Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer

Abstract

Even if wild-type and-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 ,, and extracellular domain mutations as well as 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. Twenty-two - wild-type, -negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver 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. mutations and amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand, and ectodomain mutations were much rarer. Patients with acquired 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. 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. .

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

“…This is similar to what has been observed in other ctDNA studies in solid tumors (26, 27). In gastrointestinal cancers, detection of amplification of potentially targetable RTKs, including HER2 and MET, is likely to be clinically relevant, as these events have been shown to mediate acquired resistance and are themselves targetable using therapies currently approved in other tumor types or in active clinical trials, including the NCI-MATCH and TAPUR studies (3, 6, 28).…”

Cell-Free DNA Profiling to Discover Mechanisms of Exceptional Response to Cabozantinib Plus Panitumumab in a Patient With Treatment Refractory Metastatic Colorectal Cancer

“…Additionally, access to treatment-refractory tumor tissue and molecular heterogeneity complicates testing efforts (24, 46). Given these limitations, cfDNA profiling may be the optimal approach for detection of MET amplification in the treatment refractory setting (47).…”

“…Bardelli et al (22) found that MET amplification emerged in post-treatment tumor biopsies of 3 out of 7 patients with metastatic CRC who developed acquired resistance to cetuximab or panitumumab (22). In a separate cohort of 22 patients with RAS and BRAF wild-type, HER2/MET negative metastatic CRC who developed resistance to anti-EGFR therapy, in situ hybridization (ISH) of the tumor tissue biopsies identified MET amplification as one of the most common genomic alterations (24). …”

Molecular Diagnostics in Clinical Oncology

“…The analysis of treatment-resistant tumors may require repetitive biopsies, which is not feasible if one considers a direct analysis of visceral, bone, or brain metastases. Furthermore, while intratumoral heterogeneity with regard to actionable mutations in treatment-naïve tumors is limited, the evolution of tumor-resistant lumps under the pressure of systemic treatment may utilize a multitude of alternative pathways even within the same patient (Suda et al, 2010; Pietrantonio et al, 2017). Liquid biopsy is expected to provide a more integral portrait of molecular events underlying tumor progression as compared to a single tissue-take (Gremel et al, 2016; Oxnard et al, 2016; Goodall et al, 2017).…”