8/2/2018 Study Background 10 www.wisdomstudy.org www.wisdomstudy.org Screening for breast cancer… • There are more RCTs on breast cancer screening than any other cancer screening • Cochrane collaboration, US Preventive Services Taskforce, Canadian Task Force on Preventive Health Care, a UK Independent Review and International Agency for Research on Cancer all concluded that there was evidence of breast cancer mortality reduction in range of 15-32% (depending on age range examined) • Almost all high income countries have mammographic screening established in some form. Typical breast screening participants are not 25 year old supermodels… www.wisdomstudy.org www.wisdomstudy.org Is screening effective in reducing mortality? Age Group Mortality Deaths Prevented Reduction per 10,000 women screened over 10 years 39-39 8% (ns) 3 50-59 14% 8 60-69 33% 21 70-74 22% (ns) 13 www.wisdomstudy.org www.wisdomstudy.org 1
8/2/2018 Are the findings of ‘old’ RCTs Is screening effective in reducing mortality? still relevant? • Screening reduces breast cancer mortality 15%-20% • Women 40-59 y: reduction in breast cancer mortality smaller magnitude and • Many of the RCTs were conducted in the 1970-80s. less statistically significant • Treatment of breast cancer has improved • Women 60-69 y, reduction highly significant substantially since then. • Women 70-74 y, reduction has not been shown to be significant • Argument is that earlier diagnosis may no longer be • As much as two-thirds of the reduction in breast cancer mortality particularly relevant. could be explained by improved treatment and not early • detection (Welch, NEJM, 2016) Mammography technology has also improved and can now detect tiny breast abnormalities • Screening has not been shown to reduce all-cause mortality (calcifications) that are benign www.wisdomstudy.org www.wisdomstudy.org But there is controversy? What are the harms? Why? • False positive results • Unnecessary follow-up tests and biopsies (IARC estimates 20%) • Anxiety and psychological distress • How good were the studies? • Overdiagnosis • What are the harms of breast cancer • Cancer that would never have progressed to clinical importance screening? in absence of screening (20-50% of screen detected tumors) • Harms of treatment without any benefit • Are the findings from old RCTs still relevant • Once a cancer is diagnosed, no way to determine whether it is a given treatment improvements? case of overdiagnosis • Radiation exposure (may be a small risk) www.wisdomstudy.org www.wisdomstudy.org How good were the studies? Harms of Breast Cancer Screening: US Preventive Services Taskforce Report, 2016 • Concern about methodological quality of 1. False-positive results higher with annual vs. biennial screening (61% vs. 42%) some of the RCTs 2. Biopsies higher with annual vs. biennial screening (7% vs. 5%) 3. Overdiagnosis rates estimated to range from 0% to 54% in 29 studies • Varying emphasis put on the importance of 4. Women given false-positive test results report more anxiety, distress these (e.g. Cochrane vs UK Review) and breast-cancer specific worry (80 studies) 5. Some women experience substantial pain during mammography (1- • But….they are still the best evidence we have 77% in 39 studies; 11-46% decline future screening) now. 6. An estimated 2-11 screening-related deaths from radiation-induced cancer per 100,000 women using digital mammography www.wisdomstudy.org www.wisdomstudy.org 2
8/2/2018 State of Affairs for Breast Cancer Screening in the US Old Paradigm: inexorable progression • Mammography Screening is Mired in controversy, uncertainty Normal • When to start, how often to screen, overdiagnosis Cell • Based on data that is 30 and 40 years old Atypical “cancer” is one disease . . . • Impacts everyone Cell Carcinoma In Situ Stage 1 Cancer Stage 2-3 Cancer • Opportunity for improvement!! Detectable • Build a sustainable infrastructure to address a critical health issue that is resource Metastases intensive Early Detection Will Reduce Cancer Mortality Esserman et al, Lancet Oncology May 2014 death www.wisdomstudy.org www.wisdomstudy.org Increase in breast cancer rates driven Breast Cancer Screening: What It Can Be by detection of early (localized) cancers • Based on advances in: • Risk-assessment • Biology • More effective at finding “relevant” cancers • Integrated with prevention • More cost-effective: Aggregate costs for US • >$10 Billion $5 Billion with greater value • Personalized Esserman JAMA 2009 www.wisdomstudy.org www.wisdomstudy.org Dr. Karsten Jorgensen, Chief, Nordic Cochrane Center New Paradigm: Variable Progression INDOLENT LESIONS SLOW PROGRESSION RAPID PROGRESSION “The breast cancer findings also point to another flaw in existing screening strategies. They are built on centuries-old definitions of cancer and equally Normal Normal Normal Cell Cell Cell unchanged views on how best to treat them. Back then all tumorous growths Atypical were assumed to be fast-growing and potentially lethal, and therefore needed Atypical Stage 1-3 Cell/CIS Cell/CIS Cancer to be removed. But, says Jorgensen, “we shouldn’t treat all cancers the same Stage 1 Stage 1 way because they are not the same. Our knowledge of cancer biology tells us DetectableMetast Cancer Cancer asis that breast cancer represents a spectrum of really different cases of cancer that Stage 2-3 Cancer behave in very different ways. And sadly screening is not good at picking up Cancer death those cancers that we really want to pick up.” IDLE condition : “Ultralow” Risk Indolent lesions of Tumors Detectable epithelial origin Metastasis Time Magazine, 2017 course Indolent Cancer Metastasis, death rare death Early Detection Early Detection Systemic Therapy is Key www.wisdomstudy.org Will Not Impact Mortality Reduces Mortality to Reducing Mortality www.wisdomstudy.org 3
8/2/2018 New Paradigm: Design: Preference-Tolerant Randomized Trial Breast Cancer is not a single disease Tumor progression and Benefit (lack of) from Screening Enrollment Goal: Minimal Minimal Maximal Maximal Eligible benefit benefit benefit benefit 100,000 women across Patients Athena network and partners Eligibility Criteria: Consent Women 40-74 No prior history of breast cancer or DCIS Randomized Cohort Observational Cohort Potential Potential Harm Harm Randomize IDLE Tumors Annual Personalized Annual Personalized Screening Screening Screening Screening Screening should reflect our new understanding of breast cancer biology adapts over time www.wisdomstudy.org www.wisdomstudy.org Recruitment Funnel Guiding principles As of Wed, June 20 th • No woman will be screened less aggressively than existing recommendations from major professional societies • Minimize false positives • Minimize interval cancers • Minimize incidence of Stage IIB and higher disease • Women with known deleterious mutations in hereditary breast cancer genes will be screened according to National Comprehensive Cancer Network (NCCN) guidelines • Screening recommendations will be practical and scalable Shieh JNCI 2017 www.wisdomstudy.org www.wisdomstudy.org Study Aims Summary Determine if personalized screening Breast cancer screening: 1. has resulted in detection of smaller tumors but not reduced the (as compared to annual screening) provides: incidence of metastatic disease. 2. studies we rely upon for evidence are outdated but showed a reduced risk of breast cancer mortality of 14% for women in their 50s and 33% 1. Equal to or better patient safety for women in their 60s. 2. Less morbid 3. can cause harms (false-positive results, biopsies, anxiety, distress, worry 3. More accepted by women about breast cancer, radiation exposure). 4. Prevention enabling 4. has not improved to incorporate our advances in knowledge about breast cancer biology. 5. Better healthcare value WISDOM is designed to test a new way! www.wisdomstudy.org www.wisdomstudy.org 4
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