BREAST CANCER SCREENING 2012Nagi Khouri MD Associate Professor of Radiology and Oncology

Topics to be Addressed

Mammography and Controversies Other Screening Modalities Personalized Strategy for Screening Emerging Technologies

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BREAST CANCER STATISTICS USA 2011 288,130 New Cases 230,480 Invasive Cancer 57,650 DCIS 1 out of 8 Women 33% of All Female Cancers 39,520 Deaths from Breast Ca 2nd Most Common Cause of Cancer Deaths 2,140 Breast cancers in Men ( 0.8% )

BREAST CANCER IN THE WORLD

Third Most Frequent Cancer 800 Thousand in 1990 1.5 Million in 2010 Highest in N. America, W. Europe,Australia Increasing in Africa, Asia, and Middle East

BREAST CANCER RISK FACTORS Being a Woman Increasing Age Family History Hormonal Factors Biopsy Proven High Risk Tissue 2-4x Prior Personal History Breast Ca >4x

AGE DISTRIBUTION OF NEW BREAST CANCERS USAAge < 30 30-39 40-49 50-59 60-69 70-79 % In Situ 0.2 3.8 22.6 28.2 20.6 18.1 % Invasive 0.5 5.0 16.8 23.0 20.4 21.6

80+ Total

6.3 100

12.8 100

AGE DISTRIBUTION OF NEW BREAST CANCERS

Age < 30 30-39 40-49 50-59 60-69 70-79

USA 0.5% 5.0 16.8 23% 20.4 21.6

LEBANON 3.4 16.7 29.1 27 16 7 100%

80+ Total

12.3 100%

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CUMULATIVE SURVIVAL BY TUMOR SIZE WOMEN 40 74. W-E TRIAL

Tabr,L., T. Tot, P. Dean Chapter 6 Breast Cancer: The Art and Science of Early Detection with Mammography New York Thieme 2005 p.174 Reprinted by Permission

CUMULATIVE SURVIVAL BY NODE STATUS WOMEN AGED 50 59 W-E TRIAL

Tabr,L., T. Tot, P. Dean Chapter 6 Breast Cancer: The Art and Science of Early Detection with Mammography New York Thieme 2005 p.183 Reprinted by Permission

SCREENING MAMMOGRAPHY

The Best Method for Early Detection Two Views Low Dose X-Ray to Look at Internal Structure of Breasts 10% of Women Need Additional Views 10-40% of Cancers not Detectable - Breast Density Factors Yearly after age 40

Advances in MammographyCourtesy Lawrence W. Bassett, MD

1940

1965

1973

1990 1976 1988 2006

SCREENING MAMMOGRAPHY PROVEN BENEFITS

Evidence Based on Randomized Controlled Trials Involving 500,000 Women Variable Study Design (Age, Views, Interval and Duration) Mortality Reduction 25-30% at 5-7 Years

Evidence for Screening Mammography ( The Saga ) HIP Study 1963-1969: 23% Mortality Drop BCDDP Study 1973-1979: Benefit in 280K 5 Swedish Trials 1976- 1988: 31% Mortality Drop Canadian Trial 1992: No Benefit Prescreened by PE: 4x Adv. Brst Ca in Study Gp Quality of Mammography and Interpretation

Evidence for Screening Mammography ( The Saga)

1997- NCI and ACS Conferences and Statements 2000- Danish Attack- Dismissed 5/7 Trials as improper. No Benefit- Ignored Oct. 2001- New Offensive Jan. 2002- The NYT reports :NCI Panel of Advisors support Danish Review ( 9/11 members are published opponents of Screening Mammo ) March 2002 US Preventive Task Force: Screen as of 40

Evidence For Screening Mammography ( The Saga )

Edingburgh Trial : 29% Drop in Mortality UK trial: 27% Drop in Mortality Swedish Trial 20 Year FU: 32% Drop in Mortality In USA Mortality Rate has Dropped 30% in Past 20 years ( 2% per Year )

RCT may Underestimate the Average Benefit for an Individual Woman 40-50%

Benefit Underestimation in RCT

Improvement in Mammographic Techniques Improvement in Mammographic Interpretation Compliance and Contamination Prevalence Screen Number of Screening Rounds Length of Follow-up Length of Screening Intervals

US Preventive Services Task Force (USPSTF) Mammographic Screening Recommendations

Against routine screening for women 40-49, only higher risk, pt.values, benefits and harms Every other year screening for women 50-74 Insufficient evidence for screening women >74 Insufficient evidence to recommend CBE Discourage breast self examination Annals of Internal Med. 2009;151:727-737

ACS, ACR, SBI Mammographic Screening Guidelines Annually beginning at age 40 Earlier annually if premenopausal breast Ca in first degree relative ( 5-10yrs ) Annually if developed Breast Ca Annually after Dx of ADH, LCIS Annually if received chest radiation btx ages 10-30, 8-10 years after RT, not before age 25 Continue as long as life expectancy is >5-7 years

Early Detection Controversies

Mammography Benefits Overated Overdiagnosis Overtreatment Mortality Reduction from Improved Treatments rather than Early Detection

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Overdiagnosis and Overtreatment Screening for cancer may lead to earlier detection of lethal cancers but also detects harmless ones that will not cause death or symptoms The detection of such cancers, which would not have been identified clinically in someones remaining lifetime, is called overdiagnosis and can only be harmful to those who experience it. As it is not possible to distinguish between lethal and harmless cancers, all detected cancers are treated. Overdiagnosis and overtreatment are therefore inevitable

Effect of Three Decades of Screening Mammography on Breast-Cancer IncidenceArchie Bleyer, M.D., and H. Gilbert Welch, M.D., M.P.H. N Engl J Med 2012; 367:1998-2005 November 22, 2012

Effect of Three Decades of Screening Mammography on Breast-Cancer IncidenceConclusions Despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer. Although it is not certain which women have been affected, the imbalance suggests that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers, and that screening is having, at best, only a small effect on the rate of death from breast cancer.

Overdiagnosis in publicly organized mammography screening programs: systematic review of incidence trendsKarsten Juhl Jorgensen, Peter Gotzche: BMJ 2009

Overdiagnosis in publicly organized mammography screening programs: systematic review of incidence trends

Overdiagnosis was estimated at 52%, if DCIS is included, 35% for invasive carcinoma. The increase in incidence of breast cancer was closely related to the introduction of screening. One in three breast cancers detected in a population offered organized screening is overdiagnosed.

Rapid responses (4)

Screening borrows cases from the future and finding ductal carcinoma in situ prevents more aggressive breast cancers later. Leaving low-grade nonaggressive DCIS has been shown by Saunders and Page to be associated after 30 years with a cancer rate of 60% and the death rate from metastatic breast cancer of 18%

Gotzsches own country of Denmark, which lacks an organized breast cancer screening program, has the highest death rate from breast cancer in the western world.

Cancer, Detected, Diagnosed, Treated

Localized Cancer treated with high likelihood of cure (The smaller and lower stage the better the outcome) Aggressive Cancer will not do well regardless of size and stage DCIS treated, prevented from progressing Low Grade DCIS that will never progress to lethal Ca

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Limitations of Mammography

Limited Sensitivity of 60-90% related to Breast Density Masking of Cancers by Overlying Tissue in Dense Breasts Masking of Subtle Cancers in Not-so-Dense Breasts Poor Contrast between some Cancers and Surrounding Parenchyma False Positives from Overlapping Tissues

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Dense Breasts

By definition >50% fibroglandular tissue Scattered FG tissue to Extremely Dense is a spectrum- No sharp demarcations Sensitivity of mammography decreased to 50-70% 50-60% of women qualify as having dense breasts Increased density itself is a risk factor for breast cancer

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WHOLE BREAST ULTRASOUND SCREENING

Screening US Single Center Studies

Six series: 42,838 Examinations 150 Breast Cancers ( 0.35 %) 6% DCIS 94% Invasive - 70% less than 1cm 86% node-negative Higher risk women at 2-3x higher prevalence

Berg WA. Rad. Clin. NA 42 (2004) 845-851

SCREENING ULTRASOUND ACRIN 6666

2809 women with non-fatty breasts, participated, years 1-3 Elevated risk, median age 55 53% had personal history of breast cancer 43% had a family history of breast cancer 3% had atypia on a biopsy 1% had BRCA 1 or 2 mutation

CANCER DETECTION ACRIN 6666

110 women diagnosed with cancer 21% DCIS (23) , 79% Invasive carcinoma (87) 18% of those staged (12/66) were node positive 20% detected by mammography and US, 22 29% detected only by mammography, (32) 27% detected only by ultrasound (30) 24% detected by neither, 26, ( 50% seen on MRI) 8/26 (7%) had interval cancers, presenting clinically

SCREENING ULTRASOUND ACRIN 6666

Experienced specialized breast imagers Mean examination time 10 to 20 minutesINCREMENTAL CANCER DETECTION RATE 4.2 PER THOUSAND WOMEN SCREENED

CANCERS DETECTED ONLY ON ULTRASOUND ACRIN 6666

30 cancers 93% (28/30) were invasive Median size 10 mm ( 2-40 mm) 1/24 had positive node

False Positive ACRIN 6666 - Year 1 2637 participantsMammography US Only

# Participants BX

69 (2.6%)

136 (5.2%)

# Cancers

20 (29%)

12 (8.8%)

# Cyst Asp.

4 (0.2%)

43 (1.6%)

Short-term FU

59 (2.2%)

220 (8.3%)

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WHOLE BREAST ULTRASOUND SCREENING Advantages

Significantly more cancers detected in high-risk women with dense breasts Cancers detected by ultrasound only are predominantly small and usually invasive

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BREAST ULTRASOUND SCREENING Disadvantages High false-positive rate Low PPV Time-consuming Low reimbursement

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When to Consider Whole Breast US Screening?

Very High Risk Women who cannot tolerate or have MRI Intermediate Risk Women with dense breasts Average Risk with dense breasts

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AUTOMATED 3D WHOLE BREAST ULTRASOUND

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Breast Cancer Detection Automated Whole Breast Ultrasound AWBU 6425 AWBU in 4419 asymptomatic women Breast Cancer Detection doubled using AWBU with mammography from 0.36% to 0.72% 57 cancers detected, 23 on Mammo, 46 on Mammo + US Recalls 4.2% for Mammo and 7.2% for AWBU 9/11 (82%) of interval cancers were retrospectively visible on prior AWBU PPV of biopsy 38% higher than ACRINs 11%Kelly K et al. Eur Radiology (2010) 20:734-742

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BREAST MRI SCREENING IN WOMEN AT SIGNIFICANTLY HIGHER RISK

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MRI in Women at High Risk for Breast Cancer Comparative SensitivitiesAuthor, Year, Site Podo 2002, Italy Kriege 2004, Netherlands Warner 2004, Canada Kuhl 2005, Germany Lehman 2005, International Leach 2005, UK No. Ca/Screened 8/105 45/1909 22/236 43/529 4/367 33/649 Sensitivity Mammography 12.5% (1/8) 40.0% (18/45) 36.4% (8/22) US 12.5% (1/8) __ 33.3% (7/21) MRI 100% (8/8) 71.1% (32/45) 77.3% (17/22)

32.6% (14/43) 39.5% (17/43) 90.7% (39/43)25.0% (1/4) 40.0% (14/35) __ __ 100% (4/4) 77.1% (27/35)

Lehman 2007, USASardanelli 2007, Italy

6/17118/278

33.3% (2/6)

16.7% (1/6)

100% (6/6)

58.8% (10/17) 64.7% (11/17) 93.8% (15/16)

DeMartini W, Lehman C, Partridge S. Breast MRI for Cancer Detection and Characterization: A Review of Evidence-Based Clinical Application. Acad Radiol 2008; 15:408-416

MRI vs Mammography Screening in women with Familial or Genetic Predisposition Results 45 breast cancers (1CE + 4 interval Ca) 32 MRI 18 Mammo

221 DCIS

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85 DCIS

Efficacy of MRI and Mammography for Breast-Cancer Screening in Women with a Familial or Genetic Predisposition Kriege , M et al. N Engl J Med 2004; 351:427-437

Breast MRI Screening in Women at High Risk ACS, SBI, ACR Proven carriers (& relative of) BRCA1-2 mutation, by 30 Individuals at 20-25% lifetime risk, risk models based on strong family history of breast or ovarian cancer History of chest radiation btx 10-30 - 8 years after Li-Fraumeni syndrome and 1st degree relatives Cowden and Bannayan-Riley-Ruvulcaba syndromes Not currently recommended in 15-20% lifetime risk, (personal history breast or ovarian ca, ADH, ALH , LCIS)

CA Cancer J Clini 2007;53:141-169

WHOLE BREAST ULTRASOUND SCREENING vs MRI SCREENING More readily available Less expensive Better tolerated No need for intravenous injection

More time consuming for the physician Less sensitive than MRI

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Personalized Breast Cancer Screening Strategies Fatty Breasts Scattered Fibroglandular Tissue Dense Breasts Normal Risk 20-25%

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Breast Cancer Screening

Clinical Breast Examination Mammography (Digital vs. Analog) Breast Ultrasound (Handheld and/or Automated) Breast MRI

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High Lifetime Risk >20-25% CBE Mammography MRI No need for US except for second look.

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Breast Cancer Risk Assessment Models

Gail Model: http://www.cancer.gov.gov/bcrisktool/ Claus, BRCA Pro Models Tyrer-Cuzik Model: http://www.ems-trials.org/riskevaluator/

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Breast Cancer Risk Assessment The Future? The BEAM Study: Breast Estrogen and Methylation High levels of Estrogen associated with increased risk Gene Methylation refers to changes in tumor suppressor genes ( slow cell division, repair damaged DNA, cause defective cells to stop dividing)

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EMERGING MODALITIES IN BREAST IMAGING

Digital Breast Tomosynthesis ( DBT ) Contrast Enhanced Spectral Mammography ( CESM ) Molecular Breast Imaging PET of the Breast (PEM)

Limitations of Mammography

Limited Sensitivity of 60-90% related to Breast Density Masking of Cancers by Overlying Tissue in Dense Breasts Masking of Subtle Cancers in Not-so-Dense Breasts Poor Contrast between some Cancers and Surrounding Parenchyma False Positives from Overlapping Tissues

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Digital Breast Tomosynthesis

Series of low-dose images used to reconstruct tomography images at any level

Desirable Goals from Tomosynthesis

Improved Screening Sensitivity Improvement in Characterization of Lesions Improvement in Determination of Lesion Size and Extent Decrease in Recall Rates

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Variable Parameters in DBT Studies Different Manufacturers Number of Projections Angle of Tomosynthesis Number of Images obtained Post Processing Algorithms Dose

These Differences may affect Image Quality and Clinical Outcomes

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Synopsis of Breast Tomosynthesis Literature

Limited number of publications Good patient acceptance Physician preference for DBT images Improvement in characterization of lesions Cancer Visibility Higher on DBT than on FFDM Mixed opinions on calcifications evaluation Decreased recall in screening Longer physician reading time

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Images courtesy of Dr. Hak Hee Kim

Images courtesy of Dr. Hak Hee Kim

Contrast Enhanced Spectral Mammography ( CESM ) Capitalizes on Angiogenesis associated with cancer Involves bolus injection of iodinated contrast After two min. obtain 4 mammo. Views Near simultaneously obtain low and high energy images Subtraction

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Clinical CaseDense Breasts

79 years old Physical examination: 1 mass

14:01:58

Images courtesy of Dr Mizutani Mikawa Breast Cancer Clinic Miakawa-anjo, JAPAN

Pt 14

Clinical CaseDense BreastsUS: mass

MMT : IDC14:01:58 Images courtesy of Dr Mizutani Mikawa Breast Cancer Clinic Miakawa-anjo, JAPAN

Pt 14

Clinical CaseDense Breasts

14:01:58

CESM Image Lt CC 2 min.

CESM Image Lt MLO 4 min.

Images courtesy of Dr Mizutani Mikawa Breast Cancer Clinic Miakawa-anjo, JAPAN

Pt 14

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Personalized Medicine 2020 Breast Cancer (Vision) To evaluate their risk for Breast cancer, women will be offered in their early thirties a blood test or possibly a more invasive test to determine if they are at low, intermediate or high risk for breast cancer Low risk women may be offered periodic screening (every 3 to 5 years) after 50. Intermediate risk and higher risk may be offered screening annually after 35 (+/-) Mammographic screening will use state of the art 3D Tomosynthesis. Supplementary breast MRI or Ultrasound would be recommended in addition, to the higher risk women12/11/2012 86

Personalized Medicine 2020 Breast Cancer (Vision) If a cancer is diagnosed by needle biopsy, upon a discovery of an abnormality, analysis will determine whether and how to treat it, or whether it should be left for observation only. ( Preventing Overtreatment) If the cancer is to be treated, the analysis will determine what specific treatment to give with the highest response, from a variety of options ( Personalized Medicine)

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THANK YOU