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Young Women and Breast Cancer: The Future of Care

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  1. Young Women and Breast Cancer: The Future of Care Julie R. Gralow, M.D. Jill Bennett Endowed Professor of Breast Cancer Director, Breast Medical Oncology University of Washington School of Medicine Fred Hutchinson Cancer Research Center Seattle Cancer Care Alliance

  2. Breast Cancer in Young Women is a Relatively Rare Disease… (Hankey et al, JNCI 1994)

  3. …However, Breast Cancer is the Most Common Cancer in US Women Starting at Age 30 Top 5 Cancers by Age Group Source: National Cancer Institute, SEER Cancer Statistics Review 1975-2009

  4. Incidence of Breast Cancer in Young Women • Over 12,000 women under age 40 are diagnosed yearly with invasive breast cancer in the US alone (+2,000 DCIS) • Tens of thousands more worldwide (ACS Research, SEER 2008; Porter, N Engl J Med 2008)

  5. Breast Cancer in Young Women is Different • Tumor differences • More ER negative, high grade disease • More HER-2 positive • Patient differences • Biologic • Psychosocial

  6. How Can We Improve Breast Cancer Outcomes in Young Women?

  7. Bridging the Gaps: Current Issues in Medical Research on Young Women and Breast CancerA Basis for Advocacy and ActionYoung Survival Coalition White Paper 2001 • Epidemiological Aspects: Incidence of Early Onset Breast Cancer • Pathological Aspects: Is Breast Cancer a More Aggressive Disease in Younger Women? • Medical Treatment of Younger Women at Risk and with Breast Cancer • Diagnostics and Screening Tools for Younger Women • Ovarian Function: Premature Menopause and Subsequent Pregnancy after Breast Cancer

  8. Young Survival Coalition Research Think TankFebruary 7-8, 2013 • Attendees: Educated advocates and multi-disciplinary group of medical and research expertsSix groups focused on: • Risk Factors • Treatment • Fertility • Pregnancy • Metastases • Quality of Life

  9. Which research questions, if answered, would significantly impact the quality and quantity of life for young women diagnosed with breast cancer? YSC Criteria for Priority Questions

  10. Young Survival Coalition Research Think TankFebruary 7-8, 2013 • Workgroups formulated approximately 60 questions, based on the current state of the evidence • Each group presented their recommended top three goals • Approx 26 hours of meeting audio files to transcribe and comb through • Still a lot of work to do before the new research agenda is finalized and shared • Collaboration is key, along with the strategic goal of focusing on young women

  11. http://www.cancer.gov/cancertopics/aya Advisory Committee on Breast Cancer in Young Women CDC has convened an Advisory Committee on Breast Cancer in Young Women (ACBCYW), a federal advisory committee established by the Education and Awareness Requires Learning Young (EARLY) Act http://www.cdc.gov/cancer/breast/what_cdc_is_doing/young_women.htm

  12. European School of Oncology Breast Cancer in Young Women Conference (BCY1)Dublin, Ireland, November 2012 MAIN TOPICS • Hereditary breast cancer• Diagnostic tools in young women• Local therapy• Systemic therapy• Pregnancy and breast cancer• Fertility preservation• Psychosocial aspects• Management of side effects

  13. How Can We Improve Breast Cancer Outcomes in Young Women? • Prevention • Earlier Detection • Better Treatment • Survivorship and Long-term Follow-up

  14. How Can We Improve Breast Cancer Outcomes in Young Women? • Prevention • Earlier Detection • Better Treatment • Survivorship and Long-term Follow-up

  15. Breast Cancer Risk Factors: Genetics 15-20% 5-10% 70-80%

  16. Genes that Cause Hereditary Susceptibility to Breast Cancer • BRCA1 and BRCA2 • Breast cancer risk 50 - 85% • Early onset, 1/2 diagnosed by age 41 • Second primary breast cancer 40 - 60% • Male breast cancer (BRCA2) 6% • Ovarian cancer risk 10 - 40% • TP53 (Li Fraumeni syndrome) • PTEN (Cowden’s syndrome) • CHK2 • low penetrance – breast cancer risk doubled? • Undiscovered genes

  17. UW Laboratory Medicine: New BROCA Test for Hereditary Cancer RiskT Walsh, E Swisher, MC King • Useful for evaluation of patients with suspected hereditary cancer predisposition, with focus on syndromes that include breast or ovarian cancer • Depending on the gene involved, these cancers may co-occur with other cancer types (colorectal, endometrial, pancreatic, endocrine, or melanoma) • If mutations in BRCA1 or BRCA2 are suspected, these should be evaluated with a separate test • BROCA uses next-generation sequencing to detect mutations in 40 genes • The assay completely sequences all exons and flanking introns of these genes AND detects large deletions, duplications, and mosaicism

  18. Breast Cancer Risk Factors: Lifestyle McTiernan, Oncologist 2003; Hamijima, Br J Ca 2002

  19. Physical Activity and Breast Cancer Women’s Health Initiative (WHI)McTiernan A et al, JAMA 2003 • Patients: 74,171 women ages 50-79 • 1,780 cases of breast cancer diagnosed over 5 yrs • Study: evaluated incidence of breast cancer correlated to physical activity at age 18, 35, 50 • Results: • Regular strenuous physical activity at age 35 had 14% reduction in breast cancer risk (similar at age 18, 50) • 1.25-2.5 hrs/wk brisk walking had 18% decreased risk • Greatest reduction seen with >10 hrs/wk brisk walking

  20. New York Breast Cancer Study: Breast and Ovarian Cancer Risks in Jewish Women with BRCA1/2 MutationsKing MC et al, Science 2003 In women with BRCA1/2 mutations who developed breast cancer, regular exercise delayed age of onset by 10 years

  21. Exercise Can Impact Breast Cancer Survival Exercise and Survival After Breast Cancer Diagnosis(Nurses Health Study)Holmes MD et al, JAMA 2005 Patients: 2,987 nurses with early stage breast cancer Physical activity categories: • LOW: < 3 MET hours per week • LOW/MED: 3-8.9 MET hours/week • MED/HIGH: 9-14.9 MET hours/week • HIGH: > 24 MET hours/week (3 MET hours/week equal to walking average pace of 2-3 miles per hour for 1 hour) • Results: Compared to women with LOW physical activity, risk of dying of breast cancer was: • 20% less for LOW/MED exercise • 40-50% less for MED/HIGH and HIGH exercise (at least 3 hours per week walking at average pace)

  22. Ongoing Study SWOG S1008:Feasibility Study of a Weight Loss Intervention in Breast and Colorectal Cancer E N R O L L Eligibility Criteria: Female Age > 21 years Postmenopausal Stage I-III breast/colorectal CA 6 - 24 mospost-treatment BMI > 25 kg/m2 Sedentary 12 Month Weight Loss Program: Curves exercise (goal: 220 min/wk of mod-intense activity) + Curves diet (low-fat, high fruit/veg,1500 kcal/d) + Telephone-based behavioral counseling (14 sessions over 12 mos) • Secondary Endpoints: • Anthropometric measures/ body composition • Physical activity • Diet • Biomarkers • Quality of life • Program acceptability • Primary Endpoints (12 months): • Feasibility in Breast ; Colorectal • >5% change in weight in Breast; Colorectal

  23. Breast Cancer Risk Reduction • Primary Prevention • Lifestyle • Chemoprevention • Prophylactic surgery

  24. Ongoing SWOG S0812: Vitamin D in Premenopausal Women at High Risk for Breast Cancer (PI: K Crew) Activation: November 2011 Accrual Goal: 200 • Eligibility: • Premenopausal, Age 18-50 • 5-yr Gail risk ≥1.67% or • lifetime risk ≥20% • BRCA1/2, PTEN, p53 mutation • ADH, ALH, LCIS, DCIS (including • microinvasive and T1a) • Stage I-II breast CA, >5yrs in • remission • 25(OH)D ≤32ng/ml R A N D O M I Z E Cholecalciferol (vit D3) 20,000 IU weekly x 1yr Matching placebo x 1yr Vitamin D3 600 IU qd Baseline data collection: Follow-up data collection: Mammogram Mammogram Core breast biopsy Core breast biopsy Blood Blood Primary Endpoint: Change in mammographic density Secondary Endpoints: Serum and tissue-based biomarkers, toxicity

  25. Ongoing Phase II Low Dose Tamoxifen in Lymphoma Survivors for Breast Cancer Risk ReductionPI: M Palomares • Eligibility: • childhood and young adult cancer survivors treated with chest radiation R A N D O M I Z E Tamoxifen 5 mg daily x 2 yrs Placebo x 2 yrs Baseline data collection: Follow-up data collection: Mammogram Mammogram Core breast biopsy Core breast biopsy BloodBlood Primary Endpoint: Change in mammographic density Secondary Endpoints: Serum and tissue-based biomarkers, toxicity

  26. How Can We Improve Breast Cancer Outcomes in Young Women? • Prevention • Earlier Detection • Better Treatment • Survivorship and Long-term Follow-up

  27. Young Women Present with More Advanced Disease • Delays in diagnosis • Lack of reliable screening • Lack of awareness of risk or difficult to diagnose: • “Too young for breast cancer” • breast cancer during pregnancy • Access to care issues

  28. Diagnosis, imaging and staging in young women should follow standard algorithms • Consideration should be given to breast MRI in young women, particularly in the setting of very dense breast tissue or a genetic predisposition to the disease • For BRCA 1/2 mutation carriers and others at extremely high risk based on family history or predisposing mutations in other genes, and for those at increased risk because of therapeutic radiation in adolescence, annual surveillance is recommended Diagnosis and imaging for staging and follow-up

  29. Early Detection of Breast Cancer: The Controversy Around Breast Imaging Mammogram • Ultrasound • Magnetic Resonance Imaging (MRI)

  30. Mammography is Less Sensitive in Younger Women • Screening mammograms miss up to 25% of breast cancers in women in their 40s, compared to 10% of cancers for older women • Digital (vs film) mammography may be better for younger women and women with dense breasts

  31. A Newly Recognized Breast Cancer Risk Factor: Mammographic Density Several states have now mandated reporting of high breast density as seen on mammograms to both patient and primary care provider

  32. American Cancer Society Recommendations for Breast Cancer Screening 2013 • Mammography: Annually beginning at age 40 and continuing as long as the woman is in good health • Health Professional’s Exam: About every 3 years between 20-39, then annually • Self-Exam: An option for women beginning at about age 20 • MRI:Women at high risk (> 20% lifetime) should get a mammogram and MRI yearly. Women at moderately increased risk (15-20%) should talk with their health care providers about MRI screening.

  33. % Breast Screening in Young Women with Hereditary Risk for Breast CancerKriege M et al, NEJM 2004 • Patients: 1,909 Dutch women with elevated risk of breast cancer • average age 40 years; 358 BRCA1/2 + • Screening: Clinical breast exam every 6 months, mammography and MRI yearly • Results (3 years): 51 tumors detected Breast MRI is better at detecting cancer than mammogram in high risk women, but has a higher rate of “false positives”

  34. How Can We Improve Breast Cancer Outcomes in Young Women? • Prevention • Earlier Detection • Better Treatment • Survivorship and Long-term Follow-up

  35. Should Treatments be Different in Young Women with Breast Cancer?

  36. General Statements Young age by itself should not be the reason to prescribe more aggressive therapy then general recommendations Both in early and advanced settings, choice of treatment should include the biological characteristics of the tumour (ER/PR, HER-2, proliferation, grade), tumor stage, hormonal milieu*, and patient's comorbidities * Young does not always mean pre-menopausal

  37. Fertility preservation • Before any treatment decision, young women must be advised to have fertility and contraception specialized counselling

  38. Genomic 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

  39. What’s the Latest?Triple Negative Breast Cancer is a Highly Diverse Group of Cancers 6 subtypes of TNBC identified by gene expression array! Lehmann BD, et al. J Clin Invest 121:2750-67, 2011

  40. Endocrine Therapy Estrogen Receptor and Breast Cancer Aromatase inhibitors, ovarian suppression Cell Growth and Division Estrogen Estrogen Receptor SERMS (tamoxifen) SERDS (fulvestrant)

  41. ATLAS: Adjuvant Tamoxifen Longer Against Shorter (5 vs 10 Years) • Patients: 6846 women with breast cancer completing 5 years of tamoxifen • 54% node-negative • Analysis only includes documented ER+ patients • Randomized to continue tamoxifen to year 10, or stop at year 5 • Reporting on 8 yrs median follow-up: compliance, recurrence, death Davies C et al. Presented at SABCS 2012, Abstract number S1-2

  42. ATLAS: Adjuvant Tamoxifen Longer Against Shorter (5 vs 10 Years) Compliance after 2 years 80% Davies C et al. Presented at SABCS 2012, Abstract number S1-2

  43. ATLAS: Adjuvant Tamoxifen Longer Against Shorter (5 vs 10 Years) • Only had access to toxicity related to hospitalization or death • Toxicities for 10 vs 5 years tamoxifen (from Lancet publication: Davies C et al, Lancet 2012, epub ahead of print) • Pulmonary embolus HR 1.87 p=0.01 • Stroke HR 1.06 (ns) • Ischemic heart disease HR 0.76 p=0.02 • Endometrial cancer HR 1.74 p=0.0002 (3.1% vs 1.6%) Davies C et al. Presented at SABCS2012, Abstract number S1-2

  44. ATLAS: Adjuvant Tamoxifen Longer Against Shorter (5 vs 10 Years) • How to incorporate into practice: • Weighing risks vs benefits • Need to estimate woman’s residual risk of recurrence after 5 years of tamoxifen • Half of deaths NOT breast cancer related! • Really only applicable in premenopausal women • AIs standard in postmenopausal • For women who have become postmenopausal while on tamoxifen, consider AI (ie NCIC MA17 study) • Patient acceptance • QOL issues on tamoxifen (hot flashes, night sweats, insomnia) • Generalizability to other endocrine agents (longer duration AIs)? Davies C et al. Presented at SABCS2012, Abstract number S1-2

  45. Ongoing IBCSG 24-02: Suppression of Ovarian Function Trial (SOFT)PI: A. Goldhirsch • Does ovarian function suppression add to the standard in premenopausal women (tamoxifen)? • Is an aromatase inhibitor of added benefit in premenopausal women when the ovaries are suppressed? Premenopausal, ER+, ovarian function intact after chemo or no chemo Tamoxifen vs. Tamoxifen + OFS vs. Exemestane (Aromasin) + OFS

  46. ABCSG-012: Adjuvant Hormonal Therapy in PremenopausalBreast Cancer Patients Gnant M et al, NEJM 360, 2009 1800 premenopausal women with ER+ early breast cancer Goserelin 3 years (ovarian suppression) Anastrozole (Arimidex) Tamoxifen Zoledronic acid 4mg q6 mo Control Control Zoledronic acid 4mg q6 mo

  47. ABCSG-12 Trial of Endocrine TherapyGnant M et al, NEJM 360, 2009 47.8 months median follow-up • Conclusion: No difference between tamoxifen and anastrozole • A trend towards tamoxifen being better?

  48. Can Bisphosphonates Prevent Cancer Recurrences?ABCSG-12: Premenopausal Breast Cancer Pts Receiving Adjuvant Hormonal RxGnant M et al, N Engl J Med 360:679-691, 2009 100 90 80 70 DFS 60 50 Disease-Free Survival, % First Event per Patient, n 40 30 No of Hazard Ratio (95% CI) Events vs No ZOL P Value ZOL 54 0.64 (0.46 to 0.91) .01 No ZOL 83 20 10 0 0 12 24 36 48 60 72 84 Time since Randomization, months (n = 904) (n = 899) 35% reduction in recurrences from adding zoledronic acid – but very few recurrences! Median follow-up = 48 months

  49. Chemotherapy: THE PAST2000 NCI Consensus Development Conference on Adjuvant Breast Cancer Chemotherapy should be offered to the majority of women with early stage breast cancer regardless of size, lymph node, menopausal or hormone receptor status