr 1 2015


  • Anti-EGFR mAbs
  • EGFR acquired mutation
  • KRAS acquired mutation
  • ctDNA

ASJC Scopus subject areas

  • Hematology
  • Oncology


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