Heterogeneous resistance mechanisms in an EGFR exon 19-mutated non-small cell lung cancer patient treated with erlotinib: Persistent FGFR3 -mutation, localized transformation to EGFR -mutated SCLC, and acquired T790M EGFR -mutation

Abstract

Patients with epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer (NSCLC) obtain substantial clinical benefit from EGFR tyrosine-kinase inhibitors (TKIs), but will ultimately develop TKI-resistance resulting in median progression-free survival of 9-15 months during first-line TKI-therapy. However, type and timing of TKI-resistance cannot be predicted and several mechanisms may simultaneously/subsequently occur during TKI-treatment. In this respect, we present a 49 year-old Caucasian male ex-smoker with metastatic pulmonary adenocarcinoma (ADC) that concomitantly harbored an EGFR exon 19-mutation (p.E746_A750delELREA) and a previously unreported 2bp frame-shift microdeletion in the fibroblast growth factor receptor 3 (FGFR3; p.D785fs*31) gene. Interestingly, FGFR3-mutations have previously been described in other cancer types of Caucasian patients and may represent an alternative pathway to EGFR-signaling. The patient received first-line erlotinib but after only 7 weeks showed metastatic pleural effusion, in which transformation to small cell lung cancer (SCLC) that retained the EGFR- and FGFR3-mutations was identified. Consequently, standard carboplatin-etoposide regimen for SCLC combined with erlotinib continuation was implemented obtaining significant objective response. However, after completing 6 cycles of this combination, new pulmonary and hepatic metastases appeared and showed persistence of the original EGFR- and FGFR3-mutated ADC phenotype together with acquisition of the erlotinib-resistant T790M EGFR-mutation. The patient rapidly deteriorated and deceased. Thus, this advanced EGFR-mutated NSCLC displayed very rapid onset and heterogeneous genetic and phenotypic mechanisms of TKI-resistance occurring at different times and locations of metastatic disease: concomitant FGFR3-mutation before and during TKI-treatment as potential intrinsic mechanism for the rapid progression; transformation to SCLC at first progression during TKI-therapy; acquired T790M EGFR-mutation at second progression. Our case also underlines that, when achievable, rebiopsies of progressive sites during TKI-treatment are important for identifying heterogeneous histopathological and molecular resistance mechanisms and better defining possible treatment modifications.

Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment

“…Additionally, lung ADC may contain oncogenic FGFR3-TACC3 fusions that may function as bypass-mechanism associated with intrinsic/acquired resistance to EGFR-TKIs reversible by FGFR-inhibitors [ 54 – 56 ]. As we recently described elsewhere, our advanced EGFR -mutant ADC-case with concomitant FGFR3 -mutation displayed mixed response, with pleural metastasis progressing already 7 weeks after initiating first-line erlotinib-treatment, whereas other metastatic sites progressed only 6 months later after acquiring additional p.T790M EGFR -mutation [ 57 ].…”

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

“…This study suggested the contribution of FGFR3 signaling to T790M-mediated erlotinib resistance in lung cancer patients. 109 In addition, treatment with FGFR inhibitors restored the sensitivity to EGFR-TKIs in primary drug-resistant SCLC cells. 110 Therefore, FGFR activation is one of the possible causes of developed resistance to EGFR-TKIs in lung cancer patients.…”

“…Caucasian male ex-smoker with metastasized pulmonary ADC harboring an EGFR exon 19 deletion and an unreported 2-bp frame-shift microdeletion in FGFR3 showed transformation from ADC to SCLC within 7 weeks of the initiation of erlotinib treatment. 109 Further, following the completion of six cycles of erlotinib treatment, an additional EGFR T790M mutation appeared which caused erlotinib resistance. This study suggested the contribution of FGFR3 signaling to T790M-mediated erlotinib resistance in lung cancer patients.…”

Unexpected favorable outcome to etoposide and cisplatin in a small cell lung cancer transformed patient: a case report

“…Several studies have reported transient response to EP regiments after the development of SCLC transformation. 17,18 Here, we reported an unexpected case of a favorable response to EP of an EGFR-mutant patient who developed SCLC transformation as resistance to erlotinib with a PFS of 7.7 months.…”

“…9,10 Numerous studies have documented such cases. [15][16][17] Most patients who developed SCLC transformation are often associated with aggressive clinical behaviors and poor prognosis with a median overall survival (OS) of 6 months. Several studies have reported transient response to EP regiments after the development of SCLC transformation.…”