肺癌篩查與診治的最新發(fā)展匯報(bào)人：發(fā)病率

死亡率Top

10cancers

in

Hong

Kong

in

20192019年香港十大癌癥統(tǒng)計(jì)數(shù)字Precisionmedicine精準(zhǔn)醫(yī)療?Identificationoftreatmentapproachesthatwillbeeffectiveforwhichpatientsbasedongenetic,environmental,andlifestylefactors.基于遺傳,環(huán)境和生活方式因素確定對(duì)患者有效的醫(yī)療方法?盡量延長(zhǎng)病患的存活期?癥狀得以減輕?改善并提高生活質(zhì)素肺癌?每年新增病例數(shù)超過(guò)4000例，仍然是男性和女性的首要

癌癥殺手。肺癌治療個(gè)人化?腫瘤之分類及分期?個(gè)人的健康情況與選擇?癌細(xì)胞中存有的「標(biāo)靶」或生物標(biāo)記肺癌治療最理想目標(biāo)?根除腫瘤選擇最好的肺癌治療方式01?確診02?肺癌細(xì)胞的病理類型03?臨床或(病理)分期04?體能狀況Bronchoscopy支氣管鏡檢查MainlydiagnosticPulmonaryInterventions胸肺介入術(shù)AutofluorescentBronchoscopy螢光氣管鏡EBUS-TBNA支氣管鏡內(nèi)超聲波檢查氣管鏡內(nèi)超聲波or導(dǎo)航式氣管鏡Endobronchial

ValvesBronchialThermoplastyPleuroscopy

胸膜鏡Cryoprobe/APC< 支氣管鏡內(nèi)超聲波檢查

(EBUS)導(dǎo)航式氣管鏡不同肺癌種類有不同的基因變化肺腺癌

肺鱗片癌肺癌TNM分期TPrimaryTumor腫瘤腫瘤本身的大小和入侵鄰近器官的情形NRegionalLymphNode淋巴結(jié)擴(kuò)散到區(qū)域淋巴的情形MDistantMetastasis轉(zhuǎn)移擴(kuò)散到肺部以外的器官標(biāo)靶測(cè)試化療±電療

化療±?手術(shù)切除標(biāo)靶測(cè)試V肺癌治療方式手術(shù)切除復(fù)發(fā)非小細(xì)胞肺癌

小細(xì)胞肺癌化療或標(biāo)靶治療或免疫療法早期

局部晚期

晚期局限型

擴(kuò)散型化療電療合并V適用于初期肺癌患者區(qū)域性的局部治療方式局部癥狀控制，包括腫瘤造成咳血或是局部肺葉塌陷，以及手術(shù)后的預(yù)防局

部復(fù)發(fā)及控制可與化學(xué)治療合并使用提升局部晚期肺癌的治療，或?yàn)橥砥诜伟┗颊呔徑庵?/p>

療之用對(duì)小細(xì)胞肺癌治療之效果顯著在非小細(xì)胞肺癌方面，可單獨(dú)使用或與放射線治療合用標(biāo)靶治療免疫療法手術(shù)切除放射治療化學(xué)治療生物治療肺癌治療方式西方人東方人東西方人的肺癌基因不同標(biāo)靶治療?針對(duì)癌細(xì)胞中存有的「標(biāo)靶」,用專一性的藥物攻擊這些「標(biāo)靶」來(lái)殺死癌細(xì)胞,但對(duì)

正常細(xì)胞則不造成或只有很低的傷害?應(yīng)用于第一線或第二線化學(xué)治療后有再度惡

化的非小細(xì)胞肺癌病患?當(dāng)肺癌細(xì)胞存有EGFR基因突變時(shí),更可采用EGFR-TK作I為第一線治療標(biāo)靶治療類別標(biāo)靶或生物標(biāo)記測(cè)試藥物EGFR-TKI表皮生長(zhǎng)因子受體(EGFR)基因第十八至二十一段存有基因突變Gefitinib,ErlotinibAfatinib,DacomitinibEGFRT790MinhibitorEGFRT790MmutationOsimertinibEML4-ALKinhibitorEML4-ALK移動(dòng)融合基因CrizotinibCeritinib,Alectinib,Brigatinib,LorlatinibROS1inhibitorROS1移動(dòng)融合基因Crizotinib,EntrectinibEGFR基因突變EGFR-TKIcompeteswith

ATPto

preventactivationofthe

EGFRandinitiationofdownstreamsignallingInhibitionofapoptosisMetastasisLigand

上皮生長(zhǎng)因子EGFR

上皮生長(zhǎng)因子受體ProliferationInvasionAngiogenesisHeerbstetal2002標(biāo)靶治療上皮生長(zhǎng)因子受體抑制劑EGFRinhibitionEGFR-TKIDistributionofmutationtypes(%ofmutations)Literature

reviewAsianstudiesNon-AsianstudiesMost

prevalent

mutationtypesLiterature

(n=1523)Literature

(n=583)Exon

19deletion51%58%Exon21

point

mutation

L858R42%32%Exon

202%6%Exon

18

G719A/C3%2%Exon

21

L861Q1%1%P

loopαChelix21

20

19

18

耐藥性突變EGFR

基因突變Some

patients

had

more

than

one

mutation

type

AstraZeneca

data

on

file

2009ATPbinding

cleftC-lobe

N-lobeTransmembrane

regionRegulatory

domain藥敏性突變藥敏性突變Extracellular

domain耐藥性突變TKdomainA-loop標(biāo)靶治療前

標(biāo)靶治療六周后標(biāo)靶治療?皮膚紅疹及異常?腹瀉常見(jiàn)?間質(zhì)性肺炎?出血,血栓塞,穿腸?影響視力0102個(gè)別標(biāo)靶治療可引起之罕見(jiàn)副作用Paronchyiawith

ingrowntoenail甲溝炎血液檢測(cè)EGFR基因突變藥敏性突變耐藥性突變FAT4KEAP1FAT3LRP1BCSMD30%20%

40%

60%

80%

100%FrequencyOncogeneandtumorsuppressorfromCOSMIC

CensusannotationDistinctDistributionandGenderDifference

of

CommonDriverMutationsn23,145nonsynonymous

somaticvariantsn

55%were

detected

at

the

RNA

level.27The

Lung

Ambition

AllianceEGFRTP53RBM10FAT1CDC27PTPRBRNF213FAT4RB1KMT2CPIK3CAZFHX3ATP2B3KRASLRP1BTET1TET2USP6APCKMT2DMED12SLC34A2SPENATMNF1PDE4DIPSETD2Taiwan

(nothypermutated)Imielinskiet

al.,

2012TCGA,2014Taiwan

(all)Campbellet

al.

2016Taiwan

Cancer

Moonshot

Proteogenomic

Study

Group,

Cell2020RBM10CDC27RB1FAT1504540356420mutations/MbMissense,ALK融合基因andROS1融合基因

BADS6K

ErKIP3

Tumor

cell

proliferationInversionALK

fusion

protein*TranslocationALK

1.

InamuraKetal.J

ThoracOncol2008;3:13–17.2.Soda

M

et

al.Proc

Natl

Acad

Sci

USA2008;105:19893–19897.Figurebasedon:ChiarleRetal.NatRevCancer

2008;8(1):11–23;Mossé

YPetal.Clin

Cancer

Res2009;15(18):5609–5614.ALK

Pathway*

SubcellularlocalizationoftheALKfusiongene,while

likelytooccurinthecytoplasm,is

not

confirmed.1,2Cellsurvival

PI3K

STAT3/5

AKTmTOR

PLC-Y

PIP2

RAS

MEKOrAnaplasticLymphomaKinase(ALK)rearrangement Biomarkers:ALKimmunohistochemical

stainingFirstline:CrizotinibSecondlineorbeyond:

Ceritinib/Alectinib/LorlatinibClinicalindications:

ALKre-arrangedorIHC+vetumororsystemic

chemo/immunotherapyor

ALKFISHTumorResponsestoCrizotinibforPatientswith

ALK-positive

NSCLC

Progressivedisease

Stabledisease

Confirmed

partial

response

Confirmedcomplete

response*Partialresponsepatientswith

100%changehavenon-target

disease

present

*6040200–20–40–60–80–100Kwak

EL

et

al.N

Engl

J

Med

2010;363:1693-703.

Copyright

?2010

Massachusetts

Medical

Society.Maximumchangeintumorsize

(%)–30%肺癌治療效果評(píng)估及跟進(jìn)計(jì)算機(jī)掃描或正電子-計(jì)算機(jī)

雙容掃描纖維支氣管

內(nèi)視鏡檢查平片X光放射同位素骨掃描T790M

cells

willexist

at

averylow

level

inthetumourAs

the

T790M

cellscontinueto

grow,progression

occursEGFR-TKIs抗藥性EGFRT790M

mutationThis

enables

the

refractory

T790Mcellstogrow

out

and

become

a

more

dominant

proportion

oftumourWhentumoursare

treated

withfirstgeneration

TKI,

the

EGFRm

cells

die.OsimertinibPotentinhibitionofT790MPotentinhibitionof

EGFRmLowactivityonwt

EGFRDelay/stop

T790M

resistanceSimilartogefitinib,erlotinib,afatinibLowerrash,diarrhoea第三代EGFR標(biāo)靶藥and

T790M基因突變wtEGFR

EGFRmT790M06/201408/201408/2013Patient

1,

LYP,

F/67,

non-smokerLUL

lobectomy,

pIII

AdenoCa,adjMIP

x410/1997Back

and

chest

pain

!Pleural

Bx:

AdenoCa,

Del

19Gefitinib

x6/523604/201906/201607/2016Patient

1,

LYP,

F/67,

non-smokerGefitinib

x2yearsL

shoulder

painRe-biopsy:AdenoCaDel

19

+T790MOsimertinib

x2.5yearsNo

more

Lshoulder

painOsimertinib

x2weeks↓L

shoulder

pain37Immunotherapy免疫療法免疫療法免疫療法與化療比較免疫療法與化療比較之副作用不同干擾甲狀腺及皮質(zhì)醇分泌，免疫性肺炎Anti-PD1

in

EGFR/ALK+vetumorEGFR-TKI

Re-biopsyonprogressionNonewmutationEGFR

T790M

mutantbevacizumabORImmune-checkpoint

Inhibitor(1st

linewith/outchemo,

or2nd

linesettingesp

after

chemo)ALKrearrangementCrizotinibDiseaseprogressionConsider2nd

/3rd非小細(xì)胞肺癌Advancedstagenon-small

celllungcancerin

Asiansgeneration

ALK

inhibitorPlatinum-based

chemotherapy

+/-

耐藥性突變Non-sensitizingmutation

(exon18,

20)ASensitisingmutations,del

19,

L858R,

etc藥敏性突變

EGFR

mutant免疫療法或化療或混合治療NoALKrearrangement3rd

generation

EGFR-TKIEGFRwildtype低劑量胸腔計(jì)算機(jī)掃描應(yīng)用于肺癌篩查之成效1)年齡在55

至

80

歲之間2)是現(xiàn)在或前吸煙者，有30年

的吸煙史3)從沒(méi)有被診斷有肺癌低劑量胸腔計(jì)算機(jī)掃描及肺癌篩查研究46Canada–VancouverCanada–AlbertaAustralia

–

BrisbaneAustralia

–

PerthAustralia

–

Melbourne

1,

RoyalMelbourneHospitalAustralia

–

Melbourne2,

EpworthAustralia

–SydneyHongKong

(Dr.

DavidLam)UnitedKingdomTotal25Aug2016,21Nov

202017Jun2015,8

Dec

20175May

2017,

13

Dec

201911Jan2017,6

Dec

201930May2017,

13

Feb

202017Apr2018,

10

Dec20199

Dec2017,

17

Dec

201921Apr2018,4Jan20202Nov

2015,

15

Sep

2017低劑量胸腔計(jì)算機(jī)掃描及肺癌篩查研究InternationalLungScreeningTrial:aprospective,cohortstudy2138(36.7%)805(13.8%)596(10.2%)591(10.2%)407

(7.0%)127

(2.2%)378

(6.5%)128

(2.2%)649(11.1%)581964

[3.0%]25

[3.11%]17

[2.85%]18

[3.05%]8

[1.97%]2

[1.57%]4

[1.06%]3

[2.xx%]36

[5.55%]177

[3.04%]Screening

sites(Site

principal

investigator)Number

scanned(%of

study

total)Recruitmentperiod:Dateoffirst,lastbaselinescansLungcancersdetected[detection%ofscanned]Tammenmagi

MCetal,

ILST

Consortiumn

Keyinclusioncriterian

55-75y/oan

NeversmokingorSI

10

PYandhad

quit15yrsn

Havingoneofthefollowingrisksn

familyhistoryoflungcancer(≤

3-degree)n

environmentaltobaccosmokinghistoryn

chroniclungdisease(TB,

COPD)n

cookingindexb

≥

110n

cookingwithout

usingventilationn

NegativeCXR低劑量胸腔計(jì)算機(jī)掃描應(yīng)用于非吸煙者之肺癌篩查研究TaiwanLungCancerScreening

in

NeverSmokerTrial

(TALENT)From

Feb2015toJuly2019,

17medicalcentresparticipatedn

Datacutoff:September30,2020n

13,207subjectsscreened,

12,011enrolledn

6009(50%)withfamilyhistorya

SubjectswithlungcancerFH:

50yrs

or

theage

atdiagnosisoftheyoungestlungcancercaseinthefamilyb

2/7xdayswithcookingbypan-frying,

stir-frying,

ordeep-fryingin

1week

(maximum=21)xYrswithcooking48The

Lung

Ambition

AllianceLow-dose

chest

CTBiomarkers(blood,urine)

Questionnaire(FH,PH)posStandardCEchestCTBx

or

F/UNon-smoking55-75y/olung

cancer

risksposBxor

F/UposnegYang

PCet

al,

TALENT

Study

Group,

Taiwan

2021CXR低劑量胸腔計(jì)算機(jī)掃描應(yīng)用于非吸煙者之肺癌篩查研究TALENTT0

LungCancer

Detection

Rate?

T0lung

cancer

detection

rate:313/12,011=2.6%,

NLST:

1.1%,

NELSON:

0.9%?

Invasive

lung

cancer:255/12,011=2.1%.

Multiple

primary

lung

cancer:

17.9%?

LDCT

positive:

17.4%;

LDCT

features:GGO47%,S

19%,

PS34%?

Invasive

procedures:3.4%;

No

procedure-related

mortality?

Lung

cancer

confirmed:96.5%stage

0-1.?

Prevalence

of

lung

cancer

w/or

w/o

family

history:

3.2%vs2.0%

(p<

0.001)HistologicDiagnosis(n)Adenocarcinomainsitu

(AIS)58Minimallyinvasiveadenocarcinoma(MIA)71Invasiveadenocarcinoma(INAD)183Adenosquamous

carcinoma1Total313Stage0

58Stage

IA

218Stage

IB26Stage

IIA0Stage

IIB3Stage

IIIA

2Stage

IIIB

1Stage

IV

549The

Lung

Ambition

AllianceYang

PCet

al,

TALENT

Study

Group,

Taiwan

2021應(yīng)用低劑量胸腔計(jì)算機(jī)掃描肺癌篩查項(xiàng)目可提早發(fā)現(xiàn)肺癌

及其他疾病

肺氣腫（慢性阻塞性肺?。?，鈣化性冠心血管病，等等 But

it

gives

a

lot

of

lung

nodules

肺結(jié)節(jié)

Various

sizes

大小不一Various

shapes

型狀不一Various

composition

屬性不一Various

numbers

數(shù)目不一RelativelyhighchanceofbenignToosmallforcharacterizationKeepobservewithstandardofcare

surveillanceBenignvs

malignant?RecruitforbiomarkerstudySolitary,size6–

30

mm

Ground-glassorsemisolidMultiple肺結(jié)節(jié)之不確定性HighchanceofcancerWorkupforcancerSolitaryormultiple

Largestone>

30Solitary,size<

6mmmm跟進(jìn)處理肺結(jié)節(jié)之參考指引TheFleischnerSocietyGuidelinesforManagementofIncidental

Pulmonary

Nodules1Informmanagementforpatients

≥35years

ofage,

nonimmunocompromisedpatients,andthosewithout

aknown

malignancy2,aaIndividualized

management

is

required

forthe

finding

of

incidental

lung

nodules

in

adults

younger

than

35years

ofage

or

in

patients

who

are

immunocompromisedor

have

a

known

malignancy.

bDimensions

are

average

of

long

and

short

axes,

rounded

tothe

nearest

millimeter.

cConsider

all

relevant

riskfactors.

dOptional.

eOptionaliflow

risk.fIfunchangedand

solid

componentremains

<6

mm.CT,computed

tomography;

mo;

months;

PET,

positron

emission

tomography;

Y,years.1.Anderson

IJ,Davis

AM.

JAMA.20