My Journey in Endocrine Therapy for Breast Cancergbcc2016.gbcc.kr/upload/Ian Smith_My Journey with...
Transcript of My Journey in Endocrine Therapy for Breast Cancergbcc2016.gbcc.kr/upload/Ian Smith_My Journey with...
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My Journey in Endocrine Therapy for Breast Cancer
Ian E SmithRoyal Marsden Hospital and Institute of Cancer Research,
London
April 2019, Korea
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On the Treatment of Inoperable Cases of Carcinoma of
the Mamma: Suggestions of a New Method of
Treatment, with Illustrative Cases.
Lancet, 2 (1896) 104
On the Treatment of Inoperable Cases of Carcinoma of
the Mamma: Suggestions of a New Method of
Treatment, with Illustrative Cases.
George Thomas Beatson Lancet, 2 (1896) 104
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Early Types of Endocrine Therapyfor Breast Cancer
Oophorectomy
Adrenalectomy
Hypophysectomy
Oestrogens
Androgens
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Oestrogen Receptor (ER)
Jensen and Jacobsen (1962)
3H-estrogen bound by target tissues in rats
- uterus, vagina, pituitary
Could the binding of estrogen by breast cancer determine
endocrine response?
and
Would the absence of estrogen binding (ER-negative)
indicate poor likelihood of response?
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Estrogen Receptor
80% of Breast Cancers ER+ve
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HER2 Immunohistochemical Staining
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Some Breast Cancers Are Very Sensitive
to Estrogen Withdrawal
6 mo
Letrozole
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Tamoxifen
Br J Cancer. 1971 June; 25(2): 270–275
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• In ER+ve metastatic breast cancer:
• 86 clinical studies involving 5353 patients
• 30% response rate; 20% stable disease
• Median Response Durations up to 24 months
• But resistance occurs sooner or later
Litherland S and Jackson IM Cancer Treat Rev 1988;15:183–94.
Tamoxifen Efficacy
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Adjuvant Tamoxifen Oxford Analysis 2006
0.49 0.68 0.77
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Led to:
•Low dose AG as an AI
•Letrozole - first in man
•Letrozole –phase 1
•BIG 1-98
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Inhibiting the Effects of Estrogen
AndrogensSub cut tissuesMuscleLiverbreast
Tumor cell
Nucleus
Inhibition of cell
proliferation
AntiestrogensTamoxifen
Aromatase inhibitorsAnastrozole
LetrozoleExemestane
X
Aromatase
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Adjuvant Letrozole v Tamoxifen:BIG 1-98 Median 8 Years FU
Regan et al Lancet Oncology 12:1101 2011
DFS OS
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Aromatase Inhibitors v Tamoxifen in Early Breast Cancer: Meta-analysis
Recurrence Deaths
EBCTCG Lancet 2015
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Endocrine Therapy in Breast Cancer
• Only effective in women with ER+ve cancer (75-80%)
• Tamoxifen Oestrogen antagonist. Doesn’t affect circulating E2 levels. Effective in pre-and postmenopausal women
• Aromatase Inhibitors*. Inhibit ostrogen synthesis. Dramatically reduce circulating E2 levels. Only effective in postmenopausal women. Slightly more effective than tamoxifen
*Letrozole; anastrozole; exemestane
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Tamoxifen and Aromatase InhibitorsSide Effects/Morbidity
• Both usually well tolerated compared with chemotherapy
• Tamoxifen Venous thrombo-embolism
Uterine cancer
• Aromatase Inhibitors Joint stiffness
Bone loss
Vaginal dryness
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Only 30% of patients with ER+ve metastatic breast respond to endocrine therapy and a further 20% achieve stable disease
Likewise not all patients benefit from adjuvant endocrine therapy
Why?
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SOSRAS
RAF
BasalTranscription
Machineryp160
Cross-talk Between Signal Transduction and Endocrine Pathways
Johnston SRD. Clin Cancer Res. 2005;11:889s-899s.
ERE ER Target Gene Transcription
ERCBPP
P P P
ER
Pp90RSK
AktP
MAPKP
CellSurvivalTam
Cytoplasm
Nucleus
ER
AI
P13-KP
P
P
PP
P
Cell
Growth
MEKP
PlasmaMembrane
EGFR/HER2
IGFRGrowth Factor
Estrogen
Tamoxifen
MoAb
TKI
mTOR
mTOR
inhibitor
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CDK4/6 in Breast Cancer
• Resistance to endocrine therapy
presents a major clinical challenge
• The growth of HR+ breast cancer is
dependent on Cyclin D1, a direct
transcriptional target of ER
• Cyclin D1 activates CDK 4/6
resulting in G1–S phase transition
and entry into the cell cycle1
Figure adapted from Asghar, et al. Nat Rev Drug Dis. 2015;14:130-146
M
G1G2
S
CDK1
Cyclin B
CDK1/2
Cyclin A
CDK2
Cyclin E
pRBP P P
E2F
pRB
E2F
S phase transcription program
G1/S transition
Mitogenic signalling
ERα
CDK4/6
Cyclin D
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Abemaciclib Palbociclib Ribociclib
Selective CDK 4/6 inhibitors
O’Leary B, et al. Nat Rev Clin Oncol. 2016;13(7):417–430.
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PALOMA-2 & MOLALEESA-2: Design of Phase III Studies
• Primary endpoint: PFS
• Secondary endpoints:
– Response, OS, safety, biomarkers, PROs
PALOMA-2
R
A
N
D
O
M
I
S
E
Palbociclib (125 mg QD, 3/1
schedule) + letrozole
(2.5 mg QD)
Placebo + letrozole
(2.5 mg QD)
Postmenopausal ER+
HER2– advanced
breast cancer with no
prior treatment for
advanced disease.
AI-resistant patients
excluded
N=666
(2:1)
Stratified by the presence/absence of
liver and/or lung metastases
Ribociclib (600 mg QD,
3/1 schedule) +letrozole
(2.5 mg QD)
Placebo+ letrozole
(2.5 mg QD)
• Primary endpoint: PFS
• Secondary endpoints:
– OS (key), ORR, CBR, safety
Postmenopausal
women with
HR+/HER2–
advanced breast
cancer with
no prior therapy for
advanced disease
N=668
MOLALEESA-2
R
A
N
D
O
M
I
S
E
(1:1)
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PALOMA-2
palbociclib
Finn R, et al. NEJM. 2016;375(20):1925–1936
mPFS (months)
Palbociclib–letrozole: 24.8
Placebo–letrozole: 14.5
MONALEESA-2
ribociclib
Hortobagyi G, et al. NEJM. 2016;375(18):1738–1748
mPFS (months)
ribociclib–letrozole: NR
placebo–letrozole: 14.7
PALOMA-2 & MONALEESA-2: PFS
mPFS (months)
Ribociclib–letrozole: NR
Placebo–letrozole: 14.7
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The Role of Adjuvant Chemotherapy in ER+ve Early Breast Cancer
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EBCCTG Oxford 2006
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Adjuvant chemotherapy is also an effective treatment for some patients with ER+ve breast cancer
So how can we select which patients only need endocrine therapy alone, and which need additional treatment (eg chemotherapy or a CD4/6 inhibitor)?
The Big Current Question in the Adjuvant
Treatment of Early Breast Cancer
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Rate distant recurrence as
continuous function of recurrence score
Likelihood of distant recurrence
according to recurrence score
•21 gene assay
•Includes PgR
•Formalin-fixed PE
•Based on B14 and B20 Trials
•N-ve ER+ve
Paik et al NEJM 2004; 351;2817
Genomic Health Multi-Gene Assay: Oncotype DX
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Genomic Platforms to Identify Prognosis in ER+ Early Breast Cancer
Oncotype DX
Prosigna
Endopredict
Mammoprint
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An Important Thing About Breast Cancer
• Anatomically, the primary offers a unique
opportunity to assess systemic therapies
• We should take advantage of this as much
as possible
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Neoadjuvant Therapy for Breast Cancer:Opportunity for Serial Molecular Markers (eg Proliferation) in the Individual Patient
2 weeks
Pre-
biopsy
2 week
biopsy
0 2
40
30
20
10
0
Ki6
7 (
%)
WeeksKI KI
AI
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IMPACT: 2 Week Effect of Anastrozole on Ki67
in Individual Patients
0 2
40
30
20
10
0
Ki6
7 (
%)
Weeks
Innate biology –
Prognostic
Reflects treatment
sensitivity
in the individual patient-
Predict outcome better?
2 weeks
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0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
Rel
ap
se F
ree
Su
rviv
al
%
Years since randomisation
Relapse Free Survival by baseline LnKi67
<=2.25
2.25-2.99
3+
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
Rel
ap
se F
ree
Su
rviv
al
%
Years since Randomisation
Relapse Free Survival by 2 week LnKi67
<=0.8
0.81-1.99
2+
RFS by Ki67 in IMPACT: Pre vs 2 Week
2 weeks endocrine therapy
Multivariate analysis HR 2.01 p 0.002Not significant
Dowsett, Smith et al JNCI 2007
p 0.03 p 0.003
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3
5
Postmenopausal ER-positive early breast cancer
RANDOMIZE
2:1 ratio
PERIOPERATIVE THERAPY
AI* treatment for 2 weeks
SURGERY
AI for 2 weeks post-op
NO PERIOPERATIVE
THERAPY
2 weeks
SURGERY
Further treatment in accordance with local practice
Baseline
core
biopsy
2 week
core
excision
biopsy
POETIC: Pre-Operative Endocrine Therapy:
Individualising Care (UK)
4486pts. 130 UK centres. >16,000 bloods. >10,000 tumour samples
Smith I, Robertson J, Bliss J, Dowsett M and many others*Aromatase
Inhibitor
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100
75
50
25
0
% s
urv
ivin
g T
TR
event fr
ee
0 1 2 3 4 5Time post randomization (years)
TTR* by baseline Ki67 – peri-op AI patients
Unadjusted HR: 2.60 (95% CI 1.82 – 3.73)
Log-rank test p<0.0001
L (Ki 67 <10%)
H (Ki67 >10%)
Ki67B %
Total
5yr Absolute
risk
95%CI
L 31% 4.9% 3.5, 7.0
H 69% 12.1% 10.1, 14.1
*Time to recurrence
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100
75
50
25
0
% s
urv
ivin
g T
TR
event fr
ee
0 1 2 3 4 5Time post randomization (years)
H
100
75
50
25
0
% s
urv
ivin
g T
TR
event fr
ee
0 1 2 3 4 5Time post randomization (years)
H, L
H, H
100
75
50
25
0
% s
urv
ivin
g T
TR
eve
nt fr
ee
0 1 2 3 4 5Time post randomization (years)
L, L
In patients with Ki67B≥10%:
HR for Ki672W≥10% is 2.22 (95%CI: 1.68, 2.94; p<0.001)
TTR* by baseline and 2-week Ki67 – Peri-op AI
Ki67B Ki672w %
Total
TTR
Events
5yr Absolute
risk 95%CI
L L 30% 31 4.5% 3.1, 6.6
H L 48% 101 8.9% 7.1, 11.0
H H 22% 96 19.6% 15.9, 24.1
*Time to recurrence
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Conclusions (1)
• Endocrine therapy is an enormously important treatment for women with ER+ve breast cancer (75-80% of total)
• It acts either by blocking E2 stimulation of the cancer (tamoxifen) or by switching off synthesis (aromatase inhibitors, ovarian suppression)
• It is not always effective – primary or secondary resistance
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Conclusions (2)
• Targeted therapies are emerging to block endocrine resistance pathways eg CD4/6 inhibitors
• A major current challenge is to identify which patients with ER+ early breast cancer require additional adjuvant therapies (chemotherapy, CD4/6 inhibitors) to standard endocrine therapy
• Short term preoperative endocrine therapy to measure the effect of endocrine therapy on Ki67 offers a simple potential new approach to this.
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Cell free DNA (cfDNA) is released into the blood ofpatients with a wide range of malignancies
Only a low fraction of cfDNA constists of tumour-derived DNA or circulating tumour DNA (ctDNA) theremainder being derived from non-cancerous somaticcells
ctDNA is detected in >90% patients with metastatic breast cancer
The frequency of tumor specific alterations in the blood is as low as 0.01%
Half life short 1.5hrs
Diehl et al Nat Med 2008
Perkins G et al PLoS ONE 2011
Forshew et al STM 2012
Dawson et al NEJM 2013
Crowley et al Nat Rev Clin Oncol 2013
Bettegowda et al STM 2014
Circulating Tumour DNA (ctDNA)
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Genomic Mutations in ER+ Advanced Breast Cancer. ESR 1
Zhang Q.X et al. Cancer Res 1997 Li S et al. Cell Reports 2013 Toy W et al. Nat Gen 2013
Robinson DR et al. Nat Gen 2013 Merenbakh-Lamin K et al. Cancer Res 2013 Jeselsohn R et al. Clin Cancer Res 2014
Genomic alterations in ER+ tumors
40
35
30
25
20
15
10
5
0
Alt
era
tio
n P
erc
en
tag
e
TP
53
PIK
3C
A
CC
ND
1
MC
L1
MY
C
FG
FR
1
ES
R1
ER
BB
2
AK
T1
NF
1
PT
EN
Primary
Metastasis
P < .05
ESR1 mutations occur in ~20% of endocrine
resistant ER positive breast cancer
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ESR1 mutations in ctDNA Confer Resistance to Subsequent Aromatase Inhibitor
Schiavon et al AACR 2015, STM 2015
Retrospective single centre series
PFS on subsequent AI therapy
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Fribbens C, et al. J Clin Onc. 2016;34(25):2961-8
ESR1 wild type
ESR1 wild typeESR1 mutated
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PALOMA3 (Fulvestrant + Palbociclib)
by ESR1 mutation statusESR1 Mutant (25%) ESR1 Wild type
HR = 0.43 95% CI 0.25 – 0.74, p = 0.002 HR = 0.49 95% CI 0.35 – 0.70, p < 0.001
Fulvestrant-Palbociclib
Fulvestrant-Placebo
Fulvestrant-Palbociclib
Fulvestrant-Placebo
O’Leary et al. AACR, 2016. Fribbens et al. J Clin Oncol, 2016
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Hypothesis• ESR-1 mutations are induced by AI exposure
• Fulvestrant overrides the mutation by degrading the receptor
• Palbociclib overrides the mutation by blocking a constitutively active ‘escape’ pathway
• Late relapses are likely to have a high incidence of ESR1 mutations
• They are therefore more likely to be controlled by fulvestrant or a CD4/6 combination therapy than by an AI alone