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Approaches to Metastatic Disease in Breast Cancer

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Title: Approaches to Metastatic Disease in Breast Cancer


1
Approaches to Metastatic Disease in Breast Cancer
  • Anne F. Schott, MD
  • University of Michigan
  • July 9, 2005

2
The Goals
  • Prolonged survival
  • Palliation of symptoms primarily by decreasing
    disease bulk
  • Not cure in the vast majority of patients
  • How to optimally use the tools we have to
    maximize patient quality of life and lengthen
    survival?

3
Patient Case 1
  • 46 year old woman, breast cancer 1998,
    postmenopausal due to TAH, presents with a
    supraclavicular lymph node
  • Biopsy ER positive, PR negative, Her-2 negative
  • Prior therapy AC x 4 and tamoxifen x 5 years,
    completed two years ago
  • Staging evaluation with CT scan shows pleural
    metastases, several small lung metastases, and
    slightly enlarged mediastinal lymph nodes

4
Options in this case
  • Chemotherapy
  • Chemotherapy combined with hormonal therapy
  • Hormonal therapy
  • Clinical trial

5
Chemotherapy vs Tamoxifen vs Concurrent Therapy
  • Although median survival not improved for chemo
    over tamoxifen, RR increased patients did not
    all cross over
  • Led to recommendation of hormonal therapy first
    retest in modern day?

ANZ BCTG 7802
6
Concurrent chemotherapy and hormonal therapy
  • No survival benefit seen in metastatic setting
    with combined tamoxifen with cytotoxic
    chemotherapy
  • Adjuvant setting suggests similar outcome (SWOG
    8814), again with tamoxifen
  • Would this hold true for aromatase inhibitors?

7
Why Use Hormonal Therapy Alone Metastatic Disease?
  • ER rich tumors less responsive to chemotherapy
  • less likely to have pCR in neoadjuvant setting
  • less likely to benefit in adjuvant setting
  • Hormonal therapy can be used longer than
    chemotherapy with fewer side effects
  • Minimal disease, asymptomatic disease,
    non-life-threatening disease if ER or PR positive
    should get hormonal therapy
  • bone-only metastases, bone/pleura, lymph node

8
Selection of Hormonal Agents-Postmenopausal
  • Aromatase inhibitors superior to tamoxifen first
    line
  • Fulvestrant equal to anastrozole, following
    tamoxifen failure

9
NCI-sponsored clinical trials for hormone
responsive metastatic disease (Luminal A and B)
  • What is the role of combination endocrine therapy
    in metastatic disease?
  • CALGB 40302 fulvestrant /- lapatinib
  • CALGB 40301 letrozole and tipifarnib
  • ECOG hormone /- bevicizumab
  • S0226 anastrozole /- fulvestrant
  • What new agents can be used in hormonal
    combinations to overcome endocrine resistance?

10
Patient case 2
  • 38 year old diagnosed 2003, Stage II ER-, PR-,
    Her-2 neu
  • Received AC-Taxol, lumpectomy and RT
  • Recurred in breast, bone, liver, lymph nodes
    biopsy confirmed same receptor profile
  • Highly symptomatic

11
Active single agents in breast cancer
  • Taxanes
  • Docetaxel, paclitaxel
  • Anthracyclines
  • Doxorubicin, epirubicin, liposomal doxorubicin
  • Alkylating agents
  • Fluoropyrimidines
  • 5-FU, capecitabine
  • Vinorelbine
  • Ixabepilone (epothilone)
  • Gemcitabine
  • Platinums

12
Concept of Additive, Synergistic, and Additive
Combination Regimens
Additive

Synergistic
Antagonistic
13
Commonly Used Combination Therapies Preclinical
Predictions
  • Doxorubicin cyclophosphamide
  • Doxorubicin Docetaxel
  • Docetaxel capecitabine
  • Platinums taxanes
  • Gemcitabine taxanes
  • Gemcitabine cisplatinum
  • Vinorelbine docetaxel
  • Vinorelbine capecitabine
  • Cyclophosphamide capecitabine
  • Additive
  • Antagonistic
  • Synergistic
  • Synergistic
  • Synergistic
  • Additive
  • Synergistic
  • Additive
  • Synergistic

14
Combination A-Taxol vs. Single Agent Sequential
E1193
15
Combination Capecitabine Docetaxel
Crossover in only 25 of patients (non-US
population)
16
Gemcitabine-Paclitaxel Combination
17
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18
Combination vs. Single Agent Chemotherapy
  • Consistent increases in response rate with
    combination vs. single agent therapy
  • Consistent increase in toxicity as well
  • Increase in response rate could be seen with
    either synergistic, additive, OR ANTAGONISTIC
    combinations
  • The only true test of a survival benefit (for
    combination vs use at all) in patients who are
    not gravely ill includes a crossover design

19
Selection of chemotherapy agents in metastatic
disease
  • Prior therapy (anthracycline, taxane)
  • Residual toxicity (neuropathy)
  • GI function (capecitabine)
  • ?Triple negative phenotype and platinum
    combinations
  • ?Expression profiling?

20
New Agents in Metastatic Breast Cancer
21
Lapatinib plus Capecitabine for HER2-Positive
Advanced Breast Cancer
  • Charles E. Geyer, M.D., John Forster, M.Sc.,
    Deborah Lindquist, M.D., Stephen Chan, M.D., C.
    Gilles Romieu, M.D., Tadeusz Pienkowski, M.D.,
    Ph.D., Agnieszka Jagiello-Gruszfeld, M.D., John
    Crown, M.D., Arlene Chan, M.D., Bella Kaufman,
    M.D., Dimosthenis Skarlos, M.D., Mario Campone,
    M.D., Neville Davidson, M.D., Mark Berger, M.D.,
    Cristina Oliva, M.D., Stephen D. Rubin, M.D.,
    Steven Stein, M.D., and David Cameron, M.D.

N Engl J Med Volume 355(26)2733-2743 December
28, 2006
22
Cumulative Incidence of Disease Progression or
Death from Breast Cancer According to the
Assessment of the Independent Review Committee
(Panel A) Kaplan-Meier Estimates of Overall
Survival (Panel B) Cumulative Incidence of
Disease Progression or Death from Breast Cancer
According to the Site Investigators' Assessments
(Panel C)
Geyer CE et al. N Engl J Med 20063552733-2743
23
Efficacy End Points in the Intention-to-Treat
Population
Geyer CE et al. N Engl J Med 20063552733-2743
24
Adverse Events
Geyer CE et al. N Engl J Med 20063552733-2743
25
Conclusion
  • Lapatinib plus capecitabine is superior to
    capecitabine alone in women with HER2-positive
    advanced breast cancer that has progressed after
    treatment with regimens that included an
    anthracycline, a taxane, and trastuzumab

26
From the Ixabepilone Drug Label
27
From the Ixebepilone Drug Label
28
Ixabepilone Summary
  • As monotherapy, ixabepilone produced a modest
    response rate of 12.4 in patients with locally
    advanced or metastatic breast cancer whose tumors
    had progressed following treatment with
    anthracyclines, taxanes, and capecitabine in a
    single-arm, multicenter clinical trial (n126).
  • However, ixabepilone did improve progression-free
    survival when combined with capecitabine compared
    to capecitabine alone in patients who were
    previously treated with anthracyclines and
    taxanes in an open-label, multicenter, randomized
    clinical trial (n752) (Prod Info IXEMPRA(TM) IV
    injection, 2007).

29
Bevacizumab in breast cancer
  • E2100
  • 722 patients randomized
  • First line chemotherapy weekly Taxol

30
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31
Conclusion
  • Initial therapy of metastatic breast cancer with
    paclitaxel plus bevacizumab prolongs
    progression-free survival, but not overall
    survival, as compared with paclitaxel alone.

32
Measuring the benefit of therapies for metastatic
disease
  • Improved quality of life and survival are the
    goals
  • Are there surrogate markers for these?
  • Response rate
  • Time to progression
  • QOL measurements
  • Others?

33
Measuring treatment benefit clinical trial
methodologies focus on tumor response
  • Plain films
  • CT scan
  • Bone scan
  • MRI
  • PET scan
  • MUC-1 based tumor antigens
  • CEA, CA 125
  • Circulating Tumor Cells
  • Other biological markers of response

34
CTC at 1st Follow-up predict PFS
1st Follow-up (3 - 4 wk) N 163 Log rank p lt
0.0001
100
90
80
lt5 CTC (n114) 5 CTC (n49)
70
60
Probability of Progression Free Survival
7 mos
50
2.1 mos
40
30
20
10
0
0
5
10
15
20
25
30
35
40
45
55
60
65
70
75
80
50
Time from Baseline (Weeks)
First Followup
35
S0500 Trial Schema
Metastatic Breast Cancer Starting 1st Line
Chemotherapy N 350
  • 2 x 8ml CellSave tubes
  • 1 x 10mL EDTA
  • Processed at
  • Immunicon
  • Impath Labs

End 1st cycle / blood draw 5-7 days prior to
next cycle
5CTC
Group B - Randomized N 104
End Therapy / Final Blood draw

Analysis Report 1º End Points PFS
(Progression / RECIST) OS (12 month
follow-up) 2º End point QOL (SWOG Method)
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