EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes

Abstract

Purpose Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non–small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized. Methods We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed. Results We included 67 patients—38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation. Conclusion There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.

Deep and Prolonged Response to Aurora A Kinase Inhibitor and Subsequently to Nivolumab in MYCL1-Driven Small-Cell Lung Cancer: Case Report and Literature Review

“…SCLC occurring in nonsmokers has been previously reported [15]. More recently, SCLC has been seen in the de-evolution of EGFRdriven NSCLC [16]. Our patient did not have EGFR mutations at any time in his disease course.…”

Plasma screening for the T790M mutation of EGFR and phase 2 study of osimertinib efficacy in plasma T790M–positive non–small cell lung cancer: West Japan Oncology Group 8815L/LPS study

“…Approximately 3% to 10% of instances of acquired resistance to EGFR TKIs in patients with lung adenocarcinoma have been found to be associated with histological transformation to small cell lung cancer. Moreover, <10% of such small cell lung cancer tumors in patients who have developed resistance to first‐ or second‐generation EGFR TKIs have been found to harbor an EGFR T790M mutation . Only a small number of T790M‐positive patients, therefore, appear to manifest such histological transformation.…”

EGFR T790M detection in formalin‐fixed paraffin‐embedded tissues of patients with lung cancer using RNA‐based in situ hybridization: A preliminary feasibility study

“…Herein, rebiopsy is considered from the recurrent tumor before the therapy with third‐generation EGFR TKIs that targeted T790M and EGFR sensitive mutation simultaneously, and also because of its necessity for acquisition of tumor tissue for pathological diagnosis (several studies showed NSCLC transform to small‐cell lung cancer after treatment with EGFR‐TKIs), even though it is difficult to obtain adequate tissue from the recurrent tumor of every patient. Therefore, performing a liquid biopsy (e.g., circulating tumor DNA, ctDNA) as a substitute for cancer tissue was not appropriate in any case . On the other hand, the cancer tissue was almost exhausted after the H&E and IHC staining of the specimens in cases of rebiopsy, so there was no tissue left for further EGFR T790M testing, and ctDNA had to be used as a surrogate for determination of EGFR status.…”