Mesenchymal–epithelial transition factor (MET) amplification has been suggested either as a de novo or acquired mechanism of resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. However, even if MET amplification has been widely described in the preclinical setting, only a few clinical data have confirmed the role of MET in the resistance to anti-EGFR treatment. A 60-year-old man presenting cholangiocarcinoma with EGFR amplification had a tumor response to anti-EGFR therapy. A new on-purpose tumor biopsy performed during tumor progression confirmed the known EGFR amplification as well as a new MET amplification. This clinical observation highlights the role of MET amplification as a mechanism of resistance to EGFR inhibitors.
Mesenchymal–epithelial transition factor (MET) amplification has been suggested as a de novo or acquired mechanism of resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. However, even if MET amplification has been largely described in the preclinical setting, only a few clinical data have confirmed the role of MET in the resistance to anti-EGFR treatment.[1–4]
A 60-year-old man diagnosed with a nonresectable intrahepatic cholangiocarcinoma received gemcitabine plus cisplatin successively (6 cycles with stable disease followed by progressive disease) and hepatic arterial infusion of oxaliplatin plus leucovorin/5-fluorouracil (8 cycles with stable disease followed by progressive disease).
The patient was offered an on-purpose tumor biopsy to detect molecular alterations by the use of comparative genomic hybridization (CGH) array (Agilent Technology, 180K) and next-generation sequencing (Ion AmpliSeq™ Cancer Hotspot Panel v2). This biopsy showed an EGFR amplification (log ratio × 1.35) and also mutations in TP53 (p.Arg273Cys), IDH2 (p. Arg172Trp), and STK11 (p.Asp127Metfs*25). After a molecular multidisciplinary tumor board, it was decided to treat the patient with erlotinib, an EGFR tyrosine kinase inhibitor. The patient experienced a rapid and impressive clinical benefit. Tumor assessment showed a partial response (−36% on target lesions) and tumor marker carbohydrate antigen 19.9 came back to normal values [Figure 1]. However, only 5 months after erlotinib initiation, we noticed clear signs of tumor progression. A new on-purpose tumor biopsy was then performed to elucidate the mechanism of resistance. This new biopsy confirmed the three mutations (TP53, IDH2, and STK11) that had already observed. No new mutations were found. CGH array also confirmed the already known EGFR amplification (log ratio 1.62). More interestingly, de novo MET amplification was found (log ratio 3.19). This amplification was confirmed by fluorescence in situ hybridization (FISH, percentage of cells with more than 5 copies = 100%; mean ratio cMET/CEN7 = 5). A retrospective analysis of the first biopsy by FISH did not show this MET amplification (mean ratio cMET/CEN7 = 1.01; percentage of cells with more than 5 copies = 4.7%). Unfortunately, the patient status deteriorated very rapidly with massive liver cytolysis, which did not allow exposing him to a MET inhibitor.
MET amplification and overexpression are the mechanisms of resistance in patients treated with EGFR inhibitors and should be tested for patients who present de novo or acquired resistance to anti-EGFR therapies [Figure 2]. Particularly, nonsmall cell lung cancer (NSCLC) patients treated with EGFR inhibitors exhibited de novo MET amplifications and EGFR mutations, suggesting acquired resistance by activating PI3K pathway.[4,5] Dual inhibition of MET and EGFR has been assessed in NSCLC patients progressing to EGFR therapy in the clinical setting with controversial results [Table 1]. A recently published phase Ib/II study, assessing capmatinib and gefitinib in NSCLC patients with EGFR-mutated and MET-dysregulated (MET-amplified or MET-overexpressing), showed promising results. Particularly, MET-amplified patients had a response rate of 47% with a median duration of response of 5.5 months. Another study the TATTON trial evaluating the potent EGFR inhibitor osimertinib with savolitinib another MET tyrosine kinase inhibitor, showed antitumor activity in a patient population with MET-driven acquired resistance to anti-EGFR therapy. In this trial, patients treated with prior first/second-generation and third-generation EGFR inhibitors had response rates of 52% and 28% as well as median time of response duration of 7.1 and 9.7 months, respectively. The larger trial SAVANNAH (NCT03778229) is currently exploring this combination in a bigger population of NSCLC patients.
MET amplification as a driving mechanism of resistance to EGFR inhibition is not restricted to one tumor type as it has been already described not only described in NSCLC but also in colorectal, esophagogastric, and ovarian cancer patients and now in cholangiocarcinoma patients.[1,3,14,15] Furthermore, MET amplification as a mechanism of resistance to EGFR inhibition has been associated with the use of tyrosine kinase inhibitor versus monoclonal antibody targeting EGFR.EGFR mutations and MET amplification in cholangiocarcinoma have been reported in 15% and 7% of studied cases. MET inhibitors are a biologically relevant treatment and may be promising in cholangiocarcinomas in monotherapy and in combination with EGFR inhibitors, although studies in this particular population are lacking.
Finally, we consider that repeated tumor biopsies and throughput molecular screening can point out the key driver aberrations in tumor growth and to understand the mechanisms of resistance.
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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
The authors disclosed no funding related to this article.
Conflicts of interest
All the authors declare institutional financial interests as part of the Drug Development Department (DITEP) from AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi. Pr. JC Soria is a full-time employee of MedImmune since September 2017. The authors declare no other conflicts of interest.
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