Approaches to Metastatic Disease in Breast Cancer

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Approaches to Metastatic Disease in Breast Cancer

• Anne F. Schott, MD
• University of Michigan
• July 9, 2005

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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?

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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

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Options in this case

• Chemotherapy
• Chemotherapy combined with hormonal therapy
• Hormonal therapy
• Clinical trial

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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
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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?

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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

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Selection of Hormonal Agents-Postmenopausal

• Aromatase inhibitors superior to tamoxifen first
  line
• Fulvestrant equal to anastrozole, following
  tamoxifen failure

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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?

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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

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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

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Concept of Additive, Synergistic, and Additive
Combination Regimens
Additive

Synergistic
Antagonistic
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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

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Combination A-Taxol vs. Single Agent Sequential
E1193
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Combination Capecitabine Docetaxel
Crossover in only 25 of patients (non-US
population)
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Gemcitabine-Paclitaxel Combination
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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

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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?

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New Agents in Metastatic Breast Cancer
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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
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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
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Efficacy End Points in the Intention-to-Treat
Population
Geyer CE et al. N Engl J Med 20063552733-2743
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Adverse Events
Geyer CE et al. N Engl J Med 20063552733-2743
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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

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From the Ixabepilone Drug Label
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From the Ixebepilone Drug Label
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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).

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Bevacizumab in breast cancer

• E2100
• 722 patients randomized
• First line chemotherapy weekly Taxol

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Conclusion

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

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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?

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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

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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
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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)