6' Breast cancer

1
Post-ASCO, June 21, 2008
BREAST CANCER HIGHLIGHTS
Martine J. Piccart-Gebhart, MD, PhD Jules Bordet
Institute, Université de Bruxelles
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ASCO 2008 BREAST CANCER
Natural history of the disease
High risk women
Early disease
Advanced disease
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Vitamin D deficiency at BC diagnosis is
associated with risk of distant recurrence and
death from early BC
Prospective COHORT study (Toronto) N 512 pre
post menopausal women Follow-up 12 years
24 Vit D normal
34 Vit D deficient
38 Vit D insufficient

• Higher risk of
• distant relapse (HR 1.94) 95 CI 1.16 3.24)
• death (HR 1.73) 95 CI 1.05
  2.86)
• Associated with high BMI, premenopause, high
  insulin,
• but remains independent prognostic factor for
  DRFS

P. Goodwin, 511
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Natural History of the Disease
ASCO 2008 Take Home Messages for Clinical
Practice
! VITAMIN D !
There is nothing to lose in measuring/correcting
vitamin D levels at BC diagnosis
5
GGI predicts higher pCR rate in ER- ER (541)
MAP-tau negativity predicts better response to
AI (560)
Genomic predictors developped separately for
ER- or ER show AUC of 0.85 for pCR prediction
(571)
Neoadjuvant AI or TAM ?
Paclitaxel ? FAC Neoadjuvant CT
ERa Serin 305- P predicts resistance (11058)
New proposed predictive tools ASCO
2008
6 gene signature derived from in vitro work
looks promising in clinical trials (1053)
Adjuvant Tamoxifen (premenopause)
Lapatinib in HER2 BC
First-line trastuzumab based therapy for
advanced HER2 BC
Higher total HER2/homodimers (Vera-Tag Assay)
predict for ? TTP and ? OS (1002)
HER2/CEP17 gt 4.0 predicts for doubling in TTP
(1053)
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Prognostic Predictive Tools
ASCO 2008 Take Home Messages for Clinical
Practice
NONE !
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ASCO 2008 Treatment of Advanced Disease

• Role of loco regional treatment modalities
• Progress in the treatment of HER2 positive
  disease
• HER2 negative disease, bevacizumab
• the emperor without clothes ?
• Triple negative disease quo vadis ?

8
Abst. 1025 von MinckwitzGBG 26/BIG 3-05 TBP
Trial Design
RANDOMI ZE

• HER2 positive MBC

Capecitabine 2500 mg/m2 d1-14 q3wkly

• Progression after/during trastuzumab

n 156

• Need of 1st/2nd line chemotherapy

Capecitabine (same dose and schedule)
Trastuzumab q3wkly
Planned sample size N482, 80 power to detect
27.5 prolongation TTP, a0.05 (one-sided)
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Abst. 1025 von MinckwitzKey Results
p0.011
p0.007
HR0.69 p0.034
HR0.76 p0.26
pNS
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Lapatinib Trastuzumab in HER2 MBC
Lapatinib 1,500 mg PO (n148)
HER2 MBC, Previous antrhacycline, taxane,
Trastuzumab (N296)
R
Lapatinib 1,000 mg PO Trastuzumab 4mg/kg IV
load, then 2 mg/kg IV weekly (n148)
OShaughnessy J, et al. J Clin Oncol 26 2008
(May 20 suppl 1015)
Courtesy F. Esteva
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Progression-Free SurvivalLapatinib trastuzumab
vs. Lapatinib in HER2 MBC progressing on or
after trastuzumab
100
80
60
Cumulative Alive without Progression
40
28
6 Mo PFS
20
13
0
0
10
20
30
40
50
60
Time from Randomization (wks)
Subjects At Risk
148 148
L LT
53 73
21 42
13 27
5 8
0 2
OShaughnessy J, et al., J Clin Oncol 26 2008
(May 20 suppl 1015)
Courtesy F. Esteva
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PERTUZUMAB
TANESPIMYCIN
HER2 or some key downstream actors
(AKT?) are worth
targeting
HER2 is still a viable target
New therapies beyond trastuzumab progression
Pertuzumab
HSP90 inhibitor
(abst. 1027)
Trastuzumab
(abst. 1026)
Targeted Chemotherapy
HER2 is used to target chemotherapy
(abst. 1028-1029)
TRASTUZUMAB-DM1
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Abst. 1026-1029Key Results
different definitions of SD ( 6m for 1026,
4m for 1027, and 6weeks for 1028,1029)
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AVADO 1st line Bevacizumab for MBC

• Maximum 9 cycles of docetaxel
• Bevacizumab continued after docetaxel
• discontinuation in responding patients
• Pts in docetaxel placebo arm allow to receive
• Bevacizumab after progression

Miles et al, ASCO 2008
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Phase III Trials E2100 and AVADO
E2100
AVADO
Taxane bev.
Taxane
Taxane bev. low/high dose
Endpoint
Taxane
RR overall RR measurable PFS (months) hazard
ratio, p OS (months) hazard ratio, p
21.2 36.9 25.2 49.2 5.9
11.8 0.60, p lt 0.0001 25.2
26.7 0.88, p 0.16
NA NA 49
55/63 8.0 8.7/8.8 vs low
0.79, p .0318 vs high 0.72, p 0.0099
NR NR vs low 0.92
(0.62, 1.37) vs high 0.68 (0.45, 1.04)
Miller, K et al. NEJM 2007 Miles, D et al.
PASCO 2008 (LBA1011)
Courtesy K. Albain
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Treatment of Advanced Disease
ASCO 2008 Take Home Messages for Clinical
Practice

• Patients with stage IV BC at diagnosis should
• not be denied locoregional therapy
• Patients with recurrent HER2 BC should
• probably be kept on anti HER2 therapies
• continuously
• There is as yet no compelling reason to
  prescribe
• bevacizumab in advanced BC

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ASCO 2008 Treatment of Early Disease

• Adj. Endocrine Therapy ATTOM
• in line with ATLAS
• Adj. chemotherapy Helps elderly women !
• TANGO the end of
• large adjuvant trials
• in all comers ?
  
• Metformin New paradigm ?
• Bisphosphonates New paradigm ?

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CALGB 49907(Target N 1800 to show equivalence
of 2 arms)
Stratification Age 65-69, 70-80, 80 PS 0-1 vs
2 HER-2/-/unk
Randomize
CMF 6 cycles or AC 4 cycles
Capecitabine (X) for 6 cycles
CMF Cyc 100 day 1-14, MTX 40 and FU
60 d1, 8Q4w AC Dox 60, Cyc 600
d1 Q3w
2000 d1-14 Q3w (in 2 divided doses)
N633 (stopped early) 71 Node ve 67 HR, 12
HER2 65 age 70 median F/U 2.4y
in view of unlikely probability that x would be
equivalent to CMI/AC
Muss et al, 507
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CALGB 49907
X2000 2.1x worse
X2000 1.85x worse
Moderate toxicity for both arms 2 treatment
related deaths in X2000 arm First trial to
suggest benefit for adjuvant chemo in elderly!
Muss et al, 507
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GONO-MIG-5
WGSG/AGO
N 2011 (515)
N 1055 (516)
Sequential E(90)Cx4?T100 x4
Combined E(90)P(175)x4
vs FEC or CMFx6
vs FE(60)Cx6
Taxanes Yes or No ?
HORG
GEICAM 9805
N 756 (521)
N 1059 (542)
Combined TAC x6
vs FACx6
vs FE(75)Cx6
3 POSITIVE TRIALS for 5Y DFS (absolute gains of
6) 1 NEGATIVE TRIAL for 5Y DFS (GONO-MIG)
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tAnGo
N3152 77 Node ve 51 HR 55
premenopausal median F/U 35m
Poole et al, 506
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tAnGo
No therapeutic advantage from the addition
of Gemcitabine
Poole et al, 506
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METFORMIN a new candidate drug for BC adjuvant
therapy

• Epidemiologic studies suggest that metformin use
  in
• diabetic patients decreases cancer incidence
  and
• related-mortality
• Laboratory data show that metformin inhibits the
  
• mTOR pathway
• A retrospective MD Anderson study of 2529 women
• receiving neoadjuvant systemic therapy shows
  higher
• pCR rates in diabetic patients on metformin
  that in
• those not receiving the drug !

S. Jiralerspong, 528
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Trial Design ABCSG-12

• Accrual 1999-2006
• 1,803 premenopausal breast cancer patients
• Endocrine-responsive (ER and/or PR positive)
• Stage III, lt10 positive nodes
• No chemotherapy except neoadjuvant
• Treatment duration 3 years

Tamoxifen 20 mg/d
Tamoxifen 20 mg/d Zoledronic Acid 4mg q6m
Surgery (RT)
Goserelin 3.6mg q28d
Randomize 1 1 1 1
Anastrozole 1 mg/d
Anastrozole 1 mg/d Zoledronic Acid 4mg q6m
M.Gnant, ASCO 2008
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ABCSG-12 ENDOCRINE QUESTIONGoserelin
Anastrozole is No Better than Goserelin
Tamoxifen
The trial is underpowered and does not rule out
a benefit
Anastrozole vs Tamoxifen HR 1.096 (95CI 0.78
1.53) (p 0.593)

• ATAC HR 0.79 for Ana vs Tam
• in 6241 women with 900 events
• BIG1-98 HR 0.82 for Let vs Tam
• in 4922 women with 770 events

The trial does not rule out potential harm

• 41 vs 29 distant reccurences

• Is a LHRH agonist able to adequately
• suppress ovarian function in all
• premenopausal women ?

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ABCSG-12 BISPHOSPHONATE QUESTIONZoledronate
on a Background of Goserelin Tam or Ana
Markedly Reduces the Risk of a DFS Event
Zoledronate vs nil HR 0.643 (95CI 0.46
0.91) (p 0.011)
The magnitude of benefit is substantial (with no
safety issues)
... and all relapses appear to be reduced ! ...
but lt 10 of the women enrolled (n 137/1803)
experienced an event !
The observed benefit could be driven by the
anastrozole cohort...
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ABCSG-12 ZOLEDRONIC ACIDWho Benefits?
SEED
SOIL

• Luminal B a/o luminal A?
• Minimal residual disease?
• Bone-avid BC phenotype?
• PTHrP?
• Bone (Marrow) Metastasis Signatures?

• Baseline osteopenia?
• Therapy-induced
• increase in bone
• turnover ?

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NSABPB34
AZURE
(BIG 1-04)
N 3323
N 3349
Clodronate x 3y vs placebo Stage I/II
Zoledronate x 5y vs nil Stage II
Other important first generation bisphosphonate tr
ials in early BC (any HR, any menop status)
Interim analysis with 472 DFS events in
summer 2008 !
Zoledronate x 5y vs nil Stage II
Ibandronate PO x 2y vs nil Stage II
GAIN
NaTan
N 3000
N 543
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Bisphosphonates antiangiogenic drugs
Bisphosphonates
Drug X
Src inhibitor
Denosumab (anti RANKL antibody)
Anti CathepsinK agents
!!! HOPE !!!