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Endocrine Therapy of Advanced Breast Cancer School of Breast Oncology
November 9th 2013
Ruth M. O’Regan, MD Professor and Vice-Chair for
Educational Affairs, Department of Hematology and Medical Oncology,
Emory University, Chief of Hematology and Medical
Oncology, Georgia Cancer Center for Excellence, Grady Memorial Hospital
Outline General principles
Endocrine agents
Fulvestrant dosing
Combinational targeting of ER
Endocrine-resistance – HER2-positive
Role of ER signaling in HER2-positive breast cancers
Principle 1: Likelihood of benefit from endocrine therapy can be predicted by…
Disease Free
Interval
DFI Age Menopausal Status # Organ Sites ECOG PS ER/PR status Well differentiated Low S phase, diploid Primary/Previous Rx
Median Survival
Change in receptor status impacts outcome in the metastatic setting
Receptor discordance in primary and metastatic breast cancers relatively common resulting in treatment changes in up to 15% of patients
Changes in receptors impact prognosis
Most common change is in hormone receptors especially PgR going from positive to negative (represents a change from luminal A to luminal B?)
Changes in HER2 less common
Recurrent cancer should be biopsied at least once
Amir et al, Locatelli et al, Karlsson et al PASCO 2010
Principle 2: Patients achieving stable disease do just as well as patients whose tumors respond
0
100
0 1 2 3 4
Years From Randomization
80
60
40
20
At 2-Year Risk Deaths Estimate
CR or PR 33 10 85%
Stable 24 wk78 23 86%
Other 152 118 35%
Robertson JF, et al. Breast Cancer Res Treat. 1999;58:157-162.
Sur
viva
l (%
)
Clinical Benefit = CR + PR + Stable 24 wks
R E S I S T A N C E
40% 30% 25% 15%
Principle 3: If it works the first-time….
1st Line
2nd Line
3rd
Line 4th
Line
Endocrine therapy
Bottom-line
Endocrine therapy works and should be given first-line to patients with hormone-responsive MBC Chemotherapy only indicated for: life-threatening visceral mets or when endocrine therapy options fail and/or exhausted
Use of 21-gene recurrence score in MBC
Objective – To determine whether the 21-gene Recurrence Score®
provides clinically meaningful information in patients with de novo stage IV breast cancer enrolled in TBCRC 013.
Eligibility – Metastatic breast cancer with intact primary*
– Tissue from primary tumor and metastatic lesion
– 110 pts (86%) with pre-treatment primary tumor samples suitable for 21-gene Recurrence Score® analysis
– Included patients with ER-negative and HER2-positive disease
King et al Proc ASCO 2013 * small number developed mets within 3-months of diagnosis
Time to 1st Progression by Risk Group
Median TTP, mos RS<18 RS18-30 RS≥31 Log rank, p
All pts (n=102) 32 (16-NR) 20 (15-NR) 15 (9-21) 0.046 ER+ (n=86) 32 (16-NR) 20 (15-NR) 15 (9-25) 0.034
ER+HER2- (n=70) 32 (16-NR) 20 (15-NR) 15 (9-26) 0.013
RS<18
RS 18-30
RS ≥31
months
% p
rogr
ess
ion
free
2yr Overall Survival by Risk Group
2 yr OS, % RS<18 RS18-30 RS ≥31 Log rank, p
All pts (n=102) 100 (78-100) 100 (78-100) 80 (69-93) 0.049
ER+ (n=86) 100 (78-100) 100 (78-100) 77 (64-94) 0.016
ER+HER2- (n=70) 100 (78-100) 100 (75-100) 69 (51-93) 0.001
RS<18
RS 18-30
RS ≥ 31
% a
live
wit
h d
isea
se
ER+ pts treated with 1st line endocrine tx high RS shorter TTP
ER positive (IHC) ER pos Her 2 neg
Median TTP, mos RS<18 RS18-30 RS ≥31 Log rank, p
ER+ (n=50) NR (18-NR) 22 (13-NR) 15 (8-NR) 0.009
ER+HER2- (n=49) NR (18-NR) 22 (13-NR) 15 (8-NR) 0.016
RS<18
RS 18-30
RS ≥31
% p
rogr
ess
ion
free
ER+ pts treated with 1st line chemotherapy No difference in TTP by RS
ER positive ER pos Her 2 neg
Median TTP, mos RS<18 RS18-30 RS ≥31 Log rank, p
ER+ (n=36) 10.5 (4-NR) 20 (12-NR) 16 (9-NR) 0.54
ER+HER2- (n=21) 10.5 (4-NR) 18 (12-NR) 13 (9-NR) 0.56
RS<18
RS 18-30
RS ≥ 31
% p
rogr
ess
ion
free
Endocrine Agents for Breast Cancer
• SERMs Tamoxifen Toremifene Raloxifene
• Estrogens Estradiol DES, EE2
• ER-Down Regulator Fulvestrant
• Aromatase Inhibitors Anastrozole Letrozole Exemestane
• Progestins Megestrol Acetate MPA
• Androgens Fluoxymesterone
Quick summary of older trials
Tamoxifen effective regardless of menopausal status and only agent approved for premenopausal patients (combination ovarian ablation + tamoxifen > tamoxifen alone)
All aromatase inhibitors > tamoxifen in first-line setting (9 to 11 months PFS AI vs 6 months TAM)
Non-steroidal AIs are cross-resistant Steroidal and non-steroidal are not cross-
resistant and can be used sequentially
Fulvestrant Equivalent to anastrozole in patients with
metastatic breast cancer previously treated with tamoxifen (FDA approved for antiestrogen treated MBC)
Equivalent to tamoxifen in first-line treatment of ER-positive MBC
Equivalent to exemestane in patients with MBC previously treated with non-steroidal AIs
Dose and schedule may have been sub-optimal in earlier trials
Howell et al JCO 2004, Gradishar JCO 2008
EFECT: Time to progression (ITT)
Proportion of patients progression-free
Months At risk: Fulvestrant Exemestane
3.7 3.7 Median (months)
HR = 0.963, 95% CI (0.819, 1.133), p=0.6531
Cox analysis, p=0.7021
Exemestane Fulvestrant
Fulvestrant*
Exemestane
0 3 6 9 12 15 18 21 24 27
0.0
0.2
0.4
0.6
0.8
1.0
351 195 96 50 25 12 4 2
342 190 98 41 21 12 8 6
0
1
0
0
Gradishar et al JCO 2008 *500mg D1 250mg D14, q28d
CONFIRM Phase III Trial of Fulvestrant in ER-Positive Advanced Breast Cancer: Efficacy
Di Leo et al. JCO2010
Fulvestrant
500 mg
(n = 362)
Fulvestrant
250 mg
(n = 374)
HR/OR (95%
CI) P Value
Median TTP 6.5 months 5.5 months 0.80 (0.68-0.94) .006
ORR 9% 10% 0.94 (0.57-1.55) NR
CBR 46% 40% 1.28 (0.95-1.71) NR
Median Duration
of Benefit 16.6 months 13.9 months NR NR
•57.5% of patients had received prior antiestrogens, and 42.5% had received prior AIs •Approximately one third had demonstrated no response to prior hormonotherapy
FIRST Study Design
Robertson JF, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-3., JCO 2009
Endpoints at primary DCO Primary endpoint •Clinical benefit rate Secondary endpoints •Objective response rate •Time to progression •Duration of response •Duration of clinical benefit •Safety Exploratory endpoints •Best response to subsequent therapy
Randomization (1:1), open-label first-line ER+ postmenopausal patients
with advanced breast cancer (target, n = 200; actual, n = 205)
Fulvestrant 500 mg (500 mg IM on Days 0, 14, and 28, and every 28 days
thereafter)
Anastrozole 1 mg (1 mg PO daily)
Progression
Follow-up
Progression
Follow-up
DCO = data cut-off
FIRST: Efficacy Outcomes at Follow-Up Analysis
CI = confidence interval; TTF = time to treatment failure; TTP = time to progression
Outcome
Median, months
Hazard ratio (95% CI) P value
Fulvestrant (n = 102)
Anastrozole (n = 103)
TTP 23.4 13.1 0.66 (0.47-0.92) .01
TTF 17.6 12.7 0.73 (0.54-1.00) .05
TTP (adjusted for predefined covariates)
-- -- 0.64 (0.46-0.90) .01
Robertson JF, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-3.
SWOG S0226 Phase III Trial of Anastrozole +
Fulvestrant 250 vs Anastrozole Alone
Mehta et al NEJM 2012.
FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg
PO qday*
ANASTROZOLE 1 mg PO qday*
N = 707
Post menopausal women with HR+ advanced breast
cancer, untreated with
HR for advanced disease
Primary PFS
Secondary OS
FUL + ANA n = 355
ANA n = 352
HR P value
PFS (mo) 15.0 13.5 0.80 0.007
OS (mo) median 47.7 41.3 0.81 0.049
*Crossover to fulvestrant 500 mg allowed after progression
FACT: Phase III Study of Anastrozole +
Fulvestrant 250 vs Anastrozole Alone
Bergh et al. J Clin Oncol. 2012;30(16):1919-1925
FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg PO
qday
ANASTROZOLE 1 mg PO qday
N = 514
Pre/Post menopausal
women with HR+ advanced breast
cancer, untreated with
HR for advanced disease
Primary TTP
Secondary TTF, ORR,
CBR, Safety, OS
FUL + ANA n = 256
ANA n = 254
HR P value
TTP (mo) 10.8 10.2 0.72 0.91
OS (mo) median 37.8 38.2 1.00
Sequencing: which order is best?
All we know from a series of phase 2 trials is that agents with different mechanisms of action can be sequencing successfully
The exception is using non-steroidal aromatase inhibitors – sequencing letrozole and anastrozole does not work
Unclear which order is best – EFECT trial suggests it may not matter
AI or Fulvestrant* probably good choices as 1st line therapy
* Fulvestrant not approved in 1st line setting
Mechanisms of hormone resistance
From Johnston CCR 2005
ER Target Gene Transcription
SOS
P P
P P
PI3-K
Akt
P P
RAS RAF
MEK
MAPK p90RSK
ER
P p160
Basal Transcription
Machinery CBP ER ER P P P
ERE
Plasma Membrane
Cytoplasm
Nucleus
E2
SERD
AI T
IGF1R EGFR/HER2
Increased signaling through PI3-K pathway
Increased upstream signaling through EGFR and/or IGF-IR and or VEGFR
VEGFR
Absence or undetectable target
HER2-positive breast cancers are intrinsically resistant to endocrine therapy
Transfection of ER-positive breast cancer cells with HER2 renders them resistant to tamoxifen
Retrospective analyses of trials in the ER-positive metastatic setting show a worse outcome for cancers that co-express HER2, compared to those that do not
Median progression free survival is less than 6 months for ER+ HER2+ MBC treated with aromatase inhibitors
Benz BRCT BRCT 1992, De Laurentiis J Clin Oncol 2005, Kaufman J Clin Oncol 2009, Johnston J Clin Oncol 2009
LET LET LET ANAST ANAST
Prog
ress
ion
free s
urvi
val(
mon
ths)
HER2- HER2+/-
Outcome for patients with ER+ metastatic breast cancer based on HER2 status
Kaufman J Clin Oncol 2009, Johnston J Clin Oncol 2009, Bonneterre Cancer 2001, Moridisen J Clin Oncol 2003, Nahta BRCT 2012
Progression-free survival in patients with HR-positive, HER2-positive MBC
103 48 31 17 14 13 11 9 4 1 1 0 0 A + H
104 36 22 9 5 4 2 1 0 0 0 0 0 A
CI, confidence interval PFS = time from randomisation to date of progressive disease or death
Probability 1.0
0.8
0.6
0.4
0.2
0 5 10 15 20 25 30 35 40 45 50 55 60 Months
95% CI
3.7, 7.0 2.0, 4.6
p value
0.0016
Median PFS
4.8 months 2.4 months
Events
87 99
0.0
No. at risk
Kaufman et al JCO 2009
Johnston et al., JCO 2009
ITT HER2+ HER2-
let
(n=644)
let + lap
(n=642)
let
(n=108)
let + lap
(n=111)
let
(n=474)
let + lap
(n=478)
PFS (months) 10.8 11.9 3.0 8.2 13.4 13.7
HR 0.86; P =.026 HR 0.71; P =.019 HR 0.90; P =.188
ORR 28% 30% 15% 28% 32% 33%
P =.262 P =.021 P =.726
CBR 51% 56% 29% 48% 56% 58%
P =.096 P =.003 P =.761
OS (months) NR NR 32.3 33.3 NR NR
NR HR 0.74; P =.113 NR
Letrozole ± Lapatinib in HR-positive MBC
TAMRAD Study Design
Stratification: Primary or secondary hormone resistance
– Primary: Relapse during adjuvant AI; progression within 6 months of starting AI
treatment in metastatic setting
– Secondary: Late relapse (≥6 months) or prior response and subsequent
progression to metastatic AI treatment
No crossover planned
Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6.
• Randomized Phase II
• HR-positive MBC with prior exposure to aromatase inhibitors (AI)
A: Tamoxifen 20 mg/day (TAM)
B: Tamoxifen 20 mg/day + RAD001 10 mg/day (TAM + RAD)
R
TAMRAD: Time to Progression
TAM 4.5 mo. TAM + RAD 8.6 mo.
Hazard Ratio (HR) = 0.53 (95% CI: 0.35-0.81) Exploratory log-rank: P = .0026
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 Pr
obab
ilit
y of
sur
viva
l
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Months
Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6.
Primary endpoint: Clinical benefit rate improved from 42% with TAM to 61% with TAM + RAD (p=.045 exploratory analysis)
Effects of mTORC1 Activation
Treilleux I. ASCO 2013. Abstract 510.
Markers of Treatment Response Everolimus Response in ER+ MBC
Treilleux I. ASCO 2013. Abstract 510.
TAM, tamoxifen; RAD, RAD-001 (everolimus)
Markers of Treatment Response Everolimus Response in ER+ MBC
Treilleux I. ASCO 2013. Abstract 510.
TAM, tamoxifen; RAD, RAD-001 (everolimus).
2 1
Everolimus 10 mg/day + Exemestane 25 mg/day
(N = 485)
Placebo + Exemestane 25 mg/day
(N = 239)
BOLERO-2: Trial Design
ABC: advanced breast cancer, NSAI: non steroidal aromatase inhibitors, HER2-: human epidermal growth factor receptor 2 – negative; PFS: progression-free survival; PK: pharmacokinetics
Stratification:
1. Sensitivity to prior hormonal therapy
2. Presence of visceral disease
No cross-over
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.
34
N = 724
Postmenopausal ER+ HER2- ABC refractory to letrozole or anastrozole
PFS
OS ORR
Bone Markers Safety
PK
BOLERO-2: Addition of everolimus to exemestane improves PFS in HR+ MBC
Time (weeks)
HR = 0.36 (95% CI: 0.27–0.47)
EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months
Log rank P value = 3.3 x 10 -15
0 12 6 18 24 30 36 48 60 42 54 72 66 78
80
60
40
20
100
0 Prob
abilit
y of
Eve
nt (
%)
Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239)
Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. Baselga et al ESMO 2011
Markers of Treatment Response Everolimus Response in BOLERO-2
Hortobagyi G. ASCO 2013. Abstract 509.
EVE, everolimus; PBO, placebo.
Phase 2 Trial of CDK 4/6 inhibitor PD0332991 in first-line metastatic
HR-positive breast cancer
ER-positive Her2-
negative MBC
N=66 Letrozole
PD 0332991 Letrozole
Part 1
ER-positive Her2-
negative MBC with
CCDN1 amp and/or loss
of p16
N=99
Letrozole
PD 0332991 Letrozole
Part 2
Stratification • Disease site (visceral vs bone-only vs other) • Disease-free interval (> 12 mths vs ≤ 12 mths from adjuvant to recurrence or de novo advanced disease
Primary Endpoint: PFS
Finn et al SABCS 2012
Most Common AEs
Adverse Event (n)
PD 0332991
Letrozole (n=83)
Letrozole
(n=77)
Grade 1/2 3 4 1/2 3 4
Neutropenia 19 46 5 3 1 0
Fatigue 29 2 2 21 1 0
Anemia 20 4 1 3 1 0
Nausea 19 2 0 10 1 0
Hot flashes 19 0 0 12 0 0
Alopecia 18 0 0 3 0 0
Arthralgias 18 0 0 14 1 0
Thrombocytopenia 11 1 0 0 0 0
Stomatitis 10 0 0 1 0 0
Finn et al SABCS 2012
Phase 3 trial of PD-0332991 (Palbociclib)
Primary endpoint: PFS
Finn RS. ASCO 2013. Abstract 652.
Summary other targeted agents in HR-positive MBC
Bevazicumab does not significantly improve TTP when added to letrozole in first-line setting (LEA trial)
Inhibition of IGF1R does not enhance activity of aromatase inhibition
Addition of HDAC inhibitor, Entinostat, to endocrine therapy improved overall survival (confirmatory ECOG trial planned)
Martin et al SABCS 2012, Robertson et al Lancet Onc 2013, Yardley et al J Clin Oncol 2013
HER2 trumps ER when both receptors are expressed…..
But is this true for all ER+ HER+ breast cancers?
T T T T T L L L L T/L T/L T/L T/L P T/P T/P
P P -> FEC FEC -> P D EC -> D
Perc
ent
PC
R
Pathologic complete response is consistently lower in ER+ HER2+ breast cancers compared to
ER- HER2+ breast cancers
Reviewed in Nahta and O’Regan BRCT 2012
PCR is prognostic in ER- cancer but not ER+ cancers that co-express HER2
von Mitchwitz et al SABCS 2011
ER-negative, HER2-positive ER-positive, HER2-positive
Why is this important?
We may (and probably are) over-treating a subgroup of ER+, HER2+ breast cancers in the adjuvant setting
This subgroup of patients with ER+, HER2+ breast cancers may suffer late recurrences (similar to what we see with luminal A cancers)
Can we identify this subgroup?
HER2+/HR-
HER2+/ER+
HER2+/ER+++
Perc
ent
PC
R
ER expression
Likelihood of PCR is inversely related to level of ER expression for HER2+ breast cancers
Bhargava Mod Path 2011, Nahta BRCT 2012
Prognostic ability of 70-gene signature in HER2+, ER+ cancers: untreated patients (n = 89)
Knauer et al BJC 2010
C40601: HER2+ Subtypes by Hormone Receptor (HR)
HR-negative HR-positive
Carey et al Proc ASCO 2013
ER ER
ERE
FOXO3a
PI3-K
AKT
HER2 HER1/2/3
FOXO3a
ER-regulated gene transcription
x
Ras
MEK
Erk1/2
Nucleus
Cytoplasm
Membrane
ER ER
ERE
FOXO3a
PI3-K
AKT
HER2 HER1/2/3
ER-regulated gene transcription
Ras
MEK
Erk1/2
Nucleus
Cytoplasm
Membrane
TKI x x
TRAST
HER2 signaling decreases ER activation and inhibition of HER2 increases ER-regulated gene transcription
Xia PNAS 2006, Valabrega Oncogene 2005
Clinical relevance of this cross-talk
Inhibition of HER2 without inhibition of ER may increase ER signaling allowing ER to act as an escape mechanism – This could contribute to the lower PCR seen in ER+
HER2+ breast cancers and have potential implications in the metastatic setting
– There may be a subset of ER+ HER2+ breast cancers where ER inhibition is critical (more important than chemotherapy)
Response to pre-operative trastuzumab and lapatinib ± letrozole (12 weeks)
0 10 20 30 40 50 60
pCR
(%
)
70
All ER+
ER -
40%
21% 28%
53%
56%
48%
All ER+
ER-
pCR pCR + npCR
Rinawi CCR 2013 npCR = < 1cm residual cancer in the breast
Andre F, et al. J Clin Oncol 22: 3302, 2004
Receptor positive
Receptor negative
We have made progress!