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

• Published in: Journal of clinical oncology Vol. 37; no. 4; pp. 278 - 285
• Main Authors: Marcoux, Nicolas, Gettinger, Scott N., O’Kane, Grainne, Arbour, Kathryn C., Neal, Joel W., Husain, Hatim, Evans, Tracey L., Brahmer, Julie R., Muzikansky, Alona, Bonomi, Philip D., del Prete, Salvatore, Wurtz, Anna, Farago, Anna F., Dias-Santagata, Dora, Mino-Kenudson, Mari, Reckamp, Karen L., Yu, Helena A., Wakelee, Heather A., Shepherd, Frances A., Piotrowska, Zofia, Sequist, Lecia V.
• Format: Journal Article
• Language: English
• Published: United States American Society of Clinical Oncology 01.02.2019
• Subjects: Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - mortality; Adenocarcinoma of Lung - secondary; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - genetics; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - secondary; Class I Phosphatidylinositol 3-Kinases - genetics; ErbB Receptors - genetics; Female; Genetic Predisposition to Disease; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Middle Aged; Mutation; Neoplasm Grading; North America; Phenotype; RAPID COMMUNICATIONS; Retinoblastoma Binding Proteins - genetics; Retrospective Studies; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - mortality; Small Cell Lung Carcinoma - secondary; Time Factors; Treatment Outcome; Tumor Suppressor Protein p53 - genetics; Ubiquitin-Protein Ligases - genetics; North America
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/JCO.18.01585

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. 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. 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. 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.