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Advances in Adjuvant Systemic Therapy of Breast Cancer

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Advances in Adjuvant Systemic Therapy of Breast Cancer. Anne F. Schott, MD ... Comparison of Adjuvant Breast Cancer Trials of Clodronate vs. Placebo/Control ... – PowerPoint PPT presentation

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Title: Advances in Adjuvant Systemic Therapy of Breast Cancer


1
Advances in Adjuvant Systemic Therapy of Breast
Cancer
  • Anne F. Schott, MD
  • University of Michigan

2
Who to Treat With What?
  • Current struggles in the real world

3
When all you have is a hammer
  • Chemotherapy
  • Endocrine therapy
  • Targeted therapy (ie trastuzumab)
  • Radiotherapy

4
Patient Example
  • A 44 year old healthy premenopausal woman has the
    following pathologic diagnosis
  • Left breast lumpectomy Invasive ductal carcinoma
    (1.8 cm), Bloom-Richardson grade 2. No
    angiolymphatic invasion.
  • Sentinel lymph node biopsy 2/4 lymph nodes
    positive, ALND no more nodes
  • ER positive (96), PR positive (84), Her-2/neu
    2, FISH negative (ratio 1.37)

5
Adjuvant! 8.0 10-Year Prognosis
6
NCCN Guidelines 2008
7
Worldwide Overview Chemotherapy vs no
chemotherapy, by age ER, ratio of recurrence
rates in years 0-4
Sir Richard Peto, SABCS, 2007
8
Common Adjuvant Regimens
20
20
9
Worldwide Overview Taxane vs no chemo Age lt50
Sir Richard Peto, SABCS, 2007
10
What is standard treatment?
X
  • Trastuzumab-containing regimen
  • Oncotype Dx, treat if intermediate or high risk
  • No chemotherapy
  • 2nd Generation chemotherapy (TC, FEC)
  • 3rd Generation chemotherapy (TAC, FEC-D,
    ddAC-Taxol)

X
X
11
2nd Versus 3rd Generation Regimen Differences in
Relapse at 10 years (Adjuvant! 8.0)
2nd Generation Regimen
3rd Generation Regimen
12
HER2 is Predictive of Paclitaxel Benefit By
Estrogen Receptor Disease Free Survival
n 1322
ER Neg
ER Pos
paclitaxel
paclitaxel
No paclitaxel
HER2 NEG
No paclitaxel
paclitaxel
paclitaxel
HER2 POS
No paclitaxel
No paclitaxel
Years
Hayes D.F., et al. N Engl J Med. 3571496-506,
2007
13
Common Adjuvant Regimens
20
20
14
US Oncology TC vs AC
Doxorubicin 60 mg/m2 IV Day 1 Cyclophosphamide
600 mg/m2 IV Day 1 Every 21 days x 4 cycles
RANDOMIZE
Docetaxel 75 mg/m2 IV Day 1 Cyclophosphamide 60
0 mg/m2 IV Day 1 Every 21 days x 4 cycles
15
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16
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17
2nd Generation Adjuvant Chemo Trials
CALGB 40101 ddAC versus ddTaxol
18
3rd Generation Adjuvant Chemo Trials
19
Can Bisphosphonates Prevent Bone Metastasis?
20
Effects of Bisphosphonates on Antitumor Activity
in Preclinical Models
Tumor-induced osteolysis Tumor cell proliferation
and viability Metastatic behavior of tumor cells
Activity of cytostatic drugs Angiogenesis Tumor
burden in vivo
21
Comparison of Adjuvant Breast Cancer Trials of
Clodronate vs. Placebo/Control
  • Diel/Jaschke Powles Saarto
  • No. of patients 290 1069 299
  • Treatment site single multi-center single
    institution institution
  • Selection BM Stage I-III LN
  • Treatment length (y) 2 2 3
  • Control arm observation placebo observation
  • Follow-up time (y) 8.5 10 10
  • Skeletal effect (5 yrs) NS
  • Overall survival NS

Jaschke et al. Proc ASCO, 2004 Powles et al.
Breast Cancer Res, 2006 Saarto et al. Acta Oncol
4380-82, 2004
22
Adjuvant Clodronate vs Placebo Survival
Powles TJ et al, Br Cancer Res, 2006
23
Phase III Studies of Bisphosphonates Vs.
Placebo/Control as Adjuvant Therapy for Breast
Cancer with DFS Endpoint
  • NSABP B-34 (3 years) n3,200 stage I-II
  • Placebo
  • vs.
  • Clodronate 1,600 mg po qd

Closed
  • BIG/AZURE (5 years) n3,300 stage
    II-III
  • Control
  • vs.
  • Zoledronic acid 4 mg IV q mo x 6, followed by q3
    mo x 2 yrs, followed by q6 mo

Closed
  • German/GAIN (2 years) LN
    positive
  • ETC vs. EC-TX
  • x
  • Ibandronate 50 mg po qd vs observation

Open
24
ABCSG-12 Trial Design
  • 1,803 premenopausal breast cancer patients
  • Endocrine-responsive
  • Stage III, lt10 positive nodes
  • No chemotherapy except neoadjuvant
  • Treatment duration 3 years

25
First DFS Events (ITT Population)
60 months HR0.64 P.011
ASCO 2008 meeting, Gnant
26
SWOG 0307
Current accrual 1958/4500
  • Drug Dose Route Interval
  • Arm 1
  • Zoledronic acid 4 mg IV q4 wks x 6,
    then q3 mo x 2.5 yrs
  • Arm 2
  • Clodronate 1,600 mg oral daily x 3 yrs
  • Arm 3
  • Ibandronate 50 mg oral daily x 3 yrs

Zoledronic acid dose adjusted for baseline renal
function
27
First DFS Events (ITT Population)
60 months HR1.096 P.593
ASCO 2008 meeting, Gnant
28
What Endocrine Therapy?
  • Aromatase inhibitors are indicated in the
    adjuvant treatment of postmenopausal women,
    either alone or following tamoxifen
  • Early data does not support superiority of
    aromatase inhibitors in premenopausal women
  • Many women become menopausal with chemotherapy

29
Bleeding after Chemotherapy by Patient Age
Petrek et al JCO 2006
30
Bleeding after Chemotherapy by Type of Regimen
Petrek et al JCO 2006
31
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32
Schema
HR patients with postmenopausal E2, amenorrhea gt
8 weeks
Start AI therapy
Monitor E2 levels at 2, 4, 6, 8, 10, 12
wks Measure other hormone levels less often
E2lt10
E2 10-20
E2gt20
Continue AI therapy, monitoring (18 mo)
Recheck E2 levels in 1 week
Off study
E2lt10
E2gt10
33
Patient Example Adjuvant Systemic Therapy
Recommendations
  • 2nd or 3rd generation chemotherapy
  • Chemotherapy trial
  • Bisphosphonate trial S0307
  • Tamoxifen
  • SOFT clinical trial
  • If menopausal, switch to AI after 2-5 years of
    tamoxifen
  • Early switch endocrine therapy trial APPEL

34
Neoadjuvant Chemotherapy Issues and
Controversies
35
Patient Example
  • BL is a 58 year old postmenopausal woman who was
    discovered to have a 3.0 cm breast mass on
    imaging
  • ER 89, PR 7, H2N 1
  • Surgeon feels breast conservation possible but
    better cosmesis after neoadjuvant therapy

36
NSABP B-18
Operable Breast Cancer
Stratification
Age
Clinical Tumor Size
Clinical Nodal Status
Operation
AC x 4
TAM if gt50 yrs.
AC x 4
Operation
TAM if gt50 y
37
B-18Lumpectomy Rate
P lt 0.01
80
60
68
60
40
20
0
Preop Chemo
Postop Chemo
38
Local Therapy
  • Pros
  • Downstaging of primary tumor and lymph nodes
  • Less radical local-regional therapy needed
  • Breast conservation possible more often
  • Cons
  • Pathologic nodal staging requires additional
    procedure
  • FNA of nodes
  • up-front SLNB
  • Local treatment delayed for nonresponders
  • Decisions for XRT complicated

39
Systemic Therapy
  • Pros
  • In vivo assessment of response, could potentially
    improve treatment by tailoring based on
    response
  • Good biologic model to evaluate effects of
    chemotherapy tumors
  • Predicitve factor development
  • Acceleration of adjuvant regimen development
  • Cons
  • Potential for overtreatment in some subsets of
    patients
  • Unclear what to do in ER positive, node negative
    disease

40
Which tumors gt 1, lt5 cm definitely get
chemotherapy (pre or post)?
41
Which tumors gt 1, lt5 cm definitely get endocrine
therapy (pre or post)?
42
Patient Recommendations
  • Sentinel Lymph Node Biopsy
  • 0/1 lymph node positive

43
Patient Example OncotypeDX Results
44
Probability of pathologic complete response (pCR)
as a function of Recurrence Score
doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2)
every 3 weeks x 3, followed by weekly paclitaxel
(80 mg/m2) x 12.
Gianni, L. et al. J Clin Oncol 237265-7277 2005
  • Gianni, L. et al. J Clin Oncol 237265-7277 2005

45
Recurrence Score Predicts CR to Neoadjuvant
Docetaxel (Chang, BCRT 2008)
46
Patient Recommendations (Level 3 evidence)
  • Sentinel Lymph Node Biopsy
  • 0/1 lymph node positive
  • Begin neoadjuvant hormonal therapy
  • Send Recurrence Score
  • Low risk, no chemotherapy
  • Intermediate risk, consider chemotherapy if poor
    response
  • High risk, chemotherapy

47
Using the Neoadjuvant Model To Develop New
Systemic Therapies
48
Common Adjuvant Regimens
20
20
49
pCR as Surrogate Marker for DFS
Bear, et al. JCO. May 1, 2006
50
pCR in The Neoadjuvant Model Would Have Predicted
Trastuzumab Efficacy
Journal of Clinical Oncology, Vol 23, No 16 (June
1), 2005 pp. 3676-3685
51
National Neoadjuvant Chemo Trials
52
Diffusion MRI Functional Diffusion Mapping
Red increase ADC Green stable ADC Blue
decrease ADC
53
Schema

Part One
Part Two
Pre-Treatment Evaluation
10 patients
14 patients
Baseline MRI
Chemotherapy A
Repeat Baseline MRI
Post-Chemo A MRI
Chemotherapy A
Pre-Chemo B MRI
Post-Chemo A MRI
Chemotherapy B
Chemotherapy B
Post-Chemo B MRI
Surgery
54
Diffusion MRI, Interim Results
55
Diffusion MRI Interim Results
56
Whats the Goal?
  • Select patients who will require systemic therapy
    for neoadjuvant treatment
  • Find predictive factors (either before or early
    in treatment) that allow for accurate tailoring
    of therapy
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