I have adopted the USPSTF guidelines in my practice. Discussion Points. Re-Thinking Screening In the Context of Breast Cancer Biology

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1 Re-Thinking Screening In the Context of Breast Cancer Biology I have adopted the USPSTF guidelines in my practice Laura Esserman M.D., M.B.A. Professor of Surgery and Radiology, UCSF Director, Carol Franc Buck Breast Care Center A. True B. False 67% 33% 1 A. B. 2 Discussion Points Impact of screening on Incidence rates There is value in routine screening for breast cancer risk assessment A. True B. False 83% 17% Heterogeneity of breast cancer impact on screening benefit DCIS: Is it the right precursor? USPSTF data analysis and recommendations and fit with biologic understanding of breast cancer Impact of modern treatment on screening benefit Message for women (public) Vision for moving forward Use Biological Insight to Improve Approach to Screening A. B

2 Screening in the Headlines Shift Discussion about Screening FROM: Good vs Bad TO: Clarity on Contribution, Limits FIND: Opportunities to Improve JAMA Oct Hypothetical Screening Scenarios For Both Breast and Prostate, Incidence Rates Have Risen and Remain Higher BREAST So improvement in the fraction of early Each cancers of these detected scenarios is NOT result the in the same right metric improvement and does in not the tell ratio the of story. early The stage denominator cancers as of a cancers fraction detected of total is critical. cancers detected PROSTATE 8 2

3 THE DATA: Increase in detection of localized(ln-) breast cancers without concomitant decrease in regional(ln+) cancers is seen in programs around the world Screening is Complex Because Cancer is Complex United States SEER 9 Reg Female IBC, all ages The Netherlands Netherlands Cancer Reg Female IBC, ages All breast cancers are not the same Incidence of Triple Negative Tumors in Populations Not all populations are at equal risk for the same tumor types Expression arrays show that tumors arise from different cell types, and that these tumor types have different outcomes 50 Poorly Differentiated Plus E Receptor Negative (%) % 31.8% * 10.1% 17.7% Perou PNAS White African American Asian Hispanic * HR 4.70, 95% CI Esserman, Hylton 2001 F Olopade, R Chlebowski ASCO

4 Screening Effectiveness is Likely to Be Tied to Biology of Tumor Type Mimimal benefit Maximal benefit Observation Hypothesis In the setting of screening, the biology of screen detected lesions should differ from that of tumors that present as clinical masses Potential Harm Screen detected cancers: biologically lower risk Interval cancers: biologically higher risk Screening should reflect our new understanding of breast cancer biology 14 HAS THE BIOLOGY OF BREAST CANCERS THAT ARE DETECTED CHANGED OVER TIME? 15 Effect of screening on the detection of good and poor prognosis breast cancers Yiwey Shieh, Laura Esserman, Laura Van t Veer Dan Moore, Emiel JT Rutgers, Michael Knauer,Valesca Retel, Stella Mook, Sabine Linn, Flora E van Leeuwen, Annuska Glas Early Detection Research Network, UCSF Dean s Summer Research Fellowship 4

5 Study Design Large database of 862 patients with known 70-gene prognosis signature outcomes from previous European trials. Selected node-negative cases only. Cohort 1: Prior to screening era: pts diagnosed No population-wide screening in countries of origin thus low uptake of mammography. Cohort 2: Screening era: pts diagnosed in 17 community-based hosptials (RASTER) in the Netherlands, where screening uptake is approx 80%. subset of screen-detected cancers Analyzed 2 age groups separately: Age 49-60: screened in cohort 2 but not cohort 1 (TEST) <40 years: not screened in either cohort (CONTROL) Findings As age increases, the proportion (both cohorts) of grade 1 tumors increases MammaPrint low (good risk) tumors increase Hormone receptor positive tumors increase Distribution of good/poor risk tumors Does not shift in women under the age of % good risk Substantially shifts in women aged Cohort 1: 40% good risk (no screening) Cohort 2: 58% good risk ( screening ) 67% good risk in screen detected cancers Shieh Esserman, van t Veer ASCO Defining IDLE Tumors 70 gene Prognosis Signature: Ultra-low Threshold 70 significant prognosis genes 70-gene prognosis signature index score distribution Women aged High Ultralow Threshold van t Veer et al., Nature,

6 30% of Screen Detected Are Categorized as Ultralow Risk Cancers Women aged DO PATIENTS WITH LARGER TUMORS ACTUALLY HAVE DIFFERENT BIOLOGY THAN SCREEN DETECTED CANCERS? Shieh Esserman, van t Veer ASCO Interval Cancers Tumors that present as clinical masses between normal mammograms Usually higher in grade, more often in younger women Suggest that current screening modalities not useful for these cancers Populations at risk for interval cancers are targeted for more frequent and intensive screening (e.g. BRCA1 carriers) CALGB INTERSPORE ACRIN NCICB CALGB / and ACRIN 6657 Investigation of Serial studies to Predict Your Therapeutic Response with I SPY WITH MY LITTLE EYE Imaging and Molecular Ana- Lysis A BIO-MARKER BEGINING WITH X 6

7 I-SPY : Poor Prognosis Tumors 70 significant prognosis genes Estimating Expected Interval Cancer Rates in I-SPY Based on rates in the Norrbotten Mammography Screening Program 70 Gene Prognosis Signature Good Signature 9% Poor Signature 91% Mean Tumor Size= 6.0 Present as clinical mass 55% < Age 50 van t Veer et al., Nature,2002 Age Expected IC Rate % % % % I-SPY Age Distribution 34% 53% 13% 0% Expected IC in I-SPY Expected IC Rate in I-SPY (22/68) 32% Observed IC Rate in I-SPY (57/68) LIN ASCO 84% 2009 Lessons from Molecular Profiling For Certain Biologic Types Early Detection May NOT Be the Optimal Strategy for Reducing Mortality Younger women are much more likely to have poor prognosis cancers Poor prognosis cancers are more likely to be interval cancers Women who undergo screening are more likely to have good prognosis cancers cancersdetected, and more ultralow risk cancers are being detected today. (IDLE tumors). Molecular profiling at the time of diagnosis could potentially identify IDLE tumors, and enable consideration/testing of less intervention

8 Natural History Surgical Treatment Alone- No adjuvant Tx Outcomes Node Negative and Positive Guy s Data Base % of pts had up to 30 year follow-up (median 20 yrs) Blocks/slides available 346/565 patients ER, PR, HER2, Grade reassessed Contra-lateral cases eliminated Risk Partitioning Identifies most homogenous subsets based on DSS R-PART (CART) Esserman et al BCRT 2011 Lessons Learned from Natural History Surgical Treatment- No adjuvant Tx Growth and progression trajectory varies significantly across tumor types These tumor types are likely to benefit differently from screening Esserman et al BCRT

9 DCIS Has Increased 500 Fold Since the Advent of Mammographic Screening... Figure 2. SEER9 Age-adjusted incidence rate of breast cancer by stage ( ) In Situ disease: Detection has increased by 500% HAVE WE IDENTIFIED THE RIGHT PRECURSOR LESION? Incidence rate (per 100,000) Localized Regional In Situ In situ Rate Localized Rate Regional Rate Distant Rate 34 0 Metastatic Year of diagnosis 35 Incidence of CIS type over time Timing of Progression DCIS total Noncomedo 5-20 years DCIS Cervical Cancer Rates Have Decreased Pap Smears, detection, treatment of CIN 20 Figure 1a. SEER9 age-adjusted incidence rate of cervical cancer ( ) Comedo 1-5 years DCIS LCIS Incidence rate (per 100,000) Li et. al Cancer Epidemiology, Biomarkers & Prevention Year of diagnosis 37 9

10 In comparison Relative reduction in mortality, Relative change in incidence, Breast 20% +18% Colon 32% -17% Cervix 55% -52% Most amorphous calcifications are biopsied (called BIRADS 4) because they might be low/intermediate grade DCIS Low intermediate grade DCIS probably progress over a 5-20 year time frame LOW/INTERMEDIATE GRADEDCIS SHOULD NOT BE A SCREENING TARGET 39 Overdiagnosisis NOT Limited to Breast Cancer Precursors of Some Biologic Types of Tumors (ultralow risk or IDLE tumors) should not be the target of early detection WE WANT TO FIND THE RIGHT PRECURSORS 25-70% of cancers may fall into the category of overdiagnosis Challenge: Redefine cancer 40 Welch, Black JNCI May

11 U.S. Preventive Task Force Guidelines Women most likely to benefit are in the age group Data analysis from randomized trials led to the US Preventive Task Force Recommendations on breast cancer screening, which are not inconsistent with several preceeding analyses DOES THE UNDERLYING BIOLOGY OF BREAST CANCER SUPPORT SIMILAR CONCLUSIONS? Women over 75 should not routinely be screened Comorbidities will determine benefit Women in their 40 s should discuss the risks and benefits of mammographic screening How Biology Helps Us to Understand the Screening Recommendations More common in young women Cancers most likely to benefit from screening More common in older women Likely the cancers that benefit most from screening progress at a pace where screening every months is sufficient 45 11

12 Impact of Screening is Reduced in the Setting of Optimal Breast Ca Treatment Taking Advantage of Staggered Introduction of Screening Kalager NEJM 2010 The Swedish Randomized Screening Trials were conducted prior to the use of adjuvant therapy About 1/3 of Observed Reduction in Mortality Can Be Ascribed to Screening CISNET Modelers Predicted Exact Same Result Reduction in Mortality from Adjuvant Treatment vs. Screening Screening programs in the U.K. and Sweden helped to introduce multidisciplinary breast cancer treatment and this further reduces mortality Kalager et. al. NEJM 2010 R M N G E S W D Current treatment makes up for 2/3 of the benefit that was ascribed to screening in the pretreatment era 48 Courtesy of Don 49 12

13 So Where Are We? 200,000 women diagnosed every year in the United States 45,000 women die every year In spite of screening, rate of locally advanced cancers have not changed much Women who present with larger tumors are often younger, at highest risk to die and least likely to benefit from screening Breast cancer rates (IDC, DCIS) have increased, some of which is likely from screening We CAN and MUST do better Screening: 7-10 Billion $ per year For this large expenditure of resources, can we make it better? Next Steps in Improving Screening Current Screening Approach Has Some Benefit But it is limited and will not result in a cure for breast cancer Work to reduce the negative impact of screening Appropriately reduce frequency Rethink thresholds for biopsy and communicate risk better Biopsy is recommended BIRADS 4 (3-95% risk either DCIS or IDC) Recognize that indolent cancers are more often detected Start screening with risk assessment Identify highest risk patients prevention counseling Level 1 evidence for Tamoxifen, Raloxifene: sporadic risk Level 2 evidence for prophylactic surgery: BRCA carriers Consider reclassification of lower grade DCIS as high risk lesions year trajectory for progression

14 ATHENA Breast Health Network: A University of California initiated system-wide demonstration project DATA IN Web based Patient Surveys Automated Risk Assessments Risk Models/Web Services Molecular Tests Disease Staging Treatment Decisions Outcomes PATIENTS AND PARTICIPATING SITES RESEARCH/QUALITY IMPROVEMENT Biomarker Discovery Biomarker Validation Biospecimen Repository Comparative Effectiveness Research Strategies for Personalized Medicine Evidence-based Management 54 KNOWLEDGE OUT Personalized Risk Profile Personalized Biopsy Benefit Personalized Breast Cancer Treatment Options Options for Risk-based Trials Connection to BreastCancerTrials.org Patient Survey Data Patient Report - Summary of inputs - Summary of risk (TBD) Overview of Athena Risk Assessment Process Breast Cancer Risk Assessment Models Web Services Risk Estimates -risk categories and referrals PCP Report - Summary of risk - Recommendations for follow-up Web-based Decision Aid Breast Health Specialists Risk Assessment Models Web services provide automated risk assessments for 4 validated models: Biological risk factors Gail model (atypia/adh, reproductive factors) BCSC Density model Hereditary risk factors Claus risk model BRCApro model 14

15 Risk Assessment and Patient Preferences Should Drive Prevention Decisions Top 10% of the NHS as compared to the lowest 10% had close to a threefold increase in risk. Rockhill JNCI

16 Next Steps for Improving Outcomes for Women with High Risk Cancers Women who present with palpable cancers, locally advanced disease need better treatment options We need to focus on patients with the worst outcomes, at a time when their disease is curable Find the right drug, for the right patient, at the right time... NOW I-SPY 2 TRIAL is one model Metastatic setting PHASE 2 PHASE 3 Years Chemo Follow-Up Period Chemo Surgery FINDINGS Surgery Adjuvant Setting Neoadjuvant Approach: 1 year knowledge turn APPROVAL 62 I-SPY 2 Adaptive Trial Design Screening MRI Biopsy Blood Draw MUGA/ECHO CT/PET R A N D O M I Z E O N S T U D Y Consent #2 Treatment Consent Paclitaxel * (12 weekly cycles) Paclitaxel* + Investigational Agent A (12 weekly cycles) Paclitaxel* + Investigational Agent B (12 weekly cycles) MRI Biopsy Blood Draw MRI Blood Draw AC (4 cycles) AC (4 cycles) AC (4 cycles) * HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab. MRI Blood Draw S U R G E R Y Tissue Five Critical Components: Neoadjuvant Setting Molecular and Imaging Biomarker Guidance Multiple Drugs Tested Simultaneously Common Platform for Sharing Data Adaptive Trial Design THE GOAL: Find failures and successes early, accelerate approval for successful agents biomarker pairs 16

17 I-SPY 2 Participating Sites What Messages Should We Deliver to the Public? WHAT SHOULD WE TELL WOMEN? 67 Screening is but one of the tools to reduce mortality from breast cancer Risk assessment and risk reduction Know your family history, your risk factors, and options for prevention Lifestyle Maintaining a BMI < 25% Regular exercise Know your body and what your breasts feel like 50% of women find their own cancer Don t ignore a new mass even if you had a recent normal mammogram Know you have options and can discuss risks and benefits: Screening between the age of 40-50, over 70 or 75 Recommendation for a biopsy for BIRADS 4 A diagnosis of DCIS or invasive cancer Know that you have time to consider your options Ask about participating in clinical trials (breastcancertrials.org) 68 Vision for Moving Forward Develop and use tools to discriminate cancers with high vs. low risk for metastasis Redefine cancer : develop and validate tools for ultralow risk Rename non-life threatening cancers IDLE tumors Reduce treatment interventions for minimal risk disease For high risk disease, find more effective systemic therapy Provide better information to women undergoing screening Avoid screening populations where there is little or no benefit Reconsider threshold for recommending biopsy Focus on Prevention as well as Screening Screening should include tools to identify patients at risk for developing aggressive disease, and offer preventive interventions Undertake large scale demonstration projects ATHENA Identify risk factors for specific tumor types Integrate the process of clinical care and research!!! 69 17

18 I will adopt the USPSTF guidelines in my practice A. True B. False 74% 26% There is value in routine screening for breast cancer risk assessment A. True B. False A. B. 70 0% 0% 10 A. B. Countdown 71 18