Elsevier

The Lancet Oncology

Volume 16, Issue 4, April 2015, Pages e165-e172
The Lancet Oncology

Review
Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin

https://doi.org/10.1016/S1470-2045(14)71180-5Get rights and content

Summary

Lung cancer is the most common cause of cancer deaths worldwide. The two broad histological subtypes of lung cancer are small-cell lung cancer (SCLC), which is the cause of 15% of cases, and non-small-cell lung cancer (NSCLC), which accounts for 85% of cases and includes adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma. Although NSCLC and SCLC are commonly thought to be different diseases owing to their distinct biology and genomic abnormalities, the idea that these malignant disorders might share common cells of origin has been gaining support. This idea has been supported by the unexpected findings that a subset of NSCLCs with mutated EGFR return as SCLC when resistance to EGFR tyrosine kinase inhibitors develops. Additionally, other case reports have described the coexistence of NSCLC and SCLC, further challenging the commonly accepted view of their distinct lineages. Here, we summarise the published clinical observations and biology underlying tumours with combined SCLC and NSCLC histology and cancers that transform from adenocarcinoma to SCLC. We also discuss pre-clinical studies pointing to common potential cells of origin, and speculate how the distinct paths of differentiation are determined by the genomics of each disease.

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

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.

References (64)

  • E Norkowski et al.

    Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology

    J Thorac Oncol

    (2013)
  • S Watanabe et al.

    Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma

    Lung Cancer

    (2013)
  • S Popat et al.

    Transformation to “high grade” neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma

    Lung Cancer

    (2013)
  • TH Shiao et al.

    Epidermal growth factor receptor mutations in small cell lung cancer: a brief report

    J Thorac Oncol

    (2011)
  • J Araki et al.

    Efficacy of the tyrosine kinase inhibitor gefitinib in a patient with metastatic small cell lung cancer

    Lung Cancer

    (2005)
  • I Okamoto et al.

    EGFR mutation in gefitinib-responsive small-cell lung cancer

    Ann Oncol

    (2006)
  • Y Kurahara et al.

    Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke

    Clin Lung Cancer

    (2012)
  • AM Moore et al.

    Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: a Hoosier Oncology Group phase II trial

    Lung Cancer

    (2006)
  • M Imielinski et al.

    Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing

    Cell

    (2012)
  • LV Sequist et al.

    Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice

    Ann Oncol

    (2011)
  • R Meuwissen et al.

    Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model

    Cancer Cell

    (2003)
  • KD Sutherland et al.

    Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung

    Cancer Cell

    (2011)
  • PJ Miettinen et al.

    Impaired lung branching morphogenesis in the absence of functional EGF receptor

    Dev Biol

    (1997)
  • M Maemondo et al.

    Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR

    N Engl J Med

    (2010)
  • LV Sequist et al.

    Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

    J Clin Oncol

    (2013)
  • TS Mok et al.

    Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma

    N Engl J Med

    (2009)
  • JA Engelman et al.

    Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

    Clin Cancer Res

    (2008)
  • LV Sequist et al.

    Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors

    Sci Transl Med

    (2011)
  • HA Yu et al.

    Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers

    Clin Cancer Res

    (2013)
  • GP Kalemkerian et al.

    Small cell lung cancer

    J Natl Compr Canc Netw

    (2013)
  • GV Scagliotti et al.

    Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer

    J Clin Oncol

    (2008)
  • MA Socinski et al.

    Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer

    J Clin Oncol

    (2009)
  • Cited by (687)

    View all citing articles on Scopus
    View full text