Abstract
EGFR-mutated lung adenocarcinoma patients who received tyrosine kinase inhibitors (TKIs) may initially respond to therapy, but over time, resistance eventually occurs. In a small population (5–10%), these patients can have a histological transformation to SCLC. Nine patients with EGFR-mutated lung adenocarcinoma who transformed to SCLC were evaluated at City of Hope. Patient clinical and pathology data, including multiple next-generation sequencing (NGS) results, clinical therapies, histology, and outcomes, were collected across multiple time points. Descriptive statistics were utilized to visualize and interpret the clinical therapeutic timeline and molecular transformation profiles for these patients. All patients received at least one line of EGFR TKI therapies prior to small cell lung cancer transformation, including erlotinib, afatinib, and osimertinib. Two patients also received chemotherapy prior to transformation (one with immunotherapy). The median months to small cell lung cancer transformation was 16 months, ranging from 4–49 months. The median overall survival (OS) was 29 months from diagnosis, with the minimum of 16 months and maximum of 62 months. The majority of patients had EGFR exon 19 deletion (n = 7, 77.8%), and no patients had a change of original oncogenic EGFR mutation over the different time points. Though a TP53 mutation was detected in eight patients (88.9%) either at the first biopsy or the subsequent biopsies, an RB1 alteration was only detected in one patient at presentation, and three patients upon subsequent biopsies (n = 4, 44.4%). Each patient had a unique molecular profile in the subsequent molecular testing post-transformation, but BRAF alterations occurred frequently, including BRAF rearrangement (n = 1), fusion (n = 1), and amplification (n = 1). Our results showed that EGFR-mutated lung adenocarcinoma to SCLC transformation patients have a unique histological, molecular, and clinical profile over multiple time points, with further heterogeneity that is not currently reported in the literature, and we suggest more work is required to better understand the molecular heterogeneity and clinical outcomes over time for this EGFR TKI resistance subtype.
Highlights
EGFR-directed tyrosine kinase inhibitors (TKIs) have become the standard of care for EGFR-mutated (EGFRm) patients, with improved outcomes, but most patients eventually progress due to secondary resistance mutations [1,2]
A total of nine patients diagnosed with non-small cell lung cancer (NSCLC), and who had an oncogenic EGFR alteration detected through next-generation sequencing (NGS), were seen for follow-up from 2014 through 2021 at City of Hope (Table 2)
EGFR TKI therapy was continued alongside chemotherapy for four patients immediately after transformation, and the remaining had EGFR TKI therapy following the completion of their chemotherapy regimen
Summary
EGFR-directed tyrosine kinase inhibitors (TKIs) have become the standard of care for EGFR-mutated (EGFRm) patients, with improved outcomes, but most patients eventually progress due to secondary resistance mutations [1,2]. In a small percentage of the EGFR-treated population (3–15%), the patient’s tumor has a histological transformation from non-small cell lung cancer (NSCLC), adenocarcinoma in particular, to neuroendocrine differentiated histology, small cell lung cancer (SCLC) [3,4]. The clinical history and unique genomic profiles of patients with smallcell lung cancer transformation are still poorly understood—and several studies showed differential findings regarding acquired mutations and treatment responses for this patient population [6,7]. Early detection and confirmation of this resistance are important because SCLC-chemotherapeutic treatment has been shown to be clinically effective, and may improve outcomes for these patients [3,8]. Our study aimed to detail and catalog the longitudinal sequencing profiles of nine EGFR-mutated patients who had pathology-confirmed small cell lung cancer transformation, as well as identify any biomarker patterns associated with improved survival
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