TKCC/Garvan Cancer Biology Seminars Seminal clinical ... · SERD: Fulvestrant. The University of...
Transcript of TKCC/Garvan Cancer Biology Seminars Seminal clinical ... · SERD: Fulvestrant. The University of...
The University of Sydney Page 1
TKCC/Garvan Cancer Biology Seminars
Seminal clinical trials in ER+ Breast Cancer
Elgene LimLab Head: Connie Johnson Breast Cancer Laboratory
Snr Medical Oncologist: TKCC
The University of Sydney Page 2
Breast cancer is a molecularly heterogeneous disease
Perou et al, Nature 2000; Sorlie et al, 2001; Sotiriou et al. PNAS 2003
Overall Survival
Pre-trastuzumab era
Luminal A
Luminal B
HER2 amplified
TNBC
HER2Lum BLum ABasal
BRCA1 BRCA2
The University of Sydney Page 3
Breast cancer is a molecularly heterogeneous disease
TCGA, Nature 2012
The University of Sydney Page 4
ER dependent and independent signaling pathways
Cui et al, Trends Mol Med 2012
The University of Sydney Page 5
Cofactor Dynamics in ER regulated transcription
Shang et al, Cell 2000
ER Cofactors
The University of Sydney Page 6
ESR mutations reported prior to 2013
Study Number of
Samples
ER status Mutations Frequency of
Mutations
Karnik PS,
Can Res 94
5 prim. BRCA
35 met. BRCA
ER+
ER+
E352V(prim.)
S432fs (met)
454fs (met)
5% of all mets
10% in TR
mets
Roody N,
JNCI 1995
118 prim.
BRCA
70 prim. BRCA
ER+
ER-
N69K (ER-)
M396V (ER-)
1% of ER-
prim.
Zhang QX,
Can Res 97
30 met. BRCA N/A S47T
K531E
Y537N
10% of mets.
TCGA,
Nature 2012
501 prim.
BRCA
Luminal 351
HER2+ 57
Basal-like 93
N27fs (ER+)
P222S(ER+)
0.4% of prim.
0.6% of
luminal
The University of Sydney Page 7
ESR mutations in metastatic endocrine resistant breast cancer
Jesselsohn et al, Nature RV Clin Onc 2015
The University of Sydney Page 8Lim & Winer, Oncology 2012
Long natural history of ER+ Breast Cancer
ChemoTx Alternative
endocrine
strategy
Prevention:
Extended
Endocrine therapy
Treatment
at relapse
Earl
y B
CM
BC Progression on Tx
Early Late
De Novo
Late relapse
ChemoTx Alternative
endocrine
strategy
Endocrine therapy
The University of Sydney Page 9
Dormant Metastasis in ER+ Breast Cancer
Braun et al. NEJM 2005
Pooled analysis of BM
micrometastases in
4703 pts with stage I-
III breast cancer, of
whom 1499 had
hormonal therapy only
BM micrometastases
is a predictor of poor
outcome on
multivariate analyses
The University of Sydney Page 10
Summary of Endocrine treatments for Breast Cancer
Adrenals
Pituitary
Ovaries
FSH/LH
Hypothalamus
Pulsatile GnRH
Adipose
ER
Cell Proliferation
Differentiation
GnRH agonist
Oophorectomy
Chemotherapy
Aromatase
Inhibitors
SERM: Tamoxifen
SERD: Fulvestrant
The University of Sydney Page 11
ER+ breast cancers are sensitive to endocrine therapy
EBCTCG Overview, Lancet 2011
Harvey et al. JCO 1999
The University of Sydney Page 12
Adjuvant AI’s have lower recurrence rates cf Tamoxifen
EBCTCG Overview. Lancet 2015
Meta-Analsysis 5 yrs Tam vs 5 yrs AI
RFS BC Mortality
The University of Sydney Page 13
Benefits of extended adjuvant endocrine therapy
(Atlas trial: 5 vs 10yr Tam)
Breast Cancer Mortality Overall Survival
10 yrs tam. vs 5:
aTTom trial
(n=6934 ER+)
10 yrs tam. vs 5:
ATLAS trial*
(n=10,543 ER+)
10 yrs tam. vs 5:
combined
(n=17,477 ER+)
10 yrs tam. vs 5:
combined
(n=17,477 ER+)
yrs 5-91.08
(0.85-1.38 )
0.92
(0.77-1.09)
0.97
(0.84-1.15)
0.99 (0.89-
1.10)
yrs 10+0.75†
(0.63-0.90)
0.75§
(0.63-0.90)
0.75†
(0.65-0.86)
0.84† (0.77-
0.93)
All
years
0.88‡
(0.74-1.03)
0.83‡
(0.73-0.94)
0.85‡
(0.77-0.94)
0.91‡
(0.84-0.97)
†p=0.007‡p=0.1
†p=0.0007‡p=0.008
†p=0.00004‡p=0.001
§p=0.002 ‡p=0.004
Davies et al, Lancet 2013
The University of Sydney Page 14
Benefits of extended adjuvant endocrine therapy
(Atlas trial: 5 vs 10yr Tam)
Davies et al, Lancet 2013
RFS BC Mortality
The University of Sydney Page 15
Benefits of extended adjuvant endocrine therapy
(MA17 trial: Tam AI)
Goss et al, JNCI 2005
DFS OS
Tamoxifen for 4.5-6 yrs
Postmenopausal
N=5,187
PLACEBO
LETROZOLE
5 yrs rx planned
OS in node +
The University of Sydney Page 16Cuzick et al, Lancet 2007
Recurrence Death After Recurrence
Does OS add to Tam in premenopausal women?
LHRH meta-analysis of 11,906 pts (16 trials). 1013 pts had LHRH agonist added to Tamoxifen.
No statistically significant reduction in HR for recurrence and death after recurrence with addition of LHRH agonist to Tamoxifen
The University of Sydney Page 17
Benefits of adding OS to adjuvant endocrine therapy
(SOFT trial: Tam vs Tam + OS vs AI + OS)
Francis et al, NEJM 2015
The University of Sydney Page 18
Benefits of adding chemotx to endocrine therapy
Pagani et al, Breast Cancer Res Treat 2009
Combined analyses of IBCSG Trial VII and IBCSG 12-93
Post and perimenopausal women N = 893
Benefit of adding chemotherapy only in the low to intermediate ER levels
The University of Sydney Page 19
Multigene tests to predict prognosis and chemotx benefit:
Oncotype RS
Paik et al, NEJM 2004, J Clin Oncol 2006
1) Quantifies The Likelihood Of (early) Recurrence In Women With
ER+ Breast cancer
2) Predicts The Magnitude Of Chemotherapy benefit
3) Can be performed on FFPE
The University of Sydney Page 20
All PatientsRS < 18
RS 18-30 RS > 30
Paik et al, NEJM 2004, J Clin Oncol 2006
Multigene tests to predict prognosis and chemotx benefit:
Oncotype RS
The University of Sydney Page 21
ABCSG-12 Trial
Zoledronic acid improves DFS and OS compared to endocrine therapy alone
Δ=4.0% Δ=1.6%
N = 1803,Premenopausal, Stage 1 & II, ER+, 30% node pos, Only preop Chemo allowedMed FU 84m
Tam
Tam + ZA (4mg/6mth)
Anastrazole
Anas + ZA (4mg/6mth)
RSurgery± RT
Goserelin
PEP: DFS SEP: OS
Gnant et al. Lancet Onc 2011
The University of Sydney Page 22
ZA OS benefit primarily in >40 subgroup
The anticancer potential of ZA may best be realized in a low estrogen environment
Gnant et al. SABCS 2011
The University of Sydney Page 23De Boer et al. SABCS 2011
DFS in post-menopausal subsets in ZA trials
The anticancer potential of ZA may best be realized in a low estrogen environment
The University of Sydney Page 24
Summary of Adjuvant anti-estrogen therapy options
Postmenopausal
• 5 yrs AI or 5 yrs Tam
• Tam 2-5yrs > 5 yrs
AI
• AI beyond 5 yrs
(No trial data)
Perimenopausal
• Tam 2-5yrs > 5 yrs
AI (switch after
menopause)
• OS + AI
Premenopausal
• 5 yrs Tam
• 10yrs Tam
• OS + AI
• AI only in confirmed post menopausal pts
• Consider OS in high risk pts, if chemotx not given or in young pts whose periods have resumed after chemotx
• Consider Extended therapy (>5yrs) in high risk pts
The University of Sydney Page 25
Alternative growth signaling pathways in endocrine resistance
Johnston, JNCI 2015
The University of Sydney Page 26
Mechanisms of endocrine resistance
ESR1 mutations
Genomic
Complexity
Fuqua et al, BCRT 2014
Ellis et al, Nature 2014
ESR enhancer hypermethylation
Stone et al, Nat Comm 2015
The University of Sydney Page 2727
FIRST trial: P2 Fulvestrant vs AI
Robertson JFR, BCRT 2012; 136: 503–511.
*Previous endocrine
therapy for early disease
completed >12 months
before randomization
permitted
*In confirmatory FALCON
study no prior endocrine
therapy permitted
FAS ANA
TTP23.4
months
13.1
months
The University of Sydney Page 28
SWOG 1222 trial: PIII Fulvestrant + AI in MBC
Mehta et al, NEJM 2012
• 1st line study, 39% de novo (No prior endocrine therapy)
• >12 months from completion of adjuvant AI or prior adj Tam
• Cross over permitted
PFS OS
The University of Sydney Page 29
Multiple abrations erlead to PI3K pathway activation
Di Cosimo & Baselga. Clin Can Res 2009
Sites of mutation/deletion that result in aberrant activation
PI3KCA activating mutation
Uterus 30%
Breast 25%
Colon 15%
Bladder 15%
The University of Sydney Page 30
PI3K component Type of mutation Incidence
P110α (PIK3CA) Mutation 27%
P110α (PIK3CA) Amplification 8.7%
P110β (PIK3CB) Amplification 5%
PDPK1 Amplification and overexpression 20%
AKT1 Mutation (E17K) 3.7%
AKT2 Amplification 3%
PTEN Loss of heterozygosity 24.9%
PTEN Mutation 6%
PI3K pathway alterations in BC
Liu et al. Nat RV Drug Dis 2009
PIK3CA mutations: More common in ER+ and HER2+ subtypes
Series of 590 pts
The University of Sydney Page 31
Function of p110 isoforms
Liu et al. Nat RV Drug Dis 2009
major
P110β is the major isoform mediating PTEN deficient tumorigenesis
(Jia et al, Nature 2008, Wee et al, PNAS 2008)
P110α is the major isoform mediating RTK/Ras mediated
tumorigenesis
(Samuels et al, Cancer Cell 2005, Berns et al, Cancer Cell 2007)
P110α and P110β: ubiquitous
P 110δ: immune system
The University of Sydney Page 32
PI3K pw alteration and BC subtype
PIK3CA
mut
AKT1
mut
PTEN
mut
PTEN
protein loss
PDK1
amp
INPP4B
del
RAS/RAF
mut
P53
mut
Breast
(total)
339/1261
(26.9%)
27/1008
(2.6%)
6/209 (2.3%)
25/110
(22.7%)
27/129
(20.9%)≈ 20%
2/406
(0.5%)
46/121
(38%)
Breast
HR+
101/305
(33.1%)
6/232
(2.6%)
4/131
(3.4%)
10/69
(14.5%)
16/79
(23.2%)Rare
18/73
(24.6%)
Breast
HER2+
24/98
(24.5%)0/75 0/33
2/18
(11%)
5/19
(26.3%)Rare
14/23
(60.9%)
Breast
TNBC
21/262
(8%)0/111 0/41
11/21
(52%)
2/15
(13.3%)≈ 60%
12/22
(63.6%)
Ovarian2/332
(0.6%)
2/332
(0.6%)
4/132
(3%)≈ 40% Rare ≈ 20%
12/428
(2.8%)
90/132
(68%)
Endometrial73/246
(30%)
3/150
(2%)
20/76
(26%)≈ 50% Rare ≈ 8%
44/206
(21%)
9/96
(9%)
Unpublished data: SU2C Not included: PIK3CA amp
The University of Sydney Page 33
TamRAD trial: PII Tamoxifen + Everolimus in MBC
Bachelot et al, J Clin Oncol 2012
n = 111
Prior exposure to AI
No cross over
Median FU 22 mths
– Primary End Point: Clinical Benefit rate @ 6 mths
– Tam = 42.1% (29.1-55.9)
– Tam + RAD001 = 61.1% (46.9-74.1)
– Secondary End Points
TTP OS
The University of Sydney Page 34
Benefit of Everolimus primarily in 2°endocrine resistance
Bachelot et al, J Clin Oncol 2012
Primary hormone resistance (n = 54)
(Relapse during adjuvant AI or < 6m
after starting AI for MBC)
Tam: 3.8 m vs Tam + RAD: 5.4 m
HR = 0.70 (0.40 – 1.21)
Secondary hormone resistance (n = 56)(Relapse ≥ 6m on adjuvant AI or prior AI response and subsequent progression)Tam: 4.6 m vs Tam + RAD: 14.8 mHR = 0.46 (0.26 – 0.83)
The University of Sydney Page 35
Bolero 2 trial: PIII AI + Everolimus in MBC
Baselga et al, NEJM 2014
PFS
OS
EVE +
EXEEXE
mPFS
7.8
month
s
3.2
month
s
Patients refractory to prior
NSAI therapy:
- Recurrence during or
within 12 months after
end of adjuvant
treatment; OR
- Progression during or
within 1 month after
end of treatment for
advanced disease
Piccart et al, Ann Onc 2014
The University of Sydney Page 36
Impact on Treatment by Genetic Status
The Most Frequently Altered Single Genes and Pathways
Positive treatment effect in
favor of everolimus across the
various genetic marker
subgroups
Pathway composition• PI3K: PIK3CA, PTEN, AKT (PIK3CA Alt:
47.6%, total alteration: 55.5%)
• Cell Cycle: CCND1, CDK4, CDK6,
CDKN2A, CDKN2B, (CCND1 Alt: 31.3%,
total alteration: 35.7%)
• p53: TP53, MDM2, MDM4 (TP53 Alt:
23.3%, total alteration: 36.1%)
• FGFR1/2: FGFR1, FGFR2 (FGFR1 Alt:
18.1%, total alteration: 21.1%)log10 (hazard)
-0.6 -0.4 -0.2 0.0
WT : PI3K
Alt : PI3K
WT : PIK3CA
Alt : PIK3CA
WT : Cell Cycle
Alt : Cell Cycle
WT : CCND1
Alt : CCND1
WT : p53
Alt : p53
WT : TP53
Alt : TP53
WT : FGFR1/2
Alt: FGFR1/2
WT : FGFR1
Alt : FGFR1
EVE+EXE better
Genetically altered (Alt)
Wild Type (WT)
Hortobagyi et al. ASCO 2011
The University of Sydney Page 37
Progression of the cell cycle is driven by CDKs
Asghar et al. Nat Rv Drug Disc 2015
The University of Sydney Page 38
Paloma 3 trial: PIII Fulvestrant + Palbociclib in MBC
Turner et al, NEJM 2015
Patients refractory to prior
NSAI therapy:
- Recurrence during or
within 12 months after
end of adjuvant
treatment; OR
- Progression during or
within 1 month after
end of treatment for
advanced disease
PAL +
FULFUL
mPFS
9.2
month
s
3.8
month
s
The University of Sydney Page 39| Presentation Title | Presenter Name | Date | Subject | Business Use Only39
PALOMA-3 trial: subgroup analyses
Turner NC, NEJM 2015; 373:209-19.
The University of Sydney Page 40
Paloma 1: PII AI + Palbociclib in MBC
Finn et al, Lancet Onc 2015
Patients with recurrence
<12 months since
adjuvant treatment were
excluded
PAL +
LETLET
mPFS20.2
months
10.2
months
The University of Sydney Page 41| Presentation Title | Presenter Name | Date | Subject | Business Use Only41
PALOMA-1: PFS subgroup analyses
Finn RS, Lancet Oncol 2015; 16: 25–35.
The University of Sydney Page 42
1. Comprehensive Molecular Portraits of Human
Breast tumours. TCGA. Nature 2012.
2. The natural history of luminal breast cancer. Lim
and Winer. Oncology 2012.
3. ESR1 mutations -a mechanism for acquired
endocrine resistance in breast cancer. Jesselsohn
et al. Nat RV Clin Oncol 2015.
4. Adjuvant Endocrine Therapy for Women With
Hormone Receptor+ Breast Cancer: ASCO
Clinical Practice Guideline. Bernstein et al. JCO
2014.
5. Aromatase inhibitors versus tamoxifen in early
breast cancer: patient-level meta-analysis of the
randomised trials. EBCTCG. Lancet 2015.
6. Prognostic Value of Ki67 Expression After Short-
Term Presurgical Endocrine Therapy for Primary
Breast Cancer. Dowsett et al. JNCI 2007.
7. Randomized Trial of Letrozole Following
Tamoxifen as Extended Adjuvant Therapy in
Receptor + Breast Cancer. Goss et al. JNCI
2005.
8. Long-term effects of continuing adjuvant tamoxifen
to 10 years versus stopping at 5 years after
diagnosis of oestrogen receptor + breast cancer:
ATLAS, a randomised trial. Davies et al. Lancet
2013.
9. Adjuvant Ovarian Suppression in Premenopausal
Breast Cancer. Francis et al. NEJM 2015.
10. A Multigene Assay to Predict Recurrence of
Tamoxifen-Treated, Node-Negative Breast
Cancer. Paik et al. NEJM 2004.
11. Combination Anastrozole and Fulvestrant in
Metastatic Breast Cancer. Mehta et al. NEJM
2012.
12. Everolimus in Postmenopausal Hormone-Receptor
+ Advanced Breast Cancer. Baselga et al. NEJM
2012.
13. Palbociclib in Hormone-Receptor + Advanced
Breast Cancer. Turner et al. NEJM 2015.