Title: Approaches to Metastatic Disease in Breast Cancer
1Approaches to Metastatic Disease in Breast Cancer
- Anne F. Schott, MD
- University of Michigan
- July 9, 2005
2The 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?
3Patient 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
4Options in this case
- Chemotherapy
- Chemotherapy combined with hormonal therapy
- Hormonal therapy
- Clinical trial
5Chemotherapy 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
6Concurrent 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?
7Why 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
8Selection of Hormonal Agents-Postmenopausal
- Aromatase inhibitors superior to tamoxifen first
line - Fulvestrant equal to anastrozole, following
tamoxifen failure
9NCI-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?
10Patient 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
11Active single agents in breast cancer
- Taxanes
- Docetaxel, paclitaxel
- Anthracyclines
- Doxorubicin, epirubicin, liposomal doxorubicin
- Alkylating agents
- Fluoropyrimidines
- 5-FU, capecitabine
- Vinorelbine
- Ixabepilone (epothilone)
- Gemcitabine
- Platinums
12Concept of Additive, Synergistic, and Additive
Combination Regimens
Additive
Synergistic
Antagonistic
13Commonly 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
14Combination A-Taxol vs. Single Agent Sequential
E1193
15Combination Capecitabine Docetaxel
Crossover in only 25 of patients (non-US
population)
16Gemcitabine-Paclitaxel Combination
17(No Transcript)
18Combination 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
19Selection of chemotherapy agents in metastatic
disease
- Prior therapy (anthracycline, taxane)
- Residual toxicity (neuropathy)
- GI function (capecitabine)
- ?Triple negative phenotype and platinum
combinations - ?Expression profiling?
20New Agents in Metastatic Breast Cancer
21Lapatinib 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
22Cumulative 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
23Efficacy End Points in the Intention-to-Treat
Population
Geyer CE et al. N Engl J Med 20063552733-2743
24Adverse Events
Geyer CE et al. N Engl J Med 20063552733-2743
25Conclusion
- 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
26From the Ixabepilone Drug Label
27From the Ixebepilone Drug Label
28Ixabepilone 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).
29Bevacizumab in breast cancer
- E2100
- 722 patients randomized
- First line chemotherapy weekly Taxol
30(No Transcript)
31Conclusion
- Initial therapy of metastatic breast cancer with
paclitaxel plus bevacizumab prolongs
progression-free survival, but not overall
survival, as compared with paclitaxel alone.
32Measuring 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?
33Measuring 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
34CTC 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
35S0500 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)