We used the following search terms in PubMed and selected articles on the basis of relevance to transformation from adenocarcinoma to SCLC: “adenocarcinoma to small cell transformation”, “EGFR mutant lung cancer and mechanisms of resistance”, “cell of origin of small cell lung cancer”, “cell of origin of adenocarcinoma, genomics and small cell lung cancer”, and “combined histology small cell lung cancer”. All dates and languages were included in the search.
ReviewTransformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin
Introduction
Lung cancer is the leading cause of cancer death in both men and women worldwide. WHO classifies lung cancer into two broad histological subtypes: non-small-cell lung cancer (NSCLC) which is the cause of about 85% of cases, and small-cell lung cancer (SCLC), which accounts for the remaining 15%. NSCLC is further subdivided into adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma. The approval by the US Food and Drug Administration to introduce targeted therapies against EGFR, such as erlotinib and afatinib, has revolutionised the treatment of a subset of adenocarcinomas that have EGFR-activating mutations;1, 2, 3, 4, 5, 6 however, acquired resistance develops after about 12 months.7, 8 Repeat biopsy samples from patients with EGFR-mutant cancers have shown that several mechanisms bring about the acquired resistance, including the rare but consistent observation of histological transformation from adenocarcinoma to SCLC.9, 10 Transformation to SCLC suggests that both adenocarcinoma and SCLC arise from a common cell type. Here, we explore the cellular and molecular relationship of adenocarcinoma to SCLC by discussing the clinical experience of combined-histology tumours and transformation from adenocarcinoma to SCLC.
Section snippets
Combined SCLC and NSCLC histology
Treatment strategies for lung cancer are based on the assumption that an individual patient's cancer is purely of one subtype.11, 12 For example, limited-stage SCLC and localised NSCLC are both potentially curable diseases, but their treatment strategies differ substantially.11, 13, 14 Surgery has been largely abandoned as a treatment modality in patients with limited-stage SCLC, which is now treated with concurrent chemotherapy and radiotherapy.11 By contrast, patients with localised stage I
EGFR-mutant adenocarcinoma and transformation to SCLC
Three EGFR inhibitors—erlotinib, gefitinib, and afatinib—are now used worldwide for first-line treatment of lung cancers that have EGFR-activating mutations, and their use has greatly changed clinical practice. However, within an average time of 12 months,7 resistance develops, and samples from repeat biopsies have shown several distinct mechanisms of acquired resistance to EGFR inhibitors. The most common resistance mechanism is a Thr790Met mutation in EGFR, which increases the affinity of the
EGFR mutations in de-novo SCLC
Two large case series29, 30 have investigated whether EGFR mutations occur de novo in classic SCLC (table 2).26, 29, 30, 31, 32, 33, 34, 35 In the series reported by Tatematsu and colleagues,30 five of 122 patients had EGFR-mutated SCLC. These patients had a history of heavy smoking (average of 30 pack-years), but a significantly lower pack-year smoking history than that of patients who did not have EGFR mutations. Three of the five patients with EGFR-mutant SCLC had combined small-cell and
Genomic analysis of SCLC and adenocarcinoma
Genomic analyses have improved understanding of the pathways that are dysregulated in each specific tumour type. These efforts aim to identify oncogenic driver mutations, copy number changes, and translocations that can be targeted therapeutically. In adenocarcinoma, these sequencing efforts have resulted in the identification of several mutated oncogenic drivers and tumour suppressor genes and have validated the high prevalence of KRAS and EGFR mutations.40 In clinical practice, the standard
RB1 inactivation as a defining feature of SCLC
Inactivation of RB1 has long been known to have an important role in the tumorigenesis of SCLC. In 2003, a mouse model of SCLC was developed by means of conditional knockout of Tp53 and Rb1.48 Further studies with this model have shown that Rb1 inactivation is essential for the development of SCLC. Mutation or loss of RB1 has been found in 100% of the human SCLC tumours sequenced.46 Furthermore, a proteomic study that compared SCLC and NSCLC cell lines showed that RB1 was quantitatively the
Adenocarcinoma and SCLC cells of origin
The appreciation that some adenocarcinomas and SCLC have the plasticity to switch histologies raises the possibility of the existence of shared cells of origin and greater plasticity than originally appreciated. Historically, SCLC was thought to arise from neuroendocrine cells within the distal part of the conducting airway because SCLC expresses neuroendocrine markers and typically develops in a central location. By contrast, adenocarcinomas are more commonly localised peripherally and were
Conclusions
Current understanding suggests that both combined-histology tumours and transformation are more common in lung cancers that have EGFR-activating mutations than in EGFR-wild-type tumours. The basis could be that the cell of origin of some EGFR-mutant adenocarcinomas, type II alveolar cells, also have the potential to become SCLC. Many examples used in this review reflect experiences with EGFR-mutant cancer, but the possibility remains that this clinical experience is biased by a greater number
Search strategy and selection criteria
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