Guidelines for Breast Cancer Screening: an Update SBI Breast Imaging Symposium 2016 Austin Texas, April 7, 2016

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+ years, 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, 45; with the option to start at Annual 40-54: Biennial 55+, ASCO 40 with option to continue annual screening ACR, ACOG, 40 Annual NCCN, NCBC USPSTF, AAFP, 50; the decision to begin Biennial, 40+ ACP screening between ages 40- 49 should be individualized based on risk and values

Organization Stopping Age ACS, ASBS, Continue screening as long as health is good and life ASCO expectancy is at least 10 years ACOG Shared decisions 75+ ACR Continue screening as long as health is good and life expectancy is at least 5-7 years, and there is willingness to undergo additional testing

NCCN Consider comorbidity and therapeutic decisions

USPSTF, AAFP, 74; Insufficient evidence to recommend for or against ACP 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 years? – 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 Not recommended Against clinicians teaching (BSE) BSE (D) Clinical Breast Not recommended Insufficient evidence (I). Exam (CBE) Mammography 40-44: Opportunity for 40-49: Individual decision (C) USPSTF GRADES informed decision, Annual Biennial (A & B, C, D, I) 45-54 (S): Annual Ages 50-74: Biennial (B)

ACS Ages 75+ : Insufficient S = Strong 55+ Biennial, with option evidence (I) Q = Qualified, if to continue annual not labeled screening 75+ Continue screening as long as health is good and life expectancy 10+ yrs. Guideline Development Methodology, ACS & USPSTF Areas of Similarity Areas of Dissimilarity

ACS USPSTF Measuring disease Absolute risk in 1, 5, 10 year age Absolute risk in 10 year age burden groups groups Incidence, Mortality, Incidence- Mortality based mortality, Premature mortality Evidence of Randomized controlled trials Randomized controlled trials benefit (less) (more) Observational studies (more) Modeling (less) Modeling (more) Emphasis on Individual Population benefit Absolute benefit (higher) Absolute benefit (lower) Emphasis on False positives (less) False positives (more) harms Biopsy (less) Biopsy (more) Anxiety (less) Anxiety (more) Overdiagnosis (less) Overdiagnosis (more)

Age to Begin Screening—Key Issues & Evidence • Data on the burden of disease – Incidence – Inc idence-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 Probability of being % of BC Incidence diagnosed in the 1 deaths by rate per year intervalb age at 100,000a % 1 in N diagnosisc 35 years 44.9 0.0% 2,212 1% 36 years 51.9 0.1% 1,943 1% 37 years 61.6 0.1% 1,713 1% 38 years 65.9 0.1% 1,440 1% 39 years 79 0.1% 1,232 1% Risk between ages 40-41 40 years 106.3 0.1% 1,076 1% is 9 in 10,000. The recall 41 years 109.8 0.1% 954 1% rate is 1,600 – 2,000 per 42 years 120.9 0.1% 857 1% 10,000 (about 1 in 5) 43 years 130.6 0.1% 774 1% 44 years 148.3 0.1% 706 2% 45 years 165.9 0.2% 648 2%

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 years prior, S Age Distribution of Invasive Female Breast Cancer Cases, 2007-2011

14% 13% 12% 12% 12% 12%

10% 10% 9%

8% 8% 6% 6% 6% 6%

4% 3%

2% 1% <1% <1% 0% 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+ years years years years years years years years years years years years years years

Source: SEER 18 registries. Distribution of Breast Cancer Deaths by Age at Diagnosis, 2007-2011

2,000 11% 11% 1,800 11%

1,600 10% 9% 9% 9% 1,400 8% 8% 1,200 7%

1,000

800 5%

600 deaths cancer breast of No. 400 2%

200 1% <1% 0 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+ years years years years years years years years years years years years years years Age at diagnosis

Source: SEER 9 registries, patients followed for 15 years 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%

10% 10% 9%

8% 7%

6% 5% % of total YLL due to BC due YLL total % of 5% 4% 4% 2% 2% 2% 2% 0% 0% 0% 85+ 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 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

16 Study ID RR (95% CI)

Canadian NBSS-1 14 1.06 (0.80, 1.40) Canadian NBSS-2 1.02 (0.78, 1.33) Edinburgh 0.71 (0.53, 0.95) HIP 12 0.77 (0.62, 0.97) Two-County Trial 0.69 (0.56, 0.84) Malmo-1 10 0.82 (0.67, 1.00) Malmo-2 0.64 (0.39, 1.06) Stockholm 0.91 (0.65, 1.27) Gothenburg 8 0.76 (0.56, 1.04) UK Age Trial 0.83 (0.66, 1.04)

Overall 6 0.79 (0.73, 0.86)

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

Relative Incidence Relative Mortality Study Node + Tumor (N+)

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 years of screening

Age Mortality rate per Breast cancer Deaths prevented with 100,000 person mortality screening years reduction RR 10, 000 women over 10 years 39-49 36 0.92 2.9 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 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 years

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

RR = 0.74; 95% CI 0.66 – 0.83)

Cancer 2010; published online: 29 SEP 2010 Pan-Canadian Study of Mammography Screening • Comparison of breast cancer screening among exposed (2.8 million) and non- exposed 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

40% fewer deaths JNCI 2014;106(11) Perspective on the Benefit of Screening in Average Risk Women: ACS (2015) & USPSTF (2016) Areas of Agreement Areas of Disagreement Evidence ACS USPSTF Randomized Low RCT relative risks measure Low RCT relative risks Trials (RCT) efficacy, Not effectiveness measure efficacy and effectiveness Benefits increasing with age Meta-analysis Discount value of meta-analysis Prioritize meta-analysis of the RCTs Consider features of individual RCTs Does not consider outcomes of individual RCTs Observational More influential for measuring Reviewed, but did not influence Studies effectiveness than RCTs estimate of benefit Emphasis on exposure to screening Accepts relative benefits are similar in all age groups Modeling Considered, but less influential Very influential, and preferred Studies than empirical data 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 years with breast cancer diagnosed within 1 year of an annual or within 2 years 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 Compared interval cancer Focused on lack of head to Trials (RCT) rates in the RCTs by age head RCTs comparing 1 vs. 2 year screening

Observational Relied on supplemental Discounted results of Studies analysis of Breast Cancer observational studies Surveillance Consortium data

Modeling studies Judged modeling studies Relied entirely on modeling. not suitable due to lack of hybrid models that tailored age and screening interval

Benefit vs. harms Harms not a factor in Harms an important factor in determining the screening determining the screening interval interval, both false positives & overdiagnosis Distribution of breast cancer deaths by age at diagnosis, 2007-2011

2,000 11% 11% 34% 1,800 11%

1,600 10% 9% 9% 9% 1,400 8% 8% 1,200 7%

1,000

800 5%

600

Number Deaths of Cancer Breast 400 2%

200 1% <1% 0 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+ years years years years years years years years years years years years years years Age at diagnosis

Source: SEER 9 registries, patients followed for 15 years after diagnosis. 38 Perspective on Age to Stop Screening: ACS (2015) & USPSTF (2016) Areas of Agreement Areas of Disagreement

Evidence ACS USPSTF

Randomized RCT data are limited RCT data are limited Trials (RCT)

Observational and Yes No Modeling Studies

Primary Emphasis Longevity and remaining Lack of RCT data years of life in good health Ease of detection & Comorbidity treatment Overdiagnosis Benefit vs. harms Favorable within defined Uncertain boundaries (good health and longevity) Adverse Outcomes Associated with Screening (aka “harms”)

• In recent years 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

40 Annual 20 Biennial

0 40-49 50-59 Overall • 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.

• 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 years.” • “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 Ideal method for measuring Accept estimates from some (RCT) overdiagnosis, but existing RCTs (Malmo and CNBSS) and RCTs too limited ignore others (Two County & UK Age Trial) Observational Wide range of estimates (0-> Noted, but USPSTF relied on Studies 50%) RCT estimates Methodology highly variable Modeling Studies Considered, but less Very influential, and preferred influential than empirical over observational data data Critical Evaluation Yes No of Estimates Estimate Judged quality of estimates Lives saved (1) vs. number to be low overdiagnosed (2-3)….this Lifetime risk approach (1%) 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 years. 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 years 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