A chi os
de
B onconeumología
60
(2024)
88–94
www.a chb onconeumol.o g
O iginal
A icle
Compa ison
o
Clinical
and
Gene ic
Cha ac e is ics
Be ween
Younge
and
Olde
Lung
Cance
Pa ien s
C is ina
Candal-Ped ei aa,b,
Albe o
Ruano-Ra inaa,b,c,∗,
Vi ginia
Cal o
de
Juand,
Manuel
Coboe,
José
Manuel
T igoe,
Del ys
Rod íguez-Ab eu ,
Anna
Es i al ,
En ic
Ca ce enyg,
Ma c
Cucu ullg,
Ra ael
López
Cas oh,
And ea
Medinah,
Rosa io
Ga cía
Campeloi,
Pa icia
Co dei o
Gonzálezi,
Ampa o
Sánchez-Gas aldoj,
Joaquim
Bosch-Ba e ak,
Ba omeu
Massu íl,
Manuel
Dóminem,
Ca los
Campsn,
Ana
Lau a
O egao,
Al edo
Sánchez-He nándezp,
Ma ía
Gui ado
Risue˜
noq,
Edel
del
Ba co
Mo illo ,
Albe o
Ga ido
Fe nándezs,
Ma iano
P o enciod
aP e en i e
Medicine
and
Public
Heal h,
Uni e si y
o
San iago
de
Compos ela,
San iago
de
Compos ela,
Galicia,
Spain
bHeal h
Resea ch
Ins i u e
o
San iago
de
Compos ela
(Ins i u o
de
In es igación
Sani a ia
de
San iago
de
Compos ela-IDIS),
San iago
de
Compos ela,
Galicia,
Spain
cConso ium
o
Biomedical
Resea ch
in
Epidemiology
and
Public
Heal h
(CIBER
en
Epidemiología
y
Salud
Pública-CIBERESP),
Mad id,
Spain
dOncology
Depa men ,
Pue a
de
Hie o
Uni e si y
Teaching
Hospi al,
Majadahonda,
Spain
eUGC
Medical
Oncology
In e cen e s,
Regional
and
Vi gen
de
la
Vic o ia
Uni e si y
Teaching
Hospi als,
Malaga,
IBIMA,
Malaga,
Spain
G an
Cana ia
Island
Hospi al,
Las
Palmas
de
G an
Cana ia,
Spain
gMedical
Oncology
Depa men ,
Ca alonian
Oncology
Ins i u e,
Badalona-Ge mans
T ias
i
Pujol
Hospi al,
B-ARGO
G oup,
Spain
hMedical
Oncology
Sec ion,
Valladolid
Uni e si y
Clinical
Teaching
Hospi al,
Spain
iDepa men
o
Oncology,
A
Co u˜
na
Uni e si y
Teaching
Hospi al
Complex,
Co u˜
na,
Spain
jVi gen
del
Rocio
Uni e si y
Teaching
Hospi al,
Se ille,
Spain
kCa alonian
Oncology
Ins i u e,
D .
Josep
T ue a
Uni e si y
Teaching
Hospi al,
Gi ona,
Spain
lD .
Balmis
Uni e si y
Teaching
Hospi al,
Alican e
Heal h
Resea ch
and
Biomedical
Ins i u e
(ISABIAL),
Alican e,
Spain
mJiménez
Díaz
Founda ion
Uni e si y
Hospi al,
IIS-FJD,
Mad id,
Spain
nDepa men
o
Medical
Oncology,
Ca alan
Ins i u e
o
Oncology,
Doc o
Josep
T ue a
Uni e si y
Hospi al
and
P ecision
Oncology
G oup
(OncoGIR-P o),
Gi ona
Biomedical
Resea ch
Ins i u e
(IDIBGI),
Gi ona,
Spain
oJaén
Hospi al
Complex,
Jaén,
Spain
pCas ellón
P o incial
Hospi al,
Cas ellón,
Spain
qDepa men
o
Oncology,
Elche
Uni e si y
Gene al
Teaching
Hospi al,
Elche,
Spain
Medical
Oncology
Depa men ,
Salamanca
Uni e si y
Heal hca e
Complex-IBSAL,
Salamanca,
Spain
sÁl a o
Cunquei o
Uni e si y
Teaching
Hospi al,
Vigo,
Spain
a
i
c
l
e
i
n
o
A icle
his o y:
Recei ed
6
No embe
2023
Accep ed
12
Decembe
2023
A ailable
online
18
Decembe
2023
Keywo ds:
Cha ac e is ics
Gene ic
al e a ions
Lung
cance
Young
pa ien s
Epide mal
g ow h
ac o
ecep o
Anaplas ic
lymphoma
kinase
a
b
s
a
c
In oduc ion:
The
aim
o
his
s udy
was
o
analyze
he
clinical
and
gene ic
cha ac e is ics
o
young
lung
cance
cases,
and
o
compa e
hem
wi h
hose
o
olde
cases.
Me hods:
We
used
he
Tho acic
Tumo s
Regis y
(TTR)
as
a
da a
sou ce
ep esen a i e
o
lung
cance
cases
diagnosed
in
Spain,
and
included
all
cases
egis e ed
un il
9/01/2023
which
had
in o ma ion
on
age
a
diagnosis
o
he
da a
needed
o
calcula e
i .
We
pe o med
a
desc ip i e
s a is ical
analysis
and
fi ed
logis ic
eg essions
o
analyze
how
di e en
cha ac e is ics
influenced
being
a
younge
lung
cance
pa ien .
Resul s:
A
o al
o
26,336
subjec s
we e
included.
Lung
cance
cases
<50
yea s
old
had
a
highe
p obabili y
o
being
women
(OR:
1.38;
95%
CI:
1.21–1.57),
being
in
s age
III
o
IV
(OR:
1.32;
95%
CI:
1.08–1.62),
no
ha ing
como bidi ies
(OR:
5.21;
95%
CI:
4.59–5.91),
p esen ing
wi h
symp oms
a
diagnosis
(OR:
1.53;
95%
CI:
1.29–1.81),
and
ha ing
ALK
ansloca ion
(OR:
7.61;
95%
CI:
1.25–46.32)
and
HER2
mu a ion
(OR:
5.71;
95%
CI:
1.34–24.33),
compa ed
wi h
subjec s
≥50
yea s.
Among
subjec s
<35
yea s
old
(n
=
61),
ou
s udy
obse ed
a
highe
p opo ion
o
women
(59.0%
s.
26.6%;
p
<
0.001),
ne e
smoke s
(45.8%
s.
10.3%;
p
<
0.001),
no
como bidi ies
(21.3%
s.
74.0%;
p
<
0.001);
ALK
ansloca ion
(33.3%
s.
4.4%;
p
<
0.001)
and
ROS1
mu a ion
(14.3%
s.
2.3%;
p
=
0.01),
compa ed
wi h
subjec s
≥35
yea s.
∗Co esponding
au ho .
E-mail
add ess:
[email p o ec ed]
(A.
Ruano-Ra ina).
h ps://doi.o g/10.1016/j.a b es.2023.12.005
0300-2896/©
2023
The
Au ho (s).
Published
by
Else ie
Espa˜
na,
S.L.U.
on
behal
o
SEPAR.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://
c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
C.
Candal-Ped ei a,
A.
Ruano-Ra ina,
V.
Cal o
de
Juan
e
al.
A chi os
de
B onconeumología
60
(2024)
88–94
Conclusions:
Lung
cance
displays
di e ences
by
age
a
diagnosis
which
may
ha e
impo an
implica ions
o
i s
clinical
managemen .
©
2023
The
Au ho (s).
Published
by
Else ie
Espa˜
na,
S.L.U.
on
behal
o
SEPAR.
This
is
an
open
access
a icle
unde
he
CC
BY-NC-ND
license
(h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
In oduc ion
In
2020,
lung
cance
anked
as
he
p incipal
cause
o
cance -
ela ed
mo ali y
wi h
18%
o
o al
dea hs
wo ldwide,
ollowed
by
colo ec al
cance
and
li e
cance ,
wi h
9.4%
and
8.3%
o
all
cance - ela ed
dea hs,
espec i ely.1Age
is
an
impo an
ac o
in
he
appea ance
and
p og ession
o
lung
cance .
Hence,
acco ding
o
da a
sou ced
om
he
Su i al
Epidemiology
and
End
Resul s
(SEER),
he
median
age
a
diagnosis
s ands
a
71
yea s,2 hough
he e
is
a
wide
age
dis ibu ion.
The
lung
cance
mo ali y
a e
in
subjec s
aged
50
yea s
and
olde
was
84.6
dea hs
pe
100,000
pop-
ula ion
in
2020,
whe eas
o
subjec s
aged
unde
50
yea s
i
was
1.2
pe
100,000
popula ion.2This
indica es
ha
he
incidence
o
lung
cance
in
pe sons
unde
he
age
o
50
yea s
is
no
ha
uncommon.1
In
Spain,
an
es ima ed
22,266
lung
cance
cases
a e
going
o
be
diagnosed
in
2023,
7,146
o
whom
can
be
assumed
o
be
subjec s
unde
he
age
o
65
yea s,
accoun ing
o
32%
o
all
lung
cance
cases.3
In
ecen
yea s,
a
numbe
o
s udies
ha e
sugges ed
ha
he e
a e
di e ences
in
he
clinical
cha ac e is ics
o
subjec s
who
de elop
lung
cance
a
ea lie
ages,
as
compa ed
wi h
olde
subjec s,4–13 desc ibing
lung
cance
in
young
subjec s
as
a
unique
en i y.
P e ious
s udies
ha e
concluded
ha
lung
can-
ce
which
de elop
in
younge
subjec s
end
o
appea
mo e
equen ly
in
women
and
ne e
smoke s.14,15 Fu he mo e,
in
younge
subjec s,
he e
is
a
p edominance
o
adenoca cinoma
and
umo s
a
mo e
ad anced
s ages.6,7,10 Mo eo e ,
a
numbe
o
s udies
ha e
obse ed
a
g ea e
p opo ion
o
ce ain
geno-
ypes
o
gene ic
al e a ions
in
younge
subjec s,
including
a
highe
equency
o
mu a ions
o
he
epide mal
g ow h
ac o
ecep-
o
(EGFR)
and
ansloca ions
in ol ing
anaplas ic
lymphoma
kinase
(ALK).16,17 Ye ,
he
esul s
di e
be ween
geno ypes,18 and
a
ecen
sys ema ic
e iew
has
concluded
ha
he e
a e
dis-
c epancies
in
he
associa ion
be ween
he
p esence
o
gene ic
al e a ions
and
age.12 The
p esence
o
some
o
hese
al e a ions
is
associa ed
wi h
be e
su i al.7,19 While
di e en
s udies
ha e
obse ed
be e
p ognosis
in
younge
subjec s,13,17 o he
s ud-
ies
howe e
epo
lowe
su i al
in
compa ison
wi h
olde
subjec s.10,11,15
The
di e ences
obse ed
sugges
ha
he
biology
o
lung
cance
may
di e
by
age
a
diagnosis,13 some hing
ha
can
esul
in
a
mo e
agg essi e
disease
in
young
subjec s,
as
indeed
happens
wi h
o he
umo s
diagnosed
a
ea ly
ages.20 Iden ifica ion
o
possible
di e ences,
bo h
clinical
and
gene ic,
be ween
younge
and
olde
lung
cance
cases
may
ha e
impo an
implica ions
when
i
comes
o
he
diagnosis,
ea men
and
clinical
ca e
o
pa ien s,
u nishing
in o ma ion
on
he
ac o s
ha
influence
he
de elopmen
o
he
disease
in
younge
subjec s
and
leading
o
he
po en ial
de ec ion
o
d i e
genes
in
hese
subjec s,
which
may
in
u n
ha e
implica ions
o
he
ea men
s a egy
o
be
pu sued.10
Due
o
he
low
incidence
o
lung
cance
in
young
popula ion,
he e
a e
ha dly
any
s udies
wi h
a
su ficien
sample
size
ha
ha e
compa ed
he
clinical
and
gene ic
cha ac e is ics
o
lung
cance
by
age
a
diagnosis,
pa icula ly
in
subjec s
aged
unde
50
yea s
o
in
he
Caucasian
popula ion.
This
s udy
he e o e
sough
o
ana-
lyze
he
clinical
and
gene ic
cha ac e is ics
o
lung
cance
cases
diagnosed
in
Spain,
by
age
a
diagnosis,
and
compa e
hese
cha -
ac e is ics
in
subjec s
unde
he
age
o
50
wi h
hose
in
subjec s
aged
50
yea s
and
olde .
To
achie e
his,
we
used
a
ep esen a i e
da abase
o
lung
cance
cases
diagnosed
in
Spain.
Me hods
S udy
Design
and
Sample
Selec ion
We
ca ied
ou
an
analy ical
c oss-sec ional
s udy,
using
he
Tho acic
Tumo s
Regis y
(TTR)
o
he
Spanish
Lung
Cance
G oup
(G upo
Espa˜
nol
de
Cánce
de
Pulmón)
as
ou
da a
sou ce.
The
TTR
is
a
monog aphic
lung
cance
egis y
whose
me hodology
has
been
p e iously
desc ibed.21 In
summa y,
he
TTR
is
a
mul icen-
e
p ospec i e
s udy
in ol ing
80
hospi als
h oughou
Spain,
designed
wi h
a
consecu i e
sampling
me hod.
The
cases
a e
sub-
jec s
diagnosed
wi h
lung
cance
o
o he
ho acic
umo s,
wi hou
any
es ic ion
on
gende
o
age,
and
ega dless
o
whe he
hey
a e
ecei ing
ea men
o
no .
The
cases
a e
collec ed
by
oncolo-
gis s
a
he
pa icipa ing
hospi als.
This
egis y
has
ecen ly
been
shown
o
be
ep esen a i e
o
lung
cance
cases
diagnosed
in
Spain
by
sex
and
age.21 The
TTR
was
egis e ed
in
ClinicalT ials.go
(NCT02942458),
and
he
s udy
p o ocol
was
app o ed
by
he
ins i-
u ional
commi ee
o
he
Pue a
de
Hie o
Uni e si y
Teaching
Hospi al
(Majadahonda,
Mad id)
(no.
PI
148/15).
Fo
s udy
pu poses,
we
used
all
cance
cases
included
in
he
TTR
un il
9
Janua y
2023
which
had
in o ma ion
on
age
a
diagnosis
o
he
da a
needed
o
calcula e
i
(da e
o
bi h
and
da e
a
diagnosis).
Subjec s
diagnosed
wi h
hymoma
o
meso helioma
(n
=
360)
we e
excluded
om
he
analysis.
Fo
each
subjec
included,
he
ollowing
cha ac e is ics
we e
collec ed:
sex,
age,
smoking
habi ,
obacco
use
(in
pack-yea s),
s age
a
diagnosis,
his ologic
ype,
p esence
o
como bidi ies,
and
p esence
o
symp oms
a
diagnosis.
Age
was
ca ego ized
in o:
unde
50
yea s
(wi h
a
subg oup
o
cases
aged
35
yea s
o
younge
a
diagnosis);
and
50
yea s
and
olde .
In
addi ion,
we
eco ded
he
gene ic
al e a ions
o
subjec s
who
unde wen
a
se ies
o
molecu-
la
de e mina ions
a
diagnosis,
including
he
ollowing:
EGFR,
ALK,
KRAS,
BRAF,
mu a ion
in
HER2,
ROS1,
NTRK,
FGFR1,
PDL1,
HER2,
RET,
and
MET.
S a is ical
Analysis
We
fi s
desc ibed
he
clinical
cha ac e is ics
o
subjec s
diag-
nosed
wi h
lung
cance
included
in
he
s udy,
bo h
o e all
and
by
age
a
diagnosis,
ca ego ized
as
unde
50
yea s
and
50
yea s
and
olde .
Quan i a i e
a iables
we e
exp essed
as
median
and
in e qua ile
ange,
and
ca ego ical
a iables
as
absolu e
and
ela-
i e
equencies.
To
desc ibe
he
gene ic
al e a ions
o
he
sample,
pe cen
posi-
i i y
was
calcula ed.
Fo
each
molecula
de e mina ion
analyzed,
he
numbe
o
subjec s
wi h
a
posi i e
de e mina ion
(i.e.,
al e -
a ion)
was
di ided
by
he
numbe
o
subjec s
in
whom
his
molecula
de e mina ion
had
been
measu ed,
by
age
g oup.
Fo
each
cha ac e is ic,
di e ences
be ween
g oups
we e
e al-
ua ed
using
bi a ia e
logis ic
eg ession.
Va iables
wi h
a
p
<
0.20
in
he
bi a ia e
analysis
we e
included
in
wo
mul i a ia e
logis-
ic
eg ession
models:
clinical
cha ac e is ics
we e
included
in
one
and
gene ic
al e a ions
in
he
o he ,
wi h
bo h
being
adjus ed
o
he
a iables
included
in
he
model
and
o
sex
and
smoking
habi .
We
calcula ed
he
odds
a ios
(ORs)
accompanied
by
hei
95%
con-
fidence
in e als
(95%
CIs).
We
also
pe o med
an
addi ional
analysis,
by
di iding
he
sam-
ple
in o
subjec s
aged
unde
35
yea s
and
aged
35
yea s
and
olde
and
ca ying
ou
a
bi a ia e
analysis.
The
small
sample
size
in
he
89
C.
Candal-Ped ei a,
A.
Ruano-Ra ina,
V.
Cal o
de
Juan
e
al.
A chi os
de
B onconeumología
60
(2024)
88–94
Table
1
Clinical
Cha ac e is ics
o
Subjec s,
Bo h
O e all
and
by
Age
G oup
a
Diagnosis.
To al
<50
yea s
≥50
yea s
p-Value
N
=
26,336
N
=
1197
N
=
25,139
Sex
<0.001
Men
19,313
(73.3%)
679
(56.7%)
18,634
(74.1%)
Women
7023
(26.7%)
518
(43.3%)
6505
(25.9%)
Smoking
habi a<0.001
Ne e
smoke
2699
(10.4%)
248
(21.0%)
2451
(9.9%)
Ex-smoke
(>1
yea )
12,030
(46.3%)
288
(24.3%)
11,742
(47.3%)
Smoke
11,270
(43.3%)
647
(54.7%)
10,623
(42.8%)
Packs-yea
49
(35–69) 27
(17–34) 50
(36–70) <0.001
S age
a
diagnosisb<0.001
0
27
(0.1%)
2
(0.2%)
25
(0.1%)
I
2330
(8.8%)
56
(4.7%)
2274
(9.0%)
II
1817
(6.9%)
72
(6.0%)
1745
(6.9%)
III
6080
(23.1%)
242
(20.2%)
5838
(23.2%)
IV
12,175
(46.2%)
709
(59.2%)
11,466
(45.6%)
Limi ed
SCLC
1207
(4.6%)
33
(2.8%)
1174
(4.7%)
Ex ended
SCLC
2380
(9.0%)
70
(5.8%)
2310
(9.2%)
O he
317
(1.2%) 13
(1.1%) 304
(1.2%)
His ologic
ypec<0.001
Adenoca cinoma
13,728
(52.1%)
842
(70.3%)
12,886
(51.3%)
Adenosquamous
299
(1.1%)
11
(0.9%)
288
(1.1%)
Squamous
6350
(24.1%)
99
(8.3%)
6251
(24.9%)
La ge
cell
ca cinoma
541
(2.1%)
26
(2.2%)
515
(2.0%)
Sa coma oid
72
(0.3%)
10
(0.8%)
62
(0.2%)
Undi e en ia ed/NOS
631
(2.4%) 30
(2.5%) 601
(2.4%)
Small-cell
ca cinoma
3758
(14.3%)
110
(9.2%)
3648
(14.5%)
La ge
cell
neu oendoc ine
ca cinoma
371
(1.4%)
16
(1.3%)
355
(1.4%)
Ca cinoid
159
(0.6%)
27
(2.3%)
132
(0.5%)
O he s
425
(1.6%)
26
(2.2%)
399
(1.6%)
P esence
o
como bidi ies <0.001
No
6885
(26.1%)
785
(65.6%)
6100
(24.3%)
Yes
19,451
(73.9%)
412
(34.4%)
19,039
(75.7%)
P esence
o
symp oms
a
diagnosis
<0.001
No
5554
(21.1%)
197
(16.5%)
5357
(21.3%)
Yes
20,782
(78.9%)
1000
(83.5%)
19,782
(78.7%)
IQR:
in e qua ile
ange;
NOS:
no
o he wise
specified;
SCLC:
small-cell
lung
cance .
a337
missing
alues.
b3
missing
alues.
c2
missing
alues.
Table
2
Numbe
o
Subjec s
Wi h
Posi i e
Molecula
De e mina ions
(Al e a ions)
and
Pe cen
Posi i i y,aby
Age
G oup
a
Diagnosis.
<50
Yea s
≥50
Yea s
p-Value
N
=
1197
N
=
25,139
EGFR
129
(10.8%)
1559
(6.2%)
<0.001
ALK
101
(14.2%)
350
(3.7%)
<0.001
KRAS
37
(27.6%)
543
(29.7%)
0.61
BRAF
10
(4.9%)
124
(4.4%)
0.75
Mu a ion
in
HER2
3
(10.0%)
10
(3.3%)
0.07
ROS1
13
(2.9%)
132
(2.3%)
0.42
NTRK
0
(0.0%)
8
(1.0%)
0.41
FGFR1
0
(0.0%)
14
(4.9%)
0.20
PDL1
311
(55.8%)
5408
(55.0%)
0.62
HER2
0
(0.0%)
15
(5.2%)
0.20
RET
5
(7.4%)
17
(2.3%)
0.01
MET
10
(11.1%)
70
(8.2%)
0.34
aPe cen
posi i i y
was
calcula ed
by
di iding
he
numbe
o
subjec s
wi h
posi i e
de e mina ions
by
he
o al
numbe
o
subjec s
in
whom
his
de e mina ion
had
been
measu ed,
o
each
g oup.
g oup
o
subjec s
aged
unde
35
yea s
mean
ha
a
mul i a ia e
logis ic
eg ession
could
no
be
pe o med.
S a is ical
significance
was
se
a
p
<
0.05.
All
s a is ical
analyses
we e
pe o med
using
he
S a a
.17.
compu e
so wa e
p og am.
Resul s
A
o al
o
27,416
lung
cance
cases
we e
included
in
he
TTR
a
9
Janua y
2023.
Ul ima ely,
26,336
subjec s
who
ulfilled
he
p ees ablished
selec ion
c i e ia
we e
included
in
his
analysis.
Tables
1
and
2
show
he
clinical
and
gene ic
cha ac e is ics
o
he
sample,
bo h
o e all
and
by
age
g oup
a
diagnosis.
The
p opo ion
o
women
was
highe
in
subjec s
aged
unde
50
yea s
(43.3%
s.
25.9%;
p
<
0.001),
as
we e
he
p opo ions
o
ne e
smoke s
(21.0%
s.
9.9%,
p
<
0.001)
and
o
subjec s
wi hou
como -
bidi y
(65.6%
s.
24.3%;
p
<
0.001),
as
compa ed
wi h
subjec s
aged
50
yea s
and
olde .
Simila ly,
in ensi y
o
smoking
in
pack-yea s
was
lowe
in
subjec s
unde
50
yea s
o
age
(27
s.
50;
p
<
0.001)
(Table
1).
Highe
p opo ions
o
EGFR,
ALK
and
RET
al e a ions
we e
obse ed
in
subjec s
unde
he
age
o
50
yea s
(p
<
0.05)
han
in
subjec s
aged
50
yea s
and
olde
(Table
2).
90
C.
Candal-Ped ei a,
A.
Ruano-Ra ina,
V.
Cal o
de
Juan
e
al.
A chi os
de
B onconeumología
60
(2024)
88–94
Table
3
Mul i a ia e
Logis ic
Reg ession
o
he
Clinical
Cha ac e is ics
o
Subjec s:
Subjec s
Unde
he
Age
o
50
Yea s
Compa ed
Wi h
Subjec s
Aged
50
Yea s
and
Olde .
Odds
Ra io
95%
Confidence
In e al
p-Value
Sex
Men
1.00
( e )
Women
1.38
1.21
–
1.57
<0.001
Smoking
habi
Ne e
smoke
1.00
( e )
Smoke
0.43
0.36
–
0.52
<0.001
Ex-smoke
(>1
yea )
0.93
0.78
–
1.11
0.43
His ologic
ype
Adenoca cinoma
1.00
( e )
Adenosquamous
0.77
0.41
–
1.43
0.41
Squamous
0.32
0.26
–
0.40
<0.001
La ge
cell
ca cinoma
0.84
0.56
–
1.28
0.42
Sa coma oid
2.53
1.23
–
5.21
0.01
Undi e en ia ed/NOS
0.85
0.58
–
1.25
0.42
Small-cell
ca cinoma
1.24
0.39
–
3.94
0.71
La ge
cell
neu oendoc ine
ca cinoma
0.88
0.52
–
1.48
0.62
Ca cinoid
3.90
2.41
–
6.32
<0.001
O he s
1.09 0.71 –
1.65
0.70
S age
a
diagnosis
I–II
1.00
( e )
III–IV
1.32
1.08
–
1.62
0.01
Limi ed
o
ex ended
SCLC
0.49
0.15
–
1.58
0.23
O he
0.59
0.22
–
1.57
0.29
P esence
o
como bidi ies
No
5.21 4.59 –
5.91
<0.001
Yes
1.00
( e )
P esence
o
symp oms
a
diagnosis
No
1.00
( e )
Yes
1.53
1.29
–
1.81
<0.001
n
=
25,995.
A
o al
o
341
pa icipan s
had
missing
da a
o
a
leas
one
a iable
included
in
he
model:
337
we e
missing
da a
o
smoking
habi ,
2
o
his ological
ype,
and
3
o
s age
a
diagnosis
(one
pa icipan
had
missing
in o ma ion
o
bo h
his ological
ype
and
s age
a
diagnosis).
The
mul i a ia e
analysis
o
he
clinical
cha ac e is ics
o
sub-
jec s
(Table
3)
showed
ha
lung
cance
cases
aged
unde
50
yea s
had
a
highe
likelihood
o
being
women
(OR
1.38;
95%
CI
1.21–1.57),
p esen ing
wi h
s ages
III
o
IV
a
diagnosis
(OR
1.32;
95%
CI
1.08–1.62),
no
ha ing
como bidi ies
(OR
5.21;
95%
CI
4.59–5.91),
and
p esen ing
wi h
symp oms
a
diagnosis
(OR
1.53;
95%
CI
1.29–1.81)
han
did
subjec s
aged
50
yea s
and
olde .
Table
4
shows
he
logis ic
eg ession
o
gene ic
al e a ions,
adjus ed
o
sex
and
smoking
habi .
Subjec s
unde
he
age
o
50
yea s
had
a
highe
isk
o
p esen ing
wi h
ALK
ansloca ion
(OR
7.61;
95%
CI
1.25–46.32)
and
mu a ion
in
HER2
(OR
5.71;
95%
CI
1.34–24.33)
han
did
subjec s
aged
50
yea s
and
olde .
Among
subjec s
unde
he
age
o
35
yea s
(n
=
61),
he e
was
a
highe
p opo ion
o
women
(59.0%
s.
26.6%;
p
<
0.001),
ne e
smoke s
(45.8%
s.
10.3%;
p
<
0.001),
subjec s
wi hou
como bidi-
ies
(21.3%
s.
78.9%;
p
<
0.001),
and
wi h
ALK
ansloca ion
(33.3%
s.
4.3%;
p
<
0.001)
and
mu a ion
in
ROS1
(14.3%
s.
2.3%;
p
=
0.01),
as
compa ed
wi h
subjec s
aged
35
yea s
and
olde
(Table
5).
Discussion
The
esul s
o
his
s udy
show
ha
lung
cance
cases
diagnosed
be o e
he
age
o
50
yea s
(as
well
as
35
yea s)
p esen
wi h
clinical
and
gene ic
cha ac e is ics
di e en
om
hose
o
subjec s
diag-
nosed
a
a
highe
age.
Diagnosis
in
younge
subjec s
is
hus
mo e
equen
in
women,
wi h
a
g ea e
p edominance
o
ne e
smoke s,
a
mo e
ad anced
s age,
and
a
highe
equency
o
adenoca cinoma.
In
e ms
o
gene ic
al e a ions,
subjec s
unde
he
age
o
50
yea s
a
diagnosis
a e
se en
imes
mo e
likely
o
p esen
wi h
ALK
anslo-
ca ion
and
5
imes
mo e
likely
o
ha e
mu a ions
in
HER2.
The
esul s
ob ained
sugges
ha ,
in
gene al,
diagnosis
o
lung
cance
be o e
he
age
o
50
and
35
yea s
occu s
mo e
equen ly
in
women.
Howe e ,
due
o
he
low
sample
size
o
subjec s
unde
35
yea s
o
age,
u u e
s udies
should
confi m
hese
findings.
Addi-
ionally,
diagnosis
be o e
he
age
o
50
yea s
occu
a
a
la e
s age
(p esence
o
s age
IV
a
diagnosis
is
59%
in
younge
subjec s
s.
45.6%
in
olde
subjec s).
O he
s udies
ha e
also
obse ed
a
la e
diagnosis
o
lung
cance
in
younge
subjec s.
Sub amanian
e
al., 14
iden ified
57.4%
o
cases
in
s age
IV
among
subjec s
aged
40
yea s
and
younge
s.
43.0%
o
cases
o
ad anced
cance
in
olde
subjec s;
and
he
esul s
o
Rich
e
al.,8a e
simila .
The e
could
be
a
numbe
o
easons
o
his
la e
diagnosis:
one
o
hese
is
ha
physicians
migh
wai
longe
be o e
pe o ming
imaging
es s,
as
a
esul
o
uling
ou
he
possibili y
o
lung
cance
in
younge
pe sons.
I
could
also
be
a ibu ed
o
he
ac
ha
he
younges
subjec s
appea
o
delay
longe
in
p esen ing
wi h
symp oms
sugges i e
o
lung
cance ,
and
he e o e
ake
longe
o
consul
hei
physician.6,15 I
should
be
no ed,
howe e ,
ha ,
unlike
o he
s udies,7 his
di e ence
in
s age
a
diagnosis
was
no
obse ed
when
subjec s
aged
unde
35
yea s
we e
analyzed
sepa a ely.
Ano he
possible
explana ion
is
ha
pul-
mona y
cance s
in
young
subjec s
a e
mo e
agg essi e.
This
is
a
plausible
hypo hesis,
since
doubling
ime
would
be
mo e
apid
on
pa ien s
p esen ing
a
a
younge
age
and
hus
inc ease
he
likeli-
hood
o
hei
being
diagnosed
a
an
ad anced
s age.
Ano he
impo an
esul
o
ou
s udy
is
he
lowe
p esence
o
smoking
in
subjec s
diagnosed
a
a
younge
age.
In
he
s udy
sub-
jec s,
he
equency
o
ne e
smoke s
unde
he
age
o
50
was
close
on
21%,
whe eas
in
hose
o e
he
age
o
50,
he
equency
was
almos
10%.
The
p e alence
o
smoking
alls
e en
lowe
among
subjec s
unde
he
age
o
35,
wi h
he
equency
o
ne e
smok-
e s
being
somewha
highe
han
45%
in
his
g oup.
The
esul s
o
Rich
e
al.,8sugges
some hing
simila ,
on
finding
lowe
a es
o
obacco- ela ed
umo s
in
he
younges
g oup
o
subjec s.
This
sugges s
ha
eally
young
subjec s
wi h
diagnosis
o
lung
cance
may
p esen
wi h
isk
ac o s
o
he
disease
o he
han
smoking,
such
as
g ea e
suscep ibili y
o
gene ic
p edisposi ion.22 In
addi-
ion
o
he
di e ences
p esen
in
gene ic
cha ac e is ics,
he e
a e
o he
isk
ac o s
ha
should
be
bo ne
in
mind,
such
as
occupa-
ional
exposu es,
exposu e
o
adon,
en i onmen al
pollu ion,
and
91
C.
Candal-Ped ei a,
A.
Ruano-Ra ina,
V.
Cal o
de
Juan
e
al.
A chi os
de
B onconeumología
60
(2024)
88–94
Table
4
Mul i a ia e
Logis ic
Reg ession
o
Gene ic
Cha ac e is icsa:
Subjec s
Unde
he
Age
o
50
Yea s
Compa ed
Wi h
Subjec s
Aged
50
Yea s
and
Olde .
Odds
Ra io
95%
Confidence
In e al
p-Value
Posi i e
EGFR
3.22
0.92
11.52
0.07
Posi i e
ALK 7.61 1.25 46.32
0.03
Posi i e
HER2Mu
5.71
1.34
24.33
0.02
aAdjus ed
o
sex
and
smoking
habi .
RET
mu a ions
we e
no
included
because
he e
we e
e y
ew
subjec s
in
whom
his
al e a ion
was
eco ded.
Table
5
Desc ip ion
o
he
Sample
by
Age
a
Diagnosis:
Subjec s
Unde
he
Age
o
35
Yea s
Compa ed
Wi h
Subjec s
Aged
35
Yea s
and
Olde .
<35
Yea s
≥35
Yea s
p-Value
N
=
61
N
=
26,275
Sex
<0.001
Men
25
(41.0%)
19,288
(73.4%)
Women
36
(59.0%) 6987
(26.6%)
Smoking
habi a<0.001
Ne e
smoke
27
(45.8%)
2672
(10.3%)
Ex-smoke
(>1
yea ) 12
(20.3%) 12,018
(46.3%)
Smoke
20
(33.9%)
11,250
(43.4%)
Packs-yea
(median-IQR)
11.5
(5–15)
49
(35–69)
<0.001
S age
a
diagnosisb0.068
0
0
(0.0%)
27
(0.1%)
I
6
(9.8%)
2324
(8.8%)
II
8
(13.1%)
1809
(6.9%)
III
13
(21.3%) 6067
(23.1%)
IV
27
(44.3%)
12,148
(46.2%)
Limi ed
SCLC
2
(3.3%)
1205
(4.6%)
Ex ended
SCLC
2
(3.3%)
2378
(9.1%)
O he
3
(4.9%)
314
(1.2%)
His ologic
ypec<0.001
Adenoca cinoma
37
(60.7%)
13,691
(52.1%)
Adenosquamous
0
(0.0%)
299
(1.1%)
Squamous
5
(8.2%)
6345
(24.2%)
La ge
cell
ca cinoma
0
(0.0%)
541
(2.1%)
Sa coma oid
1
(1.6%)
71
(0.3%)
Undi e en ia ed/NOS
1
(1.6%)
630
(2.4%)
Small-cell
ca cinoma 4
(6.6%)
3754
(14.3%)
La ge
cell
neu oendoc ine
ca cinoma
0
(0.0%)
371
(1.4%)
Ca cinoid
11
(18.0%)
148
(0.6%)
O he
2
(3.3%)
423
(1.6%)
P esence
o
como bidi ies
<0.001
Yes
13
(21.3%)
19,438
(74.0%)
P esence
o
symp oms
a
diagnosis
0.97
Yes
48
(78.7%)
20,734
(78.9%)
Gene ic
cha ac e is icsd
EGFR
5
(8.2%)
1,683
(6.4%)
0.57
ALK
10
(33.3%)
441
(4.3%)
<0.001
KRAS
1
(16.7%)
579
(29.6%)
0.49
BRAF
0
(0.0%)
134
(4.5%)
HER2Mu
0
(0.0%)
13
(4.0%)
ROS1
3
(14.3%)
142
(2.3%)
<0.001
NTRK
0
(0.0%)
8
(0.9%)
FGFR1
0
(0.0%)
14
(4.4%)
PDL1
14
(58.3%)
5705
(55.1%)
0.70
HER2
0
(0.0%)
15
(4.7%)
RET
0
(0.0%)
22
(2.7%)
MET
0
(0.0%)
80
(8.5%)
a337
missing
alues.
b3
missing
alues.
c2
missing
alues.
dThe
able
shows
he
numbe
o
subjec s
who
es ed
posi i e
on
each
de e mina ion
and
pe cen
posi i i y.
Pe cen
posi i i y
was
calcula ed
by
di iding
he
numbe
o
subjec s
wi h
posi i e
de e mina ion
by
he
o al
numbe
o
subjec s
in
whom
his
de e mina ion
had
been
measu ed,
o
each
o
he
age
g oups.
socioeconomic
le el.22 Un o una ely,
we
ha e
no
da a
ela ing
o
o he
exposu es
o
he
subjec s
included,
which
migh
lead
us
o
hink
o
an
al e na i e
isk
ac o
o
obacco
use
o
gene ic
p e-
disposi ion.
I
should
be
no ed
ha
p e ious
s udies
ha e
indeed
associa ed
exposu e
o
adon
wi h
mu a ions
in
he
EGFR
gene
and
ALK
ansloca ion9in
a
s udy
conduc ed
on
ne e
smoke s,
so
ha
his
hypo hesis
should
no
be
uled
ou .
In
e ms
o
gene ic
al e a ions,
he
esul s
o
his
s udy
ag ee
wi h
o he s
ca ied
ou
p e iously
in
o he
geog aphic
con ex s.
A
ecen
s udy
conduc ed
in
he
Uni ed
Kingdom
wi h
248
sub-
jec s
unde
he
age
o
50
yea s
ound
ha
he
EGFR
mu a ion
and
ALK
ansloca ion
we e
p esen
in
19%
and
10%
o
he
subjec s,
espec i ely.6Fu he mo e,
KRAS
mu a ion
was
p esen
in
12%
o
he
subjec s.
O he
s udies
conduc ed
in
Asia17,23 and
Ame ica10
ha e
epo ed
simila
esul s.
Tha
said,
howe e ,
a
s udy
con-
duc ed
in
he
Czech
Republic
ound
a
highe
p opo ion
o
mu a ion
in
EGFR
in
olde
subjec s,
whe eas
he
con a y
was
obse ed
o
ALK
ansloca ions.4De ec ion
o
he
EGFR
mu a ion
appea s
o
be
associa ed
wi h
non-smoke s,
since
di e en
s udies
ha e
ound
an
in e se
ela ionship
be ween
his
mu a ion
and
smoking.24–26
92

C.
Candal-Ped ei a,
A.
Ruano-Ra ina,
V.
Cal o
de
Juan
e
al.
A chi os
de
B onconeumología
60
(2024)
88–94
This
finding
is
also
equen
in
he
Asian
popula ion,
in
which
i
is
mo e
usual
o
be
a
ne e
smoke
and
he e
is
a
highe
equency
o
EGFR
mu a ions.6This
ag ees
wi h
wha
was
obse ed
in
ou
s udy,
in
which
mos
o
he
younges
subjec s
we e
ne e
smok-
e s
and
p esen ed
wi h
his
mu a ion.
Fu he mo e,
whe eas
he
o igin
o
ce ain
mu a ions
is
linked
o
he
ca cinogens
in
obacco
(e.g.,
KRAS),
he
specific
cause
o
EGFR
mu a ions
is
no
ye
clea .27
Cu en ly,
a
conside able
numbe
o
gene ic
mu a ions
ha e
been
iden ified
and
used
o
guide
oncologic
ea men s.22 In
ecen
decades,
specific
ea men s
a ge ed
a
EGFR,
ALK
and
ROS1
al e -
a ions
ha e
been
implemen ed,
enhancing
he
su i al
o
hese
pa ien s.
The
scien ific
e idence
sugges s
ha ,
when
he
ele an
gene ic
al e a ions
a e
iden ified,
he
mos
e ec i e
ea men
can
be
selec ed
o
each
pa ien ,
he eby
imp o ing
he
clinical
esul s.
One
s udy
asce ained
ha ,
om
he
age
o
50
yea s
onwa ds,
he
incidence
o
hese
ypes
o
mu a ions
dec eases.10 Despi e
he
ac
ha
di e en
s udies
ha e
ound
wo se
su i al
in
young
subjec s
wi h
lung
cance ,
a
ecen
s udy
has
obse ed
ha
su i al
o
hese
subjec s
inc eased
no ably
a e
ecei ing
a ge ed
ea men .6The
scien ific
e idence
seems
o
suppo
he
need
o
pe sonalized
oncologic
ea men s
in
young
subjec s
wi h
diagnosis
o
lung
can-
ce .
Fu he mo e,
iden i ying
hese
mu a ions
may
be
use ul
when
i
comes
o
de eloping
new
bioma ke s
ha
would
allow
o
ea ly
de ec ion
o
lung
cance
in
young
subjec s,28 no
a ailable
in
cu -
en ly
implemen ed
sc eening
p og ams.
This
s udy
has
a
se ies
o
ad an ages.
One
o
hem
is
he
ep e-
sen a i eness
o
all
pa ien s
diagnosed
wi h
lung
cance
in
Spain,
as
p e iously
epo ed.29 Secondly,
he
ac
ha
he e
is
uni e -
sal
heal h
co e age
in
Spain
is
ele an ,
since
i
implies
ha
he
pa ien s
included,
coming
o
he
mos
pa
om
public
hospi als,
p ope ly
ep esen
he
whole
popula ion.
In
addi ion
o
he
abo e-
men ioned
sample
size.
A
u he
ad an age
lies
in
he
ac
ha
he
cases
included
we e
all
diagnosed
om
he
end
o
2016
onwa ds,
which
no
only
allows
o
good
empo al
compa abili y
be ween
hese
pa ien s
and
hose
who
a e
cu en ly
being
ea ed
elsewhe e,
bu
would
also
lead
one
o
assume
ha
he e
a e
no
missing
cases
due
o
he
absence
o
molecula
analysis
o
he
genes
in
ques ion,
some hing
ha
does
occu
in
he
oldes
cases
se ies.
This
s udy
also
has
a
se ies
o
limi a ions.
Al hough
he
ini-
ial
sample
size
is
qui e
la ge
(n
=
26,336),
4.5%
we e
pa icipan s
younge
han
50
yea s
and
only
0.2%
we e
younge
han
35
yea s.
I
is
impo an
o
no e
ha
mos
s udies
wi h
a
simila
objec i e
o
ou s
also
had
a
small
sample
size
in
pa ien s
younge
han
50
yea s,
as
he
incidence
a
hese
ages
is
e y
low.
Apa
om
hose
al eady
men ioned,
i.e.,
no
ha ing
da a
on
pa icipan s’
occupa ions
o
exposu e
o
adon,
he e
a e
also
no
da a
on
he
possible
ole
played
by
o he
human
ca cinogens,
such
as
exposu e
o
second-hand
obacco
smoke
o
en i onmen al
pollu ion
pe
se.
S udying
o he
isk
ac o s
o
lung
cance
would
be
in e es ing,
especially
because
he
p e alence
o
obacco
consump ion
is
dec easing
o e all.
Addi-
ionally,
he
cu -poin
o
50
yea s
o
di e en ia ing
young
om
‘non-young’
subjec s
may
seem
a bi a y.
I
is
ue
ha
he e
does
no
appea
o
be
consensus
when
i
comes
o
defining
lung
cance
in
young
subjec s,
gi en
ha
some
s udies
se
he
cu -poin
a
35
o
45
yea s.
E en
so,
a
ecen
s udy
has
iden ified
50
yea s
as
he
age
om
which
incidence
o
a ge
geno ypes
dec eases.10 A
u he
limi a ion
would
be
he
po en ial
selec ion
o
pa icipa ion
bias
o
he
subjec s
in
he
TTR,
howe e ,
in
ou
opinion,
i
is
unlikely
as
he
pa icipan s
we e
ec ui ed
by
oncologis s
using
consecu i e
sampling.
In
conclusion,
his
s udy
shows
ha
pa ien s
diagnosed
wi h
lung
cance
be o e
he
age
o
50
yea s
p esen
wi h
clinical
and
gene ic
cha ac e is ics
di e en
om
hose
diagnosed
a
mo e
ad anced
ages,
including
a
g ea e
p edominance
o
women,
ne e
smoke s,
diagnosis
a
la e
s ages,
and
a
highe
equency
o
EGFR
mu a ion
and
ALK
ansloca ion.
These
esul s
highligh
he
impo ance
o
conside ing
he
indi idualized
p ofile
o
each
young
pa ien
wi h
lung
cance ,
in
o de
o
o e
pe sonalized
ea men s.
Fu he mo e,
iden ifica ion
o
gene ic
mu a ions
associa ed
wi h
lung
cance
in
young
subjec s
may
imp o e
he
diagnosis
o
he
disease
in
his
age
g oup.
This
may
be
impo an
a
heal h
cen e s
o
in
heal h
sys ems
whe e
he e
may
no
be
su ficien
esou ces
o
make
gene
panels
o
all
pa ien s,
sugges ing
ha ,
in
his
con ex ,
hei
use
in
young
pa ien s
should
pe haps
be
p io i ized,
since
i
inc eases
he
likelihood
o
finding
mu a ions
ha
espond
o
spe-
cific
ea men s.
Mo eo e ,
s anda dizing
he
pe o ming
o
he
gene ic
analysis
ac oss
heal h
cen e s
is
essen ial,
gi en
he
exis ing
he e ogenei y
among
hem.
Da a
A ailabili y
The
da a
suppo ing
he
esul s
o
his
wo k
a e
a ailable
upon
easonable
eques
(email:
[email p o ec ed]).
E hics
App o al
The
Tho acic
Tumo s
Regis y
was
egis e ed
in
ClinicalT i-
als.go
(NCT02942458),
and
he
s udy
p o ocol
was
app o ed
by
he
ins i u ional
commi ee
o
he
Pue a
de
Hie o
Uni e si y
Teaching
Hospi al
(Majadahonda,
Mad id)
(no.
PI
148/15).
Au ho s’
Con ibu ions
ARR:
concep ualiza ion,
me hodology,
supe ision,
w i ing-
e iew
and
edi ing.
MP:
concep ualiza ion,
me hodology,
supe i-
sion,
w i ing- e iew
and
edi ing.
CCP:
me hodology,
da a
cu a ion,
o mal
analysis,
isualiza ion,
w i ing-o iginal
d a .
The
es
o
he
au ho s:
in es iga ion,
esou ces,
w i ing- e iew
and
edi ing.
Funding
None.
Conflic s
o
In e es s
The
au ho s
decla e
ha
he e
a e
no
conflic s
o
in e es
wi h
espec
o
he
publica ion
o
his
pape .
Acknowledgmen s
None.
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