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 BartolomeoAlberto Bardelli, Filippo De Braud

Research output: Contribution to journalArticlepeer-review


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 METamplification showed worse PFS on anti-EGFRs.Wedetected 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
JournalClinical Cancer Research
Publication statusPublished - 2016


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