Guidelines for Breast Cancer Screening: An Update SBI Breast Imaging Symposium 2016 Austin Texas, April 7, 2016 Robert A. Smith, PhD Cancer Control Department American Cancer Society Atlanta, GA
I have no conflicts of interest to report
Some Historic Observations about Breast Cancer Screening Guidelines For the past 30+, organizations have differed in their recommendations Over time, a growing number of organizations have issued guidelines, and these guidelines have clustered among like-minded organizations Endorsement and use of guidelines also have clustered among like-minded policy makers While end-users lament different recommendations, there is little chance that this situation will change soon
Breast Cancer Screening Guidelines--2016 At what age should average risk women start, and how often should screening take place? Organization Starting Age Screening Interval ACS, ASBS, ASCO ACR, ACOG, NCCN, NCBC USPSTF, AAFP, ACP 45; with the option to start at 40 Annual 40-54: Biennial 55+, with option to continue annual screening 40 Annual 50; the decision to begin screening between ages 40-49 should be individualized based on risk and values Biennial, 40+ ACS=American Cancer Society; ASBS=American Society of Breast Surgeons; ASCO=American Society of Surgical Oncology; USPSTF=U.S. Preventive Services Task Force; ACOG=American College of Obstetricians and Gynecologists; NCCN=National Comprehensive Cancer Network; NCBC= National Consortium of Breast Centers; AAFP=American Academy of Family Physicians; ACP=American College of Physicians;
Breast Cancer Screening Guidelines--2016 At what age should average risk women stop screening? Organization ACS, ASBS, ASCO Stopping Age Continue screening as long as health is good and life expectancy is at least 10 ACOG Shared decisions 75+ ACR NCCN USPSTF, AAFP, ACP Continue screening as long as health is good and life expectancy is at least 5-7, and there is willingness to undergo additional testing Consider comorbidity and therapeutic decisions 74; Insufficient evidence to recommend for or against screening ACS=American Cancer Society; ASBS=American Society of Breast Surgeons; ASCO=American Society of Surgical Oncology; USPSTF=U.S. Preventive Services Task Force; ACOG=American College of Obstetricians and Gynecologists; NCCN=National Comprehensive Center Network; NCBC=National Consortium of Breast Centers; AAFP=American Academy of Family Physicians; ACP=American College of Physicians;
What accounts for the differences between the ACS and USPSTF Guidelines? Decisions Age to begin screening: 40 vs. 45 vs. 50? The inter-screening interval: 1 vs. 2? Age to stop screening: Age vs. health status Basic building blocks What data were considered, and not considered? Are judgments/opinions apparent? If so, what factors appear to influence judgments/opinions
Current Breast Cancer Screening Guideline for Average Risk Women: ACS (2015) & USPSTF (2016) Areas of Agreement Areas of Disagreement Recommendation ACS USPSTF Breast Self Exam (BSE) Clinical Breast Exam (CBE) Mammography USPSTF GRADES (A & B, C, D, I) ACS S = Strong Q = Qualified, if not labeled Not recommended Not recommended 40-44: Opportunity for informed decision, Annual 45-54 (S): Annual 55+ Biennial, with option to continue annual screening 75+ Continue screening as long as health is good and life expectancy 10+ yrs. Against clinicians teaching BSE (D) Insufficient evidence (I). 40-49: Individual decision (C) Biennial Ages 50-74: Biennial (B) Ages 75+ : Insufficient evidence (I)
Guideline Development Methodology, ACS & USPSTF Areas of Similarity Areas of Dissimilarity Measuring disease burden ACS Absolute risk in 1, 5, 10 year age groups Incidence, Mortality, Incidencebased mortality, Premature mortality USPSTF Absolute risk in 10 year age groups Mortality Evidence of benefit Emphasis on benefit Emphasis on harms Randomized controlled trials (less) Observational studies (more) Modeling (less) Individual Absolute benefit (higher) False positives (less) Biopsy (less) Anxiety (less) Overdiagnosis (less) Randomized controlled trials (more) Modeling (more) Population Absolute benefit (lower) False positives (more) Biopsy (more) Anxiety (more) Overdiagnosis (more)
Age to Begin Screening Key Issues & Evidence Data on the burden of disease Incidence Incidence-based mortality Premature mortality Data on the relative and absolute benefit of screening Mortality reduction is the common denominator between guidelines How endpoints are measured is a key difference between guidelines Data on harms associated with screening To what degree is the magnitude of harms considered? How good are the data on different harms
Age-Specific Disease Burden
30-34 0.1
Breast Cancer in Younger Women Breast cancer in younger women Incidence rate per Probability of being diagnosed in the 1 year interval b % of BC deaths by age at 100,000 a % 1 in N diagnosis c 35 44.9 0.0% 2,212 1% 36 51.9 0.1% 1,943 1% 37 61.6 0.1% 1,713 1% 38 65.9 0.1% 1,440 1% 39 79 0.1% 1,232 1% 40 106.3 0.1% 1,076 1% 41 109.8 0.1% 954 1% 42 120.9 0.1% 857 1% 43 130.6 0.1% 774 1% 44 148.3 0.1% 706 2% 45 165.9 0.2% 648 2% Risk between ages 40-41 is 9 in 10,000. The recall rate is 1,600 2,000 per 10,000 (about 1 in 5) a. Delay-adjusted incidence rates, SEER 18, 2008-2012 b. SEER 18, 2010-2012 c. Distribution of BC deaths (2008-2012) from a BC diagnosis up to 15 prior, S
Age Distribution of Invasive Female Breast Cancer Cases, 2007-2011 14% 12% 13% 12% 12% 12% 10% 10% 9% 8% 8% 6% 6% 6% 6% 4% 3% 2% 0% <1% 20-24 <1% 25-29 1% 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Source: SEER 18 registries.
Distribution of Breast Cancer Deaths by Age at Diagnosis, 2007-2011 2,000 1,800 11% 11% 11% No. of breast cancer deaths 1,600 1,400 1,200 1,000 800 600 400 2% 5% 7% 10% 9% 9% 9% 8% 8% 200 0 <1% 20-24 1% 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age at diagnosis Source: SEER 9 registries, patients followed for 15 after diagnosis.
Distribution of Years of Life Lost due to Death from Breast Cancer by Age at Diagnosis Distribution of YLL from breast cancer by age at diagnosis 16% 15% 15% 14% 12% 13% 12% % of total YLL due to BC 10% 8% 6% 4% 5% 9% 10% 7% 5% 4% 2% 2% 2% 2% 0% 0% 0% 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-89 80-84 85+ Age at diagnosis 15
Perspective on risk between ages 40-49 At ages 40-44, risk of being diagnosed with breast cancer is low, but is increasing every year. During the 10 year period between ages 45-49 and 50-54, risk also is increasing, but for these 22 million women, risk is more similar than different Three conclusions: 1. The period between age 40-49 is characterized by a period of lower risk in the early 40s, and higher risk in the later 40s 2. The logic for beginning screening at age 50 also extends to age 45 3. Considering risk in 10 year age groups obscures important differences between large age-specific subgroups
The Evolving Evidence for Mammography Screening the Randomized Trials
RCTs of screening mammography: Overall results in terms of breast cancer mortality Study ID Canadian NBSS-1 Canadian NBSS-2 Edinburgh HIP Two-County Trial Malmo-1 Malmo-2 Stockholm Gothenburg UK Age Trial Overall 16 14 12 10 8 6 RR (95% CI) 1.06 (0.80, 1.40) 1.02 (0.78, 1.33) 0.71 (0.53, 0.95) 0.77 (0.62, 0.97) 0.69 (0.56, 0.84) 0.82 (0.67, 1.00) 0.64 (0.39, 1.06) 0.91 (0.65, 1.27) 0.76 (0.56, 1.04) 0.83 (0.66, 1.04) 0.79 (0.73, 0.86) 4 2 0-1.0 0.0 1.0 2.0 3.0 0 1 Overall RR = 0.79 (95% CI: 0.73, 0.86) Tabar, et al. Breast J, 2014 Heterogeneity p = 0.3
Tabar, et al. Breast J, 2014
Summary of RCT Relative Incidence of Node Positive Tumors and Relative Mortality Women Aged 40-49 Study Relative Incidence Node + Tumor (N+) Relative Mortality Two County (W-E).84 (16% < N+).87 (13% < deaths) Malmo.56 (44% < N+).64 (36% < deaths) Gothenburg.64 (36% < N+).56 (44% < deaths) Stockholm.98 (2% < N+) 1.01 (1% > deaths) HIP.82 (18% < N+).77 (27% < deaths) Edinburgh.73 (27% < N+).81 (19% < deaths) NBSS-1 1.40 (40% > N+).97 (3% < deaths) * * * Mortality reductions are statistically significant
USPSTF Meta-Analysis of the RCTs, Women Ages 39-49 Overall RR = 0.92, or an 8% breast cancer mortality reduction associated with an invitation to screening. Adjusting RCT RR s to the long accrual method diminishes the estimate of benefit Nelson, et al. Annals of Internal Medicine, 2016
Figure 2: Effects of Invitation to screening on the relative risk of being diagnosed with a stage III+ tumor, or tumor 4 or 5 cm in size Women aged 39-49 yrs Women aged 50+ yrs
USPSTF Meta-Analysis of the RCTs, Women Ages 39-49, and Estimate of Absolute Benefit over 10 of screening Age Mortality rate per 100,000 person What s wrong with this estimate? Screening period and follow-up period are contemporaneous, and follow-up is too short Expected deaths are too low Relative benefit of mammography is too low Overall net benefit is underestimated Nelson, et al. Annals of Internal Medicine, 2016 Breast cancer mortality reduction RR Deaths prevented with screening 10, 000 women over 10 39-49 36 0.92 2.9
The Evolving Evidence for Mammography Screening Beyond the RCTs: Trend Studies, Incidence-Based Mortality Studies, Case Control Studies
Incidence-Based Mortality Evaluations of the Impact of Modern Service Screening in Europe EUROSCREEN Group IBM studies: N = 20 In an IBM study all breast cancer deaths occurring in a population over a period of time are enrolled in the study only if the breast cancer diagnosis occurred in a certain time/age window (taking into account eligibility and opportunity to be screened), and the population is classified by screening or by invitation to screening. J Med Screen 2012;19 Suppl1:14 25
EUROSCREEN Incidence-based mortality estimates for breast cancer mortality reduction in women ages 50-69, exposed versus not-exposed to screening J Med Screen 2012;19 Suppl1:14 25
Effectiveness of Population-Based Service Screening With Mammography for Women Ages 40 to 49 Years Contemporaneous comparison of breast cancer mortality in Swedish counties offering mammography vs. those not offering mammography 1986-2005 Average follow-up = 16 Cancer 2010; published online: 29 SEP 2010
Map of Study and Control Group Areas, and Crude Cumulative Breast Cancer Mortality per 100,000 Person Years Control Group Study Group Cancer 2010; published online: 29 SEP 2010 RR = 0.74; 95% CI 0.66 0.83)
Pan-Canadian Study of Mammography Screening Comparison of breast cancer screening among exposed (2.8 million) and nonexposed women, 1990-2009 7 of 12 Canadian breast cancer programs, representing 85% of the population SMRs were calculated comparing observed mortality in participants to that expected based upon nonparticipant rates.
Standardized mortality ratios (SMRs) by Canadian province for ages at entry: Summary estimates are based upon random effects models. All statistical tests were two-sided. 40-49 44% fewer deaths 50-59 JNCI 2014;106(11) 40% fewer deaths
Perspective on the Benefit of Screening in Average Risk Women: ACS (2015) & USPSTF (2016) Areas of Agreement Areas of Disagreement Evidence ACS USPSTF Randomized Trials (RCT) Meta-analysis of the RCTs Observational Studies Modeling Studies Low RCT relative risks measure efficacy, Not effectiveness Discount value of meta-analysis Consider features of individual RCTs More influential for measuring effectiveness than RCTs Emphasis on exposure to screening Accepts relative benefits are similar in all age groups Considered, but less influential than empirical data Low RCT relative risks measure efficacy and effectiveness Benefits increasing with age Prioritize meta-analysis Does not consider outcomes of individual RCTs Reviewed, but did not influence estimate of benefit Very influential, and preferred over observational data
The Screening Interval There have been no trials that have compared annual screening with biennial screening The screening interval has been influenced by estimates of tumor growth rates & interval cancer rates Screening intervals also have been recommended based on tradeoffs between estimated mortality rates and false positive rates
Interval Cancer Rate as a Percent of the Expected Incidence in the Unscreened Population by Year Since Negative Screen, Swedish Two County Study Faster tumor growth in premenopausal women results in a higher interval cancer rate. Thus, screening intervals should be tailored to the age of the woman.
Supplemental analysis on the screening interval from NCI funded Breast Cancer Surveillance Consortium Miglioretti D, et al. Risk of less-favorable breast tumor characteristics with biennial versus annual mammography by age and menopausal status Design, setting, and participants: --15,440 women aged 40-85 with breast cancer diagnosed within 1 year of an annual or within 2 of a biennial screening mammogram performed from 1996-2011. --Updated previous analyses by using narrower screening intervals, specifically 11-14 months for annual and 23-26 months for biennial screening intervals. Main finding--among premenopausal women, biennial screeners had higher proportions of tumors with advanced stage (relative risk [RR]=1.28), larger size (RR=1.21), and any less-favorable prognostic characteristic (RR=1.11) compared with annual screeners [all RR were statistically significant]. 34
RR (95% CI) of Less-favorable Invasive Cancer Characteristics for Biennial versus Annual Screeners, by Age, Menopausal Status, and Current Hormone Therapy Use, Adjusted for Race/Ethnicity, First-Degree Family History of Breast Cancer 35
Perspective on the Screening Interval: ACS (2015) & USPSTF (2016) Areas of Agreement Areas of Disagreement Evidence ACS USPSTF Randomized Trials (RCT) Observational Studies Modeling studies Benefit vs. harms Compared interval cancer rates in the RCTs by age Relied on supplemental analysis of Breast Cancer Surveillance Consortium data Judged modeling studies not suitable due to lack of hybrid models that tailored age and screening interval Harms not a factor in determining the screening interval Focused on lack of head to head RCTs comparing 1 vs. 2 year screening Discounted results of observational studies Relied entirely on modeling. Harms an important factor in determining the screening interval, both false positives & overdiagnosis
Distribution of breast cancer deaths by age at diagnosis, 2007-2011 2,000 1,800 11% 11% 11% 34% Number of Breast Cancer Deaths 1,600 1,400 1,200 1,000 800 600 400 2% 5% 7% 10% 9% 9% 9% 8% 8% 200 0 <1% 1% 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age at diagnosis Source: SEER 9 registries, patients followed for 15 after diagnosis.
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Perspective on Age to Stop Screening: ACS (2015) & USPSTF (2016) Areas of Agreement Areas of Disagreement Evidence ACS USPSTF Randomized Trials (RCT) RCT data are limited RCT data are limited Observational and Modeling Studies Yes No Primary Emphasis Longevity and remaining of life in good health Ease of detection & treatment Lack of RCT data Comorbidity Overdiagnosis Benefit vs. harms Favorable within defined boundaries (good health and longevity) Uncertain
Adverse Outcomes Associated with Screening (aka harms ) In recent there has been growing concerns about harms associated with screening Guideline developers are obliged to scrutinize harms as well as benefits This is a challenge because there are not equivalent metrics for measuring benefits and harms 40
10 Year Probability of a False Positive Exam Based on Age at First Mammogram 60 40 20 Annual Biennial 0 Overall 40-49 50-59 False-positive recall probability: 16.3% at first mammogram 9.6% at subsequent exams Probability of false-positive biopsy recommendation: 2.5% at first mammogram 1.0% at subsequent exams
New data of the rate of False Positive Mammography results from digital mammography. First mammogram not included. Women in their 40s have the highest rate. (Source, BCSC data, Pacific NW EPC, 2015) 42
Overdiagnosis Overdiagnosis is the detection of a cancer by screening that would not have progressed to become symptomatic in a woman s lifetime. Estimates of overdiagnosis range from 0% to > 50%, and vary greatly in terms of methodologic rigor The ACS systematic evidence review Duke group judged the quality of evidence for the existence of some overdiagnosis to be HIGH, but judged the quality of evidence on the magnitude of overdiagnosis to be LOW. 43
The Marmot Report concluded that approximately 19% of cancers were overdiagnosed [This estimate was judged by many to be too high] Of the 307,000 women aged 50 52 who are invited to screening each year, [approximately] 1% would have an overdiagnosed cancer during the next 20. Given the uncertainties around the estimates, the figures quoted give a spurious impression of accuracy. Source: Marmot MG, et al. BMJ (2013) 108, 2205 2240
Perspective on Overdiagnosis: ACS (2015) & USPSTF (2016) Areas of Agreement Areas of Disagreement Evidence ACS USPSTF Randomized Trials (RCT) Observational Studies Modeling Studies Critical Evaluation of Estimates Estimate Ideal method for measuring overdiagnosis, but existing RCTs too limited Wide range of estimates (0-> 50%) Methodology highly variable Considered, but less influential than empirical data Yes Judged quality of estimates to be low Lifetime risk approach (1%) Accept estimates from some RCTs (Malmo and CNBSS) and ignore others (Two County & UK Age Trial) Noted, but USPSTF relied on RCT estimates Very influential, and preferred over observational data No Lives saved (1) vs. number overdiagnosed (2-3).this approach exaggerates the estimate of harm
Conclusions-1 There are important differences in current guidelines, but also important similarities All organizations emphasize that benefits outweigh harms at all ages All organizations endorse informed decision making All organizations endorse the importance of women being informed about benefits and limitations of screening
Conclusions-2 Ironically, the 2016 systematic review produced for the USPSTF recommendation update cites less benefit and more harms associated with mammography compared with the 2009 review However, the narrative of the USPSTF recommendation is more favorable about the benefits of screening, including screening in women under age 50
USPSTF perspective on risk between ages 40-49 For women in their 40s, the benefit still outweighs the harms, but to a smaller degree; this balance may therefore be more subject to individual values and preferences than it is in older women. Women who value the possible benefit of screening mammography more than they value avoiding its harms can make an informed decision to begin screening.
USPSTF perspective on risk between ages 40-49 It is, however, a false dichotomy to assume that the only options are to begin screening at age 40 or to wait until age 50. As women advance through their 40s, the incidence of breast cancer rises. The balance of benefit and harms may also shift accordingly over this decade, such that women in the latter half of the decade likely have a more favorable balance than women in the first half. Indeed, the CISNET models suggest that most of the benefit of screening women aged 40 to 49 would be realized by starting screening at age 45.
Conclusions-3 High adherence to even the least aggressive guideline would save more lives than the current weak adherence to regular screening The new ACS guideline allows clinicians and women to choose among options about when to begin screening, and how often to be screened The new guideline provides stronger evidence to support a choice among options.
Still.There are Legitimate Concerns About Guideline Differences The guidelines are too complicated Weak adherence to creating opportunities for informed decision making Referring clinicians are not prepared to discuss benefits, limitations, and harms associated with screening Lack of reminder systems will result in weaker adherence to recommended screening intervals 51
ACOG Consensus Workshop Core groups presented guidelines and rationale Other organizations summarized their guidelines, but also their opinions about guideline differences There is a clear sense that we must move beyond the status quo 52
Thank you