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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 TreatmentWhy Treatments Effective in One Population Are Not Always Appropriate for Other Populations • Resource differences • Cultural and social differences • Cancer differences • Patient differences • Etc….
Cancer DifferencesGenomic Profiling of Cancer: Breast Cancer is NOT One Disease!Multiple breast cancer subtypes Luminal Subtype A Luminal Subtype B Basal Subtype Normal Breast–like HER-2+ • Subtypes vary with respect to: • Likelihood of recurrence • Sites of metastases • Response to treatment • Frequency of subtypes varies across populations –additional subtypes likely exist Sorlie et al, Proc NatlAcadSci 100:8418, 2003
Patient DifferencesPharmacogenomics: 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 % of US Caucasian population 78% 15% 7% What are the genetics in the rest of the world? Tamoxifen is an inactive drug – it needs to be converted to its active forms Rapid metabolizer Intermediate metabolizer Poor metabolizer Plasma endoxifen levels Jin Y et al, J Natl Cancer Inst 2005
Ukraine Breast Cancer Assistance Project1997-2000 • 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 • Diagnosis • Treatment • Rehabilitation Treatment project goal: To define effective, practical therapies that can be delivered safely
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 Doseof 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 Control 1.0 0.9 <65% of dose 0.8 65-84% of dose 0.7 85% of dose 0.6 Probability of Overall Survival 0.5 0.4 0.3 0.2 0.1 0.0 5 10 15 20 Years after Mastectomy Bonadonna G et al, N Engl J Med 332,1995
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