Small-cell lung cancer

Abstract

Small-cell lung cancer (SCLC) represents about 15% of all lung cancers and is marked by an exceptionally high proliferative rate, strong predilection for early metastasis and poor prognosis. SCLC is strongly associated with exposure to tobacco carcinogens. Most patients have metastatic disease at diagnosis, with only one-third having earlier-stage disease that is amenable to potentially curative multimodality therapy. Genomic profiling of SCLC reveals extensive chromosomal rearrangements and a high mutation burden, almost always including functional inactivation of the tumour suppressor genes TP53 and RB1. Analyses of both human SCLC and murine models have defined subtypes of disease based on the relative expression of dominant transcriptional regulators and have also revealed substantial intratumoural heterogeneity. Aspects of this heterogeneity have been implicated in tumour evolution, metastasis and acquired therapeutic resistance. Although clinical progress in SCLC treatment has been notoriously slow, a better understanding of the biology of disease has uncovered novel vulnerabilities that might be amenable to targeted therapeutic approaches. The recent introduction of immune checkpoint blockade into the treatment of patients with SCLC is offering new hope, with a small subset of patients deriving prolonged benefit. Strategies to direct targeted therapies to those patients who are most likely to respond and to extend the durable benefit of effective antitumour immunity to a greater fraction of patients are urgently needed and are now being actively explored.

Figures

Fig. 1 |. Common sites of metastasis in SCLC.

Primary small-cell lung cancer (SCLC) tumours tend to be centrally located and are often bulky at presentation. Common sites of metastatic spread include lymphatic spread to hilar and mediastinal lymph nodes and haematogenous spread to the contralateral lung, the brain, liver, adrenal glands and bone. Circulating tumour cells are common in patients with SCLC and are found as both isolated cells and small clusters. RBC, red blood cell.

Fig. 2 |. SCLC incidence and survival statistics.

a | Age-adjusted incidence of small-cell lung cancer (SCLC) in the USA for the period 1975–2017. SCLC incidence in the USA has been declining following trends in cigarette use. Although SCLC was substantially more common in men than in women in the 1980s, the difference in incidence between the sexes has narrowed to essentially equal disease incidence by 2017. Data are from the Surveillance, Epidemiology, and End Results (SEER) registry database. b | SCLC survival probability over time by stage at time of diagnosis. SCLC survival according to clinical tumour–node–metastasis (TNM) stage using Union for International Cancer Control eighth edition criteria. An alternative staging system, that of the Veterans Administration Lung Study Group (VALSG), distinguishes between limited-stage disease (Limited; confined to one hemithorax and a single radiation port) and extensive-stage disease (Ex). TNM stages I–III generally correspond to limited-stage disease and TNM stage IV to extensive-stage disease in the VALSG staging system (vertical colour bar). The disease frequency at diagnosis by TNM stage I–IV is indicated. Part b adapted with permission from REF., Elsevier.

Fig. 3 |. Major genetic alterations and molecular subtypes of SCLC.

a | The inactivation of RB1 and TP53 (encoding retinoblastoma-associated protein (RB) and p53, respectively) is a near-ubiquitous event in human small-cell lung cancer (SCLC) tumours. Four major molecular subtypes, SCLC-A, SCLC-N, SCLC-P and SCLC-Y, have been described on the basis of high expression of the transcription factors ASCL1, NEUROD1, POU2F3 and YAP1, respectively. SCLC-P and SCLC-Y show a less neuroendocrine phenotype than SCLC-A and SCLC-N. Within the less/non-neuroendocrine category, a rare subtype with high expression of the transcription factor ATOH1 has been reported. SCLC-A tumours have been proposed to comprise two distinct subtypes (SCLC-A and SCLC-A2), with SCLC-A2 distinguished from SCLC-A by its expression of other factors, such as HES1 (REF.131). A few other genetic and epigenetic alterations have been associated with specific subtypes, including the differential expression of MYC family members and mutations in NOTCH family genes, but most recurrent mutations are found in all subtypes. b | Chromosome level copy-number alterations reported by clinical next-generation sequencing of tumours from 409 patients with SCLC. Amplified genes (AMP; red) and homozygous deleted genes (HOMDEL; blue) are plotted for each chromosome. Selected genes of interest, with chromosomal locations and frequency in SCLC tumours (percentage in parentheses) are indicated. Data in part b are from MSK-IMPACT sequencing.

Fig. 4 |. Histopathology of SCLC tumours.

a | A prototypical ‘pure’ small-cell lung cancer (SCLC), as defined by the WHO histopathological classification of SCLC. This tumour demonstrates expression of the classic neuroendocrine markers CD56 and chromogranin A (CHGA). INSM1 is a neuroendocrine marker that is positive in two of the four major molecular subtypes of SCLC, SCLC-A and SCLC-N, which are defined by their high expression of the transcription factors ASCL1 and NEUROD1, respectively. In this example, additional staining reveals consistent expression of ASCL1, with scattered NEUROD1-positive cells. b | Combined SCLC. This example demonstrates a predominant area with classic SCLC features, including the expression of CD56 and INSM1, along with a discrete subdomain with contrasting squamous (SQ) cell carcinoma features, including a more abundant cytoplasm and the expression of cytokeratin 5 (CK5), CK6 and p40. H&E, haematoxylin and eosin. Images courtesy of Natasha Rekhtman (Memorial Sloan Kettering Cancer Center, USA).

Fig. 5 |. Approaches to SCLC treatment by stage.

Drugs that received full and accelerated FDA approvals are included. Rare cases of small-cell lung cancer (SCLC) presenting as isolated pulmonary nodules (tumour–node–metastasis (TNM) stage I) may be amenable to surgical resection or treatment with stereotactic ablative radiotherapy (SABR) and adjuvant chemotherapy. More commonly, localized or locally advanced disease (TNM stages I–III) is treated with concomitant chemoradiotherapy (ChemoRT), with consideration of prophylactic cranial irradiation (PCI) in responding patients. Metastatic disease (TNM stage IV) is treated with chemotherapy with or without a PDL1 inhibitor (PDL1i; chemoIO), followed by maintenance PDL1i therapy for up to 1 year. The role of consolidative chest radiotherapy (Consolidation RT) in the context of chemoIO is unclear. For recurrent disease, current approved agents for second-line treatment in the USA include topotecan and lurbinectedin; for third-line and beyond, the indicated anti-PD1 immunotherapy drugs can be considered but their role is also unclear in patients treated with first-line chemoIO.

Fig. 6 |. Representative therapeutic targets of interest in SCLC.

a | Antitumour immunity. Antibodies disrupting the PD1–PDL1 interaction have demonstrated clinical efficacy in small-cell lung cancer (SCLC). An antibody blocking the T cell-inhibitory receptor TIGIT and a bispecific T cell engager (BiTE) cross-targeting DLL3 on SCLC tumour cells and CD3 on T cells are currently in clinical trials in patients with SCLC (phase III NCT04256421 and phase I NCT03319940, respectively). Antibodies blocking CD47 , the ‘don’t-eat-me’ signal for macrophages, have shown activity in preclinical models. b | Cell cycle and DNA damage repair pathways. Concomitant loss of TP53 and RB1 in SCLC abrogates multiple cell cycle checkpoints, increasing the dependence on remaining regulators of proliferation and DNA damage repair. Many key targets highlighted are being actively pursued in completed and upcoming clinical trials. The effect of EZH2 is indirect via the modulation of SLFN11 (REF.77). c | Growth and survival signalling pathways. Dependency screens implicate PKA and mTOR as essential kinases in SCLC,. BCL-2, a key regulator of apoptosis, is highly expressed in many SCLC tumours, and several studies suggest synergy between the inhibition of PI3K–mTOR and BCL-2 in SCLC,,. This strategy, targeting mTOR and BCL-2, is currently being tested in a phase I/II trial (NCT03366103). d | Epigenetic regulators. The histone acetyltransferases CREBBP and EP300 are frequent and mutually exclusive targets of inactivating mutations in SCLC. Preclinical data support the increased sensitivity of these CREBBP-inactive or EP300-inactive tumours to histone deacetylase inhibitors. The inhibition of the histone demethylase LSD1 in SCLC cell lines activates NOTCH signalling, inhibits ASCL1 expression and may have subtype-selective activity in SCLC (not shown). The histone methyltransferase EZH2 is highly expressed in SCLC and is implicated in both SCLC chemoresistance and immune escape. EZH2 inhibition with chemotherapy is currently being explored in a phase I/II clinical trial of patients with recurrent SCLC (NCT038979798).