Combined androgen blockade is the unique choice of hormone therapy at all stages of prostate cancer

1
Combined androgen blockade is the unique choice
of hormone therapy at all stages of prostate
cancer and is curative in localized disease
Fernand Labrie, MD PhDLaval University, Quebec
City, Canada
Japan Urological Association. Takeda Evening
SeminarYokohama, April 26, 2008
2
Prostate cancer is extremely dependent upon
androgens - when localized, the cancer can be
cured if androgens are properly blocked by
combined androgen blockade
3
Very important two sources of androgens in
the prostate testicles and adrenals
4
Sources of androgens in adult men (65-year old)
DHEA
40 50
Adrenal
Testosterone
Testicle
50 60
5
The prostate transforms DHEA into androgens
6
Human steroidogenic enzymes in peripheral
intracrine tissues
17b-HSD
DHEA-S
5-DIOL-S
Steroid sulfatase
1 / 5
DHEA
5-DIOL
2
3ß-HSD1
3 / 5 / 13
5a-reductase-1
DHT
4-DIONE
TESTO
5a-reductase-2
2
Aromatase
1 / 7
E2
E1
2
Steroid sulfatase
Estrogen
Androgen
E2-S
E1-S
7
DHEA stimulates prostate growth
8
Ventral Prostate Weight
30
20
10
0
Intact
Control
DHEA (10mg)
4-Dione (1.5mg)
TESTO (0.75mg)
DHT (0.1mg)
Orchiectomized
9
25-50 of androgens are made in the prostate
itself from DHEA of adrenal origin
10
A SERUM TESTOSTERINE
B PROSTATE CANCER DIHYDROTESTOSTERONE
4
6
4
Testosterone (ng/ml)
DHT (ng/g tissue)
2
2
0
0
Intact
Intact
CAST.
CAST.
11
ng/g tissue
30 patients
6
4
2
25
0
LHRH agonist flutamide
Pretreatment
Nishiyama et al Clin. Cancer Res 10, 7121-7126,
2004
12
GOOD NEWSBut much more can be achieved
13
Cancer deaths
Prostate
Breast

• 1992 40,000 46,000
• 2007 27,050 40,600

-33
-12
American Cancer Society
14
Hormone therapy on the rise
The number of men with early prostate cancers who
undergo hormone deprivation has increased
dramatically.
Percentage of men 80 and older with low-risk
disease who received hormone therapy within six
months of diagnosis
1991 4
1999 31
Source Cancer, 2005
USA TODAY, Sept 19, 2006
15
JUA PC Registration 2005
a)
b)
T1T4
T1T3 w/o meta
Initial treatment
0
1000
0
1000
2000
Cases
Cases
W/W
(5.59)
(2.92)
RRP
(13.43)
(19.73)
HxRRP
(13.96)
(19.02)
HxRRPRx
(0.71)
(0.97)
Rx
(2.05)
(3.22)
HxRx
(6.01)
(7.60)
PADT
(56.94)
(45.90)
Others
(0.37)
(0.30)
Uncertain
(0.95)
(0.00)
()
()
(Int JU, 2005)
Japanese Urological Association (2005) Akaza
(2008)
16
Common errors related to androgen blockade
1- Monotherapy (GnRH agonist alone, orchiectomy
alone or antiandrogen alone) instead of combined
androgen blockade 2- Too short duration of
treatment 3- Treatment started too
late 4- Intermittent treatment
17
GnRH ??????????? ?????????
18
First prostate cancer patient treatedwith an
GnRH agonist (Labrie et al, 1980)
12
9
Testosterone (ng/ml)
6
3
0
0
2
4
6
8
10
12
14
16
Days of treatment
19
In a metaanalysis of several studies (5000 men),
hormonal treatment given immediately versus
waiting until disease progressed, the risk of
dying from prostate cancer within 10 years
dropped by one third
R. Peto, ECCO Meeting, sept 2003
20
Seven randomized trials show that early treatment
prolongs life. No negative study exists
21
Effect of androgen blockade on prostate cancer
death
STUDY BENEFITS AT 5 YEARS EORTC, Bolla et al.
(1997) 77 (P0.01) RTOG 85-31 37 for
Gleason score 8-10 Pilepich et al.
(1997) (P0.03) Messing et al. (1999) 81
(P0.001) Granfors et al. (1998) 39
(P0.06) Hanks et al. (2000) 59 for Gleason
score 8-10 (P0.007) DAmico et al.
(2004) 41 decrease in overall death (Plt0.04)
22
Androgen blockadeis as effective asradical
prostatectomyin well differentiated prostate
cancer
Egawa et al., Int. J. Urol. 11, 304-309, 2004
23
Hokuriku district
447 stage B prostate cancers 55 had hormone
therapy only 45 had surgery hormone therapy
EGAWA et al., Int. J. Urol. 11, 304-309, 2004
24
No difference was found by the addition of
radical prostatectomy to monotherapy in stage B
cancer at 9.2 years of follow-upThe value of
prostatectomy alone or added to androgen blockade
was marginal in terms of survival
EGAWA et al., Int. J. Urol. 11, 304-309, 2004
25
With todays knowledge, monotherapy is not an
acceptable androgen blockade
26
What is combined androgen blockade?GnRH agonist
or antagonist or orchiectomyflutamide
(Eulexin), bicalutamide (Casodex) or nilutamide
(Anandron) - not with cyproterone acetate
(Androcur)
27
(No Transcript)
28
Unfortunately, in metastatic disease, the growth
factors pathways have acquired control of
prostate cancer growth
29
Receptor
Receptor
ReceptorSer/Thr kinase
Receptor
JAKTyr kinase
PLC-g
Protein kinase
SMAD
IkB kinase
PI(4,5)P2
Ser phosphorylationOligomerization
STAT
IP3
IkB
NF-kB
Tyr phosphorylationDimerization
Ca2
PhosphorylationUbiquitinationDegradation
Calcineurin
NFAT
Dephosphorylation
NF-kB
SMAD
L.C.Cantley, Science,292, 2019, 2001
Nucleus
STAT
NFAT
30
Hormone therapy has now moved to early stages of
prostate cancerwhere efficacy is much greater
31
Localized disease - Choices of treatment

• Radical prostatectomy alone Or hormone
  therapy
• Radiation therapy alone Or hormone therapy
• Hormone therapy alone
• Will be followed by hormone therapy in up to
  50 of cases

32
Can combined androgen blockade provide long-term
control or possible cure of localized prostate
cancer?
Fernand Labrie, Bernard Candas, José-Luis Gomez,
and Léonello Cusan
Urology 60, 115-119, 2002
33
Effect of duration of continuous CAB on the of
patients with PSA remaining under control for a
minimum of 5 years following cessation of CAB
100
11/12
long term control or cure
7/8
80
60

3/8
40
1/3
20
0/11
0
10
12
0
2
4
6
8
Years of continuous CAB
Labrie et al, Urology 60115-119, 2002
34
Time to progression

• 1.00

GnRH agonist
0.75
Plt0.01
Bicalutamide 80 mg (n102)
0.50
GnRH agonist alone (n102)
0.25
0
200
180
160
140
120
100
80
60
40
20
0
Weeks
Akaza et al., Asco Proc., 2005
35
 Cure of prostate cancer is almost always
possible with current androgen blockade.. H.
Akaza, 2007
36
Overall Survival
1.0
0.8
0.6
Survival rate
0.4
MAB (N102)
0.2
LHRH(N101)
p0.043 (Log-rank test)
0.0
500
1000
1500
2000
2500
0
Days after treatment
Japan Study Group for CAB Therapy in Prostate
Cancer Akaza (2008)
37
Combined androgen blockade is cytotoxic. It
kills cancer cells
38
Resistance to combined androgen blockade does not
occuror is very rarein localized disease.
39
Major objective prevent cancer from migrating
to the bones
40
PROSTATE CANCER
LOCALIZED
ADVANCED
41
The best treatment for localized prostate cancer
is likely to be long-term combined androgen
blockade alone
42
Combined androgen blockade is much more efficient
than monotherapy
43
Prostate cancer mortality Immediate versus
deferred androgen blockade
Ratio of death rates
A- Monotherapy Orchiectomy / LHRH agonist vs
Placebo
10
M
34
M -
20
B- Combined androgen blockade Orchiectomy
/ LHRH agonist pure antiandrogen (Flutamide,
Nilutamide, or Bicalutamide) vs Castration
M
90 cure
M -
Immediate
better
M Distant metastases
0
0.5
1.0
44
More than 90 of localized cancers can be cured
by combined androgen blockade(Labrie et al., J
Urol, 60 115-119, 2002)
45
When hormone therapy is used, it should always be
combined androgen blockade
46
????????????CAB(combined androgen blockade)?????
47
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48
Cancer-fighting drugs improved survival rates,
especially for cancer of the prostate, where drug
innovations have been the greatest.
NCI data from 2.1 million patients F.R.
Lichtenberg, 2004
49
Antiandrogens block the action of all androgens
approach of choice
50
TESTO
DHEA
DHT

DHT
AR
AR
TESTO
DHT
51
The need is a more potent antiandrogen which
could permit to cure localized prostate cancer in
1 to 2 years instead of 7 years
52
A
B
C
40
3
250
200
30
2
150
ng/ml
pg/ml
ng/ml
20
100
1
10
50
0
0
0
Postmeno- pausal women
Castrated men
Postmeno- pausal women
Castrated men
Postmeno- pausal women
Castrated men
Estrone sulfate
Testosterone
ADT-G3?-diol-3G17G
53
Not adding an antiandrogen to castration in men
with prostate cancer is equivalent to refusing
hormonal therapy to postmenopausal women because
they are postmenopausal
54
Inhibitors of enzymes will not be able to block
the formation of all androgens
55
HUMAN STEROIDOGENIC ENZYMES
DHEA-S
5-DIOL-FA
5-DIOL-S
CHOL
Steroid
P450sc
Steroid FA
Sulfatase
sulfatase
esterase
17b HSD-1, 5
P450c17
P450c17
5-DIOL
DHEA
17-OH-PREG
PREG
3b HSD-2
3b HSD-2
3bHSD-1,2
3b HSD-1.2
17b HSD-3, 5
17-OH-PROG
4-DIONE
PROG
TESTO
5a red-1, 2
P450c21
P50c21
5a reductase-1, 2
PSDR1 17b HSD-3, 5
DEOXYCOR- TICOSTERONE
11-DEOXY CORTISOL
DHT
A-DIONE
P450c11
Aromatase
P450c18
Aromatase
CORTICO STERONE
17b HSD-1, 7, 12
CORTISOL
E1
E2
P450c18
Sulfatase
Sulfatase
E1-S
E2-S
ALDOSTERONE
56
Androgen blockade is now recognized as a
potential cure for localized prostate cancer and
is no more considered as only palliative
57
To decrease deaths, prostate cancer must be
diagnosed at the localized stage
Screening is absolutely required
58
Diagnosis of advanced or non curable prostate
cancer can be practically eliminated by prostate
specific antigen (PSA)
Localized disease in 98 of cases.

• Labrie et al., Urology 47, 212-217, 1996

59
Quebec prostate cancer screening study

• 45-80 year old men started in 1985
• 7,348 screened
• 14,231 controls
• Median follow-up 7.93 years
• 62 reduction in deaths from prostate cancer

Labrie et al., The Prostate 59, 311-318, 2004
60
Men dont need to die from prostate cancer
anymoreif properly diagnosed and treated
61
COLLABORATORS (COMBINED ANDROGEN BLOCKADE)
ASSELIN, JACQUES AUCLAIR, CLAUDE BEAULIEU,
MICHÈLE BÉGIN, D. BÉLANGER, ALAIN BERGERON,
NICOLE BORGEAT, PIERRE BORSANYI,
JEAN-PIERRE BOSSÉ, CLAUDE BROCHU, MICHÈLE BRUN,
DANIEL CARMICHAEL, R. CARON, SIMON CANDAS,
BERNARD CHEN, C. CLICHE, JACQUES CÔTÉ,
JEAN COUET, JACQUES COUTURE, MARCEL COY,
DAVID COY, ESTHER J. CRAWFORD, DAVID CUSAN,
LEONELLO DELISLE, ROBERT DESY, LOUISE DIAMOND,
PIERRE DROUIN, JACQUES DUBÉ, DONALD DUBÉ,
JEAN-Y. DUPONT, ANDRÉ
EMOND, JEAN FAURE, NACIA FAZEKAS, ATTILA
T.A. FERLAND, LOUISE FOURNIER, ANDRÉA FRADET,
YVES FRENETTE, G. GAGNÉ, CLAUDE GAGNON,
JACQUES GAREAU, JACQUES GIASSON,
MARCELLE GIGUÈRE, MICHEL GIRARD,
JEAN-GUY GODBOUT, MARTIN GOMEZ, JOSÉ GOURDEAU,
YVES GUAY, JOCELYNE HARNOIS, C. HOULE,
JEAN-G HUSSON, JEAN-MARC KELLY, PAUL A. KLEDZIK,
GARY, S. KOUTSILIERIS, MICHEL LABERGE,
JEAN-GUY LABRIE, CLAUDE LABRIE, FERNAND LACHANCE,
ROGER LACOSTE, DANIEL LACOURSIÈRE, YVES LAGACÉ,
LISETTE
LAPOINTE, STEVEN LAROCHE, BRUNO LAVERDIÈRE,
JACQUES LEBLANC, GILLES LEFEBVRE,
FLEUR-ANGE LEMAY, ANDRÉ LEMAY, MARTIN LI,
SHENGMIN LUPIEN, PAUL J. LUO, S LUTHY,
ISABELLE LUU-THE, VAN MALENFANT, M. MANHES,
GILLES MARCHETTI, BIANCA MARTEL,
CÉLINE MASSICOTTE, J. MONFETTE, GERARD MOORJANI,
SITAL PAQUET, JEAN-PIERRE PELLETIER,
GEORGES PINAULT, SYLVIE PLANTE, MICHEL POULIN,
RICHARD POYET, PATRICK PROULX, LOUISE RAYNAUD,
JEAN-PIERRE REEVES, JERRY J. RESKO, J. ROBERT,
GILLES
ROUSSEAU, L. RUEL, FRANÇOIS SAMSON, YVAN SANDOW,
JERGEN SAVARY, MURIELLE SCHALLY, AUDREW VICTOR
SÉGUIN, CARL SIMARD, JACQUES SINGH, MOHAN SOURLA,
ANTIGONE ST-ARNAUD, RENÉ SUBURU, RAUL TETU,
BERNARD THIBAULT, MARIE-MARTHE TOLIS,
GEORGE TRUDEL, CLAUDE TURINA, E. TREMBLAY,
M. TREMBLAY, ROLAND R. TREMBLAY, YVES TRUDEL,
CLAUDE VAILLANCOURT, L. VALLIÈRES, ANDRÉ VAN DER
KWAST, T. H. VEILLEUX, RAYMONDE VON DER OHE,
M. ZHAO, H.F.
62
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63
THANK YOUVERY MUCH
64
????????????
65
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66
220,000 deaths annuallydue to prostate cancerin
the world
CA Cancer J. Clin. 55, 794-1008, 2005
-50 110,000 lives saved-90 198,000 lives
savedannually
67
A
B
C
40
5
100
4
30
75
3
-58.9
-97.4
-61
ng/ml
Plasma ng/ml
Prostate content
50
20
2
10
25
1
0
0
0
Castrated
Intact
Castrated
Intact
Castrated
Intact
Testosterone
Testosterone
Testosterone
68
Androgens

• Testis Adrenals
• Testosterone Androstenedione 6.5
  mg/day (4-dione) 3 mg/day
• Dihydrotestosterone Dehydroepiandrosterone (DHT)
  (DHEA)
• 0.1 mg/day 24 mg/day

Horton, 1978
69
Androgen blockade needs time to act efficiently
Duration of combined androgen blockade 3
months 6 months
Reduction in tumor volume 40 - 50 60 - 80
1- Vaillancourt et al., Am. J. Surg. Pathol. 20,
86, 1996 2- Van der Kwast et al. , J. Pathol.
186, 406-409, 1998
70
Effect of duration of continuous CAB on the of
patients with PSA remaining under control for a
minimum of 5 years following cessation of CAB
100
11/12
long term control or cure
7/8
80
60

3/8
40
1/3
20
0/11
0
10
12
0
2
4
6
8
Years of continuous CAB
Labrie et al, Urology 60115-119, 2002
71
Method of PADT in Japan J CaP surveillance
Risk and Hormone therapy
100
80
60
Others
MAB
LHRH or surgical castration
40
Anti-androgen monotherapy
20
0
Low Risk (N1754)
Intermediate Risk (N2023)
High Risk (N5475)
Japan Prostate Cancer Study Group (2005) Akaza
(2008)
72
Cause Specific Survival
1.0
0.8
0.6
Survival rate
0.4
MAB (N102)
LHRH(N101)
0.2
p0.092 (Log-rank test)
0.0
500
1000
1500
2000
2500
0
Days after treatment
Japan Study Group for CAB Therapy in Prostate
Cancer Akaza (2008)
73
Recent litterature has proven that combination
therapy of castration (medical or surgical) and
non-steroidal antiandrogen (maximal androgen
blockade, MAB or combined androgen blockade, CAB)
is markedly effective in non-metastatic prostate
cancer.
H. Akaza, 2008
74
Why, then, does this difference in choice of
treatment exists or why the clinical data differ
from some guidelines?
Akaza, 2008
75
More than 30 of low- or intermediate-risk
localized prostate cancers could be controlled
for long-term with only combined androgen
blockade (CAB)
Namiki, 2008
76
A kind of misunderstanding has resulted
suggesting that the usefulness of hormonal
therapy is temporary. Such erroneous common
knowledge among urologists has been unfortunately
applied like a magic formula at all stages of the
cancer.
Namiki, 2008
77
By the use of inappropriate androgen blockade,
cancer cells which could be controlled for
long-term by appropriate androgen blockade
progress to cancer cells which acquire a more
malignant potential.
Namiki, 2008
78
The old concept of androgen depletion therapy
(ADT) for prostate cancer which had been
established on the basis of clinical experience
essentially on the far advanced disease, should
be changed.
H. Akaza, 2008
79
Cure of prostate cancer is almost always
possible with androgen depletion therapy if
progression to the hormone independent cancer
which accompanies metastatic disease can be
avoided.
H. Akaza, 2008
80
 Adjuvant castration should be reclassified as a
treatment for curative intent for patients with
poor - prognosis non-metastatic prostate
cancer (Fleshner et al, Prostate Cancer and
Prostate Diseases, 1-7, 2007)
Androgen blockade curative
81
100
80
ECOG 7887
plt0.01
60
Prostate cancer specific survival ( patients)
40
20
Radical prostatectomy plus goserelin/orchiectomy
Radical prostatectomy alone
0
0
5
6
7
8
9
4
3
2
1
10
Time (years)
Median follow-up 7.1 Years All patients were high
risk at baseline (cT1-2, pN)
Prostate-cancer specific survival in M0 patients
with clinically localized prostate cancer (cT1-2)
found to have 1 positive lymph nodes at
surgery, treated with radical prostatectomy,
followed by immediate hormone therapy (n47) or
observation until disease progression (n51).
Messing et al, J. Urol 169, ABST 396, 2003
82
100
5-year survival 78
(95 CI 72, 84)
80
EORTC 22863
60
p 0.0002
Overall survival ( patients)
40
5-year survival 62
(95 CI 52, 72)
20
Radiotherapy plus goserelin
Radiotherapy alone
0
3
4
5
6
7
8
1
2
0
Time since randomization (years)
In patients with T1-4, Nx and M0 prostate cancer
treated with radiotherapy alone (n208) or
radiotherapy plus goserelin (n207).
Bolla et al, Lancet 360, 103-108, 2002.
83
2008
CA Cancer J. Clin 58, 71-96, 2008
84
Intact - normal
LHRH

Testosterone
Pituitary Gland
LH
ACTH


Testosterone
DHEA
DHT Prostate
Testis
Adrenal
85
In Japan, 50of patients receive hormonal
therapy as primary treatment at the localized
stage
86
Monotherapy(Castration or antiandrogen
alone)Insufficient treatment
87
Endocrine treatment (immediate/deferred)Prostate
cancer mortalityM- (no distant metastases
recorded)
100
Orch / GnRHa DES / EE
86.8
Annual prostate cancer death rates Immediate Def
erred Years 2.71 4.36 0-4 (SE 0.16) (SE
0.22) Years 3.40 5.10 5-9 (SE 0.25) (SE
0.35) Years 1.70 2.83 10 (SE 0.27) (SE 0.42)
6.9
80
Deferred
74.0
79.9 -7.0 (SE 1.2)
11.7
60
Estimated percentage still not dead from
Prostate cancer
62.3 11.7 (SE 1.8)
40
M0/? Logrank 2p gt 0.1NS
20
M0/? Actuarial estimate and SE - allocated
IMMEDIATE - allocated DEFERRED
0
0
5
10
years
88
Early prostate cancer (EPC) trial

• Largest study in prostate cancer Placebo
  versus 150 mg bicalutamide
• Serious flawsA- Monotherapy suboptimal
  regimenB- Too short duration of treatment EPC -
  23 (3292) 2 years of treatment (inefficient)
  - 24 (3603) 5 years (suboptimal)
  - 25 (1218) 5 years
  Total 8113 PTS

89
Choice of antiandrogen

A- Non steroidal
YES
O
O
O
H


H
O
S
N

N
N
NH
F
O
O2N
CH3
HO
O
O2N
NC
CF3
CF3
CF3

Flutamide
Nilutamide
Bicalutamide
B- Steroidal
NO
O
O
OAc
OAc
O
O
Cl
Cl
Cyproterone Acetate
Chlormadinone acetate
90
Combined androgen blockadecompared to castration
alonehas the following advantagesin metastatic
disease

• 1- More complete and partial responses
• 2- Improved control of metastatic pain
• 3- Longer disease-free survival
• 4- Longer survival

91
Kaplan-Meier Plot of Time to PSA normalization
(lt0.2ng/mL )
1.00
CAB
0.75
0.50
PSA normalization rate ()
LH-RH agonist
0.25
0.0
0
20
40
60
80
100
120
140
160
180
WEEKS
Time to PSA normalization (Weeks) - Stage C
Median estimated using the Kaplan-Meier method
92
Some cases of localized prostate cancer can be
cured by hormonal therapy alone Almost all
cases of localized prostate cancer can be cured
by combined androgen blockade
Ueno et al., Int. J. Urol, 2006
Labrie et al., 2002, Urology 60 115-119.
93
PROGRESSIONS AT 5.4 YEARS (monotherapy)
40
212/611 34.7
CASODEX (150mg)
PLACEBO
30
123/607 20.3

20
567/4061 14
343/4052 8.5
10
0/26
0
T2 Labrie et al, 2002 CAB
81 W.WAITING
T1-T4 (Mo)
Wirth et al, 2004
Iversen et al, 2004
MONOTHERAPY CASODEX (150 mg)
94
HUMAN STEROIDOGENIC AND INACTIVATING ENZYMES IN
PERIPHERAL INTRACRINE TISSUES
DHEA-S
5-DIOL-FA
5-DIOL-S
Sulfatase
DHEA Sulfotransferase
Steroid FA
Steroid
sulfatase
esterase
Estrogenic response
ADRENAL
17b HSD-1
5-DIOL
DHEA
17b HSD-2 17b HSD- 4
ER
3b HSD-1
3bHSD-1
Androgenic response
17b HSD-3, 5, 13
TESTO
4-DIONE
17b HSD-2
AR
5a reductase-1 5a reductase-2
5a reductase-1
5a reductase-2
17b HSD-3, 5, 13
Aromatase
DHT
A-DIONE
Aromatase
17b HSD-2
17b HSD-7
3a HSD-1 3a HSD-3
RoDH-1
3a HSD-1 3a HSD-3
RoDH-1
3(a b) -HSE
(3a HSD-4)
(3a HSD-4)
UGT2B28 UGT2B15
17b HSD-7
3b HSD-1
3b HSD-1
3(a b)-HSE
17b HSD-3, 5, 13
ADT
3a-DIOL
3a-DIOL-G
3(a b)-HSE
17b HSD-2
UGT2B17
3(a b)-HSE
ADT-G
Sult2B1
ADT-S
17b HSD-3, 5, 13
Sult2B1
epi-ADT
3b-DIOL
3b-Diol-5
17b HSD-2
UGT1A1
E1-G
UGT1A1
E2-G
17b HSD-1, 7, 12
E1
E2
Elimination of steroids
17b HSD-2
17b HSD-4
Sulfo- Transferase
Sulfatase
Sulfo-transferase
Sulfatase
E1-S
E2-S