The Study -saliva collection Screening Annual - PDF document

8/2/2018 The Study: fffffffffffffffff Personalized Screening Arm Women Informed to Screen Depending On Measures of risk Risk Factors Mammogram -breast density Portal enrollment Athena Health and consent Questionnaire Risk Model USPSTF -family history, comorbidities, Risk previous biopsies, age, BCSC race/ethnicity Genomic profiling -9 Gene Panel (e.g. BRCA), SNPs The Study -saliva collection Screening Annual Mammogram Annual Biennial No screening Frequency: + MRI Mammogram Mammogram until age 50 A pragmatic randomized trial Breast Health Specialist counseling 1 9 Design: Preference-Tolerant Risk thresholds & screening Randomized Trial strategies Guiding principles 100,000 women across Athena network and partners High-penetrance Moderate- mutation carrier or Eligibility Criteria: • No woman will be screened less aggressively than existing Eligible penetrance history of  Women 40-74 Patients recommendations from major professional societies mutation carrier or therapeutic chest  No prior history of age 40-49 with irradiation or • Minimize false positives breast cancer or DCIS Consent Age 40-49, Age ≥50, extremely dense 5-yr risk > 6% • Minimize interval cancers 5-yr risk < 1.3% 5-yr risk ≥ 1.3% breasts Annual • Minimize incidence of Stage IIB and higher disease Mammography Biennial Annual mammography + Randomized Cohort Observational Cohort • Women with known deleterious mutations in hereditary breast starting at 50 mammography mammography MRI cancer genes will be screened according to National Comprehensive Randomize Cancer Network (NCCN) guidelines • Screening recommendations will be practical and scalable Annual Personalized Annual Personalized Screening Screening Screening Screening adapts over time Shieh JNCI 2017 2 wisdomstudy.org Genetic testing in WISDOM Three main components : 1. “Traditional” BRCA1 & BRCA2 testing 2. Seven other genes related to elevated risk of breast cancer 3. SNP score 1

8/2/2018 3. SNP score 1. Traditional BRCA1/2 testing • One in 400-800 women have a mutation • One in 40 women with Ashkenazi Jewish heritage • Most have family history of breast, ovarian, or other cancers…. But not all! • Adopted women They found that the polygenic risk score could put women into risk categories. Compared to • Family history not known women with an average polygenic risk score: • Passed through males • Women with the highest 1% of scores were 3 times more likely to develop breast cancer • Having mutation does not • Women with the lowest 1% of scores had a 70% lower risk of developing breast cancer mean a 100% risk of cancer 3. SNP score 2. Other breast cancer genes TP53 • Very rare genetic syndromes PTEN • Cancers other than breast cancer involved STK11 • Unlikely to identify very many women across the state CDH1 ATM ~ 1 in 100 women: MRI recommended PALB2 Risk depends on mutation + age + CHEK2 family history… more complicated, • Won’t change risk assignment for but MRI recommended for most. most women • For very high or very low, it may change All women found to have a mutation in these genes will be risk assignment • Opportunity to learn about SNP scores referred for genetic counseling across race/ethnicity Integrating prevention into risk assessment 3. SNP score • “Single Nucleotide Polymorphism” Above Risk category Average Moderate High Very High • We all have millions of these– it’s normal human variation in our Average genomes <20 th percentile 20-40 th PRS 40-60 th PRS 60-80 th PRS >80 th PRS Genetic Information based on PRS CHEK2, ATM, PALB2, CDH1, BRCA1/2, • Technically easy to assess STK11 TP53, PTEN • For WISDOM, a panel of 200+ SNPs will be used Screening Mammogram Mammogram Mammogram Mammogram Mammogram — This generates a “risk score” ≥50 years ≥40 years Yearly MRI MRI Every 2 years Every 2 years Yearly Yearly — Women with high risk scores will be in a higher risk bin for screening assignment Medical & Lifestyle Tamoxifen, Tamoxifen, Lifestyle- Aromatase Aromatase based Risk inhibitors, inhibitors, Reduction Lifestyle Lifestyle Surgical Risk BSO Reduction BPM 2

8/2/2018 Summary Screening Recommendation Letters • All Screening Assignments will be delivered • Pragmatic trial: looks at screening in the “real into the participant portal world” • Genetic Results (Personalized Arm) • Preference-tolerant : Women who have a – Negative: results delivered to participant portal. strong preference or are averse to randomization can choose their study arm – Positive: Breast Health Specialist sets up an immediate telephone consult, refers to high risk • Adaptive: As we learn more about assessing programs breast cancer risk, our risk assignment processes are adjusted 13 16 Sample screening letter: Thank you… questions? wisdomstudy.org 14 17 Yearly surveys 15 3