Small Cell Lung Cancer Transformation following Treatment in EGFR-Mutated Non-Small Cell Lung Cancer

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.

Keywords: EGFR; NSCLC; SCLC; genomics; precision medicine; transformation.

Figure 1

Tissue staining of two patients with transformation. (A) H&E stained section of acinar-type adenocarcinoma grade 2, initial diagnosis, H&E ×200 (Patient 9). (B) Acinar-type adenocarcinoma, TTF1 stain ×200. (C) H&E section, small cell transformation to liver ×200. (D) Small cell transformation to liver, synaptophysin stain, ×200. (E) H&E stained section of solid-type adenocarcinoma grade 3, initial diagnosis, H&E ×200 (Patient 7). (F) Solid-type adenocarcinoma, TTF1 stain ×200. (G) H&E section, small cell transformation to liver ×200. (H) Small cell transformation to liver, synaptophysin stain ×200.

Figure 2

Mutational profile of EGFR NSCLC to neuroendocrine-transformed patients with multiple time points. NGS mutation results from both tissue and liquid biopsy were classified according to mutation subtypes, including EGFR exon 19 deletion; exon 19 deletion and amplification; exon 19 deletion, amplification, and T790M; L858R; L861Q and amplification; and other mutational subtypes, including substitution; amplification; deletion; fusion; splice site; loss; frameshift; rearrangement. The time points of the different molecular testing results are denoted by letters A-I for each patient in sequential order that they were performed.

Figure 3

Systemic treatment timeline, the incidence of transformation, and next-generation sequencing time points. The complete history of lines of therapies given for each patient, including the time to transformation, and next-generational sequencing time points, with each box delineating two months. Created with BioRender.com.