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 journalArticle

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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 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
Volume26
Issue number4
DOIs
StatePublished - Jan 1 2015

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Colorectal Neoplasms
Mutation
DNA
Neoplasms
Monoclonal Antibodies
Therapeutics
Clone Cells
Gene Frequency
Codon
Disease-Free Survival
Confidence Intervals
Emulsions
Biomarkers
Alleles
Polymerase Chain Reaction

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. / Morelli, M. P.; Overman, M. J.; Dasari, A.; Kazmi, S. M.A.; Mazard, T.; Vilar, E.; Morris, V. K.; Lee, M. S.; Herron, D.; Eng, C.; Morris, J.; Kee, B. K.; Janku, F.; Deaton, F. L.; Garrett, C.; Maru, D.; Diehl, F.; Angenendt, P.; Kopetz, Scott.

In: Annals of Oncology, Vol. 26, No. 4, 01.01.2015, p. 731-736.

Research output: Contribution to journalArticle

Morelli, MP, Overman, MJ, Dasari, A, Kazmi, SMA, Mazard, T, Vilar, E, Morris, VK, Lee, MS, Herron, D, Eng, C, Morris, J, Kee, BK, Janku, F, Deaton, FL, Garrett, C, Maru, D, Diehl, F, Angenendt, P & Kopetz, S 2015, 'Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment', Annals of Oncology, vol. 26, no. 4, pp. 731-736. https://doi.org/10.1093/annonc/mdv005
Morelli, M. P. ; Overman, M. J. ; Dasari, A. ; Kazmi, S. M.A. ; Mazard, T. ; Vilar, E. ; Morris, V. K. ; Lee, M. S. ; Herron, D. ; Eng, C. ; Morris, J. ; Kee, B. K. ; Janku, F. ; Deaton, F. L. ; Garrett, C. ; Maru, D. ; Diehl, F. ; Angenendt, P. ; Kopetz, Scott. / Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. In: Annals of Oncology. 2015 ; Vol. 26, No. 4. pp. 731-736.
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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 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.",
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T1 - Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment

AU - Morelli, M. P.

AU - Overman, M. J.

AU - Dasari, A.

AU - Kazmi, S. M.A.

AU - Mazard, T.

AU - Vilar, E.

AU - Morris, V. K.

AU - Lee, M. S.

AU - Herron, D.

AU - Eng, C.

AU - Morris, J.

AU - Kee, B. K.

AU - Janku, F.

AU - Deaton, F. L.

AU - Garrett, C.

AU - Maru, D.

AU - Diehl, F.

AU - Angenendt, P.

AU - Kopetz, Scott

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

KW - Anti-EGFR mAbs

KW - ctDNA

KW - EGFR acquired mutation

KW - KRAS acquired mutation

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