ABC1 - G.W. Sledge - Resistance to anti-HER2 therapies
MON 2011 - Slide 3 - A. Goldhirsch - Early systemic treatment
1. Early Systemic Treatment
Aron Goldhirsch, MD
Department of Medicine
European Institute of Oncology (EIO)
Oncology Institute of Southern Switzerland (IOSI)
International Breast Cancer Study Group (IBCSG)
2. Adjuvant Therapies
for Women with Breast Cancer:
Present and Future
Adjuvant Therapies are the most
important field of medical oncology
…because - they lead to CURE saving
more lives…
3. Adjuvant Treatments ...
Why are they special?
• Patient is free of overt disease
• Assumption is that:
residual microscopic disease
same characteristics as primary
similar responsiveness
• In case of doubt:
worse scenario
most convenient for the patient
• Impossible to check efficacy
4. Preoperative (Neo-Adjuvant)
Treatments
• Treating more efficiently patients with locally
advanced disease
• Information on efficacy & safety of new
therapies during the short preoperative
exposure
• I will not deal with these therapies due to time
constraints
5. Adjuvant Treatments
• Historically, the first adjuvant treatments were
ovarian function suppression (OFS) and
chemotherapies (CTs)
• The overwhelming effects of CTs and the lack of
clear advantage for OFS signed the misperception
about what should be done
• Lacking knowledge about the target was the main
problem
6. Relapse-Free Survival (A) and Overall Survival (B)
According to Treatment Group
Bonadonna G. et al, N Engl J Med 332: 901-906, 1995
7. RFS and OS According to Treatment Group N-
All 90 pts had endocrine non responsive disease!
Zambetti M. et al, Ann Oncol 7: 481-485, 1996
8. CALGB/CTSU – 49907
RFS by ER status
Receptor Negative Tumors
Receptor-Neg ative Tumors Receptor Positive Tumors
Receptor-Positive Tumors
Relapse-Free Survival
Relapse-Free Survival
By Arm
Relapse-Free Survival
Relapse-Free Survival
By Arm
0.8
0.8
Proportion Relapse-Free
Proportion Relapse-Free
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0
0 1 2 3 4 5 0 1 2 3 4 5
Years From Study Entry Years From Study Entry
CMF/AC N= 106 Events= 14 CMF/AC N= 218 Events= 21
Capecitabine N= 97 Events= 34 Capecitabine N= 209 Events= 26
No Endocrine Therapy Endocrine Therapy
9. …understanding the
Need for Tailored Treatments for
Individual Patients
• Times of «one therapy fits all» are
finished
• Maximizing efficacy of treatments means
understanding the target
10. Tailored Treatments for
Individual Patients…
• Understanding the target – should have
been particularly easy in breast cancer
• Steroid hormone receptors – the degree
of endocrine responsiveness
• HER2 positivity – response to trastuzumab
(+/- chemotherapy)
13. Thresholds for Treatment Modalities
Treatment Modality Indication Comments
Endocrine therapy* Any ER staining ER-ve PgR+ve probably
artefactual
Anti HER2 therapy* ASCO/CAP HER2+ve (30% May use clinical trial
strong staining or Fish definitions
2.2+)
Chemotherapy
A. With anti HER2 Trial evidence limited to use Logical but unproven
with or following without chemotherapy in
chemotherapy strongly ER+ve HER2+ve
B. Triple negative Most patients No proven alternative. Most
at sufficient risk
C. With endocrine therapy Variable according to risk See next table
in ER+ve HER2–ve
* Patients with pT1a pN0 and ER-ve disease might be spared adjuvant systemic therapy.
Patients with pT1a pN0 and ER+ve disease should be offered endocrine therapy alone at any case,
without considering chemotherapy.
14. Thresholds for Treatment Modalities
Treatment Indication Comments
Modality
Endocrine therapy Any ER staining ER-ve PgR+ve
probably
artefactual
15. Thresholds for Treatment Modalities
Treatment Indication Comments
Modality
Anti HER2 therapy ASCO/CAP May use clinical
HER2+ve (30% trial definitions
strong staining or
Fish 2.2+)
16. Thresholds for Treatment Modalities
Treatment Modality Indication Comments
Chemotherapy
A. With anti HER2 Trial evidence limited to Logical but unproven
use with or following without chemotherapy in
chemotherapy strongly ER+ve
HER2+ve
B. Triple negative Most patients No proven alternative.
Most at sufficient risk
C. With endocrine Variable according to See next table
therapy in ER+ve risk
HER2–ve
17. Chemotherapy in ER+ve HER2-ve
Relative Indications for Factors not useful in decision* Relative Indications for endocrine
chemotherapy: any of therapy alone
Grade 3 Grade 2 Grade 1
High proliferation** Intermediate proliferation Low proliferation
Lower ER and PgR Higher ER and PgR
level level
N 4+ N 1-3 Node negative
Peritumoral vascular invasion No PVI
(PVI)
T size > 5cm T size 2 – 5 cm T size <= 2cm***
Patient preference to use all Patient preference to avoid side
available treatments effects
* If most are present, could constitute a relative indication for chemotherapy
** As assessed by conventional or genetic assays
*** Patients with pT1a pN0 and ER+ve disease should be offered
endocrine therapy alone at any case, without considering chemotherapy
18. Treatment Modalities 2009
Endocrine Endocrine
Responsive Non-Responsive
(ER ≥ 1%) (ER = 0%)
HER2- neg. ET CT
( CT using criteria
listed on next slide)
HER2-pos. ET + Trastuzumab Trastuzumab
+ CT
+ CT
19. Treatment Selection Flowchart 2009
Estrogen Receptor ≥ 1% stained cells
Yes No
HER2-status (CAP/ASCO) HER2-status (CAP/ASCO)
Positive Negative Positive Negative
ET ET Trastuzumab CT
+ ( CT using + CT
Trastuzumab criteria listed
+ CT as threshold)
20. Central Pathology Review at IEO
(ALTTO Trial of anti-HER2 Therapy – 30nov08)
ER CENTRAL REVIEW (IEO)
Positive
LOCAL Positive
≥1% and Negative tot
LAB ≥10%
<10%
113
Positive 2481 54 2648
(4.3%)
388 107
Negative 1788 2283
(16.9%) (4.7%)
21. BIG 1-98 Postm., HR-pos
False Positive Receptor Status
94/3610 (2.6%) false positive
22. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Early Breast Cancer Trialists’
Collaborative Group
Eighth Main Meeting
Oxford
September 2010
23. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
ER level
matters
EBCTCG 2010
(unpublished)
Clear ―dose-response‖
effect for ER level
(ligand binding assays)
on TAM efficacy
24. Adjuvant Therapy for Premenopausal
Women with Endocrine-Responsive Disease
• Standard: Tamoxifen
• Standard: Ovarian Function Suppression
Plus Tamoxifen
• Role of Aromatase Inhibitors not yet
established
• Ovarian Function Suppression alone only
in extraordinary circumstances
• Do all premenopausal women with
hormone-responsive breast cancer require
chemotherapy? NOT LIKELY
25. IBCSG Trial 11-93
Prem. with N+, ER+ Disease
1993-1998
174 patients; 97% had 1-3 N+
R
A
N OFS→AC/EC x 4→Tam to 5 yrs
D
O
M
OFS→Tam to 5 yrs
I
Z
E
OFS: ovarian function suppression by
GnRH analog, oophorectomy, or ovarian RT
26. IBCSG 11-93
n=174 (1993-1998)
Premenopausal, node-positive disease (97% had 1-3 N+)
10-year med fu; Thürlimann et al, BCRT 2009;113,137-144
27. Aol analysis conducted on trial 11
IBCSG Trial 11-93 and Adjuvant! Online
RFS for AOL control (OFS+Tam)
may be underestimated
76% 10-yr RFS
64% 10-yr RFS
P=0.03
28. IBCSG Trial 15-95 Design
n = 344 (1995-2000)
R
A Standard Dose Chemotherapy (SD-CT)
N
D AC/EC x 4 → CMF x 3
O
M
Dose Intensive Chemotherapy (DI-EC)
I
Z High Dose EC x 3
E
32. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Longer therapy,
iatrogenic amenorrhea, and
survival in early breast cancer
(NSABP B-30)
Swain SM, Jeong JH, Geyer CE Jr et al
N Engl J Med. 2010 ;362:2053-65
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33. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
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Overall Survival and Disease-free Survival
«Amenorrhea was associated with improved survival regardless
of the treatment and estrogen-receptor status.»
Swain SM et al. N Engl J Med 2010;362:2053-2065
34. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Taxane-Based Chemotherapy for Node-Positive Breast Cancer
— Take-Home Lessons
«An unexpected finding in this study was
that chemotherapy-induced menopause
appeared to be associated with increased
survival among both ER-positive and ER-
negative subgroups. Ovarian suppression
has value in the treatment of breast cancer,
but the effect was logically thought to be
restricted to ER-positive disease.»
Ellis, M. NEJM 2010; 362:2122-2124
35. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Amenorrhea & ER: NSABP & IBCSG
NSABP B-30
IBCSG 13-93
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36. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Amenorrhea analysis methodology
NSABP
B-30
Anderson JR, Cain KC, Gelber RD:
Analysis of survival by tumor response. J
Clin Oncol 1:710-719, 1983
IBCSG
13-93
37. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
NSABP B-30 Landmark analysis
«By contrast, women with HR for amenorrhea (DFS)
ER-negative tumors had a
similar outcome Study ER pos ER neg
regardless of whether
NSABP
they had amenorrhea, with
NEJM
a hazard ratio for death of 0.62* 0.71*
2010
1.08 (P = 0.76) and a hazard (Jun)
ratio for disease recurrence, a IBCSG
second malignant condition, JCO
0.61 1.58
or death of 0.96 (P = 0.85).» 2006 p = 0.004 n.s.
NSABP
NEJM 0.51 0.96
2010 p < 0.001 n.s.
(Dec)
Swain SM et al.
N Engl J Med 2010;363:2268-2270 (Dec 2)
38. Adjuvant Therapy for Postmenopausal Women
with Endocrine-Responsive Disease
• Standard: should include Aromatase
Inhibitors (AIs) with some exceptions
• Standard: start with AIs if high-risk
• Switch to tamoxifen is safe and effective
• Check ovarian function if young
postmenopausal women with AIs
• Use AIs for 2-5 years
• Beyond 5 years proceed with caution
39. Trials III+IV
(1978-1981)
Postmenopausal, node-positive disease
n=463 n=320
All treatments for 1 year
43. BIG 1-98 Sequential Therapy
2-Arm Option
A Tamoxifen
B Letrozole
4-Arm Option
A Tamoxifen N=1548*
B Letrozole N=1546 N=6,182
Enrolled
C Tamoxifen Letrozole N=1548
1999-2003
D Letrozole Tamoxifen N=1540
*612 patients (40%) received
0 2 5
letrozole after the tamoxifen
YEARS arm was unblinded.
44. Breast Cancer Events
TamLet vs. Let
Overall By Nodal Status*
*42% of the population is node positive; 58% node negative
45. Breast Cancer Events
LetTam vs. Let
Overall By Nodal Status*
*42% of the population is node positive; 58% node negative
46. BIG 1-98 Overall Design
R
A
2-Arm Option
N
D A Tamoxifen N=911 N=1,828
O
M B Letrozole N=917 Enrolled
S Stratify I 1998-2000
Z
U
R
Institution E
G CT (Adjuvant/
4-Arm Option
E N=8,010*
Neoadjuvant) R A Tamoxifen N=1548
R A
Y -Prior N
-None D B Letrozole N=1546 N=6,182 *ITT: excludes
-Concurrent O
M C Tamoxifen Letrozole N=1548 Enrolled 18 patients who
withdrew
I 1999-2003 consent and did
Z
E
D Letrozole Tamoxifen N=1540 not receive
study treatment
0 2 5
YEARS
50. STEPP 5-year DFS by Composite Risk
Low Risk Intermediate Risk High Risk
All treatments All letrozole arms Letrozole 5yr
including TAM appear similar: TAM appears better than
appear similar inferior either sequence
Increasing Composite Risk
54. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
ACOSOG Z1031: A randomized
neoadjuvant comparison between
letrozole (LET), anastrozole (ANA) and
exemestane (EXE) for Postmenopausal
Women with ER Rich Stage 2/3 Breast
Cancer: Biomarker outcomes and the
predictive value of the baseline PAM50
based intrinsic subtype
Ellis M. et al. SABCS 2010 / abst. 794
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55. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Study Design
http://clinicaltrials.gov/ct/show/NCT00265759
Ellis M. et al. SABCS 2010 / abst. 794
56. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Clinical response (%) Ki67 (%)
ACOSOG Z1031 Kruskal Wallis A v E v L P= 0.4550
57. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Adjuvant versus neoadjuvant
endocrine therapy
Adjuvant Trial Result based on Neoadjuvant Result for Ki67
events Ki67 study based changes
BIG 1-98 2005 L>T P024 2003 L>T
Thürlimann et al N=8010 Ellis et al N=185
ATAC 2002 A>T=C IMPACT 2005 A>T=C
Baum et al N=9366 Dowsett et al N=147
MA27 2010 A=E Z1031 2010 A=E
Goss et al N=approx 9000 Ellis et al N=165
FACE Trial A v L? Z1031 2010 A=L
N=approx 4000 Ellis et al N=161
Ellis M. et al. SABCS 2010 / abst. 794
58. Adjuvant Chemotherapy
• No standard regimen
• No predictive test for use of individual
components
• Choose efficient treatment among many
standards, when indicated
• ER, HER2, proliferation may predict
response to ANY chemotherapy, rather
than being agent-specific
• Multigene arrays may be useful
59.
60. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Adjuvant Docetaxel for High-Risk,
Node-Negative Breast Cancer
Martin M. et al. N Engl J Med 2010; 363:2200-
2210
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61. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
GEICAM (Node - ve)
Martin M. et al. N Engl J Med 2010; 363:2200-2210
62. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Early Breast Cancer Trialists’
Collaborative Group
Eighth Main Meeting
Oxford
September 2010
63. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Anthracycline benefit is early
Recurrence as first event in trials of anthracycline-containing
regimens versus standard CMF regimens
EBCTCG 2010
(unpublished)
64. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
Taxane benefit is durable
Recurrence as first event in the trials of a taxane-plus-
anthracycline-based regimen vs a non-taxane control regimen
with the SAME, or HIGHER, total dose of anthracycline
EBCTCG 2010
(unpublished)
65. Genomic Profiles Determine Which
Patients Receive Adjuvant Chemotherapy?
• «The Panel accepts molecularly-based tools
(such as the 21-gene recurrence score assay)
or gene expression profiling (such as by the 70-
gene assay) as an adjunct to high-quality
standard histopathologic assessment to refine
risk categories.
• The Panel recognizes in many cases this may
provide more optimal individual risk allocation
for making a decision to add chemotherapy or
not.»
66. Trastuzumab
• Adjuvant Trastuzumab x 1 year with CT is
standard of care for women with high risk
HER2+ve breast cancer
• Standardised HER2 testing: accredited
lab. for all invasive breast cancers
• Concurrent v. sequential trastuzumab and
anthracycline v. other chemotherapy
remain uncertain
67. Trastuzumab:
Open Questions
• Trastuzumab for small (<1cm)
HER2+ve cancers
• Trastuzumab alone v. plus CT in
lower risk
• Duration = high priority
• Other anti-HER2 agents
68. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
First results of the NeoALTTO trial (BIG
01-06 / EGF 106903): A phase III,
randomized, open label, neoadjuvant
study of lapatinib, trastuzumab, and their
combination plus paclitaxel in women
with HER2-positive primary breast cancer
Baselga J. et al. SABCS 2010 / abst. 291
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69. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
lapatinib lapatinib
Invasive breast cancer
HER2+ R paclitaxel
T >2 cm A S
(inflammatory excluded)
LVEF 50% N u
D r FEC
N=450
O trastuzumab g trastuzumab
M paclitaxel
e 3
Stratification:
—T<5 cm vs. T>5 cm I r
— ER or PgR+ vs. both –
— N 0-1 vs. N ≥2
Z
— Conservative surgery
lapatinib y
E lapatinib
trastuzumab trastuzumab
paclitaxel
6 + 12 weeks 9 weeks 34 weeks
52 weeks of anti-ErbB2 therapy
Baselga J. et al. SABCS 2010 / abst. 291
70. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
NeoALTTO
Baselga J. et al. SABCS 2010 / abst. 291
71. San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center
December 8-12, 2010
NeoSPHERE
Gianni L. et al. SABCS 2010 / abst. 1000
72. Current & Future Trials
• Chemotherapy: still looking at the risk of relapse
• Endocrine therapies: looking at the sequence
• Targeted biological therapies: looking at the
best use (combination or sequence)
• Targeting angiogenesis and stroma
73. Oncotype DX 21 Gene
Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION ESTROGEN RS = + 0.47 x HER2 Group Score
Ki-67 ER - 0.34 x ER Group Score
STK15 PR + 1.04 x Proliferation Group Score
+ 0.10 x Invasion Group Score
Survivin Bcl2
+ 0.05 x CD68
Cyclin B1 SCUBE2 - 0.08 x GSTM1
MYBL2 - 0.07 x BAG1
GSTM1 BAG1
INVASION
Stromolysin 3 CD68 Category RS (0 – 100)
Cathepsin L2 Low risk RS < 18
REFERENCE Int risk RS ≥ 18 and < 31
Beta-actin
HER2 GAPDH High risk RS ≥ 31
GRB7 RPLPO
HER2 GUS
TFRC
74.
75. Expression Data Matrix of 70 Prognostic Markers Genes from Tumors
of 78 Breast Cancer Patients Hybridized Using the Custom Microarray
Laura J. Van’t Veer
76.
77. Current & Future Trials
• Chemotherapy: still looking at the risk of relapse
• Endocrine therapies: looking at the sequence
• Targeted biological therapies: looking at the
best use (combination or sequence)
• Targeting angiogenesis and stroma
78. S LE
Study Of Letrozole Extension
IBCSG 35-07 / BIG 1-07
Coordinating Group: IBCSG
79. S LE
After 4 to 6 Years of Prior Adjuvant Endocrine Therapy
Postmenopausal, HR-Positive, Node-Positive
R Continuous letrozole x 5 yrs
A
Stratify
N
Institution
Prior ET: D
SERM O Intermittent letrozole over 5 yrs
AI M
Both I 9 mos. 9 mos. 9 mos. 9 mos. 12 mos.
Z
E
0 6 12 18 24 30 36 42 48 54 60
Extended Adjuvant Endocrine Therapy
A: Continuous letrozole 2.5 mg daily for 5 years
B: Intermittent letrozole 2.5 mg daily for the first 9
months of years 1 through 4, followed by 12 months
in year 5
80. Effect of Intermittent Letrozole Treatment in
MCF-7Ca Xenografts
2500 Control
Off Letrozole
Mean Tumor Volume (mm3)
2250
Her-2
2000 1 5.4 6.7 1.99 0.3 1.1
1750 Letrozole p-Her-2
1500 1 3.1 3.7 2.1 1.3 1.7
p-MAPK
1250
1 4.1 5.9 0.9 0.8 1.1
1000
Back on MAPK
750 Letrozole 1 1 1 0.9 0.9 1
500 Aromatase
1 0.2 0 0.9 2.7 0.8
250
ERα
0 1 0.2 0.1 0.9 2.4 1.1
02 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
ß-Actin
Weeks
Sabnis G.J. et al. Stopping treatment can reverse acquired resistance to letrozole. Cancer Res 68: 4518-4524, 2008
81. Current & Future Trials
• Chemotherapy: still looking at the risk of relapse
• Endocrine therapies: looking at the sequence
• Targeted biological therapies: looking at the
best use (combination or sequence)
• Targeting angiogenesis and stroma
82. HER2 Targeted Trial: ALTTO
R
A Trastuzumab
N
D Lapatinib
O
M T Lapatinib
I
Z Trastuzumab+Lapatinib
E
0 6 mos 1 year
Target accrual: 8000 patients
83. Current & Future Trials
• Chemotherapy: still looking at the risk of relapse
• Endocrine therapies: looking at the sequence
• Targeted biological therapies: looking at the
best use (combination or sequence)
• Targeting angiogenesis and stroma
84. Metronomic Therapy (CM) Following Standard Adjuvant
Chemotherapy for Patients With
ER-Negative and PgR-Negative Breast Cancer
IBCSG 22-00
Strata R
A
Menopausal
N
ER <10% Status D
CT
& O
Type of CT M
PgR <10%
Institution
I
Z
CT CM x 12 mos
E
Target 900 pts
Accrual (6/2008) 718 pts
85. DF/PCC Breast Cancer SPORE
Randomized Phase II Trial of Metronomic
Chemotherapy ± Bevacizumab
CM + bevacizumab CM alone
10 (41%) PR 2 (10%) PR
Burstein H., SABCS, 2005
86. BEX Regimen in Advanced BC
Bevacizumab
10 mg/kg iv every 2 weeks
Cyclophosphamide
50 mg/day orally @ 9 a.m.
Capecitabine
500 mg x 3/day orally after meals
Dellapasqua S. et al, J Clin Oncol. 26: 4899-4905, 2008
87. BEX Results
Best response n %
Assessable patients 46
CR 1 3
PR 18 45
SD24 weeks 8 20
SD<24 weeks 8 20
PD 5 13
Overall response (CR+PR) 19 48%
95% CI 32 to 64
Clinical benefit (CR+PR+SD24 weeks) 27 68%
95% CI 51 to 81
Dellapasqua S. et al, J Clin Oncol. 26: 4899-4905, 2008