PRIMER Non-small-cell lung cancer Cesare Gridelli1, Antonio Rossi1, David P. Carbone2, Juliana Guarize3, Niki Karachaliou4, Tony Mok5, Francesco Petrella3, Lorenzo Spaggiari3 and Rafael Rosell4 Abstract | Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC), a heterogeneous class of tumours, represents approximately 85% of all new lung cancer diagnoses. Tobacco smoking remains the main risk factor for developing this disease, but radon exposure and air pollution also have a role. Most patients are diagnosed with advanced-stage disease owing to inadequate screening programmes and late onset of clinical symptoms; consequently, patients have a very poor prognosis. Several diagnostic approaches can be used for NSCLC, including X‑ray, CT and PET imaging, and histological examination of tumour biopsies. Accurate staging of the cancer is required to determine the optimal management strategy, which includes surgery, radiochemotherapy, immunotherapy and targeted approaches with anti-angiogenic monoclonal antibodies or tyrosine kinase inhibitors if tumours harbour oncogene mutations. Several of these driver mutations have been identified (for example, in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)), and therapy continues to advance to tackle acquired resistance problems. Also, palliative care has a central role in patient management and greatly improves quality of life. For an illustrated summary of this Primer, visit: http://go.nature.com/rWYFgg
Correspondence to C.G. e-mail:
[email protected] Division of Medical Oncology, S.G. Moscati Hospital, Contrada Amoretta, 83100 Avellino, Italy. Article number: 15009 doi:10.1038/nrdp.2015.9 Published online 21 May 2015
Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide1. Owing to the absence of clinical symptoms and effective screening programmes, most lung cancers are diagnosed at an advanced stage. Accurate staging of lung cancer is, however, vital because treatment options and prognosis depend on it. The TumourNode-Metastasis (TNM) classification system forms the basis for staging, and it was updated by the International Association for the Study of Lung Cancer staging committee after evaluation of outcomes in an extensive worldwide database of patients. The current (seventh) edition classifies all histotypes of lung cancer 2,3 (TABLE 1). Non-small-cell lung cancer (NSCLC), which includes adenocarcinoma (gland-forming), squamous cell carcinoma and large-cell carcinoma histosubtypes (FIG. 1), represents approximately 85% of all new lung cancer cases. Small-cell lung cancer (SCLC) accounts for the remaining 15% (REFS 4,5). This pathological classification of lung cancer is continuously adapting, and specific terminology and criteria are used to distinguish squamous cell carcinoma from adenocarcinoma, particularly in poorly differentiated tumours. Defining the exact histological subtype of lung cancer has become more important in the past few years owing to the availability of an increasing number of therapeutic agents for specific subtypes. Indeed, tumours that previously failed to be subtyped because of the lack of clear squamous or adenocarcinoma morphology can now be re‑evaluated
using a limited immunohistochemical workup to preserve tissue for molecular testing 5. Our understanding of lung cancer is rapidly evolving and increasing, particularly in relation to the molecular underpinnings of this disease. This enhanced knowledge will prove to be essential for developing a complete and accurate TNM classification system5,6, and for improvements in patient care and clinical trial design. In this Primer, we discuss the molecular mechanisms, risk factors, diagnostic procedures and screening methods for NSCLC. We describe the standard of care for each stage of this disease and its impact on patient quality of life, as well as the emerging technologies and advances that are likely to influence treatment in the next 5–10 years.
Epidemiology Lung cancer accounts for more than 1.8 million newly diagnosed cancer cases (13% of the total diagnosed cancer cases) and 1.6 million cancer-related deaths (19.4% of the total) worldwide every year 1. In the United States, the estimated number of new cases of lung cancer in 2014 was 224,210 with 159,260 estimated deaths7. In Europe, the estimated number of new cases of lung cancer in 2012 was 410,000 with 353,000 estimated deaths8. The estimated incidence and mortality of lung cancer in Africa in 2012, derived from GLOBOCAN 2012 (http:// globocan.iarc.fr/Default.aspx), was 30,314 and 27,083, respectively. These surprisingly low numbers for lung
NATURE REVIEWS | DISEASE PRIMERS
VOLUME 1 | 2015 | 1 © 2015 Macmillan Publishers Limited. All rights reserved
PRIMER Author addresses Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy. 2 James Thoracic Center, Ohio State University Medical Center, Columbus, Ohio, USA. 3 Department of Thoracic Surgery, European Institute of Oncology, Milan, Italy. 4 Catalan Institute of Oncology, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain. 5 Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong. 1
cancer in Africa are probably due to under-reporting rather than low incidence. In Asia, 1,045,000 detections and 936,051 deaths were observed1. Although the incidence of lung cancer is decreasing in developed countries, rates are rising in less developed parts of the world (Africa, South America, Eastern Europe and China). Indeed, in 2012, 58% of the estimated 1.8 million new cases worldwide occurred in less developed regions (12.9% of the total)1. A possible explanation for this finding is that these countries have less rigorous smoking regulations. Nevertheless, the highest lung cancer incidence rates in men are in North America, Europe, eastern Asia, Argentina and Uruguay, and the lowest rates are in sub-Saharan Africa (FIG. 2). In women, the highest lung cancer rates are in North America, northern Europe, Australia, New Zealand and China1,9. Furthermore, in the past 30 years, an epidemiological shift from squamous histology to adenocarcinoma histology has been noted. This shift is believed to be due to changes in smoking behaviour and cigarette manufacturing practices10,11. Specifically, filter cigarettes and ‘light’ cigarettes enable the smoker to take a deeper aspiration; the smoke reaches the deeper parts of the bronchi and alveoli, where adenocarcinoma arises. Table 1 | Stage groupings for non-small-cell lung cancer* Stage
Tumour (T)
Node (N)
Metastasis (M)
0
T in situ
N0
M0
Ia
T1a, T1b
N0
M0
Ib
T2a
N0
M0
IIa
T1a, T1b
N1
M0
T2a
N1
M0
T2b
N0
M0
T2b
N1
M0
T3
N0
M0
T1, T2
N2
M0
T3
N1, N2
M0
T4
N0, N1
M0
T4
N2
M0
Any T
N3
M0
Any T
Any N
M1a
Any T
Any N
M1b
IIb IIIa
IIIb IV
*According to the seventh edition of the Tumour-Node-Metastasis (TNM) classification system2.
Mechanisms/pathophysiology The lung is a complex yet fragile organ composed of many cell types with discrete functions that support gas exchange. With 2,000 km of airway and more than 50 m2 of extremely thin alveolar membranes, the efficient passage of oxygen and carbon dioxide between the blood and the environment occurs against a backdrop of exposure to toxic gases and fine particulate contaminants as well as infectious agents. Large inhaled particulates are cleared by ciliary action in the larger airways, whereas infectious agents are eliminated by immune and phagocytic cells. Mucus-producing cells and neuroendocrine cells also have roles in maintaining the gas exchange function. This complex community of cells can undergo an accumulation of cell autonomous and microenvironmental adaptations that alter the balance of cell division and death and enable avoidance of immune recognition, leading to cancer 12. The accumulation of regulatory alterations that lead to cancer can arise from years of exposure to tobacco smoke, resulting in structural damage that manifests as chronic obstructive pulmonary disease and emphysema. Smoke exposure can lead to a well-characterized series of morphological changes of the bronchial epithelium progressing from basal cell hyperplasia to metaplasia, severe dysplasia to carcinoma in situ and, finally, frank carcinoma13. This series of changes is primarily associated with the squamous subtype of NSCLC. By contrast, adenocarcinomas can also arise in the context of heavy carcinogen exposure and underlying lung damage, but they are generally considered to be the dominant subtype in never-smokers with low carcinogen exposure14. The progression of adenocarcinomas is associated with less well-characterized premalignant lesions called atypical adenomatous hyperplasia. New concepts for small solitary adenocarcinomas are introduced such as adenocarcinoma in situ with pure lepidic growth and minimally invasive adenocarcinoma with predominantly lepidic growth and ≤5 mm invasion4,15. The pathological classification of lung cancer is continually changing, with a need for specific terminology and criteria to distinguish squamous cell carcinoma from adenocarcinoma, particularly in poorly differentiated tumours16. SCLCs also typically occur in the context of heavy carcinogen exposure, but they arise from the rare pulmonary neuroendocrine cells and do not have well-characterized preneoplastic lesions. Genetic alterations and pathways A wide variety of lung cancers with different character istics exist, ranging from relatively indolent and surgically resectable SCLCs to highly aggressive and widely metastatic NSCLCs. The identification of driver oncogene mutations in a subset of tumours was pivotal in understanding these differences in lung cancer. These acquired genetic mutations in kinases result in constitutive signalling and, in susceptible cells, this leads to oncogenic transformation that is nearly independent of other alterations. Oncogenes implicated in NSCLC include activating mutations in the epidermal growth factor receptor (EGFR) gene and translocations of the
2 | 2015 | VOLUME 1
www.nature.com/nrdp © 2015 Macmillan Publishers Limited. All rights reserved
PRIMER Lung cancer 15%
85%
Small-cell lung cancer 30%
Non-small-cell lung cancer 70% Non-squamous
Squamous 10%
90%
Large-cell carcinoma ■ Large-cell neuroendocrine carcinoma
Adenocarcinoma ■ Mixed subtypes ■ Lepidic (non-mucinous or mucinous) ■ Acinar ■ Papillary ■ Micropapillary ■ Solid
Figure 1 | Lung cancer classification. Terminology and Nature Reviews | Disease Primers criteria for adenocarcinoma, squamous cell carcinoma and large-cell carcinoma in small biopsies and cytology5.
anaplastic lymphoma kinase (ALK) gene. Translocations of ALK place the ALK kinase domain under the control of 5′ sequences and promoter elements of multiple other partners, most commonly echinoderm microtubuleassociated protein-like 4 (EMAP4; encoded by EMAL4), but also kinesin 1 heavy chain (UKHC; encoded by KIF5B), among others 17. Comprehensive genomic studies have determined the genomic landscape of lung cancers18–22 (FIG. 3). Lung tumours from smokers have among the highest number of somatic alterations, with approximately ten mutations per megabase. Tumours from neversmokers have approximately one-tenth the number of
somatic mutations as those from smokers. At this level of analytic detail, every tumour is unique, and a more comprehensive understanding of the roles of these abnormalities should result in better therapies in the future. The EGFR and ALK driver abnormalities occur primarily in adenocarcinomas (10–60%), with a strong variation by smoking habits (more frequent in neversmokers)23. This variation also extends to geographical region; the prevalence of these driver abnormalities is low in white individuals of European descent (~10%) and high in those of Asian descent (~60%) for unclear reasons. Several targeted therapies have been developed for tumours harbouring EGFR and ALK mutations, which have a very high fractional response rate. However, not all mutations are alike (FIG. 4). The most common EGFR mutations are the exon 19 deletion (E746–A750), and the exon 21 (L858R) and exon 18 (G719C, G719S, G719A) substitutions, all of which are responsive to therapy 23. However, the exon 20 insertion is also a driver mutation, but it is not inhibited by any of the current therapies24. Tumours eventually acquire resistance to these targeted therapies; however, the mechanisms by which resistance occurs are not yet completely understood. Nevertheless, the most common resistance mutation that arises in EGFR-mutated lung cancers is the T790M mutation (also on exon 20), and highly effective third-generation inhibitors are now available25. It is fascinating to note that the same EGFRT790M mutation that causes acquired resistance to first-generation EGFR inhibitors is rarely seen in the germ line, and thus is rarely associated with inherited susceptibility to lung cancer 26–28. Less common abnormalities have also been established as targets, including translocations of RET, ROS1 and receptor tyrosine kinases, mutations in BRAF, MET (encoding the hepatocyte growth factor (HGF) receptor) and HER2 (also known as ERBB2), and amplifications
Annual incidence per 100,000 people 0–10 11–20 21–30 31–40 41–>50
Nature Reviews | Disease Primers Figure 2 | Annual incidence of lung cancer per 100,000 people in 2012. Figure from REF. 168 , Nature Publishing Group. Data from GLOBOCAN 2012 (http://globocan.iarc.fr/Default.aspx).
NATURE REVIEWS | DISEASE PRIMERS
VOLUME 1 | 2015 | 3 © 2015 Macmillan Publishers Limited. All rights reserved
PRIMER a 100
Histological subtypes Lung adenocarcinoma Lung squamous cell carcinoma Small-cell lung cancer
Copy number alterations
90 80 70 60 50 40 30 20 10
TP 53 M R B ut 1 SO Mu PI X A t K3 m CA p KR Am AS p TP Mu 6 CD 3 A t K m CD N2A p KN D 2 el KE A M AP ut ST 1 M K1 ut FG 1 M FR ut 1 A NF mp 1 EG Mu NO FR t TC Mu H t PI 1 M K3 CA ut BR Mu AR AF M t SM ID1 ut AR A M CA ut 4 M Mu ET t HE Am R2 p Am p
0
Mutation
b
ALK (2–4%) Lung adenocarcinoma
Lung squamous cell carcinoma
FGFR1 (
