Comment

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Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of

pemetrexed in combination with cisplatin versus cisplatin alone in
patients with malignant pleural mesothelioma. J Clin Oncol 2003;
21: 263644.
Ladanyi M, Zauderer MG, Krug LM, et al. New strategies in pleural
mesothelioma: BAP1 and NF2 as novel targets for therapeutic
development and risk assessment. Clin Cancer Res 2012; 18: 448590.
Pastan I, Hassan R. Discovery of mesothelin and exploiting it as a target for
immunotherapy. Cancer Res 2014; 74: 290712.
Stahel RA, Weder W, Felley-Bosco E, et al. Searching for targets for the
systemic therapy of mesothelioma. Ann Oncol 2015; 26: 164960.
Ohta Y, Shridhar V, Bright RK, et al. VEGF and VEGF type C play an
important role in angiogenesis and lymphangiogenesis in human
malignant mesothelioma tumours. Br J Cancer 1999; 81: 5461.
Strizzi L, Catalano A, Vianale G, et al. Vascular endothelial growth factor is
an autocrine growth factor in human malignant mesothelioma.
J Pathol 2001; 193: 46875.
Buikhuisen WA, Burgers JA, Vincent AD, et al. Thalidomide versus active
supportive care for maintenance in patients with malignant mesothelioma
after rst-line chemotherapy (NVALT 5): an open-label, multicentre,
randomised phase 3 study. Lancet Oncol 2013; 14: 54351.

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Dubey S, Janne PA, Krug L, et al. A phase II study of sorafenib in malignant

mesothelioma: results of Cancer and Leukemia Group B 30307.
J Thorac Oncol 2010; 5: 165561.
Jahan T, Gu L, Kratzke R, et al. Vatalanib in malignant mesothelioma:
a phase II trial by the Cancer and Leukemia Group B (CALGB 30107).
Lung Cancer 2012; 76: 39396.
Nowak AK, Millward MJ, Creaney J, et al. A phase II study of intermittent
sunitinib malate as second-line therapy in progressive malignant pleural
mesothelioma. J Thorac Oncol 2012; 7: 144956.
Zalcman G, Mazieres J, Margery J, et al, on behalf of the French Cooperative
Thoracic Intergroup (IFCT). Bevacizumab for newly diagnosed pleural
mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study
(MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 2015;
published online Dec 21. http://dx.doi.org/10.1016/S0140-6736(15)01238-6.
Kindler HL, Karrison TG, Gandara DR, et al. Multicenter, double-blind,
placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus
bevacizumab or placebo in patients with malignant mesothelioma.
J Clin Oncol 2012; 30: 250915.
Hellmann MD, Kris MG, Rudin CM. Medians and milestones in describing
the path to cancer cures: telling tails. JAMA Oncol 2015; published online
Nov 19. DOI:10.1001/jamaoncol.2015.4345.

Large-scale screening for somatic mutations in lung cancer

Published Online
January 14, 2016
http://dx.doi.org/10.1016/
S0140-6736(15)01125-3
See Articles page 1415

1354

Lung cancer is the leading cause of cancer-related death

worldwide. More than 85% of cases are classied as nonsmall-cell lung cancer (NSCLC), with predicted 5-year
survival of 16%. However, technological advances in
the past decade, including the introduction of nextgeneration sequencing, have allowed for identication
of several genetic mutations.1 These mutations are
considered to be actionable oncogenic drivers (ie,
treatable with specic drugs) since they cause specic
subclasses of NSCLC, and therefore can be targeted with
selective inhibitors. One example is NSCLC harbouring
mutations in the epidermal growth factor receptor (EGFR)
gene, mainly associated with lung adenocarcinoma. In
view of these advances, chemotherapy can no longer be
regarded as the standard treatment for all patients, but
rather the default treatment for those without oncogenic
driver mutations.2 In an unprecedented endeavour
reported in The Lancet, the French National Cancer
Institute (INCa), together with the French Cooperative
Thoracic Intergroup (IFCT), have reported on a 1-year
nationwide programme assessing testing for EGFR,
HER2 (also known as ERBB2), KRAS, BRAF, and PIK3CA
mutations, as well as ALK rearrangements in NSCLC,
with the aim of selecting genotype-directed therapy and
studying associations with survival.3 This work, by Fabrice
Barlesi and colleagues, builds on earlier studies which
established actionable oncogenic mutations in NSCLC.
EGFR mutations were identied in 17% of 2105 patient
samples screened in a Spanish Lung Cancer Group central

laboratory from 129 institutions in Spain. In this study,

overall survival for 217 patients who received erlotinib (a
tyrosine kinase inhibitor) was 27 months.4 EGFR inhibition
leads to the collapse of downstream signalling pathways
such as mitogen-activated protein kinase (MAPK) and
AKT protein kinase (gure). Other actionable oncogenic
mutations have been reported in lung adenocarcinoma,
including HER2, MET, and RIT1, and fusion oncogenes
involving ALK, ROS1, NRG1, NTRK1, and RET. Screening
should also be performed for KRAS and BRAF mutations
before selecting treatment1,58 (gure). In squamous-cell
carcinoma and small-cell lung carcinomas, several novel
driver mutations are being investigated as potentially
actionable targets: amplication of FGFR1, PIK3CA,9 and
the sequence of the entire 32 kb coding region of DDR2.5,10
DDR2 mutations can be detected at a frequency of 3% in
both adenocarcinoma and squamous-cell carcinoma.11
On the basis of this knowledge, new initiatives for
treatment of lung squamous-cell carcinoma are in
progress, such as the Lung Cancer Master Protocol (LungMAP), a unique publicprivate partnership in the USA,
including the US Food and Drug Administration.12 The
Network Genomic Medicine (NGM) in Cologne, Germany,
was the rst group to describe distribution of genotypes
and survival with targeted therapy compared with
chemotherapy in distinct genotypes.10 Since then, the
NGM has made great progress, implementing genotyping
by next-generation sequencing as well as other initiatives
in implementing genomic-driven treatment trials, such
www.thelancet.com Vol 387 April 2, 2016

Comment

as for ROS1 (EUCROSS; NCT02183870).13 The Lung

Cancer Mutation Consortium (LCMC) determined
the frequency of oncogenic drivers, the proportion of
patients treated with genotype-directed therapy, and
survival in 1007 patients in the USA. LCMC investigators
tracked patients with oncogenic drivers and reported
that most were placed in trials with targeted therapies,
with an overall median survival of 349 years compared
with 238 years for patients with driver mutations but
not treated with targeted therapy, or 208 years for those
with no mutation identied (p<0001).14 The LCMC 2.0
adds ROS1 and RET to the panel of genes being screened
by next-generation sequencing platforms.
In Barlesi and colleagues study,3 28 certied laboratories,
mostly using Sanger sequencing, analysed samples from
17 664 patients with NSCLC. A genetic driver alteration
was recorded in about 50% of the analyses. The presence
of a genetic alteration aected rst-line treatment for 51%
of patients, and was associated with better outcomes, with
median survival of 165 months for patients with a genetic
alteration compared with 118 months for patients
without a genetic alteration (p<00001).3 Breaking down
overall survival according to the type of actionable driver
mutations, median survival was not reached in patients
with EGFR mutations and was 207 months in patients
with ALK rearrangements. These ndings are in agreement
with those of the LCMC study, in which most patients
with EGFR mutations were treated with EGFR tyrosine
kinase inhibitors and those with ALK rearrangements
with crizotinib.14 In Japan, advances in actionable genomic
driver mutations have led to similar initiatives to detect
lung cancer with rare driver oncogenes in advanced nonsquamous NSCLC without EGFR mutations. A nationwide
genomic screening network (LC-SCRUM-Japan) started in
February, 2013, and includes 184 Japanese institutions.
In March, 2015, genomic analysis by next-generation
sequencing multiplexing diagnostics was included.
13 pharmaceutical companies are participating, with the
aim of delivering promising drugs to patients on the basis
of genomic screening.15
The French nationwide IFCT-INCa project, along with
initiatives from the NGM in Germany, the LC-SCRUM in
Japan, and the LCMC in the USA, as well as many single
institutions, private companies, and advocacy groups, are
making great progress in the treatment of lung cancer
and breaking through the barrier of poor survival in
NSCLC. These initiatives are paving the way to solve issues
www.thelancet.com Vol 387 April 2, 2016

Mutations in adenocarcinoma

NTRK1 17%
ROS1 17%
RIT1 22%
DDR2 29%
NRG1 32%

RET 07%
HER2 19%

Mutations in squamous-cell carcinoma

DDR2 3%

PIK3CA
12%

KRAS
255%

ALK 39%
MET
exon 14
42%

PTEN
10%

FGFR1
20%

BRAF
69%

Other or
wild type
55%

Wild type
208%

NF1
81%

EGFR
161%

DDR2

ROS1

ALK

EGFR

Ras

HER2

MET

FGFR1

PI3K

JAK1/2
Raf

AKT

MEK1/2

STAT3

ERK1/2

MTORC1

Legend
Complex
Group/complex
Kinase
Transcription
regulator
Relation

Figure: Genetic mutations and signalling pathways in lung cancer

Current understanding of mutation frequencies in lung cancer, with the range and frequency of mutations
diering between adenocarcinoma (A) and squamous-cell carcinoma (B). A pathway diagram (C) highlights the
main receptor tyrosine kinases currently targeted in non-small-cell lung cancer and associated downstream
signalling pathways, particularly the extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase
(PI3K)/AKT, and signal transducer and activator of transcription 3 (STAT3) pathways.6 HER2 is also known as ERBB2.

of hospital policies, regulatory approval, and insurance

coverage for the benet of patients with NSCLC.5
*Rafael Rosell, Niki Karachaliou
Catalan Institute of Oncology, Hospital Germans Trias i Pujol,
Badalona 08916, Spain (RR); and Autonomous University of
Barcelona, Germans Trias i Pujol Health Sciences Research Institute
and Hospital, Badalona, Spain (NK)
rrosell@iconcologia.net
We declare no competing interests. We thank Mark Kris, Trever Bivona,
Juergen Wolf, Reinhard Buttner, Koichi Goto, and Tetsuya Mitsudomi for
comments on an early draft of this Comment.
1
2

Chen Z, Fillmore CM, Hammerman PS, et al. Non-small-cell lung

cancers: a heterogeneous set of diseases. Nat Rev Cancer 2014; 14: 53546.
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy
as rst-line treatment for European patients with advanced EGFR mutationpositive non-small-cell lung cancer (EURTAC): a multicentre, open-label,
randomised phase 3 trial. Lancet Oncol 2012; 13: 23946.
Barlesi F, Mazieres J, Merlio J-P, et al, for the Biomarkers France
contributors. Routine molecular proling of patients with advanced
non-small-cell lung cancer: results of a 1-year nationwide programme of
the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016; published
online Jan 14. http://dx.doi.org/10.1016/S0140-6736(16)00004-0.

1355

Comment

4
5
6
7
8

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Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor

receptor mutations in lung cancer. N Engl J Med 2009; 361: 95867.
Rosell R, Bivona TG, Karachaliou N. Genetics and biomarkers in
personalisation of lung cancer treatment. Lancet 2013; 382: 72031.
Heist RS, Engelman JA. SnapShot: non-small cell lung cancer.
Cancer Cell 2012; 21: 448.e2.
Cancer Genome Atlas Research Network. Comprehensive molecular
proling of lung adenocarcinoma. Nature 2014; 511: 54350.
Paik PK, Drilon A, Fan PD, et al. Response to MET inhibitors in patients
with stage IV lung adenocarcinomas harboring MET mutations causing
exon 14 skipping. Cancer Discov 2015; 5: 84249.
Scheer M, Bos M, Gardizi M, et al. PIK3CA mutations in non-small cell
lung cancer (NSCLC): genetic heterogeneity, prognostic impact and
incidence of prior malignancies. Oncotarget 2015; 6: 131526.
Clinical Lung Cancer Genome Project (CLCGP), Network Genomic Medicine
(NGM). A genomics-based classication of human lung tumors.
Sci Transl Med 2013; 5: 209ra153.

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Konig K, Peifer M, Fassunke J, et al. Implementation of amplicon parallel

sequencing leads to improvement of diagnosis and therapy of lung cancer
patients. J Thorac Oncol 2015; 10: 104957.
Gandara DR, Hammerman PS, Sos ML, et al. Squamous cell lung cancer:
from tumor genomics to cancer therapeutics. Clin Cancer Res 2015;
21: 223643.
Rosell R, Karachaliou N, Wolf J, et al. ALK and ROS1 non-small-cell lung
cancer: two molecular subgroups sensitive to targeted therapy.
Lancet Respir Med 2014; 2: 96668.
Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic
drivers in lung cancers to select targeted drugs. JAMA 2014;
311: 19982006.
Matsumoto S, Tsuchihara K, Yoh K, et al. A new nationwide genomic
screening system in Japan for the development of targeted therapies
against advanced non-small lung cancers with rare driver mutations.
J Clin Oncol 2014; 32 (suppl): 5s. Abstract 11007.

Lean economies and innovation in mental health systems

Photo courtesy Wagner Ribeiro

Poor access to mental health care is widely reported,

although it diers according to sociopolitical and
economic contexts. In emerging economies, including
Brazil, Russia, India, China, and South Africa (BRICS),
there has been increased public investment in recent
years, but rapid economic growth in these countries has
now slowed. Precarious global transitions aect both
the burden of mental health problems and demand for
services. Innovations prompted by these transitions, in
both high-income and low-income countries, could help
meet population needs during times of economic shock,
whether scarcity or auence.
One approach is to balance protection of services with a
recognition that some mental health tasks can be shifted
to related sectors. Austerity can present an opportunity to
innovate1 and some risks might be averted by prioritising
investment to protect public mental health. In Finland
and the USA, where social benets were maintained and
enactment of parity laws improved access to mental
health care, adverse mental health events seen during
economic crises, including increased suicide, were
avoided.1,2 When there are threats of reduced funding
for mental health systems, tasks such as identication of
mental health problems, making appropriate referrals,
and providing basic treatment and support can be shifted
to related sectors including early education, housing,
primary care, and employment.3,4 With sucient training,
community workers can provide eective rst-line care for
people with severe mental illness, including psychosis.3,5
However, this approach alone is not sucient to meet
population needs. Although task-shifting is not suitable
1356

for all individuals, a tiered approach is useful. The lower

tier can focus on universal care that would target mental
health promotion and support identication of people
with common mental disorders, such as depression and
anxiety. In the top tier, limited specialised resources could
be allocated to people with complex mental health needs,
for example, treatment-resistant psychosis or forensic
cases. When coordinated, such actions can protect mental
health and create psychosocial care networks capable of
inuencing incidence, persistence, and intractability of
mental disorders.6
BRICS have historically invested little in mental
health compared with physical health, but have been
increasingly responsive to calls for augmenting or
redeploying spending. Given their leaner economies,
doing so has required innovation from which richer
countries might learn. Five factors that have played a
part in psychosocial care networks in some BRICS could
be adapted elsewhere to promote mental health. First,
embedding services in communities with integration of
community mental health workers, support for family
members, and service delivery through non-traditional
platforms. Second, judicious use of specialised workers;
utilising psychiatrists in settings with few human
and nancial resources in teaching, supervision, or
consultative roles rather than direct provision of care.
Third, improved task-sharing and co-responsibility; teams
decide together what resources and involvement are
needed to best respond to individuals needs with nontraditional providers. Fourth, active outreach through
periodic home visits in the community to identify
www.thelancet.com Vol 387 April 2, 2016