Indian J Med Res 141, January 2015, pp 5-7

Editorial

Lung cancer: Prevalent trends & emerging concepts

Lung cancer is one of the commonest cancers and in the histological characterization of lung cancer in
cause of cancer related deaths all over the world. It view of newer histology guided therapeutic modalities
accounts for 13 per cent of all new cancer cases and and genomic classification6,7. The use of generic terms
19 per cent of cancer related deaths worldwide. There non small cell and small cell lung cancer (NSCLC and
were 1.8 million new lung cancer cases estimated to SCLC), is being challenged8. In the Western countries
occur in 20121. In India, lung cancer constitutes 6.9 and most of the Asian countries9,10 adenocarcinoma
per cent of all new cancer cases and 9.3 per cent of all has surpassed squamous cell carcinoma9,10. This shift
cancer related deaths in both sexes, it is the commonest might be attributable partly to the smoking habits,
cancer and cause of cancer related mortality in men, particularly filtered cigarettes; moreover, there is also
with the highest reported incidences from Mizoram in increasing incidence of lung cancer in females and non
both males and females (Age adjusted rate 28.3 and smokers9,11,12. Most of the previous Indian studies have
28.7 per 100,000 population in males and females, described squamous cell carcinoma as the commonest
respectively)2. The time trends of lung cancer show histology13,14 however, some recent studies from
a significant rise in Delhi, Chennai and Bengaluru in two major centres are showing a changing pattern in
both sexes. The incidence and pattern of lung cancer India15,16. We have reported that adenocarcinoma has
differ as per geographic region and ethnicity and become the commonest subtype provided a careful
largely reflect the prevalence and pattern of smoking. pathology review is done16. The use of appropriate
The overall 5-year survival rate of lung cancer is dismal immunohistochemistry improves the histological sub-
with approximately 15 per cent in developed countries typing and should be used more often.
and 5 per cent in developing countries3. screening
At present more than 50 per cent of lung
by low dose computed tomography (CT) in high risk
adenocarcinomas and about a third of squamous
population demonstrated a relative risk reduction of
cell carcinomas can be characterized based on the
20 per cent in lung cancer mortality but with a false
mutation profile17. This molecular classification has
positive rate of 96 per cent4. In India where tuberculosis
led to development of targeted therapeutic strategies.
is prevalent, the applicability of such screening tool
Mutations in epidermal growth factor receptors (EGFR)
is questionable. Development of newer non invasive
best illustrate the therapeutic importance of molecular
methods/ biomarkers for early diagnosis and screening
classification. EGFR mutations strongly predict the
of high risk population is warranted.
efficacy of inhibitors of EGFR with response rates
Over the years, our understanding of disease higher than 70 per cent seen in many studies18. Two
biology has evolved. The histological classification prospective, randomized, phase 3 studies of patients
is now stretching to molecular classification. Newer with untreated metastatic NSCLC (Iressa Pan-Asia
molecular targets and driver mutations have been Study and WJTOG3405) have found that first-line
identified which play a major role in pathogenesis that gefitinib leads to longer progression-free survival (PFS)
can be addressed with therapeutic interventions5. These in patients with tumours positive for EGFR mutations
advancements have led to the development of more than does platinum based doublet chemotherapy18,19.
individualized treatment modalities, the so called era of Similarly erlotinib has also shown better response
“personalized medicine”. There has been a new interest rates and PFS as compared to chemotherapy for first

5
6 INDIAN J MED RES, january 2015

line treatment in EGFR mutation positive advanced situations and can be used for mutation testing and
NSCLC20,21. therapeutic monitoring36. The genetic heterogeneity
among various ethnic populations has brought to the
genomic expression, mutational and proteomic
stage the issue of molecular characterizations in lung
profiling studies, as well as various mouse lung tumour
cancer and the need for regional studies.
models have led to the identification of additional
molecular driver mutations22,23. Another such example Prabhat Singh Malik1 & Vinod Raina2*
of mutation driven therapy is targeting EML4-ALK 1
Department of Medical Oncology,
(echinoderm microtubule-associated protein like Dr B.R. Ambedkar Institute Rotary Cancer Hospital,
4-anaplastic lymphoma kinase) rearrangement. All India Institute of Medical Sciences
Biologically, EML4-ALK fusions result in protein New Delhi 110 029 & 2Department of Medical
oligomerisation and constitutive activation of the Oncology & Haematology, Fortis Memorial Research
kinase24. The frequency of EML4-ALK translocation Institute Sector 44, Gurgaon 122 002, Haryana, India
ranges from 3 to 7 per cent in unselected NSCLC24.
*
For correspondence:
Detection methods include reverse-transcriptase vinodraina@hotmail.com
PCR, fluorescence in-situ hybridization, and
immunohistochemistry. EML4-ALK translocations References
are generally found in tumours with wild type EGFR 1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S,
and KRAS25. Tyrosine kinase inhibitor targeting ALK, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence
and Mortality Worldwide: IARC CancerBase No. 11. Lyon,
crizotinib has shown a response rate of 65 per cent in France: International Agency for Research on Cancer; 2013.
previously treated patients of NSCLC that harbour Available from: http://globocan.iarc.fr, accessed on January
ALK rearrangement and has been approved for this 21, 2014.
indication26,27. Another ALK inhibitor certinib has 2. National Cancer Registry Programme. Three Year Report
also been recently approved based on its encouraging of Population Based Cancer Registries: 2009-2011. Indian
Council of Medical Research; 2013. Available from: http://
response rates of 56 per cent in patients who have www.ncrpindia.org, accessed on January 21, 2014.
progressed on crizotinib28.
3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,
The prevalence of specific mutation varies among 2002. CA Cancer J Clin 2005; 55 : 74-108.
various ethnic and geographic populations. For 4. National Lung Screening Trial Research Team, Aberle DR,
example, the prevalence of EGFR mutation is around Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM,
et al. Reduced lung-cancer mortality with low-dose computed
10 per cent in Caucasians while it has been reported tomographic screening. N Engl J Med 2011; 365 : 395-409.
to be as high as 60 per cent in Asians29,30. In India the 5. Pao W, Girard N. New driver mutations in non-small-cell lung
frequency of EGFR mutations has been found to be cancer. Lancet Oncol 2011; 12 : 175-80.
between 25-50 per cent in various studies31-34. 6. Standfield L, Weston AR, Barraclough H, Van Kooten M,
Pavlakis N. Histology as a treatment effect modifier in
With these advances, the validation of targeted advanced non-small cell lung cancer: a systematic review of
therapeutic compounds should ideally parallel with the evidence. Respirol Carlton Vic 2011; 16 : 1210-20.
the development of predictive biomarkers35. In this 7. Scagliotti G, Brodowicz T, Shepherd FA, Zielinski C,
context, the availability of high quality molecular Vansteenkiste J, Manegold C, et al. Treatment-by-histology
testing is pivotal and should be integrated into treatment interaction analyses in three phase III trials show superiority
of pemetrexed in nonsquamous non-small cell lung cancer.
guidelines. The accessibility of such testing to majority J Thorac Oncol 2011; 6 : 64-70.
of our population is largely limited due to the high cost.
8. Ettinger DS. NCCN Clinical Practice Guidelines in Oncology
Lack of quality control and uniformity of techniques and for Non Small Cell Lung Cancer, Ver 2.2012. National
standards among various laboratories are also issues of Comprehensive Cancer Network; 2012. Available from: www.
concern. Bulk use of these new techniques are likely nccn.com, accessed on January 21, 2014.
to reduce the cost of these tests. Adequacy of tumour 9. Valaitis J, Warren S, Gamble D. Increasing incidence of
tissue for molecular profiling is an important issue and adenocarcinoma of the lung. Cancer 1981; 47 : 1042-6.
even more relevant in lung cancer where the tissue 10. Janssen-Heijnen MLG, Coebergh J-WW. The changing
epidemiology of lung cancer in Europe. Lung Cancer 2003;
yield is limited by small core biopsies. Judicious use of 41 : 245-58.
immunohistochemistry and conservation of samples for
11. Thun MJ, Henley SJ, Burns D, Jemal A, Shanks TG, Calle EE.
molecular testing would be helpful. Cell free circulating Lung cancer death rates in lifelong nonsmokers. J Natl Cancer
tumour DNA is also emerging as a useful tool in these Inst 2006; 98 : 691-9.
 malik & raina: Lung cancer: Prevalent trends & emerging concepts 7

12. Wakelee HA, Chang ET, Gomez SL, Keegan TH, Feskanich 24. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y,
D, Clarke CA, et al. Lung cancer incidence in never smokers. Ishikawa S, et al. Identification of the transforming EML4-
J Clin Oncol 2007; 25 : 472-8. ALK fusion gene in non-small-cell lung cancer. Nature 2007;
13. Behera D, Balamugesh T. Lung cancer in India. Indian J Chest 448 : 561-6.
Dis Allied Sci 2004; 46 : 269-81. 25. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR,
14. Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Costa DB, Heist RS, et al. Clinical features and outcome of
Unchanging clinico-epidemiological profile of lung cancer in patients with non-small-cell lung cancer who harbor EML4-
north India over three decades. Cancer Epidemiol 2010; 34 : ALK. J Clin Oncol 2009; 27 : 4247-53.
101-4. 26. Camidge DR, Bang Y-J, Kwak EL, Iafrate AJ, Varella-Garcia
15. Noronha V, Dikshit R, Raut N, Joshi A, Pramesh CS, George M, Fox SB, et al. Activity and safety of crizotinib in patients
K, et al. Epidemiology of lung cancer in India: focus on the with ALK-positive non-small-cell lung cancer: updated results
differences between non-smokers and smokers: a single-centre from a phase 1 study. Lancet Oncol 2012; 13 : 1011-9.
experience. Indian J Cancer 2012; 49 : 74-81. 27. Shaw AT, Kim D-W, Nakagawa K, Seto T, Crinó L, Ahn M-J,
16. Malik PS, Sharma MC, Mohanti BK, Shukla NK, Deo S, et al. Crizotinib versus chemotherapy in advanced ALK-
Mohan A, et al. Clinico-pathological profile of lung cancer positive lung cancer. N Engl J Med 2013; 368 : 2385-94.
at AIIMS: a changing paradigm in India. Asian Pac J Cancer 28. Shaw AT, Kim D-W, Mehra R, Tan DSW, Felip E, Chow
Prev 2013; 14 : 489-94. LQM, et al. Ceritinib in ALK-rearranged non-small-cell lung
17. Stella GM, Luisetti M, Pozzi E, Comoglio PM. Oncogenes in cancer. N Engl J Med 2014; 370 : 1189-97.
non-small-cell lung cancer: emerging connections and novel 29. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal
therapeutic dynamics. Lancet Respir Med 2013; 1 : 251-61. growth factor receptor mutations in lung cancer. Nat Rev
18. Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo Cancer 2007; 7 : 169-81.
N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary 30. Shi Y, Au JS-K, Thongprasert S, Srinivasan S, Tsai C-M, Khoa
adenocarcinoma. N Engl J Med 2009; 361 : 947-57. MT, et al. A prospective, molecular epidemiology study of
19. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, EGFR mutations in Asian patients with advanced non-small-
Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in cell lung cancer of adenocarcinoma histology (PIONEER).
patients with non-small-cell lung cancer harbouring mutations J Thorac Oncol 2014; 9 : 154-62.
of the epidermal growth factor receptor (WJTOG3405): an 31. Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare
open label, randomised phase 3 trial. Lancet Oncol 2010; N, Joshi A, et al. EGFR mutations in Indian lung cancer
11 : 121-8. patients: clinical correlation and outcome to EGFR targeted
20. Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, et al. therapy. PloS One 2013; 8 : e61561.
Erlotinib versus chemotherapy as first-line treatment for
32. Veldore VH, Rao RM, Kakara S, Pattanayak S, Tejaswi R,
patients with advanced EGFR mutation-positive non-small-
Sahoo R, et al. Epidermal growth factor receptor mutation in
cell lung cancer (OPTIMAL, CTONG-0802): a multicentre,
non-small-cell lung carcinomas: a retrospective analysis of
open-label, randomised, phase 3 study. Lancet Oncol 2011;
1036 lung cancer specimens from a network of tertiary cancer
12 : 735-42.
care centers in India. Indian J Cancer 2013; 50 : 87-93.
21. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B,
33. Chougule A, Prabhash K, Noronha V, Joshi A, Thavamani A,
Felip E, et al. Erlotinib versus standard chemotherapy as first-
Chandrani P, et al. Frequency of EGFR mutations in 907 lung
line treatment for European patients with advanced EGFR
mutation-positive non-small-cell lung cancer (EURTAC): adenocarcioma patients of Indian ethnicity. PloS One 2013;
a multicentre, open-label, randomised phase 3 trial. Lancet 8 : e76164.
Oncol 2012; 13 : 239-46. 34. Sahoo R, Harini VV, Babu VC, Patil Okaly GV, Rao S,
22. Motoi N, Szoke J, Riely GJ, Seshan VE, Kris MG, Rusch Nargund A, et al. Screening for EGFR mutations in lung
VW, et al. Lung adenocarcinoma: modification of the 2004 cancer, a report from India. Lung Cancer 2011; 73 : 316-9.
WHO mixed subtype to include the major histologic subtype 35. Li T, Kung H-J, Mack PC, Gandara DR. Genotyping and
suggests correlations between papillary and micropapillary genomic profiling of non-small-cell lung cancer: implications
adenocarcinoma subtypes, EGFR mutations and gene for current and future therapies. J Clin Oncol 2013; 31 :
expression analysis. Am J Surg Pathol 2008; 32 : 810-27. 1039-49.
23. Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar 36. Oxnard GR, Paweletz CP, Kuang Y, Mach SL, O’Connell A,
JW, Lizak MJ, et al. Induction and apoptotic regression of Messineo MM, et al. Noninvasive detection of response and
lung adenocarcinomas by regulation of a K-Ras transgene in resistance in EGFR-mutant lung cancer using quantitative
the presence and absence of tumor suppressor genes. Genes next-generation genotyping of cell-free plasma DNA. Clin
Dev 2001; 15 : 3249-62. Cancer Res 2014; 20 : 1698-705.