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Breast Cancer in the Developing World:
Meeting the Unforeseen Challenge to
Women, Health, Equity
Towards an Inclusive Clinical Trials
Research Agenda
Julie R. Gralow, M.D.
Professor and Director, Breast Medical Oncology
University of Washington School of Medicine
Fred Hutchinson Cancer Research Center
Seattle Cancer Care Alliance
Towards an Inclusive Clinical Trials
Research Agenda in Breast Cancer
Areas for Study
•
•
•
•
•
•
•
Epidemiology
Risk Factors (including genetics)
Risk Reduction (Prevention)
Screening and Early Detection
Diagnosis
Treatment
Quality of Life and Survivorship
Breast Cancer Treatment
Why Treatments Effective in One Population Are
Not Always Appropriate for Other Populations
•
•
•
•
•
Resource differences
Cultural and social differences
Cancer differences
Patient differences
Etc….
Cancer Differences
Genomic Profiling of Cancer:
Breast Cancer is NOT One Disease!
Multiple breast cancer subtypes
Luminal
Subtype A
Luminal
Subtype B
Sorlie et al, Proc Natl Acad Sci
100:8418, 2003
Normal
HER-2+ Basal
Subtype Breast–like
Subtypes vary with
respect to:
• Likelihood of
recurrence
• Sites of metastases
• Response to
treatment
• Frequency of
subtypes varies
across populations
–additional
subtypes likely
exist
Patient Differences
Pharmacogenomics: Inherited Differences in
Enzymes that Metabolize Cancer Drugs Can
Lead to Differences in Efficacy and Toxicity
We inherit different forms of the
enzyme that metabolizes
tamoxifen: CYP2D6
180
160
140
120
100
80
% of US Caucasian
population
78%
What are the
15%
7%
genetics in the rest
of the world?
60
40
20
Tamoxifen is an inactive drug – it
needs to be converted to its active
forms
0
Wt/Wt
Wt/*4
*4/*4
Rapid
Intermediate
Poor
metabolizer metabolizer metabolizer
Plasma endoxifen levels
Jin Y et al, J Natl Cancer Inst 2005
Ukraine Breast Cancer
Assistance Project
1997-2000
• US Agency for
International
Development (USAID)
• Program for Appropriate
Technology in Health
(PATH)
• Ukrainian Ministry of
Health
• University of Washington
Ukraine Breast Cancer Assistance
Project Goals
• To strengthen breast cancer services
throughout Ukraine
–Screening
Treatment project goal:
–Diagnosis
To define effective,
practical therapies that
–Treatment
can be delivered safely
–Rehabilitation
Assessment of Systemic Treatment
Practice in Ukraine (3 Oblasts)
• Limited discussion of disease +
treatment – “Don’t say the word”
• Treatment decisions based on
drug cost/availability, not science
• Number of cases treated and
exact regimens difficult to
determine
• Most newly diagnosed patients
got preoperative chemotherapy
for 10-12 months
• Very low doses of chemotherapy
used – “Ukrainian women cannot
tolerate “Western” doses”
Survival Related to Delivered Dose of
Adjuvant Chemotherapy
20 Year Follow-up of a Milan Study
If chemotherapy is given, it should be given at the full
dose as proven to work in clinical trials
Overall survival
1.0
0.9
Probability of Overall Survival
Control
<65% of dose
65-84% of dose
85% of dose
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
5
Bonadonna G et al, N Engl J
Med 332,1995
10
15
20
Years after Mastectomy
Ukraine Preoperative Chemotherapy
Clinical Trial: Designed in Partnership
Pre-Treatment Evaluation
Biopsy for diagnosis of invasive breast cancer (+ tissue bank)
Evaluation of local/regional and possible metastatic disease
Preoperative Chemotherapy
ADRIAMYCIN 60 mg/m2 + CYTOXAN 600 mg/m2
Intravenously every 3 weeks x 4 doses
(Trial supplied chemotherapy only, no supplies or supportive
care drugs)
Surgery
Mastectomy or lumpectomy with lymph node dissection
Post-Surgical Treatment
Not specified per study: Could include further chemotherapy,
hormone therapy, or radiation
Ukraine Breast Cancer Assistance
Project Outcomes
• “Western” doses of
chemotherapy safe and
effective
• Education + experience
with clinical trials
• Presentation of results at
national + international
conferences
• Unexpected development:
Refusal of surgery by
some women with
significant responses
• Consent process created
dialogue between
physician and patient
From “Don’t Say the Word” in 1997
to the 1st “March for Life and Hope” in 2001
Kiev, Ukraine