Disclosure information: Update in Breast Cancer Screening Karla Kerlikowske, MDDis Update in Breast Cancer Screening Grant/Research support from: National Cancer Institute and Grail - and - Karla Kerlikowske, MD Professor of Medicine and Epidemiology and Biostatistics, UCSF Primary care physician at San Francisco VA December 8, 2017 Outline Screening mammography based on age When to start How often to screen When to stop Risk-based screening Screening women with dense breasts Screening women with MRI Evaluation of breast pain When to start screening mammography ACR, SBI, ACOG -- starting at age 40 ACS -- start at age 45 USPSTF, CDC, AAFP start at age 50 Most European countries and Canada start age 50
Measures of benefits and harms Benefits Relative reduction in breast cancer mortality Deaths averted from cancer or NNS to avert a cancer death Gain in life expectancy Harms Discomfort, cost, anxiety, inconvenience of screening test False-positive imaging and invasive follow-up testing Detection/treatment of biologically insignificant lesions Data sources, guideline grading system, member composition, value placed on benefits vs. harms Meta-analyses of screening mammography trials -- film Age RR (95% CI) NNS* 39-49 0.92 (0.75-2) 3333 50-59 0.86 (0.68-0.97) 1300 60-69 0.64 (0.45-0.92) 470 70-74 0.80 (0.51-1.28) 800 All cause 0.99 (0.97-02) mortality *Number women screened for 10 years to avert a breast cancer death Myers et al, Jama, 2015; Nelson et al, Ann Intern Med, 2016 Advanced disease reduced in screened women ages >50 Ages 39-49 Ages >50 BCSC outcomes per 10,000 digital screens Outcomes 40 49 50 59 60 69 70 74 False-positives 1,212 932 808 696 (false alarms) No. biopsies per 100 60 30 30 invasive breast cancer diagnosed False-negatives 10 11 12 13 (missed cancers) Invasive cancer 22 35 58 72 DCIS 16 18 21 23 Nelson et al, Ann Intern Med, 2016 Nelson et al, Ann Intern Med, 2016
Overdiagnosis & overtreatment from screening mammography Cases not clinically detected in the absence of screening because of lack of progression or death from other causes Canadian National Breast Screening Studies 22% of invasive cancers 37% invasive + DCIS CISNET 12% of detected cases Model estimates of biennial digital screening mammogram effectiveness Age Deaths Benign False Overdiagaverted* biopsy* positives* nosis* 50-74 7.0 146 953 19 40-49 58 576 2 *per 1,000 women screened biennially Miller et al, BMJ, 2014; Mandelblatt et al, Ann Intern Med, 2016 Mandelblatt et al, Ann Intern Med, 2016 Model estimates of biennial digital screening mammogram effectiveness Biopsy/death FP/death Age averted averted 50-74 21 136 40-49 58 576 *False positive = FP ACS rationale for starting screening at age 45 Observational studies 20-40% reduction in breast cancer mortality Breast cancer mortality similar 45 vs. 50 40-44 -- 13.2 per 100,000 45-49 -- 20.6 per 100,000 50-54 -- 30.8 per 100,000 55-59 -- 4 per 100,000 Harms higher in women 40-44 vs. 45-49 Mandelblatt et al, Ann Intern Med, 2016 Oeffinger et al, Jama, 2015
How often to screen with mammography ACR, SBI, ACOG - annual ACS - annual 45-54, biennial starting at 55 USPSTF, CDC, AAFP - biennial 50-74 Most European countries biennial; Canada q2-3; United Kingdom q3 Potential harms of screening; false-positive mammogram and biopsy, overdiagnosis Model estimates of digital screening mammogram effectiveness by interval Age & Interval Deaths* averted Benign biopsy* Falsepositive* Overdiagnosis* 50-74 y 1 y 9 228 1,798 25 2 y 7 146 953 19 40-49 y 1 y 99 1,143 5 2 y 58 576 2 *per 1,000 women screened over screening period Mandelblatt et al, Ann Intern Med, 2016 Risk of late stage disease with 2 vs. 1 year screening interval Late Tumor Factor stage >15mm 40-49 +17% +10% 50-59 -2% +9% 60-69 -1% +13% Premenopausal +28%* +21%* Postmenopausal -5% +11%* *P< 0.05 Lifetime risk of breast cancer death Deaths Risk % averted Overall 2.70 50-74 biennial 0 7 40-74 biennial 1.88 8 45-49 annual, 50-74 1.90 8 biennial 0.47 ( 0.14-9) deaths averted per 1,000 women 40-49 - Age trial per 1,000 women screened White, JNCI, 2004; Hubbard, Ann Intern Med, 2011; Miglioretti, Jama Oncol, 2015 Kerlikowske et al, Jama Intern Med, 2015; Moss et al, Lancet Oncol, 2015 16
When to stop screening mammography ACR, SBI, ACOG -- no upper age limit ACS -- continue if life expectancy >10 years USPSTF, CDC, AAFP age 74 Most European countries and Canada stop at age 70-75 Breast cancer incidence decreases with advanced age 75-84 yo 10-year breast cancer risk 3.6%; non-breast cancer death 35% Breast cancer deaths averted per 1000 women screened Stopping ages based on comorbidities Comorbidities Ref None Mild Moderate Severe Age stop 74 76 72 70 64-66 Deaths 0.8 0.9 0.6 averted* Overdiag- 0.5 0.7 0.6 0.9 0.7 nosis* *per 1,000 women screened Mild: history of MI, acute MI, ulcer, or rheumatologic disease Moderate: vascular disease, cardiovascular disease, paralysis or diabetes, or combinations of diabetes with MI, ulcer, or rheumatologic disease Severe: AIDS, COPD, mild to severe liver disease, chronic renal failure, dementia, or congestive heart failure Lee, BMJ, 2013 Lansdorp-Vogelaar et al, Ann Intern Med, 2014
Improving Benefit-Harm Ratio with Risk-Based Screening Screening most efficient if focus on women at higher risk Increases benefits for fixed number of women Decreases harms Decreases costs Breast cancer risk used to determine Starting and stopping ages Screening frequency Screening modality BCSC model ONLINE includes strong & prevalent risk factors https://tools.bcsc scc.org/bc5yearrisk/calculator.htm Breast Imaging Reporting and Data System (BI-RADS) Population attributable fraction about 26-39% a a b b c c d d Almost entirely fat Scattered fibroglandular densities Engmann et al, Jama Oncol, 2017 Heterogeneously dense Extremely dense 5-year risk (%) for 45-49y women BCSC No Family Hx Family Hx Density 5-yr risk No bx Bx No bx Bx a.4.3.5.5.8 b 0.8 0.7 1.7 c 1.2 1.7 1.6 2.6 d 1.6 2.1 2.1 3.3 Average 5-year risk >1.4% for woman 50-54 years 16% of women 40-49 Tice et al, Ann Intern Med, 2008; Tice et al, JCO, 2015
5-year risk (%) for 50-54y women BCSC No Family Hx Family Hx Density 5-yr risk No bx Bx No bx Bx a.5.4.7 0.7 1.1 b 0.9 1.4 1.4 2.2 c 1.6 2.2 2.1 3.4 d 2.1 1.7 2.8 2.7 4.4 Average 5-year risk <1.4% 70% of women 50-54 Tice, Ann Intern Med, 2008; Tice, JCO, 2015 Deaths averted per 1000 women Deaths averted vary by risk if screen women 50-74 biennial 18 16 14 12 10 8 6 4 2 4.1 5.3 8 13.8 5.2 6.5 9.2 14.7 6.3 7.7 10.6 15.8 6.5 8 10.8 15.4 0 Almost a entirely fat Scattered b densities Heterogeneously c dense Extremely d dense BI RADS Breast Density Trentham Dietz and Kerlikowske, et al. Annals of Internal Medicine (2016) Deaths averted vary by risk if screen women 50-74 triennial Deaths averted per 1000 women 14 12 10 8 6 4 2 Fewer false-positives (21-23%), benign biopsies (13-17%), overdiagnosis (8%-20%) Deaths averted vary by risk if screen women 50-74 annual Deaths averted per 1000 women 25 20 15 10 5 More deaths averted with annual screening among women at high breast cancer risk 0 3.4 4 4.8 5.1 4.4 5.1 6 6.2 6.4 7.2 8.3 8.4 11 11.5 12.4 12 Almost entirely fat Scattered densities Heterogeneously dense Extremely dense 0 4.7 6.9 8.4 8.9 6 8.7 10.4 10.9 9.1 12.3 14.3 14.7 17.2 19.4 21 20.5 Almost entirely fat Scattered densities Heterogeneously dense Extremely dense Trentham Dietz and Kerlikowske, et al. Annals of Internal Medicine (2016) Trentham Dietz and Kerlikowske, et al. Annals of Internal Medicine (2016)
Breast Cancer Risk Factors RR= >25g alcohol/day Postmenopausal HT Nullparity or age first birth >30 Body mass index >30 kg/m 2 First-degree relative with breast cancer Hx of breast biopsy RR= Two first-degree relatives with breast cancer History of proliferative disease without atypia RR= 4.0 LCIS or ADH Trentham-Dietz and Kerlikowske, et al, Ann Intern Med, 2016 Premenopausal obesity increases risk of ER- > ER+ Body mass index, kg/m 2 ER+ ER- 18 kg/m 2 (underweight) -7% -24% 22 kg/m 2 (normal) (ref) (ref) 27 kg/m 2 (overweight) +8% +28% 32 kg/m 2 (obese/grade I) 39 kg/m 2 (obese/grade II/III) Kerlikowske, et al, JNCI, 2016 +15% +48% +21% +52% Postmenopausal obesity increases risk of ER+ and ER- Breast density notification laws enacted in 31 states Body mass index, kg/m 2 ER+ ER- 18 kg/m 2 (underweight) -21% -12% 22 kg/m 2 (normal) (ref) (ref) 27 kg/m 2 (overweight) +28% +17% 32 kg/m 2 (obese/grade I) +53% +38% 39 kg/m 2 (obese/grade II/III) +78% +72% Kerlikowske, et al, JNCI, 2016 47% of women have dense breasts (heterogeneously or extremely dense) Kerlikowske et al, Ann Intern Med, 2015; Sprague et al, JNCI, 2014
High breast density masks interval invasive tumors BCSC Risk Calculator FREE iphone & ipad app BIRADS Screen- Interval cancer* Density detected Film Digital a 1.2 0.1 0.14 b 2.3 0.6 0.33 c 3.2 0.80 d 4.2 2.2 1.11 64% of interval cancers in women with BI-RADS c or d *per 1,000 women 50-59 screened Kerlikowske, NEJM, 2007; Henderson et al, AJR, 2015 Tice J, et al., JCO, 2015 Half of women with dense breasts have low 5-year risk Percentage in 5 Year Risk Group BCSC 5 year risk % 70 60 50 40 30 20 10 0 50% of women with dense breasts have low to average risk Almost entirely fat Scattered densities Hetero. Dense Extremely dense Low: 0 1 67 38 23 19 Average: >1 1.66 23 30 28 34 Intermediate: 1.67 2.49 9 21 29 22 High: >2.5 1 11 20 25 Kerlikowske, Ann Intern Med, 2015 12/15/2017 Breast Cancer Surveillance Consortium 35 High risk, high density interval cancer rate >1 per 1000 exams Interval Cancer Rate (Per 1,000 Screens) 1.5 0.5 24% of women with dense breasts at high risk of missed cancer 0.0 Almost Scattered Hetero. Extremely BCSC 5 year risk % entirely fat densities dense dense Low: 0 1 0.14 0.21 0.63 0.72 Average: >1 1.66 0.31 0.38 0.58 0.89 Intermediate: 1.67 2.49 0.48 0.43 0.83 1.17 High: >2.5% N/A 0.90 1.49 1.48 1.62 Kerlikowske, Ann Intern Med, 2015
Examples of BCSC 5-year risk Age: 62 Race/ethnicity: White 1 st -degree relative diagnosed of breast cancer: Yes Prior breast biopsy: No Breast density: Heterogeneously dense Estimated risk for developing invasive breast cancer over the next 5 years is 3.96% The average risk for a woman the same age and race/ethnicity is 1.96% Assessment; discuss supplemental screening Alternative imaging strategies for women with dense breasts Change screening frequency Screening ultrasound -- hand held; whole breast Tomosynthesis (3D) Breast MRI Odds of late stage disease with 2 vs. 1 year screening interval Age Heterogeneously Extremely group dense dense 40-49 2 (0.93-1.88) 1.89 (6-3.39) 50-74 Dense No HT 1.21 (0.92-1.61) E+P 1.56 (0.88-2.80) E only 1.19 (0.66-2.13) Low cancer detection for women with dense breasts by ultrasound Parris Hooley Weigert Exams 5519 935 8647 Cancers 10 3 24 Biopsy rate % 3.3 5.0 5.0 Cancer rate %.18.32.28 NNS 552 312 309 Whole breast US for women with dense breasts 1.9 per 1000 exams Kerlikowske, Jama Intern Med, 2013 Hooley, Radiology, 2012;Weigert, Breast J, 2012;Parris, Breast J, 2012;Brem, Radiology, 2014
Supplemental screening ultrasound is expensive Digital mammography + ultrasound 10,000 women 50-75 dense breasts 12 rounds of screening Cost per QALY -- $338,000 Additional 3 deaths averted 3500 more false-positive biopsies NNS 3300 to avert 1 breast cancer death Sprague et al, Ann Intern Med, 2014 Cancer detection by extent of density for DM vs. DBT Digital Digital + Tomo Exams 278,906 173,414 Invasive cancer rate* Non-dense 3.0 4.0 Dense 2.9 4.2 Recall rate* Non-dense 90 79 Dense 127 109 *per 1,000 exams, P< 0.001 Biopsy rate: 18.1 vs. 19.3 Rafferty et al, JAMA, 2016 Cost-effectiveness of mammography + MRI in BRCA1/2 mutation carriers Mortality Deaths ICER reduction averted* Clinical ref ref Mammography 16.4% 87 $16,751 MRI 17.8% 95 $206,384 Mammography 22.3% 118 $69,125 + MRI MRI + mammography in other high-risk women TP53, PTEN, STK11, CDH1 mutation carrier ATM, PALB2, or CHEK2 mutation carrier with positive family history of breast cancer Women with a history of mantle radiation between ages 10 30 years *per 1000 women diagnosed with breast cancer Lee, Radiology, 2010 Esserman, NPJ Breast Cancer, 2017
Risk of breast cancer with breast pain <1% Imaging not needed Bilateral, non-focal Cyclic Age <40 Consider diagnostic mammography Non-cyclic Unilateral, focal, persistent Age >40 Summary Offer biennial screening ages 50-74 or 13 mammograms in a woman s lifetime - Consider triennial screening if low density & low to average risk - Consider annual screening if high density & risk - Stop screening before 70 for women with moderate to severe comorbidities Consider biennial screening age 40-49 if 5-year breast cancer risk >1.4%, i.e., average-risk of woman 50-54 Jokich, J Am Coll Radiol, 2017 Summary Digital mammography for most women with dense breasts Women with dense breasts at high risk of interval cancer, consider tomosynthesis or supplemental screening ultrasound BRCA1 and 2 mutation carriers, annual mammography and MRI Annual mammography if a personal history of breast cancer Breast pain rarely requires breast imaging Thank you