Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer

Filippo Pietrantonio, Claudio Vernieri, Giulia Siravegna, Alessia Mennitto, Rosa Berenato, Federica Perrone, Annunziata Gloghini, Elena Tamborini, Sara Lonardi, Federica Morano, Benedetta Picciani, Adele Busico, Chiara Costanza Volpi, Antonia Martinetti, Francesca Battaglin, Ilaria Bossi, Alessio Pellegrinelli, Massimo Milione, Chiara Cremolini, Maria Di Bartolomeo & 2 others Alberto Bardelli, Filippo De Braud

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Abstract

Purpose: Even if RAS-BRAF wild-type and HER2/MET-negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence of KRAS, NRAS, and EGFR extracellular domain mutations as well as HER2/MET alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies. Experimental design: Twenty-two RAS-BRAF wild-type, HER2/MET-negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver in situ hybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue-plasma samples. Results: RAS mutations and HER2/MET amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand, BRAF and EGFR ectodomain mutations were much rarer. Patients with acquired MET amplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co-occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade. Conclusions: Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC.

Original languageEnglish
Pages (from-to)2414-2422
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number10
DOIs
Publication statusPublished - May 15 2017

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Colorectal Neoplasms
Monoclonal Antibodies
Clonal Evolution
Mutation
Silver
In Situ Hybridization
Anti-Idiotypic Antibodies
Neoplasms
Research Design
Retrospective Studies
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. / Pietrantonio, Filippo; Vernieri, Claudio; Siravegna, Giulia; Mennitto, Alessia; Berenato, Rosa; Perrone, Federica; Gloghini, Annunziata; Tamborini, Elena; Lonardi, Sara; Morano, Federica; Picciani, Benedetta; Busico, Adele; Volpi, Chiara Costanza; Martinetti, Antonia; Battaglin, Francesca; Bossi, Ilaria; Pellegrinelli, Alessio; Milione, Massimo; Cremolini, Chiara; Di Bartolomeo, Maria; Bardelli, Alberto; De Braud, Filippo.

In: Clinical Cancer Research, Vol. 23, No. 10, 15.05.2017, p. 2414-2422.

Research output: Contribution to journalArticle

Pietrantonio, Filippo ; Vernieri, Claudio ; Siravegna, Giulia ; Mennitto, Alessia ; Berenato, Rosa ; Perrone, Federica ; Gloghini, Annunziata ; Tamborini, Elena ; Lonardi, Sara ; Morano, Federica ; Picciani, Benedetta ; Busico, Adele ; Volpi, Chiara Costanza ; Martinetti, Antonia ; Battaglin, Francesca ; Bossi, Ilaria ; Pellegrinelli, Alessio ; Milione, Massimo ; Cremolini, Chiara ; Di Bartolomeo, Maria ; Bardelli, Alberto ; De Braud, Filippo. / Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 10. pp. 2414-2422.
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abstract = "Purpose: Even if RAS-BRAF wild-type and HER2/MET-negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence of KRAS, NRAS, and EGFR extracellular domain mutations as well as HER2/MET alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies. Experimental design: Twenty-two RAS-BRAF wild-type, HER2/MET-negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver in situ hybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue-plasma samples. Results: RAS mutations and HER2/MET amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand, BRAF and EGFR ectodomain mutations were much rarer. Patients with acquired MET amplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co-occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade. Conclusions: Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC.",
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T1 - Heterogeneity of acquired resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer

AU - Pietrantonio, Filippo

AU - Vernieri, Claudio

AU - Siravegna, Giulia

AU - Mennitto, Alessia

AU - Berenato, Rosa

AU - Perrone, Federica

AU - Gloghini, Annunziata

AU - Tamborini, Elena

AU - Lonardi, Sara

AU - Morano, Federica

AU - Picciani, Benedetta

AU - Busico, Adele

AU - Volpi, Chiara Costanza

AU - Martinetti, Antonia

AU - Battaglin, Francesca

AU - Bossi, Ilaria

AU - Pellegrinelli, Alessio

AU - Milione, Massimo

AU - Cremolini, Chiara

AU - Di Bartolomeo, Maria

AU - Bardelli, Alberto

AU - De Braud, Filippo

PY - 2017/5/15

Y1 - 2017/5/15

N2 - Purpose: Even if RAS-BRAF wild-type and HER2/MET-negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence of KRAS, NRAS, and EGFR extracellular domain mutations as well as HER2/MET alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies. Experimental design: Twenty-two RAS-BRAF wild-type, HER2/MET-negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver in situ hybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue-plasma samples. Results: RAS mutations and HER2/MET amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand, BRAF and EGFR ectodomain mutations were much rarer. Patients with acquired MET amplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co-occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade. Conclusions: Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC.

AB - Purpose: Even if RAS-BRAF wild-type and HER2/MET-negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence of KRAS, NRAS, and EGFR extracellular domain mutations as well as HER2/MET alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies. Experimental design: Twenty-two RAS-BRAF wild-type, HER2/MET-negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver in situ hybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue-plasma samples. Results: RAS mutations and HER2/MET amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand, BRAF and EGFR ectodomain mutations were much rarer. Patients with acquired MET amplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co-occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade. Conclusions: Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC.

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