EGFR -Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes
Open accessAbstract
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.
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Similar histological transformations have been observed after EGFR inhibitor therapy.
“Similar histological transformations have been observed after EGFR inhibitor therapy65.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [65]
Mutant EGFR directly tyrosine phosphorylates β-catenin, leading to its stabilization and nuclear accumulation.
“Mutant EGFR has further been shown to directly tyrosine phosphorylate β-catenin resulting in its stabilization and nuclear accumulation120.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [120]
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- Authors
- Marcoux, N., Gettinger, S. N., O’Kane, G., Arbour, K. C., Neal, J. W., Husain, H., Evans, T. L., Brahmer, J. R., Muzikansky, A., Bonomi, P. D., del Prete, S., Wurtz, A., Farago, A. F., Dias-Santagata, D., Mino-Kenudson, M., Reckamp, K. L., Yu, H. A., Wakelee, H. A., Shepherd, F. A., Piotrowska, Z., & Sequist, L. V.
- Affiliations
- Massachusetts General Hospital (US)
- Yale Cancer Center (US)
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- Memorial Sloan Kettering Cancer Center (US)
- Stanford Cancer Institute (US)
- University of California San Diego (US)
- Lankenau Medical Center (US)
- Johns Hopkins University (US)
- Rush University Medical Center (US)
- Bennett Cancer Center, Stamford CT
- City Of Hope National Medical Center (US)
- Princess Margaret Cancer Centre (CA)
- ORCID
- Marcoux, Nicolas
- Gettinger, Scott N.
- Arbour, Kathryn C.
- Neal, Joel W.
- Husain, Hatim
- Evans, Tracey L.
- Brahmer, Julie R.
- Muzikansky, Alona
- Bonomi, Philip D.
- 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.
- Venue
- Journal of Clinical Oncology
- Published
- 2019-02-01
- Volume
- 37
- Issue
- 4
- Pages
- 278-285
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC7001776
- OpenAlex
- W2905529840
- Cited by
- 500
- References
- 18
- Citations by year
- 2026: 63 · 2025: 82 · 2024: 75 · 2023: 65 · 2022: 70 · 2021: 61 · 2020: 51 · 2019: 31
- FWCI
- 26.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Stop Cancer
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Gilead Sciences
- Ariad Pharmaceuticals
- Alexion Pharmaceuticals
- Celgene
- Exelixis
- Clovis Oncology
- Five Prime Therapeutics
- Jounce Therapeutics
- Incyte
- Syndax Pharmaceuticals
- Genentech
- Pharmacyclics
- Foundation Medicine
- National Cancer Institute (P30CA008748, R01CA137008)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- EGFR-mutant non-small cell lung cancer, small cell lung cancer transformation, neuroendocrine carcinoma, EGFR tyrosine kinase inhibitors, EGFR exon 19 deletion, L858R mutation, T790M mutation, platinum-etoposide chemotherapy, taxanes, immunotherapy response, TP53 mutation, RB1 mutation, PIK3CA mutation, central nervous system metastasis, overall survival
- MeSH terms
- Adenocarcinoma of Lung, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, North America, Phenotype, Retrospective Studies, Time Factors, Biomarkers, Tumor, Tumor Suppressor Protein p53, Treatment Outcome, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Small Cell Lung Carcinoma, Retinoblastoma Binding Proteins, Class I Phosphatidylinositol 3-Kinases, Neoplasm Grading, ErbB Receptors
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