therapeutic strategies for patients with localized triple
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Therapeutic Strategies for Patients with Localized Triple-Negative Breast Cancer (TNBC)
Sara Hurvitz, MDProfessor of Medicine
David Geffen School of Medicine at UCLADirector, Breast Cancer Clinical Research Program
Co-Director, Santa Monica-UCLA Outpatient Oncology PracticeSanta Monica, California
88%83%
T1aN0
85%80%
T1bN0
82%
75%
T1cN0 T2N0(3cm)
82%
75% 76%
67%
T2N0(4cm)
73%
63%
T2N0(5cm)
T2N0
77%
69%
T1cN1(1LN)
73%
62%
T1cN1(2LN)
69%
57%
T1cN1(3LN)
T1N1T1N0100%
20%
40%
60%
80%
100%
10-Y
ear O
vera
ll Su
rviv
al
10y Survival as per PREDICT NHS, 50y, G2 IDC, ER/HER2/negative, Ki67+
Do all patients with TNBC need chemotherapy?
(Neo)adjuvantchemotherapy
adjuvantchemo
?
Survival with/without chemotherapy
88%83%
T1aN0
85%80%
T1bN0
82%
75%
T1cN0
100%
20%
40%
60%
80%
100%
10-Y
ear O
vera
ll Su
rviv
al
10y Survival as per PREDICT NHS, 50y, G2 IDC, ER/HER2/negative, Ki67+
T1N0
OS 15 years % pts
sTILs < 30% 59% (53-65) 51%
sTILs 30%-75% 76% (69-84) 26%
sTILs ≥ 75% 93% (88-98) 22%
sTIL prognostic in young T1N0 TNBC patients (n=481)
Independent prognostic factors:
- TILs HR 0.75- LVI HR 2.52
De Jong et al, ESMO 2020
Do all patients with TNBC need chemotherapy? Survival with/without chemotherapy
No further therapy
Chemo or Trial
OP Chemo
Adjuvant Treatment
OPChemo
Neoadjuvant Treatment
Historically if inoperable
Preoperative or Postoperative Chemotherapy in TNBC?
DownstagingFacilitates less
invasive surgery (BCS, SLN, TAD)
RCTs confirm same outcome with adjuvant/neo-
adjuvant therapy (eg NSABP18)
Metaanalysis: pCR predictive of good outcome
Articles
www.thelancet.com Published online February 14, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62422-8 5
anthracycline-based and taxane-based regimens were done, with the exception of the NOAH16 and TECHNO22 trials, which were limited to patients with HER2-positive locally advanced or infl ammatory breast cancer. Patients in the NOAH16 trial were randomly assigned to preoperative chemotherapy with or without trastuzumab, and those in the TECHNO22 trial received trastuzumab and chemo therapy followed by 1 year of adjuvant trastuzumab. In the GeparQuattro trial,11,12 patients with HER2-positive tumours received trastu-zumab con comitantly with chemotherapy. Overall, 1087 (55%) of 1989 patients with HER2-positive tumours included in the pooled analysis did not receive 1 year of adjuvant trastuzumab because they were treated before adjuvant trastuzumab trials were reported. All
patients with hormone-receptor-positive tumours were supposed to receive at least 5 years of endocrine therapy. Breast cancer subtype was established by clinic-opathological criteria, such as hormone-receptor status, HER2 overexpression, and histological grade as assessed by local pathologists. The Ki-67 labelling index had not been routinely assessed in the included studies.
11 955 patients were included in our pooled responder analysis (fi gure 1). Baseline characteristics are shown in the appendix. Median age was 49 years (IQR 43–57). 7328 patients (61%) had T2 tumours, 482 (4%) had infl ammatory breast cancer (ie, T4d tumours), and 5487 (46%) had clinically involved lymph nodes. 3572 (30%) patients had hormone-receptor-negative breast cancer, and 1989 (17%) had HER2-positive
Figure 5: Association between pCR and event-free survival, by breast cancer subtypepCR=pathological complete response. HR=hazard ratio.
Number at riskpCR
No pCR
0
20
40
60
80
100
Even
t-free
survi
val (%
)
0 1 2 3 4 5 6 7 8 9
2702491
2442226
2241978
1841616
1131017
69658
21247
684
220
21
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9
Hormone-receptor-positive, HER2-negative
1481838
1341653
1231493
1021236
55790
33517
10198
568
215
21
Hormone-receptor-positive, HER2-negative, grade 1/2
102528
92458
83376
71290
49173
30111
938
114
05
Hormone-receptor-positive, HER2-negative, grade 3
Number at riskpCR
No pCR
0
20
40
60
80
100
Even
t-free
survi
val (%
)
5861403
5271157
454918
371713
212436
120269
37106
433
23
11
HER2-positive
HR 0·49 (95% CI 0·33–0·71) HR 0·63 (95% CI 0·38–1·04) HR 0·27 (95% CI 0·14–0·50)
HR 0·39 (95% CI 0·31–0·50) HR 0·58 (95% CI 0·42–0·82) HR 0·25 (95% CI 0·18–0·34)
HR 0·24 (95% CI 0·18–0·33)
Number at riskpCR
No pCR
0
20
40
60
80
100
Even
t-free
survi
val (%
)
0 1 2 3 4 5 6 7 8 9
389768
349604
310429
250317
166198
88125
2950
1113
11
Time since randomisation (years)
Triple negative
247839
224723
194617
157484
91306
50198
1779
224
11
23
Time since randomisation (years)
HER2-positive, hormone-receptor-positive
325510
293392
250269
205200
115111
6559
1922
26
Time since randomisation (years)
HER2-positive, hormone-receptor-negative
pCR No pCR
EFS, HR 0.24OS, HR 0.16
Cortazar, Lancet 2014
Path CR ypT0/is ypN0
Residual Disease DFS in TNBC (n=296)
Adjuvant Capecitabine improves outcome
EFS, HR 0.58OS, HR 0.52
Masuda N, NEJM 2017
CreateX trial Capecitabine(6–8 cycles)
Observation
Stage I–IIIB breast cancer (ER+ or TNBC)
Neoadjuvant chemotherapy
(95% A + T)
Non pathCR
Survival in TNBC (n=296)
Masuda N, et al. N Engl J Med. 2017;376:2147–2159.; Tutt et al, NEJM 2021
Can postoperative treatment improve cure rates in patients with residual disease after preoperative chemo?
Yes, in TNBC Yes, in patients with gBRCA1/2 mutations
Recurrence-free Survival
Olympia trialOlaparib
(1 year)
Placebo(1 year)
Stage I–IIIB breast cancer
NACT Non pathCR
Adjuvant (T2 or N+)
OlympiA: 3-Year Invasive DFS
Tutt ANJ et al. N Engl J Med 2021;384:2394-405.
OlympiA: Distant Disease-Free Survival
Tutt ANJ et al. N Engl J Med 2021;384:2394-405.
3-year dDFS difference: 7.1%HR: 0.0.57, p < 0.001N = 1,836
OlympiA: Overall Survival
3-year OS difference: 3.7%HR: 0.68, p < 0.02N = 1,836
Tutt ANJ et al. N Engl J Med 2021;384:2394-405.
OlympiA: Summary of Adverse Events
Tutt ANJ et al. N Engl J Med 2021;384:2394-405.
pCR Rates without Platinum around 35%
von Minckwitz G, SABCS 2015. #S2-04; von Minckwitz G. Lancet Oncol. 2014; Castrellon AB, Oncol Rev 2017, Sikov, JCO 2015, Sikov, SABCS 2015 S2-05; Loibl, S, et al. Lancet Oncol. 2018.
41%
54%
37%
53%
CALGB 40603
Paclitaxel +/-Bevacizum.
Paclitaxel +/-Bevacizum.+Carboplatin
Paclitaxel 80 mg/m2 q1w x 12 + Carboplatin AUC 6 q3w x 4
AC x 4
AC x 4
SURGERY
GeparSixto
Paclitaxel +NPL Doxo
Paclitaxel +NPL Doxo +Carboplatin
Paclitaxel 80 mg/m2 q1w x18 + NPLD 20 mg/m2
q1w x18 + Carboplatin AUC 1.5 q1w
SURGERY
71.6%
76.5%
Ø Cb
+Cb
3a-EFS
0.84 (0.58-1.22)
Paclitaxel 80 mg/m2 q1w x 12 + Carboplatin AUC 6 q3w x 4
BrighTNess
Paclitaxel
Paclitaxel +Carboplatin
AC x 4
AC x 4
SURGERY
31%
58%
76.1%
85.8%
3a-DFS
Ø Cb
+Cb0.56 (0.33-0.96)
Addition of carboplatin increases pCR rate in TNBC to >50% with improvement of EFS/OS
Can we increase response to NACT? Role of Platinum for TNBC
68.5%
79.3%
Ø Cb
+Cb
4a-EFS
0.57 (0.36–0.91), P=0.02
Neoadjuvant Immunotherapy in early TNBC Phase 3 trials of Immunotherapy in Stage II/III TNBC
Placebo
Pembrolizumab
- PDL1+ (22C3 CPS1) 82%- N+ 52%, T3/4 26%- Carbo QW 41%
- PDL1+ (SP142≥1%) 53%- N+ 38% (34% Ate; 43% Pla)- T3/4 28%
IMpassion031
Nab-Paclitaxel + Placebo
Nab-Paclitaxel + Atezolizumab
accAC + Placebo
accAC + Atezolizumab
SURGERY
R1:1
n = 333
Keynote 522Paclitaxel +
Carboplatin + Placebo
Paclitaxel + Carboplatin +
Pembrolizumab
AC/EC + Placebo
AC/EC + Pembrolizumab
SURGERY
R2:1
n = 1174
Co-primary endpoints:• pCR (ypT0/Tis ypN0) • Event-free Survival
Co-primary endpoints:• pCR (ypT0/Tis ypN0) in ITT & PD-L1+
Schmid P, et al NEJM 2020; Mittendorf E, et al Lancet 2020.
Atezolizumab: 840 mg given IV q2w (neoadjuvant); 1200 mg IV q3w x 11 (adjuvant)Nab-paclitaxel: 125 mg/m2 given IV qw for 12 weeksDoxorubicin: 60 mg/m2 given IV q2w/Cyclophosphamide: 600 mg/m2 given IV q2w
Pembrolizumab: 200 mg given IV q3w Paclitaxel: 80 mg/m2 given IV qw for 12 weeks;Carboplatin: AUC5 q3w x 4 or AUC1.5 qw x 12Doxorubicin: 60 mg/m2 given IV q2w/Cyclophosphamide: 600 mg/m2 given IV q2w
Atezolizumab
Unblinded F/U
Cross-trial comparison between Keynote 522 and IMpassion031 should be avoided
Addition of CIT significantly improves pCR in ITT Population
Neoadjuvant CIT in TNBC: Pathological complete response
0
10
20
30
40
50
60
70
80
90
100
ypT0/Tis ypN0
pCR,
% (9
5% C
I)
64.8%
51.2%
Δ 13.6%P=0.00055
260/401 103/201
Pembro + Chemo Placebo + Chemo
Keynote 522
0
10
20
30
40
50
60
70
80
90
100
pCR
(95%
CI)
(%)
pCR (ypT0/is ypN0)
57.6%
41.1%
95/165 69/168
∆ 16.5% P = 0.0044*
Atezo + Chemo Placebo + Chemo
Impassion 031
Schmid P, et al. ESMO 2019, Schmid, et al NEJM 2020, Harbeck et al, ESMO 2020This presentation is the intellectual property of the presenter. Contact p.Schmid@qmul.ac.uk for permission to reprint and/or distribute
aHazard ratio (CI) analyzed based on a Cox regression model with treatment as a covariate stratified by the randomization stratification factors. bPrespecified P-value boundary of 0.00517 reached at this analysis. cDefined as the time from randomization to the data cutoff date of March 23, 2021.
84.5%
76.8%
Median follow-upc: 39.1 mo
Events HR (95% CI) P-value
Pembro + Chemo/Pembro 15.7% 0.63a
(0.48-0.82)
0.00031b
Pbo + Chemo/Pbo 23.8%
Addition of CIT significantly improves EFS in ITT population
Neoadjuvant CIT in TNBC: Event-free Survival
Schmid et al, ESMO 2021
Presenter: Peter Schmid, MD Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
0.1 1 10
Overall 123/784 (15.7) 93/390 (23.8) 0.63 (0.48 to 0.82)
Pembro + Chemo/Pembro Pbo + Chemo/PboHazard Ratio
(95% CI)
No. Events/No. Patients (%)
Positive 80/408 (19.6) 57/196 (29.1) 0.65 (0.46 to 0.91)Negative 43/376 (11.4) 36/194 (18.6) 0.58 (0.37 to 0.91)
T1/T2 64/581 (11.0) 59/290 (20.3) 0.51 (0.36 to 0.73)T3/T4 59/203 (29.1) 34/100 (34.0) 0.84 (0.55 to 1.28)
Every 3 weeks 50/334 (15.0) 37/167 (22.2) 0.65 (0.42 to 0.99)Weekly 71/444 (16.0) 56/220 (25.5) 0.60 (0.42 to 0.86)
Positive 98/656 (14.9) 68/317 (21.5) 0.67 (0.49 to 0.92)Negative 25/128 (19.5) 25/69 (36.2) 0.48 (0.28 to 0.85)
<65 years 103/700 (14.7) 79/342 (23.1) 0.61 (0.45 to 0.82)³65 years 20/84 (23.8) 14/48 (29.2) 0.79 (0.40 to 1.56)
0 101/678 (14.9) 80/341 (23.5) 0.60 (0.45 to 0.80)1 22/106 (20.8) 13/49 (26.5) 0.81 (0.41 to 1.62)
Nodal status
Tumor size
Carboplatin schedule
PD-L1 status
Age category
ECOG PS
Subgroup
FavorsPbo + Chemo/Pbo
FavorsPembro + Chemo/Pembro
pCR by Nodal Status
EFS in Subgroups
0
10
20
30
40
50
60
07
80
90
100
Negative Positive
pCR
, % (9
5% C
I)
64.8%
44.1%
Δ 6.3%
58.6%
Δ 20.6%
64.9%
Nodal Status and Benefit from Immunotherapy
N0 and N+ patients have similar pCRwhen treated with CIT
N0 and N+ patients have similar EFS Benefit when treated with CIT
Presenter: Peter Schmid, MD Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
0.1 1 10
Overall 123/784 (15.7) 93/390 (23.8) 0.63 (0.48 to 0.82)
Pembro + Chemo/Pembro Pbo + Chemo/PboHazard Ratio
(95% CI)
No. Events/No. Patients (%)
Positive 80/408 (19.6) 57/196 (29.1) 0.65 (0.46 to 0.91)Negative 43/376 (11.4) 36/194 (18.6) 0.58 (0.37 to 0.91)
T1/T2 64/581 (11.0) 59/290 (20.3) 0.51 (0.36 to 0.73)T3/T4 59/203 (29.1) 34/100 (34.0) 0.84 (0.55 to 1.28)
Every 3 weeks 50/334 (15.0) 37/167 (22.2) 0.65 (0.42 to 0.99)Weekly 71/444 (16.0) 56/220 (25.5) 0.60 (0.42 to 0.86)
Positive 98/656 (14.9) 68/317 (21.5) 0.67 (0.49 to 0.92)Negative 25/128 (19.5) 25/69 (36.2) 0.48 (0.28 to 0.85)
<65 years 103/700 (14.7) 79/342 (23.1) 0.61 (0.45 to 0.82)³65 years 20/84 (23.8) 14/48 (29.2) 0.79 (0.40 to 1.56)
0 101/678 (14.9) 80/341 (23.5) 0.60 (0.45 to 0.80)1 22/106 (20.8) 13/49 (26.5) 0.81 (0.41 to 1.62)
Nodal status
Tumor size
Carboplatin schedule
PD-L1 status
Age category
ECOG PS
Subgroup
FavorsPbo + Chemo/Pbo
FavorsPembro + Chemo/Pembro
pCR by PD-L1 Score
0
10
20
30
40
50
60
70
80
90
100
CPS <1
pCR
, % (9
5% C
I)
30.3%
45.3%
CPS ≥1 CPS ≥10
68.9%
54.9%
77.9%
59.8%Δ 18.3%
Δ 14.2%Δ 17.5%
EFS in Subgroups
PD-L1 Status and Benefit from Immunotherapy
PD-L1+ and PD-L1- patients have similar EFS and pCR Benefit when treated with CIT
Distant Recurrence-Free Survival
aHazard ratio (CI) analyzed based on a Cox regression model with treatment as a covariate stratified by the randomization stratification factors. Data cutoff date: March 23, 2021.
87.0%
80.7%
Events HR (95% CI)
Pembro + Chemo 12.8% 0.61a
(0.46-0.82)Pbo + Chemo 20.3%
89.7%
86.9%
Events HR (95% CI)
P-value
Pembro + Chemo 10.2% 0.72a
(0.51-1.02) 0.03214bPbo + Chemo 14.1%
Neoadjuvant CIT in TNBC: Distant RFS and Overall SurvivalOverall Survival
Schmid et al, ESMO 2021
108/201
94.4%
92.5%
56.8%
67.4%
pCR Yes
pCR No
Schmid et al, ESMO 2021
Implications KN522:1. Presence of pCR benefit
predictive of long-term outcome2. Absence of pCR benefit does not
rule out substantial benefit
Does pCR-benefit with CIT translate into survival benefit?Is there a benefit beyond achieving a pCR? Event-free Survival by pCR
KEYNOTE-522 Study: EFS(IA4)
Neoadjuvant CIT: Treatment-related side effects
Schmid P, et al. ESMO 2019, Schmid, et al NEJM 2020
0
10
20
30
40
50
60
70
80
90
100
Inci
denc
e, %
Nause
a
Alo
pecia
Anem
ia
Neutropenia
Fatig
ue
Dia
rrhea
ALT
↑
Vom
iting
Ast
henia
Const
ipatio
n
Rash
Neutrophil
count ↓
1-2Grade
3-5
Pembro + Chemo
Placebo + Chemo
Periphera
l
neuro
path
y
Treatment-Related AEs With Incidence ≥20%
62.7 63.260.3
56.655.1 55.3
46.7 47.0
41.1
37.8
29.4
23.725.5 24.7 25.5
21.924.5 25.4
23.721.1
23.7
28.8
21.8
15.2
19.721.1
Treatment-Related AEs With Incidence ≥20%Keynote 522 Neodjuvant Phase
0
10
20
30
40
50
60
70
80
90
100
Inci
denc
e, %
Arthra
lgia
Rash
Ast
henia
Fatigue
Pru
ritu
s
Dia
rrhea
ALT
↑
Neutropenia
Nause
a
Anem
ia
Hyp
oth
yroid
-
ism
Lym
phopenia
AST ↑
7.96.7
4.92.2
3.3 3.8 3.3 3.84.22.2
3.72.5 2.6 2.9 2.2 1.6 2.2 1.3 2.0 1.9 1.6
2.91.6
2.5 1.6 2.5
Treatment-Related AEs With Incidence ≥2%Keynote 522 Adjuvant Phase
Response to Discussion:
Safety:1. No new safety signals were identified2. AEs consistent with the known safety profiles3. The addition of pembrolizumab did not compromise
exposure to chemotherapy or increase the incidence of common chemotherapy-related toxicities
Presenter: Peter Schmid, MD Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.
a1 patient from pneumonitis and 1 patient from autoimmune encephalitis. Considered regardless of attribution to treatment or immune relatedness by the investigator. Related terms included in addition to preferred terms listed. Data cutoff date: March 23, 2021.
Immune-Mediated AEs in Adjuvant Phase
Hyperth
yroidis
m
Hypophy
sitis
Severe
skin
reactio
ns
Infusi
on rea
ctions
Hypothy
roidis
mColit
is
Thyroid
itis
Adrenal
insuffi
ciency
Hepatitis
Pneumoni
tis
Immune-Mediated AEs and Infusion Reactions with Incidence ≥10 Patients
0
2
4
6
8
10
12
14
16
18
20
Inci
denc
e, %
18.0
11.6
15.1
5.7 5.7
1.0
5.2
1.82.6
0
2.21.5 2.0
1.3 1.9
0.31.7
0.81.4
0.8
1-2Grade
3-5Pembro + Chemo/Pembro
Pbo + Chemo/Pbo Pembro + Chemo/Pembro
(N = 783)
Pbo + Chemo/Pbo
(N = 389)Any grade 43.6% 21.9%Grade 3-5 14.9% 2.1%Led to death 0.3%a 0Led to discontinuation of any drug
10.9% 2.6%
Pembro + Chemo/Pembro
(N = 588)
Pbo + Chemo/Pbo
(N = 331)Any grade 10.2% 6.0%Grade 3-5 2.9% 0.3%Led to death 0.2%a 0Led to discontinuation 1.4% 0.3%
0
2
4
6
8
10
12
14
16
18
a1 patient from autoimmune encephalitis. Considered regardless of attribution to treatment or immune relatedness by the investigator. Related terms included in addition to preferred terms listed. Data cutoff date: March 23, 2021.
Immune-Mediated AEs and Infusion Reactions with Incidence ≥2 Patients
20
Inci
denc
e, %
2.93.6
1.91.2
1.9
01.2
0.60
0.9 0.6 0.5 0.3 0 0.3 0
Hyperth
yroidis
m
Myocard
itis
Severe
skin
reactio
ns
Infusi
on rea
ctions
Hypothy
roidis
mAdre
nal
insuffi
ciency
Pneumoni
tisColit
is
Response to Discussion:
Immune-Mediated AEs:
1. Higher incidence of immune-mediated AEs primarily driven by endocrinopathies and skin reactions
2. AEs mostly occurred during the neoadjuvant phase with a very low incidence during the adjuvant phase
3. AEs generally low-grade, and successfully managed with treatment interruption, steroid administration, and/or hormone replacement, underscoring the importance of early identification and intervention to minimize risk and ensure continued treatment benefit
4. Although some immune-mediated AEs may be irreversible, analyses from other cancer types support the long-term safety of pembrolizumab, with no signal for late toxicities
5. Additional follow-up will inform the long-term safety of this regimen
Neoadjuvant CIT: Immune-mediated side effectsImmune-Mediated AEs in Combined Phases
Newly diagnosed TNBC • T1c/T2 N1 or • T3N0 or• locally advanced
Carboplatin (AUC2) + nab-Paclitaxel (125 mg/m2) days 1&8 q3 weeks x 8
Neoadjuvant Chemo + anti-PDL1 in TNBC: NeoTRIP Study
Primary endpoint: Event-free survival at 5 yearsKey secondary endpoints: pCR rates (ypT0/TisypN0), safety, predictive markers
OPCarboplatin +
Nab-Paclitaxel +/-Atezolizumab
R 2:1 AC/EC x 4
40.8%
43.5%
Control (no CIT)
Immunotherapy
- PDL1+ 56%- Locally advanced 49%- N+ 87%, N2/3 29%- T3/4 43%
Gianni, L, SABCS 2019
CIT trial designs in Early TNBC
OPNeoadjuvant Chemo
Immunotherapy Immunotherapy +/-
Keynote 522, Impassion031, NSABP B-59/GBG96
- Optimal antigen release- Possible over-treatment (pCR with CT)- pCR with CIT predictive of EFS?- Contribution of adjuvant therapy unclear
OPNeoadjuvant Chemo Immunoth. If suboptimal
response
Immunotherapy +/-- Reduced antigen release- Selection of high risk group- No validated definition of subop response
OPNeoadjuvant Chemo
Immunotherapy Immunotherapy +/-
Impassion030
- No/minimal antigen release- Possible over-treatment - NACT increasingly standard
OPNeoadjuvant Chemo non-path CR Immunotherapy - No/minimal antigen release- Single CIT agent efficacy limited
A-BRAVE, SWOG
De-escalation strategiesStage I
Stratified by TILs?
Stage II/III
Role of Carboplatin
with CIT
Identify optimal
responders(TILs? PDL1?)
OPChemo-free combinations?
OPChemo + CIT
Path CR ypT0/is ypN0
Residual Disease
Chemo in non pathCR?
Tailor strategies Chemo + CT?
ADC + CIT?
Role of adjuvant CIT?
Future directions in early TNBC
Based on personal communication from Prof. P. Schmid, Barts Cancer Institute.
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