1. Breast Density: Black, White and Shades of Gray Jen Rusiecki, MD VA Pittsburgh Health System Women’s Health Fellow AMWA Hot Topic 2016

2. Janice Janice is a 60 year old patient of yours who comes to your office to talk to you about a notification she received in the mail. She recently had her screening mammogram done and received a letter stating that she had “heterogeneously dense breasts” and recommending she discuss supplemental screening with you. She is confused about what this means…

3. What is the next step for Janice’s breast cancer screening? A.Digital mammography with tomosynthesis B.Ultrasonography C.Magnetic resonance imaging D.Yearly screening mammography E.Further risk stratification

4. Breast Density: Why Do We Care? Breast density makes screening more complicated – Decreased sensitivity with mammography – Increased recall rates Breast density is an independent risk factor for breast cancer 40% of women 40 to 74 have dense breasts Machida. Breast Cancer. March 2015 A B CD NOT DENSE DENSE BI-RADS 5 th ed 2013 Sprague, Ann Internal Med 2015

5. Breast Density: Timely but Controversial Legislation enacted in 24 states – Requiring notification of women with dense breasts of their breast density – Additional state and federal legislation proposed – Notification also tells patients: discuss supplemental screening with physician Unclear what “supplemental screening” should be

6. BSCS Risk Score Components: – Prior cancer or DCIS history – Age – Race – History in 1 st degree relatives – Prior biopsy – Breast density 5 yr risk: – Low < 1% – Average 1 – 1.66% – Intermediate 1.67-2.49% – High > 2.5%

7. BSCS Score and Invasive Cancer BSCS Score Invasive Cancer Cases (95% CI) per 1000 Women Almost Entirely Fat Scattered Fibroglandular Densities Heterogeneously Dense Extremely Dense Low (0- 0.99%) 0.14 (0.06- 0.26) 0.21(0.14-0.31)0.63 (0.46-0.84)0.72 (0.33- 1.37) Average (1.0- 1.66%) 0.31 (0.13- 0.65) 0.03 (0.27- 0.52) 0.58 (0.44-0.76)0.89 (0.54- 1.37) Intermediate (1.67-2.49%) 0.48(0.13-1.22)0.43 (0.29- 0.61) 0.83(0.66-1.03)1.17 (0.68- 1.87) High (>2.5%)0.90 (0.62- 1.25) 1.48 (1.2-1.81)1.62 (1.08- 2.34) Kerlikowske, Annals of Inter Med, 2015

8. BCSC Score and Imaging Strategy Supplemental Imaging Discussion Interval cancer cases Discussion/Int erval Cancer All with heterogeneously or extremely dense 100,00891124 All with extremely dense16,95619892 50-74 y with extremely or 70-74 y with heterogeneously dense 13,47016842 Risk ≥1.67% and extremely dense or risk≥ 2.5% with heterogeneously 24,41235694 40-74y with extremely or 40- 49y with heterogeneously 46,412411132 Risk ≥1.67% and heterogeneously or extremely dense breast 48,72256870 Kerlikowske, Annals of Inter Med, 2015

9. Supplemental Screening Options Digital mammography with tomosynthesis Ultrasonography MRI

10. Head to Head Comparison Recall Rates: US 14% MRI 12-14% DBT 7-11% PPV: US 3% MRI 3-30% Melnikow, Annals Inter Med, 2016 Breast cancer detection rates of supplemental screening

11. Tomosynthesis Improved Mammography Performance: Friedewald et al Rates per 1000 cases Digital Mammography Alone Digital Mammography + Tomo Percent Change P value Recall10689-17<0.001 Biopsy18190.90.004 Cancer Detection 4.35.51.2<0.001 Invasive Cancer2.94.11.2<0.001 DCIS1.4 00.95

12. Supplemental Digital Mammography with Tomosynthesis Advantages – Decreased recall rate – Increase in cancer detection rate – Improved positive predictive values for recall and biopsy – Cost effective Disadvantages – May increase radiation dosage patient receives – May require new equipment/training for techs and radiologists Friedewald. JAMA. 2014 Lee. Radiology. 274(3) McCarthy JNCI. 2014

13. Supplemental Ultrasonography Potential Advantages – Non-invasive – Low risk procedure for patients (no radiation) – Minimal improvement in screening with additional gains in cancer deaths and QALYs compared to mammography alone Disadvantages – Cost effectiveness data: >$100,000 per QALY gained – High false positive rate – Low positive predictive value Sprague. Annals of Internal Medicine 2015

14. Supplemental MRI In average risk women, no studies address MRI in women with dense breasts specifically – In contrast to women with increased risk (Gail score >20%) in which MRI is recommended High false positive rate, low PPV Expensive Requires contrast which may be poorly tolerated by patients Freer, Breast Imaging, 35(2)

15. Clinical Recommendations Breast density alone should not prompt the need for supplemental imaging Screening mammogram at age 40 (or 45) and calculate BSCS Score Dense breast: – If score >1.65% and extremely or >2.5% and heterogeneously dense breast discuss supplemental screening with tomosynthesis Normal breast density: – Engage in shared decision making about further screening frequency – Screening mammogram at age 50 and continue every other year Ultrasonography and MRI are not cost effective with high false positives and low PPV

16. What is the next step for Janice’s breast cancer screening? A.Digital mammography with tomosynthesis B.Ultrasonography C.Magnetic resonance imaging D.Yearly screening mammography E.Further risk stratification

17. What is the next step for Janice’s breast cancer screening? A.Digital mammography with tomosynthesis B.Ultrasonography C.Magnetic resonance imaging D.Yearly screening mammography E.Further risk stratification

18. Acknowledgments Dr. Rohr-Kirchgraber Dr. McNeil Drs. Karmo and Mieczkowski

19. Breast Density: Prevalence and Risk BI-RADS BREAST DENSITY PREVALENCE (PERCENT) RELATIVE RISK FOR BREAST CANCER Age <50Age >50Age <50Age>50 Almost entirely fat 4.310.20.490.59 Scattered fibroglandular densities 34.349.0 1.00 (reference) 1.00 (reference) Heterogeneously dense 47.035.51.551.46 Extremely dense 14.45.32.001.77 Sprague, Ann Internal Med 2015

20. USPTSF Guidelines 2015 Current evidence is insufficient to assess the benefits and harms of adding tomosynthesis to conventional screening mammography For women with radiologically dense breast, current evidence is insufficient to assess the benefits and harms of adjunctive ultrasound, MRI or tomosynthesis

21. States with Mandatory Notification

22. Head to Head Comparison Supplemental Imaging Mode SensitivitySpecifyPPVCancer Detection (per 1000 women) Recall Rates Ultrasound80-83%86-94%0.034.414% MRI75-100%78-94%0.03-0.333.5-28.612-14% Tomosynthesis93%*70%*0.35*5.4-6.97-11% *Gilbert, TOMMY Trial, Radiology 2015Melnikow, Annals of Int Med, 2016*Gilbert, TOMMY Trial, Radiology 2015Melnikow, Annals of Int Med, 2016

23. Ultrasound vs MRI Sensitivity: US 80-83% MRI 75-100% Specificity: US 86-94% MRI 78-94% PPV: US 0.03 MRI 0.03-0.33

24. Tomosynthesis Improves Mammography Performance European prospective studies (Skaane et al & Ciatto et al) – Improved invasive cancer detection – Reduced false positive rate – Reduced recall rate Observational studies in United States (McDonald et al) – Reduced recall rate – Recalled patients were more likely to have invasive cancer