overcoming resistance in hormonally sensitive breast cancer ruth m. o’regan, md associate...
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Overcoming Resistance in Hormonally Sensitive Breast Cancer
Ruth M. O’Regan, MDAssociate Professor, Hematology and Medical Oncology
Emory University School of Medicine
Director, Translational Breast Cancer Research Program
Director, Hematology and Medical Oncology Fellowship Program
Winship Cancer Institute
Atlanta, Georgia
Clinical UpdatesHormonally Sensitive, Early-Stage Breast Cancer
Mechanisms of SERM Resistance
Johnston CCR 2005
ER Target Gene Transcription
SOS
P P
P P
PI3-K
Akt
PP
RASRAF
MEK
MAPKp90RSK
ER
Pp160
BasalTranscription
MachineryCBPERERPPP
ERE CellGrowth
PlasmaMembrane
Cytoplasm
Nucleus
E2
SERD
AI T
IGF1REGFR/HER2
Increased signalingthrough PI3-K pathway
CCI RAD
MoAb
TKI
Increased upstream signaling throughEGFR and/or IGF-IRand or VEGFR
TKI
ABVEGFR
MoAb
TKI
Mechanisms of intrinsic and acquired resistance is likely similar
Copyright ©2003 by the National Academy of Sciences
ER+ Cancers Are Heterogenous in Outcome
Sorlie et al PNAS 2003
ER+
ER+
Efficacy of Tamoxifen Varies in ER+ Cancers
Low Risk (RS<18)N
171142
Int Risk (RS 18-30)N8569
Interaction P=0.06High Risk (RS≥31)N9979
0 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
DR
FS
PlaceboTamoxifen
1210
0 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
DR
FS
PlaceboTamoxifen
1210 0 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
DR
FS
PlaceboTamoxifen
1210
Paik et al SABCS 2004
TAM-resistant
Correlation Between Recurrence Score and Intrinsic Subtype
Recurrence
Score
Luminal A
(n = 123)
Luminal B
(n = 55)
Low 62 1
Intermediate 25 4
High 36 50
Fan et al NEJM 2006
RS = + 0.47 x HER2 Group Score
- 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1
Oncotype DX 21 Gene Recurrence Score (RS) Assay
PROLIFERATIONKi-67
STK15Survivin
Cyclin B1MYBL2
ESTROGENERPR
Bcl2SCUBE2
INVASIONStromolysin 3Cathepsin L2
HER2GRB7HER2
BAG1GSTM1
ReferenceBeta-actinGAPDHRPLPOGUSTFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies
Category RS (0 – 100)
Low risk RS < 18
Int risk RS ≥ 18 and < 31
High risk RS ≥ 31
Poor Outcome for Patients with HER2-positive MBC Treated with Endocrine Agents Alone
Agent Clinical Benefit PFS
Anastrozole 28% 2.4 months
Letrozole 29% 3.0 months
Kaufmann ESMO 2006, Johnston SABCS 2008
Cui, X. et al. J Clin Oncol; 23:7721-7735 2005
Overall Survival According to Tumor Receptor Status in Women Treated with Tamoxifen
PR is prognostic or predictive for patients treated with tamoxifen
Disease-free Survival by Ki-67 LI in BIG-1-98 (Letrozole and Tamoxifen)
• 1,252 (47%) expressed Ki-67 LI > 11% (high)
Viale G et al. SABCS 2007 Abs 64.
Possible Surrogate Markers for Hormone Resistance
ER
PR
HER2
LUM A LUM B
Low Ki-67 High Ki-67
Hormone-sensitive Hormone-resistant
RS
Mechanisms of SERM Resistance
Johnston CCR 2005
ER Target Gene Transcription
SOS
P P
P P
PI3-K
Akt
PP
RASRAF
MEK
MAPKp90RSK
ER
Pp160
BasalTranscription
MachineryCBPERERPPP
ERE CellGrowth
PlasmaMembrane
Cytoplasm
Nucleus
E2
SERD
AI T
IGF1REGFR/HER2
Increased signalingthrough PI3-K pathway
CCI RAD
MoAb
TKI
Increased upstream signaling throughEGFR and/or IGF-IRand or VEGFR
TKI
ABVEGFR
MoAb
TKI
Copyright ©2008 American Association for Cancer Research
Massarweh, S. et al. Cancer Res 2008;68:826-833
Increase in EGFR and HER2 Protein in Tamoxifen-resistant Breast Cancers in vivo
TAnDEM Study Design
• Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone
HER2-positive, HR+ MBC
(n=208)R
Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose
2 mg/kg qw until disease progression
Anastrozole1 mg daily until
disease progression
HR, hormone receptor; MBC, metastatic breast cancer; R, randomisation
Trastuzumab + AIProgression-free Survival
103 48 31 17 14 13 11 9 4 1 1 0 0A + T
104 36 22 9 5 4 2 1 0 0 0 0 0A
CI, confidence intervalPFS = 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 60Months
95% CI
3.7, 7.02.0, 4.6
P value
0.0016
Median PFS
4.8 months2.4 months
Events
8799
0.0
No. at risk
Kaufmann ESMO 2006
Patients(%)
0
10
20
30
40
50
60P=0.026
Clinical benefit
A + T (n=103)
A (n=104)
Trastuzumab + AIClinical benefit
42.7%
27.9%
Vogel JCO 2002, Kaufmann ESMO 2006
Clinical benefit with single agent trastuzumab 48%
Johnston et al., SABCS 2008, abstract 46
1° endpoint: PFS (investigator) in HR+/HER2 pts
Letrozole ± Lapatinib in HR+ MBC
Arm A: LAP 1,500 mg/d p.o.+ LET 2.5 mg/d p.o.
(n = 642)
Arm B: LET 2.5 mg/day p.o.+ Placebo
(n = 644)
(n = 1,286)
RANDOMIZE
Eligibility criteria:Postmenopausal ER+/PgR+HER2+/HER2-/unknownStage IIIb, IIIc, and IV breast cancerNo prior treatment for metastatic disease
Johnston et al., SABCS 2008, abstract 46
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
ORR28% 30% 15% 28% 32% 33%
P =.262 P =.021 P =.726
CBR51% 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+ MBC
Progression-free SurvivalHER2+ Population
LET
(N = 108)LET+ LAP(N = 111)
Progressed or died 89 (82%) 88 (79%)
Median PFS, mo 3.0 8.2
Hazard ratio (95% CI) 0.71 (0.53, 0.96)
P-value 0.019
Progression-free SurvivalITT and HER2-ve Populations
LET
(N = 474)
LET + LAP
(N = 478)
Progressed or died 342 (72%) 294 (62%)
Median PFS, mo 13.4 13.7
Hazard ratio (95% CI) 0.90 (0.77, 1.05)
P-value 0.188
LET
(N = 644)
LET + LAP
(N = 642)
Progressed or died 476 (74%) 413 (64%)
Median PFS, mo 10.8 11.9
Hazard ratio (95% CI) 0.86 (0.76, 0.98)
P-value 0.026
ITT HER2-ve *
*Centrally confirmed
Preplanned stepwise exploratory Cox proportional hazard analysis for PFS:
– HER2+ population: HR for treatment = 0.65; P = .008
– HER2(-) population: HR for treatment = 0.77; P = .010
PFS in HER2(-) population based on interval since adjuvant TAM therapy
≥6 months since discontinuation of TAM or none
<6 months since
discontinuation of TAM
LET
(n=370)LET + LAP
(n=382)LET
(n=104)
LET + LAP
(n=96)
Median PFS (months)15.0 14.7 3.1 8.3
HR 0.94; P = .522 HR 0.78; P = .117
CBR 64% 62% 32% 44%
Johnston et al., SABCS 2008, abstract 46
Hormone-sensitive Hormone-refractory
Letrozole ± Lapatinib in HR+ MBC
Phase II Anastrozole ± Gefitinib in Newly Diagnosed HR+ MBC
Cristofanilli M, et al. J Clin Oncol. 2008;26(15S): Abstract 1012.
Post menopausal women Newly diagnosed, ER and / or PR-positive MBC, No prior hormonal therapy, measurable disease
Anastrozole 1 mg PO daily
Gefitinib 250 mg PO Daily
Anastrozole 1 mg PO daily
Placebo
Multi-center, randomized, double-blind trial Primary objective: PFS Enrollment stopped early due to low accrual
R
Anastrozole ± Gefitinib in HR+ MBC Efficacy
Cristofanilli et al, ASCO 2008, abstract # 1012
Anastrozole + Gefitinib
(n = 43)Anastrozole + placebo
(n = 50)
Median PFS (months)14.5 8.2
HR (95% CI) = 0.55 (0.32 – 0.94)
Objective response rate 2% 12%
Clinical benefit rate 49% 34%
Pollak et al Nature Reviews 2004
IGF-1R Signaling
Role of IGF-1R Signaling in HR+ Breast Cancer
TAM initially inhibits IGF-1 but with the onset of resistance IGF-1R signaling is re-established
TAM-resistant cancers are more sensitive to IGF-1R signaling
Inhibitors of IGF-1R (TKI and mAB) prevent growth of TAM-resistant cells
Knowlden et al Endocrinology 2005 Massarweh, S. et al. Cancer Res 2008
Metastatic breast cancer
At least 1 prior endocrine Rx for ≥ 3 months
Disease progression within 12 months of starting last endocrine therapy ER and/or PR-positive
IMC-A12(n = 30)
IMC-A12 + most recentendocrine
therapy(n = 60)
Randomized Phase II Trial of IMC-A12 ± Hormonal Therapy in Hormone-resistant Metastatic Breast Cancer
IMC-A12 10 mg/kg every 2 weeks
R
Pilot Study of Letrozole + BevacizumabMSKCC/UCSF
N = 43
Primary endpoint: Safety/feasibility
Secondary endpoints: TTP, RR, SD > 6 mo.
Prior NS-AI allowed if no documented progression
Ovarian suppression allowed (medical or surgical)
2.5 mg orally each day
Week 0 3 6 9
Bevacizumab15 mg/kg IV
Letrozole
12
Traina, Dickler, Rugo, Hudis et al., ASCO Abstract 3050, 2006
Best Response by RECISTFeasibility Study of Letrozole Plus Bevacizumab
n (%)
Assessed for Response 43
Complete Response 0 (0%)
Partial Response 4 (9%)
Stable Disease > 24 weeks 29 (67%)
Clinical Benefit Rate 33 (76%)
Median # cycles/patient (range): 13 (1-56)Prior Rx on a NS-AI for MBC (median/range): 15 wks (1-126 wks)
Dickler ASCO Breast 2008
Progression-free Survival
Dickler ASCO Breast 2008Time (months) from Treatment start
Pro
gres
sion
-fre
e su
rviv
al
0 12 24 36 48
0.0
0.2
0.4
0.6
0.8
1.0
N = 43
Median PFS: 17.1 months [95% CI: (8.5, 26.2)]
Median wks on AI therapy pre-bevacizumab = 15.4 weeks (range 1-216 wks)
RANDOMIZE
Endocrine Rx + Bevacizumab (15 mg/kg IV q 3 wks)
Endocrine Rx + Placebo
Proof of Concept StudyCALGB 40503 First-line Endocrine Rx
± Bevacizumab for MBC
Primary Endpoint: Progression-free Survival Endocrine Rx: Physician choice of Letrozole or Tamoxifen For premenopausal women → ovarian suppression required (can start day 1 of
protocol therapy) Correlative studies: CTCs/CECs, pharmacogenomics, differential response by
luminal subtyping and PIK3CA mutation analysis
N = 442
Conclusions
HR+ cancers are clearly heterogeneous with divergent outcomes
Need to identify robust predictive factors for both luminal A and B cancers
Essential to establish molecular differences between luminal subtypes so that novel therapeutic approaches can be developed