Comparison of Clinical and Genetic Characteristics Between Younger and Older Lung Cancer Patients

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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