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Radiological screening for Breast

Cancer
Brittany Lee, HMS IV
Dr. Gillian Lieberman
Radiology clerkship
11/07 Beth Israel
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Our patient: 54F presents for screening


mammography
 Why screen for breast cancer?
 Does screening reduce breast cancer mortality?
 How should average risk women be screened?
 When do we start screening?
 Is there a difference between digital and film
mammography?
 When is breast MR appropriate?
 Is there a role for MRI to screen the contralateral
breast in patients with a new diagnosis of breast
cancer?
 Is breast MRI better for screening high risk women?
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Screening Criteria
 The Condition
 Must be important health problem.
 Epidemiology and natural history of the disease should be adequately understood.
 Must have a detectable risk factor, disease marker, latent period or early symptomatic
stage.
 The Test
 Simple, safe, precise and validated screening test.
 Acceptable to the population
 Treatment
 The treatment/intervention for patients identified through screening must be effective
and early treatment must improve outcomes compared to late treatment.
 Agreed policy on who to treat.
 Screening program
 RCT must demonstrate that screening reduced morbidity and mortality.
 The benefit of screening must outweigh the risks/side effects from the screening.
 Facilities for diagnosis and treatment should be available.
 The total cost of finding a case should be economically balanced in relation to medical
expenditure as a whole.
 Case-finding should be a continuous process.

Wilson and Jungner


1968
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Breast Cancer Incidence and



Epidemiology
As a Public Health issue:
 In the US in 2007:
 178,480 women will be diagnosed
 40,460 women will die
 Lifetime risk of breast cancer is 1:6 overall, and 1:8 for
invasive breast cancer
 Trends
 Increasing incidence since the 1940’s is attributed to:
 Introduction of screening
 Higher lifetime exposure to estrogen
 Decreased mortality since the 1990’s is attributed to:
 ? Both screening and introduction of adjuvant therapy

Jemal et al. CA Cancer J Clin. 2007.


Brittany Lee, HMS IV
Dr. Gillian Lieberman

Early evidence for screening


Trial Location Year Age N= Median RR Absolute risk
follow-up reduction reduction

HIP* New York 1963 40-64 31,000 pairs 16 years 21% 0.14%

Two Sweden 1977 40-74 77,000 Study 17 years 32% 0.18%


Country 56,000 Control *Health Insurance Plan

 The decision to embark on national screening


programs in the US and UK were based on the RR
reduction in breast cancer specific mortality of
these two early trials.

Gotzsche and Nielsen. Cochrane Review. 200


Humphrey et al. Ann Intern Med. 2002.
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Current evidence for screening


Humphrey et al. Ann Intern Med. 2002.

 Meta-analyses of seven RCT (Edinburgh excluded)


concluded mammography reduces breast cancer
mortality rates in women age 40-74
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Relative vs. Absolute Risk


 Example: A patient with cancer is trying to decide whether to
undergo radiation treatment (XRT) to reduce their risk of a
recurrence. Besides the side effects of treatment, XRT is
cumbersome requiring treatments 5 days a week for 6 weeks. XRT
reduces the risk of recurrence by 75%!!

 A relative risk reduction of 75% is “relative” to the risk of recurrence.

 If the risk of recurrence without XRT is 20%:


 Risk of recurrence with XRT = 20% - 20% * 0.75 = 5%

 Absolute risk reduction of XRT = 20% - 5% = 15%

 If the risk of recurrence without XRT is 4%:


 Risk of recurrence with XRT = 4% - 4% * 0.75 = 1%

 Absolute risk reduction of XRT = 4% - 1% = 3%


Brittany Lee, HMS IV
Dr. Gillian Lieberman

Mammography vs. Adjuvant


Chemotherapy
Berry et al. NEJM. 2007.

 Since the variability between the models was greater


for screening than treatment, there is greater
uncertainty when estimating the benefit of screening.
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Mammography vs. Adjuvant


Chemotherapy
Berry et al. NEJM. 2007.

Reductionin
Noreductionin
mortalitywith
mortalitywith
adjuvanttx
screeningalone
alone

 Screening only has a benefit if followed by adjuvant treatment


Brittany Lee, HMS IV
Dr. Gillian Lieberman

Screening Questioned
Gotzsche and Nielsen. Cochrane Review. 2006

 Meta-analysis of the seven RCTs (same Humphrey)


 The Edinburgh trial was excluded
 Two trials were adequately randomized (“best”)
 Four trials were suboptimally randomized
 Overall RR reduction = 20%
 For the “best” trials:
 RR reduction = 15%
 Absolute risk reduction is 0.05%
 Screening leads to overdiagnosis and
overtreatment:
 RR increase = 30%
 Absolute risk increase = 0.5%
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Screening Questioned
Gotzsche and Nielsen. Cochrane Review. 2006

 Conclusion:
 For every 2000 women screened over 10
years, one will have her life prolonged and 10
healthy women will be diagnosed with breast
cancer and treated unnecessarily.

 It is not clear whether screening does more


good than harm.
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Guidelines for screening


 For average risk women with lifetime risk <15%:
 Age 40-50: clinicians should discuss the risks and benefits to
mammography screening with their patients and use
patients’ values to make an individual decision
 Age 50-70: screen with mammography every 1-2 yrs
 Age > 70: screen with mammography if life expectancy is
>10 yrs

 For high risk women with lifetime risk >20-25%:


 Includes BRCA1/BRCA2 mutations, women with a strong FHx
of breast or ovarian cancer, and women who were treated
with mantle radiation for Hodgkins lymphoma
 Screen with MRI as adjunct to mammography starting at age
40 or 10 years before the diagnosis of a first degree relative

Saslow et al. CA Cancer J Clin. 2007.


Brittany Lee, HMS IV
Dr. Gillian Lieberman

Cost-effectiveness of screening
 Age Cost per year of life saved
 40-49 $105,000
 50-69 $21,400
 >65 to 75 or 80 $34,000-$88,000

 For the 40-49 and the 50-69 age group,


screening is cost-effective
 Screening is cost-effective in the oldest
age group if the women are healthy.
Salzmann et al. Ann Intern Med. 1997
Mandelblatt et al. Ann Intern Med. 2003
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Digital vs. Film Mammography


Pisano et al. NEJM. 2005.
 Study Design:
 Prospective study: 49,528 asymptomatic women underwent
both digital and film screening mammography
 Methods:
 Mammograms were interpreted by using the BIRADS system
and malignancy scale
 Breast cancer status was ascertained by breast biopsy or by f/u
mammography at > 10 m.
 Sensitivity and specificity was calculated at 365 and 455 days.
 For malignancy scale, ROC analysis was performed.
 Results/Conclusion:
 The accuracy of digital mammography was significantly higher
than film for women < 50 yo, women with dense breasts on
mammography and pre- and perimenopausal women
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Our patient: 54F presents for screening


mammography
 Her risk factors for breast cancer:
 Gender and ethnicity
 Estrogen exposure:
 Menarche at age 11
 P2G2 with first pregnancy at age 34
 Premenopausal
 No personal history of breast cancer
 Family history of post-menopausal breast cancer
in mother and paternal aunt, not Ashkenazi
ethnicity

 By the Gail Model, her lifetime risk of BC is


17.6%
Case courtesy of Dr. Valerie Fein-Zachary
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Is mammography appropriate
screening for this patient?

 Yes, her lifetime risk is <20% and


therefore, she is average risk.
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Her mammogram is negative…


“…heterogeneously dense glandular pattern
…with punctate benign calcifications seen
bilaterally.”

BI-RADS 2
Brittany Lee, HMS IV
Dr. Gillian Lieberman

BI-RADS mammography categories

 0: Need additional imaging


 1: Negative, routine follow-up
 2: Benign, routine follow-up
 3: Probably benign finding
 Follow-up with diagnostic view of the suspicious lesion in six
months
 Probability of malignancy is 2 percent
 4: Suspicious
 Core-needle biopsy or needle localization biopsy as soon as
possible
 >2 to 95 percent risk of malignancy
 Stratified further as:
 (a) Low-risk
 (b) Intermediate-risk
 (c) Moderate to high-risk
 5: Highly suggestive of malignancy
 Core-needle biopsy or needle localization biopsy as soon as
possible
 >95 percent risk of malignancy
 6: Biopsy-proven carcinoma 
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Fletcher.
UpToDate. 2007.
Brittany Lee, HMS IV
Dr. Gillian Lieberman

4 m later, she palpates a mass in her left


breast
 Mammography is repeated:
Brittany Lee, HMS IV
Dr. Gillian Lieberman

4 m later, she palpates a mass in her left


breast
 Mammography is repeated:

BI-RADS 4c
Brittany Lee, HMS IV
Dr. Gillian Lieberman

DDx of a breast mass DDx of a calcifications


on mammography
 Carcinoma of the  Carcinoma of the breast
breast  Benign calcifications in:
 Skin
 Phyllodes tumor  Arteries
 Fibroadenoma  Cysts
 Fibroadenoma with dense
 Adenoma of the nipple popcorn-like calcifications
 Intraductal papilloma  Foreign body post-trauma
Brittany Lee, HMS IV
Dr. Gillian Lieberman

An ultrasound guided core biopsy reveals a


infiltrating ductal carcinoma and DCIS
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Use of MRI to screen the contralateral


breast after an initial BC diagnosis
Lehman et al. NEJM. 2007.
 Study design:
 Prospective study of 969 women with a recent diagnosis of
unilateral breast cancer, who had no abnormalities on
clinical exam or mammography in the contralateral breast,
underwent breast MR
 Results:
 12.5% had positive MRI findings
 25% with a positive MRI were positive for cancer
 3.1% had contralateral BC detected by MRI
 Conclusion:
 MRI can detect clinically and mammographically occult BC
in the contralateral breast after a new diagnosis of breast
cancer.
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Breast MRI technique


 Without contrast: Density, architecture,
fluid-filled structures and implants

 Contrast, gadolinium, is used to


maximize cancer detection.
 Contrast agents improve detection since
malignant tumors are hypervascular and
enhance early (before normal breast
tissue) after contrast is given.
Brittany Lee, HMS IV
Dr. Gillian Lieberman

http://www.qcif.edu.au/industry/QldXRay.html
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Benign breast findings on MRI


Fibroadenoma Lactating breast Implant with bubble
T2 Post-contrast T1 No contrast T1 Post-contrast

www.mrsc.ucsf.edu/breast/picts_of_breast_mri.htm
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Malignant findings on MRI


T1 Pre-contrast IDC T1 Post-contrast IDC

T1 Pre-contrast DCIS T1 Post-contrast DCIS

www.mrsc.ucsf.edu/breast/picts_of_breast_mri.htm
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Our patient’s breast MRI


Right Breast Left Breast
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Breast MRI is better for screening high risk


women
 Multiple studies demonstrate that breast MR is more
sensitive than mammography for high risk women*

 Kriege et al. NEJM 2004:


 1909 women with lifetime risk >15% were screened every 6
month with clinical breast exam (CBE) and every year with
mammography (M) and MRI
 Median f/u of 2.9 years
 Results:
 Sensitivity was 79.5% MRI, 33.3% M and 17.9% CBE
 Specificity was 89.8% MRI, 95% M and 98.1% CBE
 Conclusion: MRI is more sensitive than mammography in
detecting tumors in women with an inherited susceptibility
to breast cancer.
*Leach et al. Lancet. 2005.
Lehman et al. Radiology. 2007.
Kriege et al. NEJM. 2004.
Kuhl et al. J Clin Oncol. 2005.
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Our patient: Summary


 54F with average risk for breast cancer had a benign findings on a
screening mammogram
 4 months later, she p/w a left breast mass
 U/S guided bx of the L lesion revealed IDC and DCIS
 Breast MRI of the contralateral breast showed a suspicious lesion
in the right posterior breast
 MR-guided bx the R lesion revealed IDC and DCIS
 No evidence of metastatic disease was seen on full-body CT and
bone scan
 Underwent bilateral mastectomy:
 Right total mastectomy with sentinel node biopsy
 Left modified radical mastectomy since grossly positive axillary nodes
were found intraoperatively
 Pathology:
 Right: IDC 0.9 cm, grade I with LVI positive and 1:1 sentinel nodes
positive. Histology was ER/PR+ and HER-2/neu negative.
 Left: IDC >7 cm, grade 3 with LVI positive and 5:9 axillary nodes
positive.
Histology was ER/PR+ and HER-2/neu positive.

Case courtesy of Dr. Valerie Fein-Zachary


Brittany Lee, HMS IV
Dr. Gillian Lieberman

Conclusion
 Does screening reduce breast cancer mortality?
 Uncertain since although 7 RCTs show that screening reduces the
relative risk of breast cancer mortality by 15-20%, not all of these trials
were randomized well and the absolute risk reduction was only 0.05-
0.1%

 How should average risk women be screened?


 Guidelines suggest to consider mammography screening at age 40 and
recommends to start everyone at age 50.
 Digital mammography is more accurate at detecting breast cancer than
film

 When do I use breast MRI?


 Screening for women >20% lifetime risk of breast cancer
 Evaluation of the ipsilateral breast for synchronous lesions in a women
with a newly diagnosed breast cancer that is believed to be more
extensive than seen on standard imaging
 Evaluation of the contralateral breast for occult disease in women with
a unilateral breast cancer that had no clinical or mammographic
abnormalities on the opposite side
 Women with mammographically occult primary disease with an
adenocarcinoma of unknown primary site in the axillary nodes
Brittany Lee, HMS IV
Dr. Gillian Lieberman

References
 Berry DA, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. NEJM. 2005. 353;
17: 1784-92.
 Boyd NF, et al. Mammographic density and the risk and Detection of Breast Cancer. NEJM. 2007. 356; 3:
227-36.
 Fletcher SW. Report of the International Workshop on Screening for Breast Cancer. J Natl Cancer Inst. 1993.
85; 20: 1644-56.
 Fletcher SW. Screening average risk women for breast cancer. 2007. UptoDate.
 Glass AG, et al. Breast cancer incidence, 1980-2006: combined roles of menopausal hormone therapy,
screening mammography, and estrogen receptor status. J Natl Cancer Inst. 2007. 99; 15: 1152-61.
 Gotzsche PC and Nielsen M. Screening for breast cancer with mammography. Cochrane Database of
Systematic Review. 2006. 4.
 Humphrey LL, et al. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services
Task Force. Ann Intern Med. 2002. 137; 5 Part 1: 347-60.
 Jemal A, et al. Cancer statistics from SEER, CA Cancer J Clin. 2007. 55; 1: 43-66.
 Kriege M, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or
genetic predisposition. NEJM. 2004. 35; 5:427-37.
 Lehman CD, et al. MRI Evaluation of the contralateral breast in women with recently diagnosed breast
cancer. NEJM. 2007. 356; 13: 1295-1303.
 Mandelblatt J, et al. The cost-effectiveness of screening mammography beyond age 65. Ann Intern Med.
2003. 139:835.
 Macura KJ, et al. Patterns of Enhancement on Breast MR Images: Interpretation and Imaging Pitfalls.
Radiographics. 2006. 26:1719-34.
 Pisano ED, et al. Diagnostic performance of digital vs. film mammography for breast-cancer screening.
NEJM. 2005. 353; 17: 1773-83.
 Ravdin PM, et al. The decrease in breast-cancer incidence in 2003 in the United States. NEJM. 2007. 356;
16: 1670-74.
 Salzmann P, et al. Cost-effectiveness of extending screening mammography guidelines to include women
40-49 years of age. Ann Intern Med. 1997. 127:955.
 Saslow D, et al. American cancer society guidelines for breast screening with MRI as an adjunct to
mammography. CA Cancer J Clin. 2007. 57; 2: 75-89.
Brittany Lee, HMS IV
Dr. Gillian Lieberman

Acknowledgements

 Residents:
 Katie Krajewski
 Anne Kim
 Senthil Palaniappun
 Andrew Bennett
 Dr. Valerie Fein-Zachary
 Dr. Gillian Lieberman
 Maria Levantakis