Advances in Adjuvant Systemic Therapy of Breast Cancer

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Advances in Adjuvant Systemic Therapy of Breast
Cancer

• Anne F. Schott, MD
• University of Michigan

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Who to Treat With What?

• Current struggles in the real world

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When all you have is a hammer

• Chemotherapy
• Endocrine therapy
• Targeted therapy (ie trastuzumab)
• Radiotherapy

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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)

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Adjuvant! 8.0 10-Year Prognosis
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NCCN Guidelines 2008
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Worldwide Overview Chemotherapy vs no
chemotherapy, by age ER, ratio of recurrence
rates in years 0-4
Sir Richard Peto, SABCS, 2007
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Common Adjuvant Regimens
20
20
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Worldwide Overview Taxane vs no chemo Age lt50
Sir Richard Peto, SABCS, 2007
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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
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2nd Versus 3rd Generation Regimen Differences in
Relapse at 10 years (Adjuvant! 8.0)
2nd Generation Regimen
3rd Generation Regimen
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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
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Common Adjuvant Regimens
20
20
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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
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2nd Generation Adjuvant Chemo Trials
CALGB 40101 ddAC versus ddTaxol
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3rd Generation Adjuvant Chemo Trials
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Can Bisphosphonates Prevent Bone Metastasis?
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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
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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
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Adjuvant Clodronate vs Placebo Survival
Powles TJ et al, Br Cancer Res, 2006
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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
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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

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First DFS Events (ITT Population)
60 months HR0.64 P.011
ASCO 2008 meeting, Gnant
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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
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First DFS Events (ITT Population)
60 months HR1.096 P.593
ASCO 2008 meeting, Gnant
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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

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Bleeding after Chemotherapy by Patient Age
Petrek et al JCO 2006
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Bleeding after Chemotherapy by Type of Regimen
Petrek et al JCO 2006
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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
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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

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Neoadjuvant Chemotherapy Issues and
Controversies
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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

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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
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B-18Lumpectomy Rate
P lt 0.01
80
60
68
60
40
20
0
Preop Chemo
Postop Chemo
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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

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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

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Which tumors gt 1, lt5 cm definitely get
chemotherapy (pre or post)?
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Which tumors gt 1, lt5 cm definitely get endocrine
therapy (pre or post)?
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Patient Recommendations

• Sentinel Lymph Node Biopsy
• 0/1 lymph node positive

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Patient Example OncotypeDX Results
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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

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Recurrence Score Predicts CR to Neoadjuvant
Docetaxel (Chang, BCRT 2008)
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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

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