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.

Etoposide/platinum plus anlotinib for patients with transformed small-cell lung cancer from EGFR-mutant lung adenocarcinoma after EGFR-TKI resistance: A retrospective and observational study

“…3) harbored only gene alterations of TP53 but without RB1 loss. These ndings indicate that RB1 loss and TP53 mutation are not universally present in transformed SCLC patients, which has also been con rmed by others (Mambetsariev et al 2022;Yu et al 2022). Additionally, PIK3CA mutation was found in 20% of the patients, and BRAF mutation occurred in 10% of the patients, suggesting the molecular heterogeneity of transformation from LUAD to SCLC.…”

Histomorphological transformation from non-small cell lung carcinoma to small cell lung carcinoma after targeted therapy or immunotherapy: A report of two cases

“…Patients with EGFR exon 19 deletion are also more likely to undergo transformation (26). Another study confirmed that the risk of SCLC transformation is six times higher in patients with concurrent EGFR, TP53, and RB1 mutations than in patients without mutations (25). Moreover, Achaete-scute homolog 1 (ASCL1) can interact with the Rb-p53 (by RB1, TP53 code, respectively) axis to promote the growth of adenocarcinoma with a higher degree of invasion (32).…”

“…Histological transformation of EGFR -mutated adenocarcinoma to SCLC was first reported in 2006 as a relatively rare mechanism of resistance ( 2 ). Among patients treated with EGFR-TKIs as targeted therapy, this mechanism accounts for 3-15% of transformation to SCLC, particularly transformation from adenocarcinoma to SCLC ( 25 ), which may constitute a potential mechanism of acquired drug resistance to EGFR-TKIs ( 26 ). Small cell transformation as a resistance mechanism for immunotherapy was first reported in 2017 by Imakita et al.…”

Durable response to afatinib rechallenge in a long‐term survivor of non‐small cell lung cancer harboring EGFR L858R and L747V mutations

“…The transformation from NSCLC to SCLC is a mechanism of resistance to EGFR‐TKIs 13,14 . Marcoux et al investigated the clinical outcomes of EGFR ‐mutated lung adenocarcinomas transforming to SCLC, showing that the median OS since the time of SCLC transformation was 10.9 months, 15 whereas another report described long‐term survival with an OS of 58 months from SCLC transformation 16 . In comparison with these reports, our patient survived for more than 142 months from the initial diagnosis of SCLC transformation, which may be partly attributed to repeated salvage surgeries and stereotactic radiotherapy along with systemic therapies.…”