November 20th, 2009…

The good, the bad, the ugly

The USPSTF recommends against routine screening mammography in women aged 40-49.

The decision to start…should be an individualized one and take patient context into account, including the patients values

regarding specific benefits and harms.”

(C recommendation)Moderate certainty that the net benefit is smallAnnals of Int. Med Nov. 2009: 151 (10) 716-726

Additional USPSTF recommendations…

Women 50 – 74 yrs: change from every 1-2 yrs to every 2 yrs

• Insufficient evidence for or against screening women after 75 yrs

Insufficient evidence for or against CBE in women > 40 yrs

Recommended against physicians teaching BSE

Annals of Int. Med Nov. 2009: 151 (10) 716-726

What was “good”?

Evidence-based guidelines are critical for medical decision making

– Outcome data should representative “real world” scenarios

• USPSTF used Breast Cancer Surveillance Consortium (BCSC) data representing a mix of breast imaging practices

– academic, private, geographically diverse

What was “bad” ?

The presentation…

Steve Breen San Diego Union Tribune 11/30/09

Signe Wilkinson Philadelphia Inquirer 11/20/09

By GINA KOLATA Published: November 21, 2009

The current dispute over mammograms gives many people who’ve been around since the 1980s a sense of déjà vu. Like archeologists arguing endlessly over the same set of

bones, cancer specialists, it can seem, have been arguing endlessly over pretty much the same set of data…..

By GINA KOLATA Published: November 21, 2009

The current dispute over mammograms gives many people who’ve been around since the 1980s a sense of déjà vu. Like archeologists arguing endlessly over the same set of

bones, cancer specialists, it can seem, have been arguing endlessly over pretty much the same set of data…..

Get a Mammogram. No Don’t. Repeat.

What was “ugly”?

Data on which analyses were based was old (same RCTs from 1980’s - 2002 used in prior USPSTF recs)

– Mortality reductions significantly less than newer trials

– False positive rates higher– Radiation risk overestimated– BCSC data from pre-digital mammo era (<2005)

Why wasn’t newer data used?

Outcomes Table

Annals of Int. Med Nov. 2009: 151 (10) 716-726

    

Diagnostic Performance of Digital versus Film Diagnostic Performance of Digital versus Film Mammography for Breast-Cancer ScreeningMammography for Breast-Cancer Screening

Etta D. Pisano, M.D., Constantine Gatsonis, Ph.D., Etta D. Pisano, M.D., Constantine Gatsonis, Ph.D., Edward Hendrick, Ph.D., Martin Yaffe, Ph.D., Janet K. Edward Hendrick, Ph.D., Martin Yaffe, Ph.D., Janet K. Baum, M.D., Suddhasatta Acharyya, Ph.D., Emily F. Baum, M.D., Suddhasatta Acharyya, Ph.D., Emily F.

Conant, M.D., Laurie L. Fajardo, M.D., Lawrence Conant, M.D., Laurie L. Fajardo, M.D., Lawrence Bassett, M.D., Carl D'Orsi, M.D., Roberta Jong, M.D., Bassett, M.D., Carl D'Orsi, M.D., Roberta Jong, M.D., Murray Rebner, M.D., for the Digital Mammographic Murray Rebner, M.D., for the Digital Mammographic

Imaging ScreeningImaging Screening Trial (DMIST) Investigators Group Trial (DMIST) Investigators Group

Published at www.nejm.org September 16, 2005Published at www.nejm.org September 16, 2005

  

Diagnostic Performance of Digital versus Film Mammography for Breast-Cancer Screening

Etta D. Pisano, M.D., Constantine Gatsonis, Ph.D., Edward Hendrick, Ph.D., Martin Yaffe, Ph.D., Janet K. Baum, M.D., Suddhasatta Acharyya, Ph.D., Emily F. Conant, M.D., Laurie L. Fajardo, M.D., Lawrence Bassett, M.D.,

Carl D'Orsi, M.D., Roberta Jong, M.D., Murray Rebner, M.D., for the Digital Mammographic Imaging Screening Trial (DMIST) Investigators Group

Published at www.nejm.org September 16, 2005

ACRIN Digital Trial 6652 - DMIST

21.5% 33.1%

78.6% 64.9%

72 cancer in 14,130 women = 5.1 cancers/1000 in women < 50 years

Age of new patient visits – Rowan Breast Center

Annals of Int. Med Nov. 2009: 151 (10) 716-726

Non- Randomized Controlled Trial

Cancer: Aug. 1, 2002/Vol 95/No. 3

The Impact of Organized Mammography Service Screening on Breast Carcinoma Mortality in Seven Swedish Counties

A Collaborative Evaluation

Stephen W.Duffy, Msc., Laszlo Tabar, M.D.Hsui-His Chen, D.D.S.Ph.D., Marit Holmqvist

Ming-Fang Yen, M.Sc.,et al.

Background: The evaluation of organized mammographic service screening programs is a major challenge in public health. In particular, there is a need to evaluate the effect of the screening program on the mortality of breast carcinoma, uncontaminated in the screening epoch by mortality from 1) cases diagnosed in the prescreening period and 2) cases diagnosed among unscreened women (i.e., nonattenders) after the initiation of organized screening.

Journal of Cancer

Cancer: Aug. 1, 2002/Vol 95/No. 3

Method: Population based screen program begun in 1978-89 • Screening performed every 1.5 - 2 years.

Conclusions: Death rate in Swedish Seven Counties decreased over past 29 yrs in proportion to % women screened• For screened women:

• Death rate decreased by 44%

For those refusing screening, no change in death rate

Effectiveness of Population-Based ServiceScreening With Mammography for Women

Ages 40 to 49 Years

Barbro Numan Hellquist, MSc1; Stephen W. Duffy, MSc2; Shahin Abdsaleh, MD, PhD3; Lena Bjo¨rneld, RN4;Pa´l Borda´s, MD5; La´szlo´ Taba´r, MD, PhD6; Bedrich Vita´k, MD, PhD7; Sophia Zackrisson, MD, PhD8;

Lennarth Nystro¨m, PhD9; and Ha˚kan Jonsson, PhD1

RESULTS: There was no significant difference in breast cancer mortality during the prescreening period. During the study period, there were 803 breast cancer deaths in the study group (7.3 million person-years) and 1238 breast cancer deaths in the control group (8.8 million person-years). The average follow-up was 16 years. The estimated RR for women who were invited to screening was 0.74 (95% CI, 0.66-0.83), and the RR for women who attended screening was 0.71 (95% CI, 0.62-0.80).

CONCLUSIONS: In this comprehensive study, mammography screening for women ages 40 to 49 years was efficient for reducing breast cancer mortality.

Journal of Cancer

Cancer: online publication 9/29/10

Swedish Screening Update 2011

Methods:•Women aged 40 -49 yrs invited to screen vs those not invited•Outcome measure breast CA death•The average follow-up 16 years (1986 to 2005)

Results:•803 deaths in study group (7.3 million person-years) •1238 deaths in control group (8.8 million person-years)

• RR for those invited to screen was 0.74 (95% CI, 0.66-0.83)• RR for those attended screening was 0.71 (95% CI, 0.62-0.80)

Those who actually participated in screening had 29% lower BCA mortality than those who were not invited to screening

Woman screened to prevent 1 death?

Estimate of 1904 women in 40’s needed to be invited to screening to prevent 1 BCA death is way off...

– Using newer data from women actually screened and followed for 20 yrs, NNI was 726

This number is even less that what was estimated by USPSTF for women in 50’s

(1339)

Annals of Int. Med Nov. 2009: 151 (10) 716-726

What about Risks?

Yes, mammography is far from perfect and the risk of a false positive is ~50% with decade of routine screening

•What are false positives?– 10% call back rate from screening– Approx. 2.4% biopsy rate (24/1000)

Nevertheless, women report they would accept trade-off of FP in favor of finding cancer early1

Schwartz LM et al. BMJ 2000;1635-40.

Cancer diagnosed in 40’s?

Cancers that occur in pre-menopausal women have a more rapid growth rate

•One in 6 breast cancer deaths are attributable to women diagnosed in their 40’s

•One third of all years lost to breast cancer deaths are due to women diagnosed in their 40’s

Wu LC et al. Ann Inten Med 2012;157;597.Shapiro S et al. HIPP and Sequelae, JHU Press 1988

Perspective:

United States Preventive Services Task Force Screening Mammography Recommendations:

Science Ignored

R. Edward Hendrick1 and Mark A. Helvie21

Objective: To examine the scientific evidence used by USPSTF to recommend against screening mammography:

•Women 40–49 years old •Against annual screening mammography in women 50 and older.

AJR 2011; 196:W112-W116

Conclusions

Averaged over six USPSTF models of benefit for annual screening:

• For 40–74 yrs: up to 39.6% mortality reduction

– 71% more lives saved than USPSTF biennial screening for 50–74 yrs olds, which had 23.2% mortality reduction

For 40–84 years: 99,829 more lives saved than USPSTF recs if

all women comply, and 64,889 more lives with the current 65%

compliance rate AJR 2011; 196:W112-W116

Potential Harms?

For screening women 40–49 yrs screened yearly?

• a recall for diagnostic workup every 12 years • a negative biopsy every 149 years • a missed breast cancer every 1,000 years • and a fatal radiation-induced breast cancer every

76,000–97,000 years

“Evidence made available to USPSTF strongly supports the mortality benefit of annual screening mammo beginning at age 40 yrs, whereas potential harms of screening with this

regimen are minor”AJR 2011; 196:W112-W116

General Population General Population

PopulationPopulation with Diseasewith Disease

The Screening Process

How Should Women Be Screened?

Risk Stratification

• Gender• Personal/Family History• Exposure history• Genetics• Serum Biomarkers• Tissue Markers from Prior Biopsy• Risk Models (Claus/Gail)

Imaging --- what quantitative measures can we use?

Boyd et al., NEJM 2007

Density as a Risk Factor

Mammographic dense tissue, percent dense area (PD) is one of strongest risk factors for

breast cancer

Women with >50% dense breasts are at 3- to 5X greater risk for breast cancer than women with density <25% 2

– Partly due to the lower sensitivity of mammo but remains even when accounting for “masking”

– Mammo dense breast tissue is rich in epithelium and stroma and association could represent activation of these cells

Mammographically dense breast tissue results in up to 3X higher false positive call-backs at

screening3 Boyd 1995, 2Tice Ann Intern Med. 2008, 3Yankaskas AJR 2001

Breast Density Estimation

Cumulus (Univ. Toronto)

PD = 42.5%

Annals of Internal MedicineEstablished in 1927 by the American College of Physicians

Using Clinical Factors and Mammographic Breast Density toEstimate Breast Cancer Risk: Development and Validation of

a New Predictive Model

Jeffrey A. Tice, MD; Steven R. Cummings, MD; Rebecca Smith-Bindman, MD; Laura Ichikawa, MS; William E. Barlow, PhD; and Karla Kerlikowske, MD

Conclusion: A breast cancer prediction model that incorporatesroutinely reported measures of breast density can estimate 5-year

risk for invasive breast cancer. Its accuracy needs to be furtherevaluated in independent populations before it can be recommended

for clinical use.

Ann Intern Med. 2008;148:337-347

Computer-Assisted Risk EstimationComputer-Assisted Risk Estimation

Identify women at high risk of breast cancer, so customized screening protocols and individualized risk reduction strategies

may be implemented

General Population General Population

Population with DiseasePopulation with Disease

Image Screening

Imaging diagnosis/guided biopsy

Risk stratification

Image assessment

Patient questionnaire

Tailored screening

recommendations

Calculated glandularity

What about DCIS?

In U.S. in 1983 (prescreening era) 4,900 women were diagnosed with DCIS

In 2010, approximately 54,000 women who will be diagnosed with DCIS (20-30% of cancers diagnosed)

http://www.seer.cancer.gov/csr/1975_2007/browse_csr.php?section=4&page=sect_04_zfig.01.html

How do we tell the bad actors from the less bad ones???

Graph shows age-adjusted incidence rates of DCIS in the United States from 1975 to 2007.

Jørgensen K J et al. Radiology 2011;260:621-627