Screening Mammography:
Facts and Fiction
Therese B. Bevers, M. D.
Professor, Clinical Cancer Prevention
Medical Director, Cancer Prevention Center
Objectives
 Outline
breast cancer screening
recommendations
 Review fundamentals of cancer
screening
 Identify trials of mammographic
screening
 Discuss recent controversies related
to screening mammography
Premise of cancer screening
 Screening
of asymptomatic individuals can
find cancers earlier than those found on
diagnostic evaluation of symptoms
 As a result of screening, more early-stage
cancers are diagnosed than late-stage
cancers
 Early-stage cancers have better outcomes
than do late-stage cancers
Breast Cancer Screening
Recommendations
For average risk women:
 Beginning
at age 40
Annual clinical breast exam
Screening mammogram
www.cancer .org
www.nccn.org
Cancer Screening
Screening
Harms
Screening
Benefits
Threshold Level
Screening Mammography
Randomized controlled trials assessing
effectiveness of mammographic screening



Health insurance plan,
US-1963
Edinburgh, UK-1978
Canadian national breast
screening trial-1980
Study 1-age 40-49
Study 2-age 50-59
Swedish
“Two County”-1977
Ostergotland, Sweden
Kopparbreg, Sweden
Malmo, Sweden-1976
Stockholm, Sweden-1981
Goteborg, Sweden-1982
Age-2006
Different ages of enrollment and screening frequency in each trial
Benefits of Screening Mammography
7 statistical models attribute
breast cancer mortality
reduction to:
 Screening mammography
28%-65% (median 46%)
 Improved
treatment
adjuvant
Less intensive treatment
 Screening
is done to find early-stage
disease.
 While all women with late-stage disease
require chemotherapy, many women
with earlier stage disease do not require
chemotherapy
Harms of
Screening Mammography
False positives
False negatives
Radiation Exposure
Overdiagnosis
False Negatives
 Screening
tests are negative but
individual has cancer
 Function of sensitivity of mammography
Uncommon
 Lower
sensitivity in women with dense
breasts
Supplemental screening now optional in
women with increased breast density
based on Texas’ Henda’s Law
Brewer NT Ann Intern Med 146 (7): 502-10, 2007.
Radiation Risk
Medical Radiation



Mammogram
CXR
CT
Chest
3 phase hepatic
Low dose CT
0.07 mSv
0.08 mSv
7 mSv
30 mSv
1.4 mSv
Non-Medical Radiation


Yearly background
Average
Denver
Chicago
Airplane 10 hours
3 - 5 mSv
6 mSv
3 mSv
0.04 mSv
www.nrc.gov
www.world-nuclear.org
Over-diagnosis
 Diagnosing
cancers that would not become
clinically relevant in a person’s lifetime
 A number of analyses have attempted to
define risk of over-diagnosis
Many factors involved in this discussion, many of
which have yet to be identified
 Over-diagnosis
is not the real problem
Problem is inability to distinguish which cancers
are life-threatening from those that are not
Real problem is over-treatment!!
Harms of Over-Treatment
 Unnecessary
interventions
e.g., mastectomy in women who would
never develop clinically relevant breast
cancer
 Significant
psychological distress
However, patients assume that cancer
left untreated will kill them
Define New Paradigm
 Are
there women with “breast cancer” who do
not require “breast cancer treatment”?
e.g. women with low-grade DCIS
Would excision and hormonal therapy produce the same
outcomes as the current standards of treatment?
 Great
question!!
Need to better understand biology of breast cancer
Need data to reassure women that less aggressive
treatment produces same outcomes
Those conditions that do not need to be treated like a
cancer should not be called cancer!!
This is not a question that is answered by screening!!!
Screening mammography
recommendation has been
focus of controversy dating
back to 1990’s
Discuss 3 controversies
 2009
US Preventive Services Task Force
(USPSTF)
Confusion regarding screening mammography
recommendations
 2012
Bleyer & Welch analysis and 2014
Helvie analysis of SEER Registry data
Suggested 1/3 of breast cancers are overdiagnosed
 2014
Canadian National Breast Cancer
Study (CNBSS)
Suggested no benefit to screening mammography
2009 US Preventive Services
Task Force Recommendation
on Screening Mammography
The Controversy:
•
•
Begin at age 40 or age 50?
Get a mammogram every
year or every other year?
2009 U.S. Preventive Services
Task Force Recommendation
The USPSTF recommends against routine
screening mammography in women aged 40 to
49 years. The decision to start regular, biennial
screening mammography before the age of 50
years should be an individual one and take into
account patient context, including the patient’s
values regarding specific benefits and harms.
(Grade C recommendation)
US Preventive Services Task Force, Ann Intern Med, 2009; 151(10):716-26.
Nelson HD. Ann Intern Med 2009;151:727-737
.
Nelson HD. Ann Intern Med 2009;151:727-737
False Positives (FP)
 Screening
tests are positive but no
cancer found on diagnostic evaluation
 Function of specificity of mammography
Not uncommon
 Breast
Cancer Surveillance Consortium:
10-yr cumulative risk of at least one FP:
61.3% risk in women starting screening
ages 40-50 yrs
49.7% for women aged 66-74 yrs
undergoing annual screening
Brewer Ann Intern Med 146 (7): 502-10, 2007.
Pace JAMA 311(13)1327-35.
Evaluation of False Positives
 ~10%
of women screened will be recalled for
additional evaluation
>80% will be normal/benign after dx evaluation
May include: add’l mmg views, u/s
15% recalled will be recommended for biopsy
 Associated
anxiety and distress
Several studies show that anxiety related to a false
positive test results does not result in a decrease
in future screening participation
Brewer Ann Intern Med 146 (7): 502-10, 2007.
Another Perspective….
 As
many as 70% of breast cancers seen in
women in their 40’s occur in women with
no risk factors
 >40% of years of life lost to breast cancer
are due to women diagnosed in their 40s
 Many women place a very high value on
the benefits and very little weight on the
harms of mammographic screening
Vastly differs from perspective of USPSTF!
Kopans D. J Am Coll Radiol, 2010.
Smith RA. CA Cancer J Clin, 2010.
Benefits vs Harms Analysis
 USPSTF
clearly identified benefits for
screening women in their 40’s but had
concerns that the harms might outweigh
the benefits
Very subjective determination
 This
should be a decision at the
individual patient-clinician level
Urgent need for tools to help clinicians and
their patients make these decisions
2009 U.S. Preventive Services
Task Force Recommendation
Recommends biennial screening
mammography for women
between the ages of 50-74 years.
(Grade B recommendation)
US Preventive Services Task Force, Ann Intern Med, 2009; 151(10):716-26.
Rationale for USPSTF
Recommendation Statement
(women aged 50-69)
 Screening
biennially
81% of the benefit of annual screening
Almost half the number of false-positives
US Preventive Services Task Force, Ann Intern Med 2009;151(10):716-26.
Benefits of Annual Mammography
 CISNET
models show 71% fewer
deaths with annual screening
mammography compared to
biennial
Hendrick RE. AJR 2011;196:W112-6.
Put another way….
Annual mammographic
screening from ages
40-84 would save
99,829 more lives than
the USPSTF
recommended
mammographic
screening of every
other year
Hendrick RE. AJR 2011;196:W112-6.
Effect of Three Decades of
Screening Mammography on
Breast-Cancer Incidence
Bleyer and Welch
N Engl J Med
2012;367:1998-2005
Aim
 Compare
incidence rates of early- and
late-stage breast cancer in women > 40
years of age from 2 time intervals to
evaluate risk of over-diagnosis from
screening mammography
 Data
source: SEER registry
Prescreening era (1976-1978)
Screening era (2006-2008)
Methods
Estimated incidence trend of breast cancer
Base case:
Assumes underlying incidence is constant
Best guess:
Assumes incidence increased by 0.25%/yr
Extreme assumption:
Assumes incidence increased by 0.5%/year
Very extreme assumption:
Assumes incidence increased by 0.5%/yr &
Baseline incidence of late-stage breast cancer
revised by using the highest incidence observed
in the data set
Bleyer. N Engl J Med 2012;367:1998-2005
Findings
From 1976-1978 through 2006-2008

Doubling of early-stage disease (includes DCIS)
112 vs 234 cases/100,000 women

69% increase in localized disease (excludes DCIS)
105 vs 178 cases/100,000 women

8% decrease in late-stage disease
102 vs 94 cases/100,000 women
Authors: “if we are shifting cancers from late to
early stage by screening, why are we not
seeing fewer late stage breast cancers?”
Conclusion
Screening mammography results in
massive over-diagnosis of breast
cancer
 In
2008, >70,000 women age 40+
overdiagnosed with breast cancer
31% of breast cancers diagnosed
Criticism
 Incidence
rates not appropriately adjusted
for the underlying temporal trend of
increasing breast cancer incidence that
existed before the introduction of
widespread screening mammography
 Breast cancer incidence increased 1%-3%
per year before the advent of screening
mammography
 In the US, the annual incidence increased
~1.2% in the longstanding Connecticut
Tumor Registry from 1940-1982.
Helvie. Cancer 2014; e-pub.
Temporal Trends
 Underlying
temporal trends appear small on
an annual basis, but impact on future
incidence over many decades is profound
 Trends directly influence calculations of earlyand late-stage disease changes and estimates
of over-diagnosis
 Due to compounding, over 30 years:
1% annual increase results in an incidence increase
of 33%
2% annual increase results in an incidence increase
of 78%
Helvie. Cancer 2014; e-pub.
Reduction in Late-Stage
Breast Cancer Incidence in
the Mammography Era
Helvie, et al
Cancer 2014; e-pub
Aim
 Determine
effect on late-stage breast
cancer incidence and total invasive
breast cancer incidence in US after
adjusting for temporal trends by
comparing SEER registry data
Prescreening era (1977-1979)
Screening era (2007-2009)
Helvie. Cancer 2014; e-pub.
Helvie Analysis
 Baseline
incidence values from 1977-9
were projected to the period 2007-9
using a range of annual percentage
change (APC)
APC values: 0.5%, 1.0%, 1.3% and 2.0%
 Compared
projected values with actual
observed values in 2007-9
Calculated changes in early-stage, late-stage
and total invasive breast cancer rates
Helvie. Cancer 2014; e-pub.
Helvie Findings
 APC
of 1.3%: Central estimate
Of the APC estimates, 1.3% APC most closely
approximated the 4-decade historic Connecticut
Tumor Registry trend of 1.2%
Late-stage disease decreased by 37%
Approximates the breast cancer mortality reduction
observed among women in US from 1990-2009
Reciprocal increase in early-stage disease of 48%
 Across
all APC estimates, decreases in latestage disease ranged from 21% at an APC of
0.5% to a 48% decrease at an APC of 2.0%
Helvie. Cancer 2014; e-pub.
Helvie Conclusions
 Without
adjusting for underlying temporal
trends in breast cancer incidence
There is an excess in incidence of breast
cancer from 2007-2009 compared with 3
decades earlier
Screening does not appear to reduce latestage disease and results in significant overdiagnosis
Helvie. Cancer 2014; e-pub.
Canadian National
Breast Screening Study
(CNBSS)
2014 Update
Miller BMJ 2014;348:366
Screening Mammography
Trials
Randomized controlled trials assessing
effectiveness of mammographic screening



Health insurance plan,
US-1963
Edinburgh, UK-1978
Canadian national breast
screening trial-1980
Study 1-age 40-49
Study 2-age 50-59
Swedish
“Two County”-1977
Ostergotland, Sweden
Kopparbreg, Sweden
Malmo, Sweden-1976
Stockholm, Sweden-1981
Goteborg, Sweden-1982
Age-2006
CNBSS Trial Design
 89,835
women aged 40-59 years
 “Randomly” assigned to annual
screening mammography vs no
mammography
 25 yrs f/u data published early 2014
Miller BMJ 2014;348:366.
CNBSS Findings
“Annual screening mammography in
women aged 40-59 does not result in a
reduction in breast cancer mortality
beyond that of physical examination
alone/usual care in the community”
Authors:
“Rationale for screening by
mammography should be urgently
reassessed by policy makers”
New York Times:
“one of the largest and most
meticulous studies ever done”
“added powerful new doubts about the
value of the screening test for women
of any age”
Miller BMJ 2014;348:366.
Kolata G. NY Times Feb 11, 2014.
CNBSS Issues
“Flawed from the beginning”
Randomization issues
Mammographic quality
Kopans AJR 1990;155:748-9.
Kopans AJR 1993;161:755-60.
Randomization Issues

Randomization occurred after performance of a
clinical breast exam
Knowledge of CBE findings creates the potential for it to
influence study allocation
In CNBSS, more women with advanced breast cancers
assigned to the intervention arm
Miller BMJ 2014;348:36.
Kopans AJR 1990;155:748-9.
Kopans AJR 1993;161:755-60.
The number of women 40-49 yrs old in the
mammography arm who had breast cancers with
4+ lymph nodes exceeded that of the control
group by 19:5 (380%)
 Unlikely to have occurred by chance
 Mimimizes/eliminates impact of mammographic
screening on breast cancer mortality
The 5-yr survival of women aged 40-49 who
underwent mammographic screening was 75%
The women in the control arm of the CNBSS had a
>90% 5-yr survival, even better than modern results
with screening and improved therapy
Miller BMJ 2014;348:36.
Kopans AJR 1990;155:748-9.
Kopans AJR 1993;161:755-60.
Quality of Mammographic Process

Image quality was suboptimal
Secondhand mammographic equipment used
Grids that reduce scatter were not utilized
Images were cloudy

Image acquisition issues
Mammography technologists were not taught proper
positioning
MLO views were not initially obtained

Radiologists were not experienced in the interpretation
of mammographic images
Reference physicist: “quality was far below state-of-theart, even for that time!!”
Miller BMJ 2014;348:36.
Kopans AJR 1990;155:748-9.
Kopans AJR 1993;161:755-60.
Although we rely on evidence from trials
of screening mammography dating back
to the early 1960s, it is important to
realize that the technology of today’s
mammograms is vastly superior
CNBSS: average size=1.9cm
Current screening detection rate is <1 cm
Bevers The ASCO Post 2014;5(6):22-23.
“Strengths of CNBSS are contrasted
by a vast collection of flaws that
render any findings, past or present,
meaningless. As a result, the study
does not provide any data in regard
to the benefits of mammography
that
“
would influence breast cancer
screening recommendations.
Bevers The ASCO Post 2014;5(6):22-23.
Where do we go
from here?
Screening mammography results
in both benefits and harms
 Benefit
Mortality reduction
Less intensive treatment
 Harms
False negatives
False positives
Radiation exposure
Overdiagnosis
Tomosynthesis: Principle of Operation
Arc of motion of x-ray tube, showing
individual exposures



X-ray tube moves in
an arc across the
breast
Series of low dose
images are acquired
from different angles
Projection images are
reconstructed into
1 mm slices
Reconstructed
Slices
{
Breast Tomosynthesis
(3D mammography)

Reconstructed slices eliminates
tissue superimposition
Improved visibility of mass lesions
Decreases recall rates
Breast Tomosynthesis
Tomosynthesis: Clinical Performance
Analysis of 281,187 digital mmg (DM) and
173,663 DM + tomo

Lower recall rate
DM
DM + tomo

Increase in invasive cancer detection rate
DM
DM + tomo


107/1000 (95% CI, 89-124)
91/1000 (95% CI, 73-108)
2.9/1000 (95% CI, 2.5-3.2)
4.1/1000 (95% CI, 3.7-4.5)
No difference in the in situ cancer detection rate
Adding tomosynthesis increased PPV
Recall: 4.3% to 6.4% (diff.=2.1%; 95% CI, 1.7%-2.5%; P<.001)
Biopsy: 24.2% to 29.2% (diff=5.0%;95% CI,3.0%-7.0%;P<.001)
Friedewald SM. JAMA 2014;311(24):2499-2507.
Summary
 Women
should be counseled
regarding the benefits, harms and
limitations of mammographic
screening
 Urgent need for decision-making tools
to help women (and their clinicians!)
determine if screening is appropriate
for them
 Individual preferences should be
considered
Mammography is not a
perfect screening test
Currently the only breast
cancer imaging modality to
have shown a reduction in
breast cancer mortality
New modalities are available
that can improve the benefit
and reduce the harms of
mammographic screening