Principes de la commande prédictive. Applications sous MATLAB.
Biologie de l onco-immunologie Valeur prédictive et ...senologie.tv/pdfs_up/5a168a771263d.pdf ·...
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SFSPM Novembre 2017 Valeur prédictive et pronostique de l’infiltrat immunitaire dans les cancers du sein traités par chimiothérapie néoadjuvante Dr Fabien REYAL Service de Chirurgie INSERM U932 Immunity and Cancer Institut Curie
Transcript of Biologie de l onco-immunologie Valeur prédictive et ...senologie.tv/pdfs_up/5a168a771263d.pdf ·...
SFSPM Novembre 2017
Valeur prédictive et pronostique de l’infiltrat immunitaire dans les cancers du sein traités par chimiothérapie
néoadjuvante
Dr Fabien REYAL
Service de ChirurgieINSERM U932 Immunity and Cancer
Institut Curie
• Role of tumor-infiltrating lymphocytes (TILs)
– High levels of TILs at diagnosis : better response to NAC
– Better prognosis (triple negative breast cancers (TNBC) and HER2-positive BC)
• TILs following neoadjuvant chemotherapy (NAC) ?
2
Tumor infiltration in the neoadjuvant setting
Myashita Dieci Loi Hamy
BC subtype TNBC TNBC TNBC HER2-pos
Numbers n=131 n=278 n=111 n=175
Pairs pre & post n=78 n=19 n=39 n=175
Analysis in pCR patients No No No Yes
Tumor infiltration and response to treatment in breast cancer
Microbiopsy Neoadjuvantchemotherapy
Surgery
BEFORE AFTER
TIL baseline TILs dynamics
DURING
TIL residual
Identify patterns of immune infiltration related to response to treatment and prognosis
NEOREP cohort Institut Curie2002-2011n=718
N=718
BMI class BMI<19 41 (5.7)
BMI: 19 to 25 414 (57.7)
BMI: 25 to 30 166 (23.2)
BMI>30 96 (13.4)
Tumor size 45.0 (20.5)
Tumor size T1 47 (6.5)
T2 482 (67.1)
T3 189 (26.3)
Clinical node status N0 282 (39.3)
N1-N2-N3 435 (60.7)
BC subtype Luminal 223 (31.1)
TNBC 320 (44.6)
HER2 175 (24.4)
Histology Ductal carcinoma NST 661 (92.6)
Other 53 (7.4)
Grade Grade I-II 211 (30.1)
Grade III 491 (69.9)
NAC regimen Anthracyclines based regimens 61 (8.5)
Anthracyclines-taxanes regimens 577 (80.4)
Others 80 (11.1)
Patients characteristics
NEOREP cohort
n=718Mean age : 48 y.o
TNBC 44%Luminal 31%HER2 24%
Median tumor size: 45mm
Anthra – taxanes (80.4%)
5Microbiopsy before NAC TIL=2% Microbiopsy before NAC TIL>60%
6Surgical Specimen after NAC TIL=2% Surgical Specimen after NAC TIL>60%
Lymphocyte PBC before neoadjuvant chemotherapy is a rare entity
Luminal 2%TN 18%HER2-positive 10%
luminal TNBC HER2
0 25 50 75 0 25 50 75 0 25 50 75
0.00
0.01
0.02
0.03
0.04
Baseline TIL levels (%)
BC subtype
luminal
TNBC
HER2
Lymphocyte predominant breast cancer
Cut-off stromal TILs : ≥ 50 or 60%
Baseline TILs vary by BC subtypeBaseline TILs are associated with agressive tumor characteristics
****
0
25
50
75
luminal TNBC HER2
BC
su
bty
pe
A***
0
25
50
75
T1 T2 T3
Clin
ical tu
mo
r siz
e
B****
0
25
50
75
Grade I−II Grade III
Gra
de
C****
0
25
50
75
<11 11−22 >22
Pre
−N
AC
mitotic ind
ex
D*
0
25
50
75
<=60% > 60%
Invasiv
e t
um
or
ce
llula
rity
E
Response to treatment
0
20
40
60
Pre
−N
AC
str
TIL
s (
%)
a
0
20
40
60
pCR No pCR
Pre
−N
AC
str
TIL
s (
%)
b
0
20
40
60
Po
st−
NA
C s
tr T
ILs (
%)
c
0
20
40
60
pCR No pCR
Po
st−
NA
C s
tr T
ILs (
%)
d lum
inal
TN
BC
HE
R2
0
20
40
60
0
20
40
60
0
20
40
60
Pre
−N
AC
str
TIL
s (
%)
alu
min
al
TN
BC
HE
R2
pCR No pCR
0
20
40
60
0
20
40
60
0
20
40
60
Pre
−N
AC
str
TIL
s (
%)
b
lum
inal
TN
BC
HE
R2
0
20
40
60
0
20
40
60
0
20
40
60
Po
st−
NA
C s
tr T
ILs (
%)
c
lum
inal
TN
BC
HE
R2
pCR No pCR
0
20
40
60
0
20
40
60
0
20
40
60
Po
st−
NA
C s
tr T
ILs (
%)
d
Baseline TIL levels* are associated with pCR
***
**
***
Luminal and TNBC and NOT in HER2+ BC
Significant interaction by BC subtype (p=0.04)
lum
inal
TN
BC
HE
R2
0
20
40
60
0
20
40
60
0
20
40
60
Pre
−N
AC
str
TIL
s (
%)
a
lum
inal
TN
BC
HE
R2
pCR RCB−I RCB−II RCB−III
0
20
40
60
0
20
40
60
0
20
40
60
Pre
−N
AC
str
TIL
s (
%)
b
lum
inal
TN
BC
HE
R2
0
20
40
60
0
20
40
60
0
20
40
60
Pre
−N
AC
IT
TIL
s (
%)
c
lum
inal
TN
BC
HE
R2
pCR RCB−I RCB−II RCB−III
0
20
40
60
0
20
40
60
0
20
40
60
Pre
−N
AC
IT
TIL
s (
%)
dBaseline TIL levels* are associated with RCB
11
0
20
40
60
Pre
−N
AC
str
TIL
s (
%)
a
0
20
40
60
pCR RCB−I RCB−II RCB−III
Pre
−N
AC
str
TIL
s (
%)
b
0
20
40
60
Po
st−
NA
C s
tr T
ILs (
%)
c
0
20
40
60
pCR RCB−I RCB−II RCB−III
Po
st−
NA
C s
tr T
ILs (
%)
d
***
***
***
In luminal and TNBC, NOT in HER2+ BC
12
0
10
20
30
40
50
luminal TNBC HER2
% p
CR Str TILs
<med
>med
A
0
20
40
luminal TNBC HER2
% p
CR
Str TILs1st tert
2nd tert
3rd tert
B
0
20
40
60
luminal TNBC HER2
% p
CR Str TILs
<60%
=>60%
C
0
20
40
60
luminal TNBC HER2
% p
CR
Str TILs=<10%
11−49%
=>50%
D
0
20
40
luminal TNBC HER2
% p
CR
Str TILs1st quart
2nd quart
3rd quart
4th quart
A
0
25
50
75
100
luminal TNBC HER2
% p
CR
Str TILs(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
(60,70]
(70,80]
(80,90]
B
Baseline TILs levels are associated with pCR in luminal and TNBC not in HER2-positive BC
TILs dynamic
TILs levels decrease after neoadjuvant chemotherapy
0
25
50
75
100
Pre Post
Str
om
al T
IL levels
(%
)
AllA
0
20
40
60
80
Pre Post
LuminalB
0
25
50
75
100
Pre Post
TNBCC
0
25
50
75
Pre Post
HER2D
15
(0,10] (10,20] (20,30] (30,40] (40,50] (50,60] (60,70] (70,80] (80,90]
0
25
50
75
100
TILs changes before and after NAC, by baseline TILs (10% classes)
TILs dynamics is strongly correlated with baseline TILs levels …
Baseline TIL levels (by 10% increment)
TILs changes before and after NAC
16
… irrespective of response to treatment
●●●●
●
●
●
●●
●
●●
●
●
●
●●●●
●
●
●●●●●
●
●
●●●
●
●
●
●
●●
●●
●
●
●
●●
●
●
●
●●
●
No pCR pCR
−50
0
50
Baseline TILs
TIL
s v
ari
ation
(a
bs.
va
l.)
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
(60,70]
(70,80]
(80,90]
−50
0
50
Ch
an
ge
in
str
TIL
leve
ls (
ab
s v
al)
pCRpCR
No pCR
A high decrease in stromal TIL levels is associated with pCR
18
High baseline TILs and high decrease of lymphocytes after NAC are associated with pCR
0
25
50
75
100
0885163048829205027860608742098325410832989707227078650108830110304859058413405093450509786070310009024380488073088809802869911105490068816306829490880072088702610823150486497058267505865760680073068190806868930784282098050509838060991058108138611043950586685058751906802200788752088714908879640989924111097109928310982308098989005875660880814098801896849610889424088138908871120583246058345105867870587483068137906824080682809068623606881150783026078508708883830889385098311409885310991340099189309919511108022058177605828210682628099096106073450881935099298308837450784387068720010808621086301109197005807910584079058417305848450585804058642205865210682153068390206845060780833078151007815420781548078415707848590788835078929108841910887013088708808885639281057098000409803830980928098189009838960581112068320506838990781283078279102023200206876020598308000490806182090090705827660787395058111910827110584164109136004870150585911068642507809310881767088441908871519581269098988510846491091326088514802035770208634080345504011510683466058790207858560984343098336611081040683914108082507815860789350078326107862250992650058323704869800887661068193106868101100983088152407878200980533109183202821920485949058570105866570680366068268906839710685397068650606871650687234078652407872750885225088556408859260886865088914108895340982695098399309879200991658110488811118881119522048664104867600580177058254705855090587638068255406837910686003068820507874630882222020151903076960400593040692205022080704799070643408006680801091080380109042940906962109090211071120881231109051010921491103553058653105877160789131098488209908259406457020624303030880602186090192510071140683681048559509899261105321111027509904311080000099157309807350986873048726411034251116364108151410850180485335058249405833440586718068066706872390782920078685207881100882872099269011126721114210048490704859180585067058579106841950685963078009608806450205586030705504049910604019890837308864800786261108221804854261082155108999605861800685947068706906875197280019078705008818470882882098412009901490990898108099411161360883399088890809802870708413098620607819280682166108010810803421105744111579808835181084524058272706841430781721078174107821100883611088808308898000986492098758809908951092031111208704856210584152068098706855240687301078966297805770607658070519202024800204750030873104060310407469070574608092510907256068217511042901106910108241907800070784398110112911070900983751099116109913410486568058348605843680889584078055508835881112767111938107896991084546109051910917661092644068258706879790781126078167508820270887006098340509867590992976111702811174290385372048687005810360581084058420707811240786547088112708893820980450098117802012480203511050605105072210601719060171306027750608199060970107065870806690090471106861041090983048687986034210606478080117609881160486252068444507851590786550098824504866831100066110040104853790486567088469908853870991593111725804844970584021058432409908350993012109221911037920990493098093006802840881441048486498819330887333108043810820601083461048581404863080583549068412006868250780888078098908864240889357098558809926381091636111531412070330780171078092408837790207988050874709043681103143108122109873220989800078061009896670486080068120008876561083715058645906866280687556078189807830020890000948295210862341092336110092111126670786932078767908824550983014098325009869700988532030179704067078503482070577107880398884765110792210815770886133058694304865210685808058676506815661089823058325406836140684886068503607826570783120078332208870708987464108262011071991116517068512702001900401768050897005085170601207060400511174781091035109194110923861092485098933911053570788651088174707841020885657068628010806220987594098122004848690484989068212410924810885886111726010800391080789110060305807200584849068450707831660785818078626908883140992138120159612049740486132058610406862060886052098144209929340305613030005703070640405818040589306079031109755080873709073241001083100139109915919083394110828211129850583117108071411201211200654120082605843310788657088736608873820887502040815708041731001444108195505841810585143058391811024881100112048527088874340990989111119107844520984767098489609905550306900040870406075128803926080093808061911002676100463704870760684754098587210860131089398108990311013441111467111399312015321202033098684809928430305012820900506859050587740088345711150171083484109094804883860781092078640708859360986507030056103050090804747058694609907050680988098349206085641006818078110710818710580609058419211140880584082088751309832600704433090779610916340783167078476309891931084984109216012051150684926078263909090020301005108065906822180890119078475009908371092218060558010907420984037098090809890000782111088735409910950582779078621007862640980606070213810818940683096088379705864181083479068167402065990305065060256807854100990502120173409901810586107070439303080800684144088205111160610682958078400507858210986307020861706882240884050098188009854530986451109247607098920680230090605007887950900084
valu
e
0
25
50
75
100
0885163048829205027860608742098325410832989707227078650108830110304859058413405093450509786070310009024380488073088809802869911105490068816306829490880072088702610823150486497058267505865760680073068190806868930784282098050509838060991058108138611043950586685058751906802200788752088714908879640989924111097109928310982308098989005875660880814098801896849610889424088138908871120583246058345105867870587483068137906824080682809068623606881150783026078508708883830889385098311409885310991340099189309919511108022058177605828210682628099096106073450881935099298308837450784387068720010808621086301109197005807910584079058417305848450585804058642205865210682153068390206845060780833078151007815420781548078415707848590788835078929108841910887013088708808885639281057098000409803830980928098189009838960581112068320506838990781283078279102023200206876020598308000490806182090090705827660787395058111910827110584164109136004870150585911068642507809310881767088441908871519581269098988510846491091326088514802035770208634080345504011510683466058790207858560984343098336611081040683914108082507815860789350078326107862250992650058323704869800887661068193106868101100983088152407878200980533109183202821920485949058570105866570680366068268906839710685397068650606871650687234078652407872750885225088556408859260886865088914108895340982695098399309879200991658110488811118881119522048664104867600580177058254705855090587638068255406837910686003068820507874630882222020151903076960400593040692205022080704799070643408006680801091080380109042940906962109090211071120881231109051010921491103553058653105877160789131098488209908259406457020624303030880602186090192510071140683681048559509899261105321111027509904311080000099157309807350986873048726411034251116364108151410850180485335058249405833440586718068066706872390782920078685207881100882872099269011126721114210048490704859180585067058579106841950685963078009608806450205586030705504049910604019890837308864800786261108221804854261082155108999605861800685947068706906875197280019078705008818470882882098412009901490990898108099411161360883399088890809802870708413098620607819280682166108010810803421105744111579808835181084524058272706841430781721078174107821100883611088808308898000986492098758809908951092031111208704856210584152068098706855240687301078966297805770607658070519202024800204750030873104060310407469070574608092510907256068217511042901106910108241907800070784398110112911070900983751099116109913410486568058348605843680889584078055508835881112767111938107896991084546109051910917661092644068258706879790781126078167508820270887006098340509867590992976111702811174290385372048687005810360581084058420707811240786547088112708893820980450098117802012480203511050605105072210601719060171306027750608199060970107065870806690090471106861041090983048687986034210606478080117609881160486252068444507851590786550098824504866831100066110040104853790486567088469908853870991593111725804844970584021058432409908350993012109221911037920990493098093006802840881441048486498819330887333108043810820601083461048581404863080583549068412006868250780888078098908864240889357098558809926381091636111531412070330780171078092408837790207988050874709043681103143108122109873220989800078061009896670486080068120008876561083715058645906866280687556078189807830020890000948295210862341092336110092111126670786932078767908824550983014098325009869700988532030179704067078503482070577107880398884765110792210815770886133058694304865210685808058676506815661089823058325406836140684886068503607826570783120078332208870708987464108262011071991116517068512702001900401768050897005085170601207060400511174781091035109194110923861092485098933911053570788651088174707841020885657068628010806220987594098122004848690484989068212410924810885886111726010800391080789110060305807200584849068450707831660785818078626908883140992138120159612049740486132058610406862060886052098144209929340305613030005703070640405818040589306079031109755080873709073241001083100139109915919083394110828211129850583117108071411201211200654120082605843310788657088736608873820887502040815708041731001444108195505841810585143058391811024881100112048527088874340990989111119107844520984767098489609905550306900040870406075128803926080093808061911002676100463704870760684754098587210860131089398108990311013441111467111399312015321202033098684809928430305012820900506859050587740088345711150171083484109094804883860781092078640708859360986507030056103050090804747058694609907050680988098349206085641006818078110710818710580609058419211140880584082088751309832600704433090779610916340783167078476309891931084984109216012051150684926078263909090020301005108065906822180890119078475009908371092218060558010907420984037098090809890000782111088735409910950582779078621007862640980606070213810818940683096088379705864181083479068167402065990305065060256807854100990502120173409901810586107070439303080800684144088205111160610682958078400507858210986307020861706882240884050098188009854530986451109247607098920680230090605007887950900084
valu
e
Median Ly density
ChangeLy density
cancer
stromal lymphocytes
Post-NAC stromal TILs
Lymphocyte-predominant breast Cancer is even rarer after NAC than before
luminal TNBC HER2
0 25 50 75 100 0 25 50 75 100 0 25 50 75 100
0.00
0.02
0.04
0.06
Post−NAC TILs (%)
BC subtype
luminal
TNBC
HER2
0
25
50
75
100
TNBC luminal HER2
% c
ase
s
TILs levels(90,100]
(80,90]
(60,70]
(50,60]
(40,50]
(30,40]
(20,30]
(10,20]
(0,10]
Luminal 1%TN 4%HER2-positive 1%
Post-NAC TILs are higher in tumors with residual disease than in pCRspecimens
0
20
40
60
perc_stromal_lymphocyte2
Post−
NA
C T
ILs (
%)
A
******************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************
0
20
40
60
perc_stromal_lymphocyte2
Post−
NA
C T
ILs (
%)
luminal
TNBC
HER2
B
******************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************
0
20
40
60
pCR No pCR
Po
st−
NA
C T
ILs (
%)
C
*** ***
luminal TNBC HER2
pCR No pCR pCR No pCR pCR No pCR
0
20
40
60
Po
st−
NA
C T
ILs (
%)
D
22
0
20
40
60
Pre
−N
AC
str
TIL
s (
%)
a
0
20
40
60
pCR RCB−I RCB−II RCB−III
Pre
−N
AC
str
TIL
s (
%)
b
0
20
40
60
Po
st−
NA
C s
tr T
ILs (
%)
c
0
20
40
60
pCR RCB−I RCB−II RCB−III
Po
st−
NA
C s
tr T
ILs (
%)
d
lum
inal
TN
BC
HE
R2
0
20
40
60
0
20
40
60
0
20
40
60
Po
st−
NA
C s
tr T
ILs (
%)
a
lum
inal
TN
BC
HE
R2
pCR RCB−I RCB−II RCB−III
0
20
40
60
0
20
40
60
0
20
40
60
Po
st−
NA
C s
tr T
ILs (
%)
b
lum
inal
TN
BC
HE
R2
0
20
40
60
0
20
40
60
0
20
40
60
Po
st−
NA
C I
T T
ILs (
%)
c
lum
inal
TN
BC
HE
R2
pCR RCB−I RCB−II RCB−III
0
20
40
60
0
20
40
60
0
20
40
60
Po
st−
NA
C I
T T
ILs (
%)
d
luminal
TNBC
HER2
NS
***
Higher post-NAC TIL levels are associated with increasing RCB only in HER2-positive BC
(Pinteraction=0.04)
23
Impact on prognosis
++
++++++++++++
+
+++++++++++++++++++++++++++++++++++ ++++++++++++++++++++++++++++ +++
+ +++ + +
+++++++++++++++++++++++++++
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++ +++++ ++++ ++++
p = 0.17
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se
−fr
ee
su
rviv
al
TILS (cut−off: 20%)
+
+
< 20%
=> 20%
TNBC
128 69 36 7 0
191 98 41 14 0=> 20%
< 20%
0 30 60 90 120
number at risk
A
++++++++++++++
++++++++
+++++++++++++++++++++++++++++++++++++++++++++++++ +++++++++++++++++++++++++++++++++++++++ +++
++ + ++++++ +
+++++++++++++++++
++
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ + + ++ ++++ ++ +++
p = 0.017
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se
−fr
ee
su
rviv
al
TILS (cut−off: 30%)
+
+
< 30%
=> 30%
TNBC
183 93 49 11 0
136 74 28 10 0=> 30%
< 30%
0 30 60 90 120
number at risk
B
+++++++++++++++++++++++++
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
+++ + ++++++++ +
++++++++++++++++
++++++ ++++++++++++++++++++++++++++++++ ++++++++++++++++ + + +++ ++ +
p = 0.001
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se
−fr
ee
su
rviv
al
TILS (cut−off: 40%)
+
+
< 40%
=> 40%
TNBC
228 118 58 14 0
91 49 19 7 0=> 40%
< 40%
0 30 60 90 120
number at risk
C
++++++++++++++++++++++++++++++
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ + ++++++++ +
+++++++++++++
++++ ++++++++++++++++++++++++++ +++++++++++++ + + + + ++ +
p = 4e−04
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se
−fr
ee
su
rviv
al
TILS (cut−off: 50%)
+
+
< 50%
=> 50%
TNBC
249 127 63 15 0
70 40 14 6 0=> 50%
< 50%
0 30 60 90 120
number at risk
D
+++++++++++++++++++++++
++++++++++
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++++ +
+++++++++++
+++ +++++++++++++++++++++++ +++++++++++ + + + +
p = 0.0016
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se−
fre
e s
urv
iva
l
TILS (cut−off: 60%)
+
+
< 60%
=> 60%
TNBC
261 134 67 17 0
58 33 10 4 0=> 60%
< 60%
0 30 60 90 120
number at risk
E
+
++++++++++
+
++++++++++++++ +++++++++++++++++++++++++ ++++++++++ +++
+ +++ + +
+++++++++++++++++
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++ +++ + + ++ +
+++++++++++++
++++ ++++++++++++++++++++++++++ +++++++++++++ + + + + ++ +
p = 0.0016
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se−
fre
e s
urv
iva
l
TILS (3 classes)
+
+
+
<= 10%
[11−49]
>= 50%
TNBC
106 54 29 7 0143 73 34 8 070 40 14 6 0>= 50%
[11−49]<= 10%
0 30 60 90 120
number at risk
F
++
++++++++++++++++++++++++++++++++++ ++++++++++++++++++++++++++++++++++++++++++++
+++++++++++++++++++
++
++++++++++ +
+ ++++++++++++++ ++++ +
+++++++++++ ++++
++++ ++++++ ++++++ ++++ +
++++
p = 0.3
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ea
se−
fre
e s
urv
iva
l
TILS (cut−off: 20%)
+
+
< 20%
=> 20%
Luminal
149 125 63 17 0
74 64 35 11 0=> 20%
< 20%
0 25 50 75
number at risk
A
++ +++++++++++++++++++++++++++++++
+++++++++++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
+++++++++++++++++
+
+++++++
++ ++ +
++ +
+
+++ ++ +++ ++
++
p = 0.79
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ea
se−
fre
e s
urv
iva
l
TILS (cut−off: 30%)
+
+
< 30%
=> 30%
Luminal
189 159 82 23 0
34 30 16 5 0=> 30%
< 30%
0 25 50 75
number at risk
B
++ ++++++++++++++++++++++++++++++++++
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
++++++++++
+++++++
+
++++
++ ++
+ + + ++ ++ ++
p = 0.4
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ease
−fr
ee
su
rviv
al
TILS (cut−off: 40%)
+
+
< 40%
=> 40%
Luminal
204 172 91 26 0
19 17 7 2 0=> 40%
< 40%
0 25 50 75
number at risk
C
++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
+++++++++++++
++++++++++
++++++++
+
++ + + + + + +
p = 0.23
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ease
−fr
ee
su
rviv
al
TILS (cut−off: 50%)
+
+
< 50%
=> 50%
Luminal
215 183 95 27 0
8 6 3 1 0=> 50%
< 50%
0 25 50 75
number at risk
D
++ ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
+++++++++++++
++++++++++
++++++++
+
+ + + + +
p = 0.29
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ea
se
−fr
ee s
urv
ival
TILS (cut−off: 60%)
+
+
< 60%
=> 60%
Luminal
218 185 95 27 0
5 4 3 1 0=> 60%
< 60%
0 25 50 75
number at risk
E
++
+++++++++++++++++++++++++++ ++++++++++++++++++++++++++
++++++++++++
++++++++
++
++++++++ + +
++ ++
++++++++++++++++++
+ ++++++++++++++++ +++++
+++++++++++++++++++++++++ ++++ +
+ +++
++ + + + + + +
p = 0.47
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ea
se
−fr
ee s
urv
ival
TILS (3 classes)
+
+
+
<= 10%
[11−49]
>= 50%
Luminal
114 94 50 16 0101 89 45 11 08 6 3 1 0>= 50%
[11−49]<= 10%
0 25 50 75
number at risk
F
++++ ++++ +++++++++++++++++++
+++++ ++++++++++++++ + + +++++++++++ +++ +++
++++++++++++++++++++++++++++++++++++++++
+++++++++++++
++ ++++++ +++++++++
+++++++++++ + +++ + ++ +
p = 0.39
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ea
se−
fre
e s
urv
iva
l
TILS (cut−off: 20%)
+
+
< 20%
=> 20%
HER2
71 54 23 6 0
104 70 32 8 0=> 20%
< 20%
0 25 50 75
number at risk
A
++++++++++++++ +++++++++++++++++++++++++++++++
++ +++++++++++++++++++ +++++++++++++++++ ++++ ++++
++++ +++++++++++++++
++++++++++++++++ +++
++ +++++ +
+++++++++++ + +++ + +
p = 0.57
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ea
se−
fre
e s
urv
iva
l
TILS (cut−off: 30%)
+
+
< 30%
=> 30%
HER2
103 77 35 8
72 47 20 6=> 30%
< 30%
0 25 50 75
number at risk
B
++++++++++++++++++ +++++++++++++++++++++++++++++++++++
+++++ +++++++++++++++++++++++++ ++++++++++++++++++++++++ ++++
+++++++++
++++++++++++++ +++ + ++ +
++++ +++++ + + + +
p = 0.8
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ease
−fr
ee
su
rviv
al
TILS (cut−off: 40%)
+
+
< 40%
=> 40%
HER2
127 94 40 11 0
48 30 15 3 0=> 40%
< 40%
0 25 50 75
number at risk
C
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
++++++ ++++++++++++++++++++++++++++ +++++++++++++++++++++++++ ++++ +
++++
++++++ ++ +
+++ ++++ + + +
p = 0.48
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ease
−fr
ee
su
rviv
al
TILS (cut−off: 50%)
+
+
< 50%
=> 50%
HER2
148 105 44 12
27 19 11 2=> 50%
< 50%
0 25 50 75
number at risk
D
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
++++++ +++++++++++++++++++++++++++
+++++++++++++++++++++++++++++ ++++ +
+ ++
++++ + + ++ ++ + + +
p = 0.49
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ea
se
−fr
ee s
urv
ival
TILS (cut−off: 60%)
+
+
< 60%
=> 60%
HER2
158 111 48 12 0
17 13 7 2 0=> 60%
< 60%
0 25 50 75
number at risk
E
++ +++++++++++
+++ ++++++
+++++++ ++ + + +++ +++ + +
++++++++++++++++++++++++++++++++++++
+++++++++++++++
+++++++++++++++++++ ++++++++++++++++++ +++ +
++++
++++++ ++ +
+++ ++++ + + +
p = 0.72
0.00
0.25
0.50
0.75
1.00
0 25 50 75
Time
Dis
ea
se
−fr
ee s
urv
ival
TILS (3 classes)
+
+
+
<= 10%
[11−49]
>= 50%
HER2
46 33 12 2102 72 32 1027 19 11 2>= 50%
[11−49]<= 10%
0 25 50 75
number at risk
F
Baseline stromal TIL levels are associated with DFS in TNBC
Baseline str TILs
Log
rela
tive
Haz
ard
++
++++++++++++
+
+++++++++++++++++++++++++++++++++++ ++++++++++++++++++++++++++++ +++
+ +++ + +
+++++++++++++++++++++++++++
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++ +++++ ++++ ++++
p = 0.17
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se
−fr
ee
su
rviv
al
TILS (cut−off: 20%)
+
+
< 20%
=> 20%
TNBC
128 69 36 7 0
191 98 41 14 0=> 20%
< 20%
0 30 60 90 120
number at risk
A
++++++++++++++
++++++++
+++++++++++++++++++++++++++++++++++++++++++++++++ +++++++++++++++++++++++++++++++++++++++ +++
++ + ++++++ +
+++++++++++++++++
++
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ + + ++ ++++ ++ +++
p = 0.017
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se
−fr
ee
su
rviv
al
TILS (cut−off: 30%)
+
+
< 30%
=> 30%
TNBC
183 93 49 11 0
136 74 28 10 0=> 30%
< 30%
0 30 60 90 120
number at risk
B
+++++++++++++++++++++++++
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
+++ + ++++++++ +
++++++++++++++++
++++++ ++++++++++++++++++++++++++++++++ ++++++++++++++++ + + +++ ++ +
p = 0.001
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se
−fr
ee
su
rviv
al
TILS (cut−off: 40%)
+
+
< 40%
=> 40%
TNBC
228 118 58 14 0
91 49 19 7 0=> 40%
< 40%
0 30 60 90 120
number at risk
C
++++++++++++++++++++++++++++++
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ + ++++++++ +
+++++++++++++
++++ ++++++++++++++++++++++++++ +++++++++++++ + + + + ++ +
p = 4e−04
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se
−fr
ee
su
rviv
al
TILS (cut−off: 50%)
+
+
< 50%
=> 50%
TNBC
249 127 63 15 0
70 40 14 6 0=> 50%
< 50%
0 30 60 90 120
number at risk
D
+++++++++++++++++++++++
++++++++++
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++++ +
+++++++++++
+++ +++++++++++++++++++++++ +++++++++++ + + + +
p = 0.0016
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se−
fre
e s
urv
iva
l
TILS (cut−off: 60%)
+
+
< 60%
=> 60%
TNBC
261 134 67 17 0
58 33 10 4 0=> 60%
< 60%
0 30 60 90 120
number at risk
E
+
++++++++++
+
++++++++++++++ +++++++++++++++++++++++++ ++++++++++ +++
+ +++ + +
+++++++++++++++++
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++ +++ + + ++ +
+++++++++++++
++++ ++++++++++++++++++++++++++ +++++++++++++ + + + + ++ +
p = 0.0016
0.00
0.25
0.50
0.75
1.00
0 30 60 90 120
Time
Dis
ea
se−
fre
e s
urv
iva
l
TILS (3 classes)
+
+
+
<= 10%
[11−49]
>= 50%
TNBC
106 54 29 7 0143 73 34 8 070 40 14 6 0>= 50%
[11−49]<= 10%
0 30 60 90 120
number at risk
F
26
0
10
20
30
40
50
luminal TNBC HER2
% p
CR Str TILs
<med
>med
A
0
20
40
luminal TNBC HER2
% p
CR
Str TILs1st tert
2nd tert
3rd tert
B
0
20
40
60
luminal TNBC HER2
% p
CR Str TILs
<60%
=>60%
C
0
20
40
60
luminal TNBC HER2
% p
CR
Str TILs=<10%
11−49%
=>50%
D
0
20
40
luminal TNBC HER2
% p
CR
Str TILs1st quart
2nd quart
3rd quart
4th quart
A
0
25
50
75
100
luminal TNBC HER2
% p
CR
Str TILs(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
(60,70]
(70,80]
(80,90]
B
Baseline str TILs
Log
rela
tive
Haz
ard
Baseline stromal TIL levels are associated with DFS in TNBC
27
Post-NAC TILs are NOT associated with DFS, but this effect differs by BC subtype
- Significant interaction with BC
subtype
- Effect of post-NAC TILs on DFS
different in TNBC / HER2-positive
(Pinteraction = 0.04)
- Effect linear : cut-off unknown ?
Adverse impact of high post-NAC TILs in RD in HER2-positive BC, but trend to protective effect in TNBC
28
Take home messages
• Confirmation association pre-NAC TILs – pCR
• Dynamics : The highest baseline TILs are, the highest their level decrease
• High TILs decrease correlates with pCR
• Different prognostic value pre and post-NAC = > Complex interactions BC subtype and TILs
• TILs subsetting is pivotal to understand mechanisms of resistance to treatment
• Assessment pre NAC & post NAC should become routine practice
29
U932 Immunity and Cancer
Anne-sophie Hamy-PetitHélène Bonsang Kitzis
Department of tumour biology
Marick LaéLucian TopiuDiane Decroze
30
Univariate Multivariate
name levels OR 95%CI pval OR 95%CI p
Age <45 y.o 1
45-55 y.o 0.97 [0.66 - 1.42] 0.877
>55 y.o 1.4 [0.93 - 2.11] 0.101
Menopausal status postmenopausal 1
premenopausal 0.8 [0.57 - 1.12] 0.193
BMI class BMI: 19 to 25 1
BMI<19 0.56 [0.24 - 1.19] 0.156
BMI: 25 to 30 0.76 [0.5 - 1.14] 0.186
BMI>30 0.9 [0.55 - 1.47] 0.69
Tumor size (2 cl) T1-T2 1
T3 0.8 [0.54 - 1.16] 0.245
Clinical nodal status N0 1
N1-N2-N3 0.9 [0.65 - 1.26] 0.546
ER status ER negative 1
ER positive 0.2 [0.13 - 0.29] <0.001
PR status PR negative 1
PR positive 0.13 [0.08 - 0.22] <0.001
HER2 status HER2 negative 1
HER2 positive 1.94 [1.35 - 2.78] <0.001
BC subtype TNBC 1 1
luminal 0.08 [0.04 - 0.15] <0.001 0.09 [ 0.04 - 0.18 ] <0.001
HER2 1.02 [0.7 - 1.48] 0.927 1.01 [ 0.68 - 1.5 ] 0.958
Histology ductal 1
other 0.82 [0.41 - 1.52] 0.543
Grade Grade I-II 1
Grade III 2.71 [1.8 - 4.16] <0.001
ki67 ki67<20 1
ki67>=20 2.56 [1.05 - 7.23] 0.051
NAC regimen Anthracyclines based regimens 1
Anthracyclines-taxanes regimens 0.98 [0.55 - 1.8] 0.936
Others 1.32 [0.64 - 2.76] 0.456
Pre-NAC mitotic index 3 Mitotic index <= 10 1
Mitotic index 11-22 1.38 [0.86 - 2.25] 0.187
Mitotic index >22 2.05 [1.34 - 3.19] 0.001
Pre-NAC tumor cellularityPre-NAC tumor cellularity (inv.) <= 60% 1
Pre-NAC tumor cellularity (inv.) > 60% 0.94 [0.68 - 1.31] 0.733
IS component (pre NAC) No pre-NAC in situ component 1
Pre-NAC in situ component 0.83 [0.51 - 1.3] 0.417
Str TIL levels (continuous) 1.03 [1.02 - 1.04] <0.001 1.03 [ 1.02 - 1.03 ] <0.001
Whole population
• Baseline TILs
(continuous or cut-
off 40%)
• BC subtype
Multivariateanalysis pCR
TNBC
Univariate Multiivariate
TNBC Class HR CI p p HR CI p
Pre-NAC parameters
Age, years <45 1 0.78
45-55 1.02 [0.63 - 1.67] 0.93
>55 0.84 [0.48 - 1.49] 0.55
Menopause status Post 1 0.47
Pre 1.18 [0.75 - 1.86] 0.47
BMI class BMI < 25 1 0.25
BMI>= 25 1.29 [0.83 - 1.98] 0.26
Tumor size T1-T2 1 <0.01
T3 1.66 [1.18 - 2.34] <0.01
Clinical node status N0 1 0.15
N1-N2-N3 1.38 [0.89 - 2.15] 0.15
Histology Ductal carcinoma NST 1 0.44
Other 1.34 [0.64 - 2.77] 0.44
Grade Grade I-II 1 0.6
Grade III 1.19 [0.61 - 2.31] 0.6
Ki 67 <20% 1 0.52
≥20% 1.32 [0.56 - 3.14] 0.52
Pre-NAC mitotic index <11 1 0.37
11-22 1.68 [0.67 - 4.22] 0.27
>22 1.81 [0.78 - 4.2] 0.17
Pre-NAC inv. tumor cellularity ≤60% 1 0.19
> 60% 0.74 [0.47 - 1.17] 0.19
Pre-NAC str TILs (cut-off 40%) < 40% 1 <0.01 1 - -
≥ 40% 0.35 [0.18 - 0.67] <0.01 0.39 [ 0.18 - 0.86 ] 0.02
Post-NAC parameters
pCR No pCR 1 <0.01
pCR 0.22 [0.12 - 0.41] <0.01
RCB index pCR 1 <0.01
RCB-I 1.39 [0.39 - 4.92] 0.61 1 - -
RCB-II 3.52 [1.84 - 6.73] <0.01 1.67 [ 0.21 - 12.99 ] 0.626
RCB-III 11.27 [5.7 - 22.26] <0.01 6.18 [ 0.79 - 48.09 ] 0.082
Post-NAC Str TILS (cut-off 25%) str TILs ≤ 25%
str TILs > 25%
Post-NAC Mitotic index ≤ 10 1 <0.01 1 - -
11-22 2.38 [0.81 - 6.97] 0.11 2.01 [ 0.68 - 5.9 ] 0.207
>22 4.89 [2.46 - 9.71] <0.01 4.92 [ 2.41 - 10.05 ] <0.001
Post-NAC inv. tumor cellularity ≤30% 1 0.07
> 30% 1.61 [0.96 - 2.7] 0.07
Post-NAC Str TILS (continuous) 0.99 [0.98-1.01] 0.79
TNBC
• Baseline TILs
• RCB
• Post-NAC mitotic
index
Multivariateanalysis DFS
32
HER2
Univariate Multiivariate
TNBC Class HR CI p p HR CI p
Pre-NAC parameters
Age, years <45 1 0.33
45-55 1.29 [0.48 - 3.43] 0.62
>55 0.42 [0.09 - 1.97] 0.27
Menopause status Post 1 0.38
Pre 1.58 [0.56 - 4.44] 0.38
BMI class BMI < 25 1 <0.01 1 - -
BMI>= 25 3.37 [1.33 - 8.57] 0.01 4.83 [ 1.75 - 13.36 ] 0.002
Tumor size T1-T2 1 0.15
T3 1.96 [0.78 - 4.98] 0.15
Clinical node status N0 1 0.57
N1-N2-N3 1.35 [0.48 - 3.8] 0.57
ER status Negative 1 0.81
Positive 1.12 [0.44 - 2.85] 0.81
PR status Negative 1 0.74
Positive 0.84 [0.29 - 2.41] 0.74
Grade Grade I-II 1 0.01 1 - -
Grade III 0.32 [0.13 - 0.81] 0.02 0.18 [ 0.06 - 0.54 ] 0.002
Pre-NAC mitotic index <11 1 0.63
11-22 0.72 [0.25 - 2.06] 0.54
>22 0.56 [0.16 - 1.92] 0.36
Pre-NAC inv. tumor cellularity ≤60% 1 0.7
> 60% 0.83 [0.33 - 2.1] 0.7
Pre-NAC str TILs (continuous) 0.61
Pre-NAC str TILs (cut-off 40%) < 40% 1 0.8
≥ 40% 1.14 [0.41 - 3.21] 0.8
Post-NAC parameters
pCR No pCR 1 <0.01
pCR 0.09 [0.01 - 0.7] 0.02
RCB index pCR 1 <0.01
RCB-I 3.29 [0.21 - 52.63] 0.4
RCB-II 11.01 [1.43 - 84.72] 0.02
RCB-III 19.99 [2.23 - 178.86] <0.01
Post-NAC Str TILS (cut-off 25%) str TILs ≤ 25% 1 <0.01 1 - -
str TILs > 25% 5.05 [1.66 - 15.36] <0.01 9.61 [ 2.51 - 36.8 ] 0.001
Post-NAC Mitotic index ≤ 10 1 0.03
11-22 1.6 [0.2 - 12.66] 0.66
>22 3.52 [1.31 - 9.47] 0.01
Post-NAC inv. tumor cellularity ≤30% 1 0.13
> 30% 2.07 [0.8 - 5.38] 0.13
Post-NAC Str TILS (continuous) 1 <0.01
HER2
• Post-NAC TILs
• Grade
• BMI
Multivariateanalysis DFS
