This review summarizes the pharmacologic properties, clinical efficacy and safety of bevacizumab in advanced lung cancer treatment, with a focus on NSCLC, EGFR-mutant NSCLC and small-cell lung cancer.
We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-βRII) by immunohistochemistry (IHC).
We present a patient with epidermal growth factor receptor (EGFR)-mutant-NSCLC who developed metastatic SCLC after initial therapy with second-generation EGFR-tyrosine kinase inhibitor, afatinib.
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 T790MEGFR-mutation at second progression.
We present two cases of SCLC harboring EGFR mutations, one in an 82 year-old male smoker with a combined SCLC and adenocarcinoma with a novel D855H point mutation in exon 21, and the second in a 68 year-old female never smoker with the L858R point mutation in exon 21.
This finding indicates that the NSCLC and SCLC components arose separately and that CSCLC are unsuitable for TKI therapy despite the presence of sensitive EGFR mutations.
Mutational analysis was possible in almost all technically successful cases; likewise, acquired-resistant mutations (55 % of EGFR mutants) and small cell lung cancer transformation were identified from the bronchoscopy specimens.
Transformation to small cell lung cancer(SCLC), although uncommonly seen, has been associated with resistance to EGFR-TKI therapy in lung adenocarcinomas.
Transformation to small cell lung carcinoma (SCLC) following treatment with EGFR tyrosine kinase inhibitors has been reported in patients with EGFR-mutant lung adenocarcinoma.
The lack of response to EGFR TKIs in EGFR mutated de novo SCLC and LCNEC reported here may indicate that tumor differentiation affects tumor dependency on EGFR as a driver oncogene.
This idea has been supported by the unexpected findings that a subset of NSCLCs with mutated EGFR return as SCLC when resistance to EGFR tyrosine kinase inhibitors develops.
We describe the case of a 61-year-old man who presented transformation from adenocarcinoma to SCLC as the manifestation of acquired resistance after EGFR-TKI treatment.
EGFR-mutant clones depopulated AZD9291-resistant tumors to below 1% (baseline, 14%-36%) in three patients with progression: one with the loss of EGFR-double mutant clones and two accompanied by transformation to small-cell carcinoma and focal fibroblast growth factor receptor 1 (FGFR1) amplification, respectively.
Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs.
EGFRT790M secondary mutation, MET gene amplification, and transformation to small cell lung cancer are well-validated mechanisms that underlie acquisition of resistance to EGFR-TKIs.
Seven adenocarcinoma components were EGFR mutated: five exon 19 deletions and two mutations in exon 21 (L833_V834delinsFL and L858R).Four SCLC components were EGFR mutated.
Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR-tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma?
Several different acquired resistance mechanisms of EGFR mutant lung adenocarcinoma to EGFR-tyrosine kinase inhibitor (TKI) therapy have been described, most recently transformation to small cell lung carcinoma (SCLC).
Unlike other cancer types, sequencing genomic approaches have been of limited success in small-cell lung cancer, i.e., no mutated oncogenes with potential driver characteristics have emerged, as it is the case for activating mutations of epidermal growth factor receptor in non-small-cell lung cancer.
The mechanisms for acquired resistance include selection of the EGFRT790M mutation in approximately 50% of cases, and MET gene amplification, PIK3CA gene mutation, transdifferentiation into small-cell lung cancer and additional rare or unkown mechanisms.