肺癌筛查与诊治的新发展

肺癌筛查与诊治的最新发展汇报人：发病率

死亡率Top

10cancers

in

Hong

Kong

in

20192019年香港十大癌症统计数字Precisionmedicine精准医疗•Identificationoftreatmentapproachesthatwillbeeffectiveforwhichpatientsbasedongenetic,environmental,andlifestylefactors.基于遗传,环境和生活方式因素确定对患者有效的医疗方法•尽量延长病患的存活期•症状得以减轻•改善并提高生活质素肺癌•每年新增病例数超过4000例，仍然是男性和女性的首要

癌症杀手。肺癌治疗个人化•肿瘤之分类及分期•个人的健康情况与选择•癌细胞中存有的「标靶」或生物标记肺癌治疗最理想目标•根除肿瘤选择最好的肺癌治疗方式01•确诊02•肺癌细胞的病理类型03•临床或(病理)分期04•体能状况Bronchoscopy支气管镜检查MainlydiagnosticPulmonaryInterventions胸肺介入术AutofluorescentBronchoscopy萤光气管镜EBUS-TBNA支气管镜内超声波检查气管镜内超声波or导航式气管镜Endobronchial

ValvesBronchialThermoplastyPleuroscopy

胸膜镜Cryoprobe/APC< 支气管镜内超声波检查

(EBUS)导航式气管镜不同肺癌种类有不同的基因变化肺腺癌

肺鳞片癌肺癌TNM分期TPrimaryTumor肿瘤肿瘤本身的大小和入侵邻近器官的情形NRegionalLymphNode淋巴结扩散到区域淋巴的情形MDistantMetastasis转移扩散到肺部以外的器官标靶测试化疗±电疗

化疗±?手术切除标靶测试V肺癌治疗方式手术切除复发非小细胞肺癌

小细胞肺癌化疗或标靶治疗或免疫疗法早期

局部晚期

晚期局限型

扩散型化疗电疗合并V适用于初期肺癌患者区域性的局部治疗方式局部症状控制，包括肿瘤造成咳血或是局部肺叶塌陷，以及手术后的预防局

部复发及控制可与化学治疗合并使用提升局部晚期肺癌的治疗，或为晚期肺癌患者缓解治

疗之用对小细胞肺癌治疗之效果显著在非小细胞肺癌方面，可单独使用或与放射线治疗合用标靶治疗免疫疗法手术切除放射治疗化学治疗生物治疗肺癌治疗方式西方人東方人东西方人的肺癌基因不同标靶治疗•针对癌细胞中存有的「标靶」,用专一性的药物攻击这些「标靶」来杀死癌细胞,但对

正常细胞则不造成或只有很低的伤害•应用于第一线或第二线化学治疗后有再度恶

化的非小细胞肺癌病患•当肺癌细胞存有EGFR基因突变时,更可采用EGFR-TK作I为第一线治疗标靶治疗类别标靶或生物标记测试药物EGFR-TKI表皮生长因子受体(EGFR)基因第十八至二十一段存有基因突变Gefitinib,ErlotinibAfatinib,DacomitinibEGFRT790MinhibitorEGFRT790MmutationOsimertinibEML4-ALKinhibitorEML4-ALK移动融合基因CrizotinibCeritinib,Alectinib,Brigatinib,LorlatinibROS1inhibitorROS1移动融合基因Crizotinib,EntrectinibEGFR基因突变EGFR-TKIcompeteswith

ATPto

preventactivationofthe

EGFRandinitiationofdownstreamsignallingInhibitionofapoptosisMetastasisLigand

上皮生长因子EGFR

上皮生长因子受体ProliferationInvasionAngiogenesisHeerbstetal2002标靶治疗上皮生长因子受体抑制剂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

耐药性突变EGFR

基因突变Some

patients

had

more

than

one

mutation

type

AstraZeneca

data

on

file

2009ATPbinding

cleftC-lobe

N-lobeTransmembrane

regionRegulatory

domain药敏性突变药敏性突变Extracellular

domain耐药性突变TKdomainA-loop标靶治疗前

标靶治疗六周后标靶治疗•皮肤红疹及异常•腹泻常见•间质性肺炎•出血,血栓塞,穿肠•影响视力0102个别标靶治疗可引起之罕见副作用Paronchyiawith

ingrowntoenail甲沟炎血液检测EGFR基因突变药敏性突变耐药性突变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%肺癌治疗效果评估及跟进计算机扫描或正电子-计算机

双容扫描纤维支气管

内视镜检查平片X光放射同位素骨扫描T790M

cells

willexist

at

averylow

level

inthetumourAs

the

T790M

cellscontinueto

grow,progression

occursEGFR-TKIs抗药性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标靶药and

T790M基因突变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免疫疗法免疫疗法免疫疗法与化疗比较免疫疗法与化疗比较之副作用不同干扰甲状腺及皮质醇分泌，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非小细胞肺癌Advancedstagenon-small

celllungcancerin

Asiansgeneration

ALK

inhibitorPlatinum-based

chemotherapy

+/-

耐药性突变Non-sensitizingmutation

(exon18,

20)ASensitisingmutations,del

19,

L858R,

etc药敏性突变

EGFR

mutant免疫疗法或化疗或混合治疗NoALKrearrangement3rd

generation

EGFR-TKIEGFRwildtype低剂量胸腔计算机扫描应用于肺癌筛查之成效1)年龄在55

至

80

岁之间2)是现在或前吸烟者，有30年

的吸烟史3)从没有被诊断有肺癌低剂量胸腔计算机扫描及肺癌筛查研究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低剂量胸腔计算机扫描及肺癌筛查研究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低剂量胸腔计算机扫描应用于非吸烟者之肺癌筛查研究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低剂量胸腔计算机扫描应用于非吸烟者之肺癌筛查研究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应用低剂量胸腔计算机扫描肺癌筛查项目可提早发现肺癌

及其他疾病

肺气肿（慢性阻塞性肺病），钙化性冠心血管病，等等 But

it

gives

a

lot

of

lung

nodules

肺结节

Various

sizes

大小不一Various

shapes

型状不一Various

composition

属性不一Various

numbers

数目不一RelativelyhighchanceofbenignToosmallforcharacterizationKeepobservewithstandardofcare

surveillanceBenignvs

malignant?RecruitforbiomarkerstudySolitary,size6–

30

mm

Ground-glassorsemisolidMultiple肺结节之不确定性HighchanceofcancerWorkupforcancerSolitaryormultiple

Largestone>

30Solitary,size<

6mmmm跟进处理肺结节之参考指引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