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Carol J. Fabian, M.D. University of Kansas Medical Center Kansas City, KS

Early Detection and Prevention: Avoiding Chemotherapy. Carol J. Fabian, M.D. University of Kansas Medical Center Kansas City, KS. October 29, 2011. Breast Cancer Statistics 2011. CA: A Cancer Journal for Clinicians 3 OCT 2011. Why Fewer Breast Cancer Deaths?. Screening

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Carol J. Fabian, M.D. University of Kansas Medical Center Kansas City, KS

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  1. Early Detection and Prevention: Avoiding Chemotherapy Carol J. Fabian, M.D. University of Kansas Medical Center Kansas City, KS October 29, 2011

  2. Breast Cancer Statistics 2011 CA: A Cancer Journal for Clinicians 3 OCT 2011

  3. Why Fewer Breast Cancer Deaths? • Screening • Smaller tumors, fewer + nodes • Adjuvant Systemic Treatment • Type/effectiveness dependent on biology • Drug therapy for primary prevention-NO • fewer breast cancers but not breast cancer deaths • 10-15 years of FU may be too soon for survival effect especially when applied to moderate risk population most of whom will never get breast ca

  4. Systemic Therapy For Early Breast Cancer 2011

  5. What We Think We Know • Anti-hormonal Rx ER+ • 5 yrs improves survival 30% • 2-3 yrs AIs after 2-3 yrs tamoxifen small additional survival benefit • Polychemotherapy ER- • Improves survival 30% • Taxanes + Anthracyclines > Anthracyclines > CMF • Polychemotherapy ER+ • Recurrence/Survival benefit depends on proportion ER+ cells, additional tumor and host characteristics • Other • Herceptin if Her-2 + • IV bisphosphonates decrease recurrence and possibly survival if ER+, low estrogen, no chemo

  6. Meta-Analysis vs Tumor Gene Expression • Targeted therapy started with ER, Her-2, Ki67 • Gained steam with gene expression panels • avoid chemotherapy in luminal A tumors ( strong ER, PR+ low Ki-67, Her-2 negative) • Will come of age with full gene sequencing, protein expression to identify pathway amplification • Tumor specific tailored therapy

  7. Host Factors Important Too! Obesity, Hormonal Milieu Polymorphisms in Metabolic Enzymes

  8. Will Personalized Cancer Treatment Render Screening Obsolete? Some think So. . . . . But probably not next year or the next

  9. Screening 2011

  10. Screening= Fewer Breast Cancer Deaths but Under Attack • Older Randomized Trials • 40-49 at least 15% improved survival • 50-69 at least 25-30% improved survival • Newer Studies • Swedish 2 county 29 year FU 31% improved survival • Age trial randomized women 40-41: 24 % improved survival • Modeling study (Welch) overdx - 13% survival benefit • 20-34% false + (requiring Bx ) after 8-10 screens <50 • Consideration in US being given to starting screening at 50 and every 2 years for 50-70 Tabar Radiology 2010, Moss Lancet 2006, Welch Arch Intern Med 2011, Johns CEBP 2010

  11. What Should We Do Now? Average Risk High Risk Start yearly screening years 10 before youngest affected relative. Hereditary breast cancer pattern, known BRCA1/2 in family , start at age 25, add MRI to mammography • 40-50: Discuss modest benefit • 50-69: Yearly screening Warner JCO 2011, Grann Breast Ca Res Treat 2011

  12. Prevention Interventions Usually Geared to Level of Risk • Very High Risk-2-3%/year (BRCA mutation) • Prophylactic Surgery • High Risk 1-2%/year (LCIS, AH + FH) • Drugs or Prevention Trials • Moderate Risk >.33<1%/yr (AH or FH alone) • Healthy Behaviors • Possibly tamoxifen under age 50 • Possibly raloxifene or an aromatase inhibitor postmenopausal women

  13. Prevention Interventions Usually Geared to Level of Risk • Very High Risk-2-3%/year (BRCA mutation) • Prophylactic Surgery • High Risk 1-2%/year (LCIS, AH + FH) • Drugs or Prevention Trials • Moderate Risk >.33<1%/yr (AH or FH alone) • Healthy Behaviors • Possibly tamoxifen under age 50 • Possibly raloxifene postmenopausal women

  14. Surgical Risk Reduction Strategies For Very High Risk Women (2%/Yr) • Oophorectomy premenopausal women ( risk by 50-70% even when women are given add back HRT) • Mastectomy ( risk by ~90%) • Cost effective and likely to provide survival advantage Hartman et al. NEJM 340:77, 1999. Rebbeck et al. NEJM 346:1616, 2002; JCO 23:7804, 2005. Grann et al Breast Ca Res and Treat 125:837 2011 Domchek et al JAMA.;304:967,2010

  15. Reduction of ER+ Cancers with Tamoxifen Tamoxifen vs Placebo Pre & Postmenopausal • 1/3-2/3 decrease ER+ cancers • No decrease ER- cancers • Menopause Symptoms • Uterine effects/cancer • Thromboembolism • Cataracts • No demonstratedsurvival advantage to date Fisher et al. J Natl Cancer Inst 90:1371,1998. Cuzick et al. Lancet 361:296, 2003

  16. Raloxifene Overcomes Some but Not All Problems Observed With Tamoxifen Median FU 47mos : Tamoxifen vs Raloxifene STAR Postmenopausal • Efficacy postmenopausal women for ER+ cancer similar to tamoxifen • Fewer uterine events • Less thrombo-embolism • Poor bioavailability-shorter half life-must be compliant • Menopausal Symptoms • No demonstrated survival advantage to date in placebo controlled trials Vogel et al JAMA 295:2727,2006

  17. 81 Mos: Tamoxifen Better than Raloxifene in Preventing Invasive Ca in Postmenopausal Women Vogel et al Cancer Prev Res 2010 6:681

  18. Tool For Estimating Prevention Benefit Postmenopausal Women • Benefit defined as prevention of life threatening events based on current age, presence of uterus and calculated GAIL risk. • Stroke, PE, and Endometrial Ca, Invasive Breast Cancer, hip fracture score = 1. • In situ cancer and DVT score=0.5 • Makes assumptions based on RR of events from WHI, BCPT-1 and STAR trials Freedman et al JCO 2011; 29: 2327

  19. Raloxifene Prevented More Life-threatening Events in Postmenopausal Women With A Uterus ( Net /10,000 ) Freedman et al JCO 2011; 29: 2327

  20. Phase III Trials New SERMS: Fewer Breast Cancers and Bone Fractures but Blood Clots Still a Problem Cummings NEJM 2010 362:686, Powles SABCS 2009 Abstract 51 Cummings NEJM 2008;359:697,Beral Lancet 2003; 362:419, La Croix Natl Cancer Inst. 2010 17;102:1706

  21. MAP-3 Trial of Exemestane Vs Placebo Exemestane 25 mg/day Postmenopausal Women 11 cases Invasive cancer N= 4488 Placebo NO Median FU time 3 years 60% Reduction Invasive Cancer Average age at randomization=62.5 yrs Average 5 year Gail Risk=2.3 % 35 cases Invasive cancer Goss et al NEJM 2011 363:2381

  22. Side Effects With AIs MAP-3 Study • Significant increase with exemestane in • Hot Flashes ( <.01) • Diarrhea (.002) & Nausea ( .04) • Musculoskeletal events (.01) • Joint and muscle pain (.01) • Fatigue (.03) • Insomnia ( .04) Goss et al NEJM 2011 363:2381

  23. “Standard” Primary Prevention Drugs • Premenopausal ( Relative Risk Reduction) • Tamoxifen (50%) • Postmenopausal (Relative Risk Reduction) • Raloxifene (40%) • Tamoxifen ( 50%) • Exemestane (60%) • Offer to women with pre-cancer ( atypical hyperplasia, LCIS,) Higher Gail <age 70 • No Survival Advantage. All cause hot flashes

  24. Hot Flash Free Interventions Currently Under Study Energy Balance Metformin Omega 3 Fatty Acids Phytoestrogens Vitamin D Hall Acta Oncologica 2010;49&57

  25. Weight Loss in Obese Women • Postmenopausal Obesity Increases risk of developing postmenopausal breast cancer and increased risk of recurrence & death after diagnosis • Etiology : Increased hormones, growth factors, cytokines, leptin, decreased adiponectin. • Risk Reduction likely to require >5-10% loss and maintenance of loss over several years • Significant and maintained loss likely in only 20 % of women entering a behavioral weight loss program. • Bariatric Surgery associated with reduced risk of breast cancer

  26. Metformin: Calorie Reduction Mimetic • Reduces insulin levels • Animal Studies mixed results • Fewer cancers obese, may be more in normal wt • Cohort studies: • less breast ca type II diabetics taking metformin • better response to chemotherapy . • 2 randomized clinical trials • 30 day pre-surgical model in early breast cancer • Adjuvant trial of women randomized to metformin or not after conventional therapy ( all BMI) Zakikhani. Cancer Res 2006;66:10269, BMJ 2005;330: 1304, Jiralerspong J Clin Oncol 2009;27:3297. Goodwin PJ, J Clin Oncol 2009;27:3271–3, Cazzaniga CEBP 2009;18:701.

  27. Omega-3 Fatty Acids Replace Pro-inflammatory Omega 6 Fatty Acids in Cell Membranes 200-500 mg EPA + DHA/day recommended for heart health Animal and correlative studies reduced breast cancer risk but probably at higher doses Brasky Ca Epi Biomarkers Prev 2010; 19:1696.

  28. Lignans Function as Natural Selective Estrogen Receptor Modulators Plant Lignan Mammalian Lignans Secoisolariciresinol (SDG) SDG Enterolactone Enterodiol Gut Bacteria Buffer effects of ER alpha Flaxseed Most Concentrated Source of SDG (100x other plants) Used in Canada to treat cylic mastalgia

  29. Favorable Lignan Pilot Study Leads to Placebo Controlled IIB Trial Low or undetectable baseline lignan levels with 10 fold increase at 6,12 mos Minimal to no side effects. Decrease in Ki-67 over 12 months in majority. Significant decrease in proportion of women with Atypia Now being studied placebo randomized trial Change Ki67 Change Ki-67 p=.0001 P<.0001 Pre-Study Post-Study Fabian et al. Cancer Prevention Res 2010

  30. Need 3000-4000 IU Vitamin D/ Day to Maintain Serum 25OH D in the 30-60 ng/ml optimal range 8oz Milk =100IU Salmon= 400 IU Total body sun exposure to minimal erythema = 10,000 IU

  31. Phase III Studies of Vitamin D for Prevention in Postmenopausal Women Chlebowski JNCI 2008; 100:1581, Lappe Am J Clin Nutr 2007; 85:1586, Chlebowski JNCI 2008;100:1581, Lappe Am J Clin Nutr 2007; 85:1586

  32. Parting Thoughts • Adjuvant Systemic Therapy reduces breast cancer deaths by 30% • Screening reduces breast cancer deaths by 15-30% . • Earlier detection may avoid chemo many instances • Risk reduction strategies reduce cancer incidence • Avoid chemo in women in whom cancer is prevented • Survival advantage for BRCA1/2 carriers undergoing oophorectomy

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