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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