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AHRQ’s Effective Health Care Program: Applying Existing Evidence to Breast Cancer Prevention and Diagnosis

Slide Presentation in Text Format

Friday, December 3, 2010

 

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  • On the top of the slide are the logos for the Department of Health and Human Services and the Agency for Healthcare Research and Quality (AHRQ).

 

Slide 2

Questions

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CALL-IN NUMBER: (888)-632-5065  ACCESS CODE:27294007#


Slide 3

Agenda

  • Brief Overview of Patient-Centered Outcomes Research and AHRQ’s Effective Health Care Program - Deborah L. Rogal, Moderator
  • Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women - Heidi Nelson, M.D., M.P.H., FACP
  • Comparative Effectiveness of Core Needle and Open Surgical Biopsy for the Diagnosis of Breast Lesions- Karen Schoelles, M.D., S.M., FACP
  • Q&A from Audience

 

CALL-IN NUMBER: (888)-632-5065 ACCESS CODE: 27294007#

 

Slide 4

Patient-Centered Outcomes Research and AHRQ’s Effective Health Care Program

Deborah L. Rogal, M.P.P.
AHRQ’s Office of Communications and Knowledge Transfer


Slide 5

Patient-Centered Outcomes Research

  • Also known as comparative effectiveness research

 

  • Unbiased and practical, evidence-based information
  • Compares drugs, devices, tests and surgeries, and approaches to health care
    • Benefits and harms
    • What is known and what isn’t

 

  • Descriptive, not prescriptive


Slide 6

A Framework for Patient-Centered Outcomes Research

This framework outlines the step-by-step process for how the development and implementation of patient-centered outcomes research leads to improvement in health care. Once a topic is nominated, a horizon scan and synthesis of the evidence is completed, followed by evidence generation. Then the research is translated, disseminated, and implemented.


Slide 7 

Research Focus: 14 Priority Conditions

  • Arthritis and nontraumatic joint disorders
  • Cancer
  • Cardiovascular disease, including stroke and hypertension
  • Dementia, including Alzheimer’s disease
  • Depression and other mental health disorders
  • Developmental delays, ADHD and autism
  • Diabetes mellitus
  • Functional limitations and disability
  • Infectious disease including HIV/AIDS
  • Obesity
  • Peptic ulcer disease and dyspepsia
  • Pregnancy including preterm birth
  • Pulmonary disease/asthma
  • Substance abuse

 

Slide 8

Research Focus: Priority Populations

  • Low-income groups

 

  • Minority groups
  • Women

 

  • Children
  • The elderly

 

  • Individuals with special health care needs, such as those with disabilities, those who need chronic care or end-of-life care, or those who live in inner-city and rural areas.


Slide 9

Effective Health Care Program Translation Products

Multiple images of different products that the Effective Health Care Program creates from the systematic review reports.  These products include CE Modules, Interactive Case Study, faculty slides, patient decision aid, policymaker summary, consumer guide, clinician guide, Web site, and executive summary.


Slide 10

Breast Cancer Resources

Two images of consumer guides titled, Reducing the Risk of Breast Cancer With Medicine: A  Guide for Women, and Having a Breast Biopsy: A Guide for Women and Their Families


Slide 11

Public Involvement

A diagram of the multiple points in the development and dissemination process where stakeholders can get involved. The process includes topic generation, topic development, topic refinement, research review, and research needs and development. The multiple ways that information is disseminated includes Web links, newsletter blurbs, articles or comment, Web conferences, and continuing education.


Slide 12

Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women

Heidi D. Nelson, M.D., M.P.H., FACP
Research Professor
Departments of Medical Informatics & Clinical Epidemiology and Medicine
Oregon Evidence-Based Practice Center
Oregon Health & Science University


Slide 13

Background

  • Prevention strategies for breast cancer currently focus on early detection with screening mammography.
  • Newer approaches target risk reduction:
  • Identification of BRCA mutation carriers
  • Prophylactic mastectomy/oophorectomy for high-risk women
  • Medications
  • Despite availability of medications that reduce risk of primary breast cancer:
  • Not commonly used in the U.S.
  • Unclear how to apply results of recently published trials in clinical practice

 

Slide 14

Background

  • Comparative effectiveness review was commissioned by AHRQ for new USPSTF recommendations.
  • Previous recommendations in 2002 include:

B Recommendation for High Risk
Clinicians should discuss chemoprevention with women at high risk for breast cancer and at low risk for adverse effects of chemoprevention.
D Recommendation for Low Risk
The USPSTF recommends against routine use of tamoxifen or raloxifene for the primary prevention of breast cancer in women at low or average risk for breast cancer.

 

Slide 15

Comparative Effectiveness Review
Summary of Available Scientific Evidence

  • Develop & prioritize topic
  • Develop key questions
  • Collect abstracts and papers by searching for published and unpublished studies and registries; and soliciting information from drug companies (to January 2009)
  • Select studies based on predetermined eligibility criteria:
    • Efficacy:  RCTs
    • Harms:  RCTs, observational studies
    • Risk Models:  discriminatory and diagnostic accuracy studies

 

Slide 16

Comparative Effectiveness Review
Summary of Available Scientific Evidence

  • Abstract data from studies meeting eligibility criteria
  • Evaluate studies for quality and applicability using predefined criteria
  • Statistically combine results of trials in meta-analyses for major health outcomes
  • Evaluate strength of evidence for each comparator and outcome using GRADE criteria
  • Interpret results in the context of strengths and limits of evidence
  • Identify future research needs

 

Slide 17

Dissemination

This slide displays images of comparative effectiveness guides and reports that are available through the Effective Health Care Program, Annals of Internal Medicine, and recommendations of the U.S. Preventive Services Task Force.


Slide 18

Key Questions

1:  In adult women without pre-existing breast cancer, what is the comparative effectiveness of selective estrogen receptor modulators (SERMs) tamoxifen citrate and raloxifene and the selective tissue estrogenic activity regulator (STEAR) tibolone when used to reduce risk for primary breast cancer on improving short-term and long-term outcomes including:

  • Invasive Breast Cancer
  • Noninvasive Breast Cancer including Ductal Carcinoma in situ (DCIS)
  • Breast Cancer Mortality
  • All-Cause Mortality
  • Osteoporotic Fractures


Slide 19

Key Questions

2:  What is the evidence for harms? 

  • Thromboembolic Events
  • Cardiovascular Events
  • Metabolic Disorders
  • Musculoskeletal Symptoms
  • Genitourinary Outcomes
  • Breast Outcomes
  • Other Malignancies
  • Ophthalmologic Disorders
  • Gastrointestinal/Hepatobiliary Disorders
  • Others Impacting Quality of Life

 

Slide 20

Key Questions

3:   How do outcomes vary by heterogeneity in subpopulations?

  • Age
  • Menopausal Status
  • Use of Exogenous Estrogen
  • Risk of Breast Cancer
  • Ethnicity and Race

4:   What methods, such as clinical risk assessment models, have been used to identify
women who could benefit from medications to reduce risk of primary breast cancer?


Slide 21

Drugs to Reduce Breast Cancer Risk

Type Brand Name Notes
Tamoxifen citrate SERM Nolvadex
Soltamox
  • Reduce breast cancer risk in high-risk women.
  • Breast cancer treatment.
Raloxifene SERM Evista
  • Reduce breast cancer risk in high-risk postmenopausal women.
  • Treatment and prevention of postmenopausal osteoporosis.
Tibolone
Not FDA
Approved
STEAR Livial
  • Prevention of postmenopausal osteoporosis
  • Treatment of vasomotor menopausal symptoms
Lasofoxifene
Not FDA approved
SERM Fablyn
  • Under development
  • Reduces bone loss
  • Reduces LDL Cholesterol

 

Slide 22

Comparators

9 Primary Prevention Trials

N (Drug vs Placebo)

Tamoxifen vs. Raloxifene Study of Tamoxifen & Raloxifene (STAR) 9872 vs. 9875

Tamoxifen
Vs.
Placebo

International Breast Cancer Intervention Study (IBIS-1) 3579 vs. 3575
National Surgical Adjuvant Breast and Bowel Project P-1 (NSABP-1) 6681 vs. 6707
Royal Marsden Hospital Trial 1238 vs. 1233
Italian Trial 2700 vs. 2708
Raloxifene
Vs.
Placebo
Multiple Outcomes of Raloxifene (MORE/CORE) 5129 vs. 2576
Raloxifene Use for the Heart (RUTH) 5044 vs. 5057
Tibolone vs. Placebo Long-term Intervention on Fractures with Tibolone (LIFT) 2249 vs. 2257
Lasofoxifene vs. Placebo Postmenopausal Evaluation and Risk Reduction with Lasofoxifene (PEARL) 2852 vs. 2852


Slide 23

Meta-Analysis of Placebo-Controlled Trials
Invasive Breast Caner

Study (yr)

Risk Ratio (95% CI)

Tamoxifen NSABP P-1 (2005) 0.57 (0.46-0.70)
IBIS (2007) 0.74 (0.58-0.94)
Marsden (2007) 0.78 (0.58-1.04)
Italian (2007) 0.80 (0.56-1.15)
Tamoxifen combined 0.70 (0.59-0.82)

Raloxifene

MORE (2004) 0.34 (0.22-0.50)
RUTH (2006) 0.56 (0.38-0.83)
Raloxifene combined 0.44 (0.27-0.71)
Tibolone LIFT (2008) 0.32 (0.13-0.80)
Lasofox PEARL (2010) 0.15 (0.04-0.50)

 

On the right of the slide there is a forest plot.  The forest plot shows the main outcome of invasive breast cancer by showing the results of the four medications in the trials that were evaluated.  For Tamoxifen, there were four placebo-controlled trials indicated in the white squares.  In the horizontal line that goes through the squares represents the confidence intervals, and the line down the middle of the forest plot shows the separation between favors drug/favors placebo.  Favors drug represents that there was a benefit of the drug, or there was significant findings compared to placebo. The favors placebo indicates that there was no difference. On the forest plot present on the slide, all of the plots are on the side labeled favors drugs and shows that there is a benefit to drug use.


Slide 24

Summary of Benefits
Events Prevented in Placebo-Controlled Trials

More Clinical Outcome

Tamoxifen
(5 trials)

Raloxifene
(2 trials)

Tibolone
(1 trial)

Lasofoxifene* (1)

Invasive Breast Cancer 8/1,000* 9/1,000 10/1,000 7/1,000
Estrogen Receptor + 8/1,000 8/1,000 NA 7/1,000
Estrogen Receptor - X x NA X
Noninvasive Cancer X x NA X
All-Cause Death X x NA X
Vertebral Fracture X 7/1,000 44/1,000 47/1,000
Nonvertebral Fracture 3/1,000 X 34/1,000 29/1,000

*Per 1,000 women-years assuming 5 years of treatment.

 

Slide 25

Summary of Benefits
Events Prevented in STAR Head-to-Head Trial

Major Clinical Outcome

Raloxifene vs Tamoxifen 2010

Invasive Breast Cancer More with Raloxifene
Estrogen Receptor +  
Estrogen Receptor -  
Noninvasive Cancer No Difference
All-Cause Death No Difference
Vertebral Fracture  
Nonvertebral Fracture  

 

Slide 26

Tamoxifen

  • Reduces breast cancer:
    • Age (≤50/>50)
    • Pre/post menopausal
    • Estrogen use (yes/no)
    • Family history of breast cancer (with/without)
    • LCIS or atypical hyperplasia
  • In National Surgical Adjuvant Breast and Bowel Project (NSABP)  P-1, cancer rates were highest and risk reduction greatest:
    • Prior atypical hyperplasia
    • Highest modified Gail model risk category (>5%)

Raloxifene

  • Reduces breast cancer:
    • Age (≤60/>60 or ≤65/>65)
    • Age at menarche
    • Parity
    • Age at first live birth
    • Body mass index (≤25/>25)

 

Slide 27

Summary of Harms
Events Caused in Placebo-Controlled Trials

Major Clinical
Outcome

Tamoxifen
(5 trials)

Raloxifene
(2 trials)

Tibolone
(1 trial)

Lasofoxifene (1)

Thromboembolic
events
4/1,000* 7/1,000 x 8/1,000
Coronary heart
disease
x x x 12/1,000 less
Stroke x x 11/1,000 7/1,000 less
Endometrial cancer 4/1,000 x NA NA
Cataracts 3/1,000** x NA NA

*Per 1,000 women-years assuming 5 years of treatment.
**Results from NSABP P-1 trial.

 

 

Slide 28

Summary of Harms
Events Caused in STAR Head-to-Head Trial

Major Clinical
Outcome
Raloxifene vs Tamoxifen 2010
Thromboembolic events More with Tamoxifen
Coronary heart disease  
Stroke  
Endometrial cancer More with Tamoxifen
Cataracts More with Tamoxifen

 

Slide 29

Common Side Effects 

Tamoxifen

  • Hot Flashes
  • Vaginal Symptoms (discharge, dryness)
  • Leg Cramps
  • Bladder Control Problems

Raloxifene

  • Hot Flashes
  • Leg Cramps
  • Musculoskeletal Problems
  • Weight Gain

Lasofoxifene

  • Leg Cramps
  • Hot Flashes
  • Vaginal Candidiasis

Tibolone

  • Vaginal Bleeding
  • Reduces Hot Flashes

 

Slide 30

Selecting Candidates for Therapy
Risk Based on Gail Model (> 1.67% 5-year Risk)

  • Age
  • Age at Menarche
  • Age at First Birth
  • Family History of Breast Cancer in First-Degree Relative
  • History of Atypical Hyperplasia
  • Prior Breast Biopsies

 

cancer.gov/bcrisktool/

 

A widget is present on the top of the slide with a man talking to a woman and the text “Breast Cancer Risk Assessment Tool, An Interactive Tool For Measuring the Risk of Invasive Breast Cancer”

 

Slide 31

Summary of Risk Model Results
Discriminatory Accuracy (16 studies of 9 models)

On this slide an X and Y axis graph is present.  The Y axis is labeled “True Positive Rate (Sensitivity) and the X axis is labeled “False Positive Rate (1-specificity).”  In the graph there are three lines identified as Excellent, Good, and Worthless.  The graph is showing the summary of research that was done on 16 studies of 9 models that were variations of the Gail model.  The range of area under the receiver operating characteristic (ROC) curve shows discriminatory accuracy.  Overall the graph shows how well to sort out individual risk with the 16 studies of the 9 models.


Slide 32

Questions

  • To submit a question:
    • Press the “Ask Question” button located at the bottom of the screen. 
    • When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. 
    • Once you have completed your question, press the “Submit” button.

 

Slide 33

Comparative Effectiveness of Core Needle and Open Surgical Biopsy for the Diagnosis of Breast Lesions

Karen Schoelles, M.D., S.M., FACP
Director, ECRI Institute Evidence-based Practice Center

 

Slide 34

Objectives

  • To describe the process of developing this comparative effectiveness review
  • To describe the findings of the review
  • To describe the implications of the review


Slide 35

Analytic Framework

This slide has a flow chart that shows the analytic framework that was used to map out how to approach the research topic.  The flow chart has boxes that are labeled P, I, C, or O.  P stands for patient population; I, Intervention; C, comparator, and O for Outcomes.  The purpose of the flow chart is to show what types of evidence the research group needed for the research topic and to show the most important questions that need to be addressed, such as adverse events and additional research.  


Slide 36

Population

  • Asymptomatic women with an abnormality identified on self-exam or by clinician exam
  • Asymptomatic women with an abnormality identified by screening imaging
    • Ultrasound – solid or mixed
    • Mammography – typically BI-RADS® 4

 

Slide 37

ACR Breast Imaging Reporting and Data System (BI-RADS®)

  • 0: Need additional imaging evaluation and/or prior mammograms for comparison
  • 1: Negative
  • 2: Benign finding
  • 3: Probably benign; initial short-interval followup suggested
  • 4: Suspicious abnormality. Biopsy should be considered
  • 5: Highly suggestive of malignancy. Appropriate action should be taken
  • 6: Known biopsy-proven malignancy

 

Slide 38

Intervention: Core Needle Biopsy (CNB)

  • Hollow core needle inserted percutaneously
  • Usually 11-, 14-, or 16-gauge needles
  • Lesion located by palpation or imaging (stereotactic mammography, ultrasound, or MRI) during the procedure
  • May be inserted multiple times or only once if using vacuum assistance

 

Slide 39

Comparator: Open Surgical Biopsy

  • Excisional: Attempted complete removal of abnormality

 

  • Incisional: Sample of the abnormality
  • Non-palpable lesions: May first use imaging to place marking wire, carbon particles, dye, etc. which is then used by the surgeon to identify the lesion in the operating room

 

Slide 40

Comparator: Clinical Followup

  • Clinical and imaging follow-up for at least 6 months


Slide 41

Methods

Searches: biopsy, breast biopsy, breast diseases, breast cancer, breast tumor, excision, incisional, large core, Mammotome (Ethicon Endosurgery, Cincinnati, OH), needle biopsy, percutaneous biopsy, stereotactic breast biopsy, surgery, etc. (September 2009)

 

Slide 42

Evaluation of the Risk of Bias in Individual Studies

This slide has a bar chart evaluating the risk of bias in individual studies.  The graph shows the major problem in the studies was the lack of good reporting of what happened to the women that had core-needle biopsies and open surgical biopsies.  The studies also did not report sufficient followup to make the research group comfortable.  The studies that were ultimately used were the ones that had at least 6 months of followup.

 

Slide 43

Test Characteristics

Test Results Disease Present Disease Absent
Positive True positives (TP) False positives (FP)
Negative False negatives (FN) True negatives (TN)

 

  • Sensitivity, specificity – commonly understood
    • Sensitivity = TP/(TP+FN)
    • Specificity = TN/(FP+TN)
  • Predictive values – incorporates prevalence
    • Positive predictive value = TP/(TP+FP)
    • Negative predictive value = TN/(FN+TN)
  • Likelihood ratios – independent of prevalence, but clinical use requires assessment of pretest probability

 

Slide 44

Test Characteristics

Test Results Disease Present Disease Absent
Positive True positives (TP) False positives (FP)
Negative False negatives (FN) True negatives (TN)
  • Likelihood ratio – useful for comparing tests
    • Positive likelihood ratio =       (TP/(TP+FN))/(FP/(FP+TN))
    • Negative likelihood ratio =     (FN/(TP+FN))/(TN/(FP+TN))
  • For this evaluation, not missing a cancer was considered the most important outcome, reflected by:
    • Sensitivity, Negative Predictive Value, and Negative Likelihood Ratio

 

Slide 45

Fagan’s Nomogram

On this slide is a Fagan nomogram.  Superimposed on the nomogram is what would be typical for a woman who has had a mammogram that shows BI-RADS for abnormalities.  The women in the nomogram typically would have about a 30 percent chance of actually eventually being found to have breast cancer.  On the left side of that diagram is the 30 percent which is the pretest probability of having cancer in this case.  On the nomogram the likelihood ratio shown is for one of the core-needle biopsy types.  The positive likelihood ratio is 54.  The solid red line drawn between the 30 percent pretest probability through the central line of likelihood ratio, crossing through the 54, on the far right of the nomogram is the posttest probability.  The posttest probability is the likelihood that a woman with a positive test for cancer using this method, if she initially had a 30 percent risk of cancer, a positive test changes your impression to about a 96 percent chance of breast cancer, so there you’re relatively certain that cancer is present. 

The diagonal dashed line going in the downward direction crosses through the likelihood ratio point at 0.04.  This is the negative likelihood ratio.  If a woman with a pretest probability of 30 percent has a negative breast biopsy using this technique and cross the line at 0.04, it can be concluded that her posttest likelihood of having breast cancer is down around 2 percent. 

Fagan TJ Letter: Nomogram for Bayes theorem. N Engl J Med 1975; 293: 257

Interactive version: http://www.cebm.net/index.aspx?o=1161 Exit Disclaimer

 

Slide 46

This slide shows the meta-analyses using a graph for the sensitivity of the different forms of biopsy.  Surgical, open surgical biopsy is assumed to be fairly close to 100 percent.   

Slide 47

This slide shows the negative likelihood ratios for the stereotactic techniques. The results are fairly close to those for the open surgical biopsy. In this case the smaller the number, the better the test is in ruling out breast cancer. 

Slide 48

This slide was not addressed during event by the presenter but shows DCIS underestimation percentage.

Slide 49

This slide was not addressed during the event by the presenter but shows ADH underestimation percentage.

Slide 50

Overall Strength of Evidence for Each Question-Outcome Pair

  • Risk of bias in the studies included to answer the question
  • Quantity of evidence (number of studies and patients)
  • Consistency of the findings across and within studies
  • Robustness of the results (sensitivity analyses)
  • Possible grades: high, moderate, low, or insufficient

 

Slide 51

Summary of Key Accuracy Findings

 

Slide 52

Summary of Key Accuracy Findings

Type of biopsy Number of missed cancers expected for every 1,000 biopsies Risk of malig- nancy following a “benign” test result Number of malig-nancies expected per 1,000 biopsy diagnoses of “high risk” lesion Number of invasive cancers expected per 1,000 biopsy diagnoses of DCIS Strength of evidence supporting the conclusion
Open surgical4 3 to 6 0 to 1% 0 0 Not rated
MRI guidance automated gun Insufficient data to estimate Insufficient
US guidance vacuum-assisted 2 to 56 0.3 to 8%

Insufficient data to estimate

Low
Stereotactic guidance vacuum-assisted 1 to 6 0.1 to 1% 177 to 264 111 to 151 Low

 

Slide 53

Post-Biopsy Probability of Having Cancer After A Negative Core-Needle Biopsy Result 

Type of biopsy Analysis results If analysis over- estimated sensitivity by 1% (e.g., sensitivity 97% rather than 98%) If analysis over- estimated sensitivity by 5% (e.g., sensitivity 93% rather than 98%) If analysis over- estimated sensitivity by 10% (e.g., sensitivity 88% rather than 98%)
Freehand automated gun 6% 6% 8% 9%
Ultrasound guidance automated gun 1% 1% 3% 5%
Stereotactic guidance automated gun 1% 1% 3% 5%
Ultrasound guidance vacuum-assisted 2% 2% 3% 6%
Stereotactic guidance vacuum assisted 0.4% 0.8% 3% 5%

 

Slide 54

For Additional Information 

Bruening W, Fontanarosa J, Tipton K, Treadwell JR, Launders J, Schoelles K. Systematic review: comparative effectiveness of core-needle and open surgical biopsy to diagnose breast lesions. Ann Intern Med. 2010 Feb 16;152(4):238-46. Epub 2009 Dec 14. PMID: 20008742


Slide 55

Questions

To submit a question:

  • Press the “Ask Question” button located at the bottom of the screen. 
  • When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. 
  • Once you have completed your question, press the “Submit” button.

 
Slide 56

For more information about…


Slide 57

Upcoming Web conferences

  • Monday, December 6 at 2 p.m. ET.

Applying Existing Evidence to Cardiac Care

  • Monday, December 13 at 11 a.m. ET.

Evidence-Based Medicine for Pharmacists
in the Patient-Centered Medical Home

  • Tuesday, December 14 at 12 p.m. ET.

Applying Existing Evidence to Diabetes Care


Slide 58

Thank you! 

  • Thank you for joining us today!
  • Please take a moment to provide us feedback at the end of this event.
  • A recording and transcript for today’s event will be available on the AHRQ Web site.