Resistance to epithelial growth factor receptor tyrosine kinase inhibitors in a patient with transformation from lung adenocarcinoma to small cell lung cancer: A case report

Abstract

First-generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved the treatment of non-small cell lung cancer (non-SCLC) with EGFR-sensitive mutations. However, acquired resistance to these drugs was inevitable. The transformation of lung adenocarcinoma to SCLC following treatment with EGFR-TKIs is a rare phenomenon that contributes to resistance to EGFR-TKIs. The present case concerns a 74-year-old man previously diagnosed with and treated for pneumonia; however, this was later pathologically confirmed as lung adenocarcinoma by transbronchial lung biopsy. Deletion of exon 19 of EGFR was identified by next-generation sequencing technology. The patient improved markedly when treated with gefitinib, but relapsed after 1 year, with markedly increased serum levels of neuron-specific enolase (NSE). Transformation to SCLC was detected by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) re-biopsy, which was negative for the deletion of exon 19 of EGFR. The patient was positive for vimentin expression and refractory to etoposide and cisplatin chemotherapy, and succumbed to the disease 18 months after diagnosis. Transformation of the disease from adenocarcinoma to SCLC may have been due to cancer heterogeneity. Re-biopsy is therefore important in EGFR-TKI-resistant patients for genetic and histological re-evaluation. NSE serum levels may also be useful for detecting early SCLC transformation.

Advances in studies of tyrosine kinase inhibitors and their acquired resistance

“…AKT activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Studies have shown that AKT inhibition, specifically, could moreuniformly enhance response and survival in patients with high pAKT levels who are at high risk for AKT-mediated resistance, as this distinct approach has the unique potential to combat the otherwise profound heterogeneity of molecular resistance events that are present in EGFR-mutant NSCLC patients with acquired EGFR-TKI resistance to improve their outcomes [ 139 , 140 ].…”

Transformation to small cell lung cancer after first-line afatinib treatment

“…Considering our case and the prior literature, clinicians should be aware that SCLC transformation can occur for all EGFR-TKI generations. Serum NSE levels may be useful for detecting early SCLC transformation [ 9 ]; however, tests for tumor markers showed normal levels of serum NSE and proGRP in the current case.…”

Histological Transformation to Small Cell Carcinoma of an Adenosquamous Carcinoma of the Lung With Epidermal Growth Factor Receptor Mutation in Exons 20 and 21 After Treatment With Erlotinib: Case Report

“…11 As for the criteria which may lead to suspect a histological transformation is the rapid increase of neuroendocrine markers in blood, as well as the poor clinical response to the treatment established, making new biopsies fundamental, especially to focus pharmacologic management. 12 It is worth mentioning that in these cases, the liquid biopsy, another diagnostic option approved for the follow-up of patients with mutations in EGFR to monitor the appearance of resistance mutations, with a sensitivity for the Thr790Met mutation of up to 70%, would not be indicated, as the evaluation of the tissue is required to perform the histological diagnosis. 13,14 In small cell carcinoma of the lung, the standard chemotherapeutic treatment is based on the combination of Cisplatin or Carboplatin plus Etoposide, with good response, both for the disease in early stages and for the advanced stage.…”