Complexity, Confusion, Uncertainty – Age Based Mammography Screening

Richard L. Theriault, D.O. F.A.C.O.I.ProfessorDepartment of Breast Medical OncologyThe University of TexasM D Anderson Cancer CenterHouston, Texas

Disclosures

I have no conflicts of interest in relation to this presentation

I will not be discussing investigational use of pharmaceuticals or devices

Objectives

Define screeningConsider populations who may

benefit from screening mammography

Understand the concepts of Number Needed to Screen (NNS) and Number Needed to Harm(NNH) in relation to outcomes for mammography screening

Evidence Based MedicineRequires the integration of best

research evidence with our clinical expertise and our patient’s unique values and circumstances

Evidence Based Medicine Strauss S. et al Third Edition

Screening for Breast Cancer with Mammography - OutlineRationale for screeningPopulation screening- who is at risk?

Sex, age, race, genetics, family historyIndividual screening – who is at risk?

Sex, age, endocrine historyWhat is the evidence for

mammography screening?◦Potential benefits◦Potential harms◦Who decides when and how to screen?◦NNI, NNH

Clinical Case PresentationA 42 year old woman requests advice and counsel regarding screening for cancer. She is concerned because her friend has recently been diagnosed with Stage III breast cancer and has been told she has an “awful” prognosis. Do you recommend screening studies for breast cancer? What do you tell her about risks and benefits of screening?

Screening

Early diagnosis of pre-symptomatic disease among well individuals in the general public

Goal – live longer or better

Requirements for Screening Disease should be an important

health problem –approximately 200,000 new breast cancer patients per annum USA

Disease should be detectable at an asymptomatic stage (preclinical)

Early stage treatment should lead to better patient outcomes

Screening test effective and accurate

Breast Cancer Sojourn Time and Lead Time

Sojourn time (ST) - duration of time that an occult breast cancer can be detected before symptoms

Lead time (LT) – the amount of time actually gained by screening before symptoms

Breast Cancer Sojourn Time and Lead Time

Mean sojourn time by age◦2 - 2.4 years age 40-49◦2.5 - 3.7 years age 50-59◦3.5 - 4.2 years age 60-69◦4 - 4.1 years age 70-74

◦Theoretically screening should detect “early” cancer, i.e. before clinically symptomatic

Breast Cancer Survival (5 year) in Relation to Disease StageStage 0 98% in situStage I >90% tumor 2 cm or lessStage II >85% lymph node positive(+)Stage III >60% tumor >5 cm, lymph

node +Stage IV >20% systemic disease

Diagnosis at lower stage ought to lead to better outcomes, therefore if screening leads to early detection (lower stage) the prognosis and survival should be better

Population ScreeningBreast Cancer Incidence and Age

Age 40-49 - 1 in 69 Age 55-59 – 1in 42Age 60-69 – 1in 29

Smith R A et al CA Cancer J Clin 2010;:99-119

Screening Recommendations andJustification

Generally accepted that mammography screening reduces breast cancer specific mortality for women age 50 - 70

Little screening data over age 70It has been recommended that

annual screening mammography begin at age 40 for women at “average risk” for breast cancer

What are the data?

Population Screening –Healthy WomenCochrane Review 2009– Screening for Breast Cancer with Mammography Randomized trials screening vs. no screening

Pub Med (through November 2008) 8 trials, 1 excluded due to bias 600,000 women Trials (3) with adequate randomization – no

reduction in breast cancer mortality at 13 years Trials (4) with suboptimal randomization

significant mortality reduction RR 0.75 RR for all 7 trials .81 (95% CI 0.74- 0.87) Number of lumpectomies and mastectomies

significantly larger in the screened group RR 1.31

Nielsen G PC Cochrane Database of Systematic Reviews 2009, Issue 4; 2009

Population Screening –Healthy WomenCochrane Review 2009– Screening for Breast Cancer with MammographyReview estimated 15% relative risk reduction in overall breast cancer mortality

30% over diagnosis and over treatmentFor every 200 women invited to

screening throughout 10 years one will have life prolonged

10 healthy women will be diagnosed as having breast cancer and be treated unnecessarily

Population Screening –Healthy WomenCochrane Review 2009– Screening for Breast Cancer with Mammography“It is not clear whether screening

does more harm than good”.

The ControversyU.S. Preventive Services Task Force

Recommendations for Screening for Breast Cancer

“The USPSTF recommends against routine screening mammography in women age 40 -49 years”.

“The decision to start regular 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”.

Annals Int Med 2009;151:716-726

USPSTF IssuesLower sensitivity and specificity for

mammography in women age 40-49Over diagnosis of breast cancerFalse positive, false negatives,

additional imaging and biopsiesRadiation exposure – unknown risk

related to radiation dose over timeProcedure related painAnxiety, distress and psychological

concerns Annals Int Med 2009;151:716-726

USPSTF Review - Data sources Randomized controlled trialsCochrane Central Register of Controlled

TrialsCochrane Database of Systematic ReviewsMeta Analysis - 8 randomized controlled

trialsEnd point - breast cancer specific mortality

Annals Int Med 2009;151:716-726

Mammography Sensitivity and SpecificitySensitivity 77-95% - proportion

of people with the target disorder who have a positive test result

Specificity 94-97% -proportion of people without the target disorder who have a negative result

Annals Int Med 2009;151:716-726

Age Sensitivity (%)b Specificity (%)c PPV1 (%)

40-44 70.8 89.8 1.5

45-49 74.3 89.8 2.3

50-54 78.4 90.9 3.3

55-59 81.6 91.5 4.6

60-64 80.0 91.9 5.4

65-69 82.5 92.4 6.3

70-74 82.9 93.1 7.9

•From Diseases of the Breast Fourth Edition p94

How good is Mammography?Performance measures for 3,603,832 Screening Mammograms

Controversy – Interpreting the EvidenceUSPSTF

◦Mortality reduction estimates with screening mammography 15% age 39-49 14% age 50-59 32% age 60-69 No effect age70-74How much mortality benefit is enough to

warrant “routine” screening??

Ann Int Med 2009;151:727-737

Cancers Detected per USPSTF ReportAge 40-49 - 1.8 invasive, 0.8 non-invasiveAge 50-59 - 3.4 invasive, 1.3 non-invasiveAge 60-69 - 5.0 invasive, 1.5 non-invasiveAge 70-79 - 6.5 invasive, 1.4 non-invasiveAge 80-89 - 7.0 invasive, 1.5 non-invasive

Ann Int Med 2009;151:727-737

USPSTF - Yield per Screening RoundNumber of mammograms per

case of invasive breast cancer◦Age 40-49 - 556◦Age 50-59 - 294◦Age 60-69 - 200◦Age 70-79 -154◦Age 80-89 – 143

◦ Ann Int Med 2009;151:727-737

USPSTF Number of Additional Imaging Studies and Biopsy(ies) By Age at Screening

Age 40-49 - 47, 5Age 50-59 - 22, 3Age 60-69 - 14, 2Age 70-79 - 10, 2Age 80-89 - 8, 1.5

Ann Int Med 2009;151:727-737

Clinical ContextAge 39-49 - Number needed to invite (NNI) to

screen 1904, to prevent one breast cancer death

Age 50-59 – NNI 1339Conclusion – “Women age 40-49 experience

the highest rate of additional imaging whereas their biopsy rate is lower than that for older women”.

“Mammography screening at any age is a tradeoff of a continuum of benefits and harms”.

Ann Int Med 2009;151:727-737

Another Perspective - Critique of the USPSTF Recommendations No scientific basis for age 50 thresh hold Lowest possible mortality benefit used in breast cancer

specific mortality calculations Computer models favored over direct data Decrease in deaths mostly due to screening, not

therapy Breast cancer not trivial in women in their 40’s No data to support only screening high-risk women Annual screening from age 40 saves the most lives Screening anxiety is not equal to death from breast

cancer All women should be informed of risks and benefits

Kopans D Radiology 2010;256 15-20

What to do? Cancer Risk Assessment

An individualized evaluation of a patient’s risk for cancer based on history and physical examination◦ Examination of breasts and nodal basins◦ Patient age◦ Family history – three generations preferred◦ Race/ethnicity◦ Endocrine history – menarche, pregnancies, exogenous

hormone exposure◦ Prior biopsy – ADH, ALH◦ Diet ◦ Physical activity◦ Environmental exposures - ETOH, XRT◦ Personal cancer history – Hodgkin’s Disease, XRT

Clinical Case Presentation42 y/o Caucasian womanFamily history – 2 first degree relatives

with breast cancer, age 45 and 75NulliparousOne prior breast biopsy – benign“moderate” ethanol intake

Is this person average risk?Should she have screening?

Cancer Risk Assessment Tools

◦Gail model (www.cancer.gov/bcrisktool)

◦Claus Model◦BRCAPRO for BRCA 1 and 2 assessment

Screening Recommendations - Society of Breast Imaging and ACRAnnual Mammographic screening from age 40Women at increased risk – BRCA mutations - annually

starting at age 30Women with histories of mantle irradiation – annually

beginning 8 years after radiation but not before age 25

Women with mothers or sisters with pre-menopausal breast cancer –beginning age 30 but not before age 25, or 10 years earlier than the age of diagnosis of the youngest affected relative whichever is later

Lee C H et al J Am Coll Radiol 2010;7:18-27

American Cancer Society Recommendations for Breast cancer Screening

Breast self examination – beginning in early 20’s (no data on risk reduction)

Clinical Breast examination – beginning in 20-30’s and every three years (no data on risk reduction)

Mammography – annually beginning age 40

Smith R A et al CA A Cancer J Clin 2010;99-119

Breast Cancer Screening with Mammography - ConclusionsThe mammography screening

recommendations of the United States Preventive Services Task Force, American Cancer Society and the American College of Radiology/Society of Breast Imaging all differ based on reviews and judgments of the same evidence base

Breast Cancer Screening with Mammography - ConclusionsEvidence review of the Cochrane Systematic

Review suggests the risks of population screening may outweigh the benefits

USPSTF review concludes there is a 15% breast cancer specific mortality relative risk reduction with screening age 50-70

Evidence review from the USPSTF suggests potential harms may outweigh the risks of “routine annual screening” in women age 40-49

Others examining the same “evidence” contend that there is no justification for excluding women age 40-49 from screening programs

Breast Cancer Screening with Mammography - ConclusionsFor women >70-75 years there are too

few data to make an evidence based recommendation and screening recommendations must be individualized

All agree that “best research evidence“ is lacking – poor study conduct, poor randomizations, different study designs, objectives, populations, end points, relative risk reductions reported

Breast Cancer Screening with Mammography - ConclusionsAll agree “best interests” of the

patient are the primary considerationAll agree the patient’s values and

preferences must be consideredAll agree that the clinician must

engage the patient in discussion of the relative risks, harms and burdens of testing in relation to individual benefit expected

Clinical Case Presentation42 year old women with anxiety

regarding her friend’s breast cancer diagnosis

2 first degree relatives with breast cancer

NulliparousPrior breast biopsyRisk assessment >1.67 %SCREEN