Current Strategies in the Detection of Breast Cancer Karla Kerlikowske, M.D. Professor of Medicine & Epidemiology and Biostatistics, UCSF
Outline ν Screening Film Mammography ν Film ν Digital ν Screening MRI ν Screening ultrasound ν CBE ν BSE
Rank of Clinical Preventive Services CPB CE Total ν Tobacco cessation 5 5 10 ν Colorectal cancer 4 4 8 ν Hypertension 5 3 8 ν Influenza 4 4 8 ν Pneumococcal 3 5 8 ν Cervical cancer 4 3 7 ν Breast cancer 4 2 6 Maciosek, Am J Prev Med,, 2006
Screening Mammography ν Radiological examination to detect unsuspected breast cancer ν Limited to CC and MLO views ν For ASYMPTOMATIC women ν Separates women into low and high probability of cancer ν Further studies needed when abnormality is identified
Screening Mammography Report Assessment Negative Benign finding Needs additional imaging tests Suspicious Malignant % Exams Risk cancer 93.9 0.1% 5.6 5-10%.4 50%.1 100%
Potential Benefits Prevent deaths from breast cancer Detection of tumor earlier opportunity for less toxic treatment improved cosmesis Decrease overall mortality
The efficacy of screening mammography to reduce breast cancer deaths in women 40-49 49 compared to women 50-69 is? 1. Similar 2. Higher 3. Lower 5 73% 14% 14% Similar Higher Lower
Meta-regression of Women Aged 40 to 49 16% reduction in breast cancer mortality among screened women at 10-12 12 years
Efficacy of Mammography for Women 40 to 49 after 10-16 16 years Mortality Reduction United Kingdom Mammography 0.83 (95% 0.7-1.04) Usual care ref Canadian Mammography + CBE 1.06 (95% 0.8-1.40) Usual care ref Moss, Lancet, 2006; Miller, Ann Intern Med, 2002 Number needed to screen for 10 years-- 2500 to avert 1 breast cancer death
Case-Control Control Studies in U.S. Communities Women 40-49 49 Mortality Reduction Elmore (2005) Mammography 0.92 (95% 0.8-1.13) within 3 yrs of dx Usual care ref Norman (2007) Mammography 0.89 (95% 0.7-1.40) within 2 yrs of dx Usual care ref
Meta-regression of Women Aged 50 to 74 30% reduction in breast cancer mortality among screened women at 5 years Number needed to screen for 20 years-- 270 to avert 1 breast cancer death
Cumulative Breast Cancer Mortality in Screened vs Non-screened Aged 70-74 Mortality per 1000 person-years 8 7 6 5 4 3 2 1 0 Unscreened ο ο ο ο ο ο ο ο ο Screened 1 2 3 4 5 6 7 8 9 10 Time (years) ο
Invasive Cancer & DCIS Incidence & 160 140 120 Breast Cancer Mortality, 1973-2003 Invasive per 100,000 100 80 60 40 Screening 24% decrease in breast cancer mortality from 1990-2003 Treatment 20 DCIS 0 19731976197919821985198819911994199720002003 Year Mortality
Five-Year Breast Cancer Survival Rates in U.S. by Stage Stage Localized Regional Distant <50 50+ <50 50+ <50 50+ 1983-90 90 90.8 95.6 70.6 74.6 20.9 17.8 1996-02 95.3 98.9 82.4 83.5 32.5 23.7 SEER, 2006
Screening & Treatment Decrease Breast Cancer Mortality 1990 2003 Number women 100,000 100,000 Number deaths 33.1 25.2 Deaths averted Screening 4.0 Treatment 4.0 Berry, NEJM, 2005 About 2300 fewer breast cancer deaths in 2006 vs. 1999
Total Mortality in Swedish Trials Age 40-49 50-59 60-69 70-74 after 16 years of Follow-up RR (95% CI) Δ per 100,000 1.0 (0.95-1.06).95 (0.92-0.98) 0.98) 53.94 (0.91-0.97) 0.97) 146 49 1.0 (0.95 59.95 (0.92 69.94 (0.91 74.99 (0.91-1.07) 1.07) Nystrom, Lancet,, 2002
How often should women aged 50-69 years should undergo mammography? 1. Every year 2. Every 1-21 2 years 3. Every 2 years 4. Every 3 years 5 42% 39% 16% 3% Every year Every 1-2 years Every 2 years Every 3 years
Biennial vs. Annual Mammography & Proportion of Late Stage Disease Interval 40-49 49 50-59 59 60-69 69 70-79 79 1 year 21% 21% 17% 14% 2 year 28% 22% 16% 13% White, JNCI, 2004 10-year survival rates 90.4% for annual & 89.2% for biennial Wai, Br J Cancer, 2005
Patient Characteristics Influence Breast Cancer Detection
HT Increases Rate of Breast Cancer and Advanced Stage Invasive Breast Cancer Advanced Disease Cancer Screen- Non-screen rate detected detected Groups per 1,000 screening exam No HT 4.3 0.77 0.30 Estrogen only >5y 4.0 0.75 0.38 Estrogen/progestin >5y 6.5* 1.07* 0.74* *P< 0.05 Kerlikowske,, JCO, 2003 Increased rate of ER-positive invasive cancer among women taking E+P >5y
Trend of HT and Breast Cancer 10 9 8 7 6 5 4 3 2 1 0 HT use 13% annual decrease in ER-positive breast cancer from 2001-2003 ER Positive ER Negative 1997 1998 1999 2000 2001 2002 2003 2004 Year of Screening Mammogr 500 400 300 200 100 0 Rate of HT Use per 1,000 Mammograms Kerlikowske, JNCI,, 2007
BI-RADS BI-RADS 1 Almost entirely fat 8.7% BI-RADS 2 Scattered densities 47.4% BI-RADS 3 Heterogeneously dense 38.6% BI-RADS 4 Extremely dense 5.2%
Rate of cancer per 1,000 screening exams increases with high breast density -- 50-59y Screen Non-screen BIRADS detected detected 1 1.5 0.1 2 3.4 0.6 3 4.5 1.3 4 4.2 2.2 Kerlikowske, NEJM,, 2007 Higher risk of advanced disease in women with BI-RADS 4 density
Performance of Screening Mammography by Family History Measure Family Hx+ Family Hx- Cancer/1000 exams 6.1 4.0 Sensitivity % 77.7 81.7 Abnormals % 12.7 10.8 Biopsies/1000 exams 16.0 13.1 Kerlikowske, Ann Intern Med, 2000
Potential Consequences of Undergoing Screening Mammography
What is the chance a woman will have an abnormal result after 10 screening exams? 1. 5% 2. 12% 3. 30% 49% 31% 20% 5% 12% 30%
ν ν ν ν ν Potential Consequences False positives multiple work-ups in healthy women creates anxiety morbidity from invasive procedures more likely to undergo repeat screening & perform BSE Detection of biologically insignificant lesions results in unnecessary surgery & radiation Rate of treatment higher in screened women results in 25-35% more surgery and radiation Intense pain with breast compression - 10-15% 15% Radiation induced cancer 1 per 10,000 women screened annually for 10 yrs
Performance of Screening Mammography by Age Measure 40-49 49 50-59 59 60-69 69 70-79 79 Positive % 8.5 7.8 7.0 6.1 PPV % 1.8 3.3 4.0 6.0 Sensitivity % 69 75 78 80 Yankaskas,, Radiology, 2005
Mammography Outcomes After 10yrs of Annual Screening AGE 40 50 60 Positive % 30 26 23 False-positive % 28 23 20 Biopsy % 7.5 10 10 Kerlikowske, JNCI,, 1997
Factors Influence Risk of False-Positive or Negative Mammography Test False positive > 3 breast biopsies Family history E+P hormone use No comparison films > 2 years since last screen Obesity False negative > 3 breast biopsies E+P hormone use High breast density Breast implants Younger age Rapid tumor growth Christiansen, JNCI,, 2000; Banks, BMJ,, 2004
Sensitivity of Digital vs Screen-Film N Digital Film < 50 yr % > 50 yr % 72 262 67 52 44 54 Premenopausal % Postmenopausal % 100 234 65 51 43 56 Dense % Nondense % 165 169 57 53 44 59 N Engl J Med 2005; 353: [10/27/05]
Annual volume 480-750 750-1000 750-1000 2500-4000 Higher Specificity if Interpret High Volume of Exams Focus on SM False-positives 12.9% 11.5% 7.6% 6.8% 750 Low 12.9% 1000 Low 11.5% 1000 High 7.6% 4000 High 6.8% Smith-Bindman Bindman,, JNCI, 2005
Invasive Cancer & DCIS Incidence & Breast Cancer Mortality, 1973-2003 160 140 120 Invasive per 100,000 100 80 60 40 Screening 1 in 1300 screening exams diagnosed with DCIS 20 DCIS 0 19731976197919821985198819911994199720002003 Year Mortality
Data Suggesting DCIS of Low Malignant Potential ν ν ν ν 15% of lesions progress to invasive cancer over 10 years Risk of death 1% to 2% over 10 years with all types of treatment Prevalent among women who die of other causes (~15%) Breast cancer incidence has not decreased in relation to increase in DCIS
Screen-detected DCIS and Invasive cancer per 1,000 exams increase with age Age 40-49 50-59 60-69 70-84 DCIS Rate* Invasive cancer Rate* 1.4 49 0.56 1.4 59 0.68 2.9 69 1.03 4.0 84 1.07 5.6 *Per 1000 screens
Risk of Invasive Cancer & DCIS after 10yrs of Screening AGE 40 50 60 Invasive cancer % 1.5 2.4 3.4 DCIS % 0.5 1.0 1.2 Kerlikowske, JNCI, 1997
70 yo women with DCIS not likely to die of breast cancer in next 10y Risk of Death in 10 years Breast Cancer Other Mammography 1.2% 25.2% Low grade DCIS 0.8% 25.6% High grade DCIS 2.0% 25.2% Kerlikowske, JNCI, 2003
The benefits of mammography outweigh the harms for women aged? 1. 50-69 years 2. 40-69 years 3. 40 and older 4. 40-79 years 67% 21% 4% 8% 50-69 years 40-69 years 40 and older 40-79 years
Cost-effectiveness of Screening Age Group Cost/yr of life saved 40 to 49 $150,000 50 to 69 $21,400 70 to 79 $73,900 Cost-effective < $50,000 Salzmann & Kerlikowske, Ann Intern Med,, 1997 & Kerlikowske, JAMA,, 1999
Current Status of Screening Mammography Recommendations ν Most major U.S. organizations (ACS, ACR, NCI, AMA, USPSTF) recommend screening starting at age 40 ν Canada and most European countries recommend or have organized programs that start screening at age 50 and stop at age 69 ν No upper age limit for most U.S. organizations (ACS, ACR, NCI, USPSTF)
Recommendations by USPSTF ν Screening mammography, with or without clinical breast examination, every 1 to 2 years for women aged 40 and older. B recommendation ν The precise age at which the benefits from screening justify the potential harms is a subjective judgment & should take into account patient preferences. Clinicians should inform women about the potential benefits (reduced chance of dying of breast cancer), potential harms (eg, false-positive results, unnecessary biopsies), & limitations of the test that apply to women their age. Humphrey, Ann Intern Med, 2002
Recommendations for Women 40-49 ν ACP: For women aged 40-49, 49, the evidence that screening mammography reduces mortality from breast cancer is weaker, and the absolute benefit of mammography is smaller, than it is for older women ν Inform women of benefits and harms ν Periodically assess risk of breast cancer ν Decision to screen based on potential benefits and harms, patient preferences, and risk profile Qaeseem,, Ann Intern Med, 2007
Women at high risk of breast should undergo which screening tests? 1. Mammography, clinical breast examination (CBE), ultrasound 2. Mammography and ultrasound 3. Mammography and MRI 4. Mammography, CBE and MRI 34% 9% 17% 40% 1 2 3 4
Screening Mutation Carriers with MRI Mammo Sono MRI CBE All Sensitivity % Specificity % 36 99.8 33 96.0 77 95.4 9.1 99.3 95 97 Sensitivity higher for MRI than mammography (71-100%), specificity lower Negative LR for mammography + MRI lower than mammography alone Warner, JAMA,, 2004; Warner, Ann Intern Med,, 2008
ACRIN Trial 6666 ν High risk asymptomatic women with dense breasts ν Mammography + Ultrasound ν Independent readings ν N= 41 breast cancer ν PPV mammography -- 7.6% (21/276) ν PPV ultrasound -- 3.6% (12/337) ν PPV mammo + ultrasound -- 1.8% (8/436) Berg, JAMA,, 2008
MRI Testing Does Not Affect Survival in Early Stage Invasive Cancer or DCIS Mammography Mammography + MRI 8-year outcomes % % Local recurrence 4 3 Overall survival 87 86 Breast cancer 95 94 survival Contralateral 6 6 Solin, JCO,, 2008
Average-risk risk women should undergo which breast examinations in addition to mammography? 1. Clinical breast examinations (CBE) 2. Breast self examinations (BSE) 3. CBE and BSE 4. None of the above 12% 11% 55% 21% 1 2 3 4
Clinical Breast Exam & Mammography CBE Mortality Reduction YES 20% NO 24% Sensitivity of CBE only 22% Kerlikowske, JAMA,, 1995; Fenton, JNCI Monogr,, 2005
Outcomes From Screening with CBE AGE 40-49 49 > 50 False-positive 1 exam 6.0% 2-3.5% 5 exams 21% 11% 10 exams 34% 19% Elmore, NEJM,, 1998
Canadian Screening Mammography Trial in Women 50 to 59 mammo + CBE CBE Invasive cancer 622 610 DCIS 71 16 Tumor < 20 mm 53% 40% Node positive 31% 35% Breast cancer deaths 107 105 RR= 1.02 Miller, JNCI,, 2000
Clinical Trials of Breast-Self Exam China Russia UK No. women 266,064 122,471 190,496 Age (y) 31-64 40-64 40-49 49 Follow-up (y) 12 15 14 Breast cancer RR= 1.04 RR= 1.0 RR=.99 mortality 2-fold more benign biopsies in screening than control group
Maximize Chance of Benefit & Minimize Chance of Harm ν Inform women of potential benefits and consequences of breast cancer screening ν Mammography at high volume facility ν Screen every 2 years from 50-69 or ten mammograms in woman s s lifetime ν Consider CBE in women 50-69 who refuse mammography ν Stop mammography screening at age 70, consider CBE if request ongoing screening ν Sufficient evidence to not recommend BSE
Additional Recommendations ν Annual screening for women aged 40-49 49 who choose to undergo mammography ν Digital mammography may be more accurate in those aged 40-49, 49, premenopausal or with dense breasts ν Mutation carriers may benefit from both MRI & mammography ν Ultrasound is not a recommended test for screening for breast cancer
Thank You