Small cell lung cancer: where do we go from here?

Abstract

Small cell lung cancer (SCLC) is an aggressive disease that accounts for approximately 14% of all lung cancers. In the United States, approximately 31,000 patients are diagnosed annually with SCLC. Despite numerous clinical trials, including at least 40 phase 3 trials since the 1970s, systemic treatment for patients with SCLC has not changed significantly in the past several decades. Consequently, the 5-year survival rate remains low at <7% overall, and most patients survive for only 1 year or less after diagnosis. Unlike nonsmall cell lung cancer (NSCLC), in which major advances have been made using targeted therapies, there are still no approved targeted drugs for SCLC. Significant barriers to progress in SCLC include 1) a lack of early detection modalities, 2) limited tumor tissue for translational research (eg, molecular profiling of DNA, RNA, and/or protein alterations) because of small diagnostic biopsies and the rare use of surgical resection in standard treatment, and 3) rapid disease progression with poor understanding of the mechanisms contributing to therapeutic resistance. In this report, the authors review the current state of SCLC treatment, recent advances in current understanding of the underlying disease biology, and opportunities to advance translational research and therapeutic approaches for patients with SCLC.

Keywords: genomics; novel therapies; proteomics; small cell lung cancer; translational research.

Figure 1

The frequency of genomic alterations is illustrated according to percentage in small cell lung cancer (SCLC). This is a representative list of the more common and/or potentially targetable alterations. An asterisk indicates the percentage that was positive for poly(ADP-ripose) polymerase 1 (PARP1) protein expression based on the number of SCLC tumors that had an immunohistochemical staining score of 31in 100% of tumor cells. TP53 indicates tumor protein 53; RB1, retinoblastoma 1; PTEN, phosphatase and tensin homolog; MYC, v-myc avian myelocytomatosis viral oncogene homolog; MYCL, v-myc avian myelocytomatosis viral oncogene lung carcinoma-derived homolog; MYCN, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog; SOX2, sex-determining region Y box 2; FGFR1, fibroblast growth factor receptor 1; CCNE1, cyclin E1; EPHA7, ephrin receptor A7.

Figure 2

Tissue limitations in the study of small cell lung cancer are illustrated. NGS indicates next-generation DNA sequencing.

Figure 3

The framework for clinical-translational research in small cell lung cancer (SCLC) is illustrated. Tissue biopsies (fine-needle aspiration and/or core-needle) are required that provide ample material for integrated molecular analysis 1) to guide clinical decision making (eg, marker-selected clinical trial) and 2) for translational/exploratory scientific analysis (eg, the identification of new targets and/or biomarkers). Patient rebiopsies at the time of progression are necessary to assess for potential new therapeutic targets and to characterize molecular features/alterations acquired in resistant disease. CLIA indicates Clinical Laboratory Improvement Amendments; NGS, next-generation DNA sequencing; CNA, copy number alterations; RT, radiotherapy.