Women Informed to Screen Depending on Measures of Risk (Wisdom Study) (WISDOM)

Enabling a Paradigm Shift: A Preference-Tolerant RCT of Personalized vs. Annual Screening for Breast Cancer (Wisdom Study)

Patient-Centered Outcomes Research Institute, Robert Wood Johnson Foundation, Color Genomics, Inc., Salesforce, National Cancer Institute (NCI), Safeway Foundation

Most physicians still use a one-size-fits-all approach to breast screening in which all women, regardless of their personal history, family history or genetics (except BRCA carriers) are recommended to have annual mammograms starting at age 40. Mammograms benefit women by detecting cancers early when they are easier to treat, but they are not perfect. Recent news stories have discussed some of the potential harms: large numbers of positive results that cause stressful recalls for additional mammograms and biopsies. With the current screening approach, half of the women who undergo annual screening for ten years will have at least one false positive biopsy. Potentially more important are cancer diagnoses for growths that might never come to clinical attention if left alone (called "overdiagnosis"). This can lead to unnecessary treatment. Even more concerning is evidence that up to 20% of breast cancers detected today may fall into the category of "overdiagnosis." This study compares annual screening with a risk-based breast cancer screening schedule, based upon each woman's personal risk of breast cancer. The investigators have designed the study to be inclusive of all, so that even women who might be nervous about being randomly assigned to receive a particular type of care (a procedure that is typical in clinical studies) will still be able to participate by choosing the type of care they receive. For participants in the risk-based screening arm, each woman will receive a personal risk assessment that includes her family and medical history, breast density measurement and tests for genes (mutations and variations) linked to the development of breast cancer. Women who have the highest personal risk of developing breast cancer will receive more frequent screening, while women with a lower personal risk would receive less frequent screening. No woman will be screened less than is recommended by the USPSTF breast cancer screening guidelines. If this study is successful, women will gain a realistic understanding of their personal risk of breast cancer as well as strategies to reduce their risk, and fewer women will suffer from the anxiety of false positive mammograms and unnecessary biopsies. The investigators believe this study has the potential to transform breast cancer screening in America.

For almost 30 years, annual mammograms for women over 40 have been a cornerstone of the US strategy to reduce mortality from breast cancer. A number of advances in the understanding of breast cancer biology, and screening in general, have led to calls to revise and improve national screening strategies (Esserman et al., 2014). In 2009, the US Preventive Services Task Force (USPSTF) introduced changes to screening guidelines, recommending that annual mammograms for all women 40-75 be replaced by biennial screening for women ages 50-75, and that screening in the 40's should be individualized by taking patient context into account, including the patient's values regarding specific benefits and harms. Despite being based on a thorough review of the scientific literature, these recommendations continue to spark debate and scientific opinion on the effectiveness of annual screening is greatly divided. On one hand the radiology and obstetrics/gynecology community argues that annual mammograms starting at 40 reduce the rate of interval cancers. On the other hand, primary care physicians and other specialists believe that annual screening results in more false-positives and unnecessary treatment and that a more targeted approach could result in fewer false-positives and less over-diagnosis without increasing the number of interval cancers. In fact it has been estimated that half of women will receive a false-positive recall over 10 years of annual screening and that as many as 20% of all breast cancers might be overdiagnosed. Since 2009 this debate has intensified, paralyzing the system and thwarting any efforts to change or improve screening. The end result is that women are frustrated and confused, and some have stopped screening altogether. Despite a vastly improved understanding of breast cancer risk, the only criteria used to establish a woman's screening recommendations is her age (and BRCA status if known), but there are risk models available that incorporate personal and family history of breast disease, endocrine exposures and breast density to assess breast cancer risk (Constantino, et al., 1999; Parmigiani, et al., 1998; Tyrer, et al., 2004; Claus, et al., 2001; Ozanne, et al., 2003). Most recently certain genetic mutations and common genetic variants (single nucleotide polymorphisms or SNPs) have been confirmed predictors as well (Darabi, et al., 2012). Therefore, advances in this understanding of breast cancer biology, risk assessment, and imaging have enabled the creation of better tools and sufficient knowledge to replace the one-size-fits-all approach to screening and to implement a new, personalized model; one that provides recommendations on when to start, when to stop, and how often to screen that depend upon well characterized measures of risk. The investigators propose to test a transformational evidence-based approach to breast screening that educates women about their actual risk, and tailors screening recommendations to them as individuals. Within the Athena Breast Health Network, the study will compare comprehensive, patient-centered risk-based screening to annual screening for women starting at age 40. The comprehensive risk assessment is based on a widely accepted risk model, the Breast Cancer Surveillance Consortium model, that includes endocrine exposures, family history and breast density, with additional genomic risk factors that include rare and uncommon major breast cancer susceptibility alleles as well as more common and recently validated single nucleotide polymorphisms (SNPs) that can, cumulatively, contribute significantly to a woman's individual risk. The study's personalized approach will recommend an age to start and stop screening as well as a frequency based upon individual risk. Women of highest risk will receive greater surveillance than those of lowest risk where the lower bound is the USPSTF recommended guidelines. In this manner, the study will focus the most effort on those most likely to develop the disease. In close collaboration with patient advocates, the study has been designed as a 5-year, preference-tolerant, 65,000 patient, randomized controlled trial of risk-based versus annual screening. Individuals uncomfortable with the potential to be assigned to a particular arm in the randomized cohort can participate in the self-assigned observational cohort, an example of the pragmatic approach taken. Total accrual is anticipated to be 100,000 women across both cohorts. A broad group of stakeholders have participated in crafting this approach, including advocates, payers, the entire range of medical specialists and primary care providers and researchers involved with breast cancer screening across the entire Athena Network, technology partners, the Office of the President at the University of California, and policy-making organizations. The study hypothesizes that risk-based screening will be an improvement over annual screening because it will be as safe, less morbid, enable more cancer prevention, less stressful and more readily accepted by women as a result of an improved understanding of their personal risk. The Athena Breast Health Network was established across the 5 University of California medical centers to develop a new, harmonized approach to breast cancer prevention, screening and treatment. Athena is among the few centers in North America to use technology to integrate risk assessment into breast screening. The investigators have developed a cadre of "breast health specialists" who provide women with counseling and support around risk and prevention. There are currently 100,000 registered Athena participants, with 30,000 new patients per year and growing with the addition of Sanford Health, one of the largest rural health networks in the country. The primary research mission of Athena is to address issues requiring a population-based approach and translate solutions to clinical practice. Athena is uniquely positioned to address the screening controversy and provide women with renewed confidence in decisions about their breast health. Risk-based screening for breast cancer is exactly the advanced, evidence-based approach to medicine described in the NIH and FDA's "Path to Personalized Medicine". If these hypotheses prove to be correct, this study will be able to establish a clear justification for its use, and provide a framework for widespread implementation that will benefit women across the country.

Women in this arm will receive Athena standard of care mammography screening, including annual mammograms. They will complete a health questionnaire and receive screening advice based on a basic risk assessment.

Women in this arm will receive risk-based screening, where risk is calculated based on a model including personal history, family history, and genetic testing. All women in the risk-based arm complete a health questionnaire, provide a saliva sample for genetic testing, and receive screening advice based on a comprehensive risk assessment. Women in this arm will be tested for a panel of 9 genes related to breast cancer risk as well as a panel of SNPs, which can further modify risk. Women will be assigned a screening start date, screening stop date, and screening frequency.

Provide a saliva sample for testing of 9 genes and a panel of single nucleotide polymorphisms (SNPs) that influence breast cancer risk

Proportion of participants who choose risk-based versus annual screening in the self-assigned cohort as a measure of acceptability

Proportion of participants who adhere to their assigned screening schedules as a measure of acceptability

Breast cancer anxiety (as measured with the Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety scale) as a measure of acceptability

Decisional regret (as measured with the Decision Regret Scale, a 5-item Likert scale) as a measure of acceptability

Inclusion Criteria: Female* Age 40 years to 74 years old Reside in California, North Dakota, South Dakota, Iowa, Minnesota, Alabama, Louisiana, Illinois OR have coverage from a participating health plan**. NOTE*: As of 2019, we are now enrolling all persons who identify as female, and will capture both their sex at birth and gender identity in the baseline survey. NOTE**: Depending on funding for study services, recruitment will expand nationwide, therefore criteria (c) will not apply if funding allows. As of 2019, recruitment is available nationwide. Exclusion Criteria: Prior Breast cancer or ductal carcinoma in situ (DCIS) diagnosis Prior prophylactic bilateral mastectomy Inability to provide consent Non-English or Spanish proficiency (Spanish participation available: June 2019)

Esserman LJ, Thompson IM, Reid B, Nelson P, Ransohoff DF, Welch HG, Hwang S, Berry DA, Kinzler KW, Black WC, Bissell M, Parnes H, Srivastava S. Addressing overdiagnosis and overtreatment in cancer: a prescription for change. Lancet Oncol. 2014 May;15(6):e234-42. doi: 10.1016/S1470-2045(13)70598-9.

Costantino JP, Gail MH, Pee D, Anderson S, Redmond CK, Benichou J, Wieand HS. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst. 1999 Sep 15;91(18):1541-8. doi: 10.1093/jnci/91.18.1541.

Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998 Jan;62(1):145-58. doi: 10.1086/301670.

Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004 Apr 15;23(7):1111-30. doi: 10.1002/sim.1668. Erratum In: Stat Med. 2005 Jan 15;24(1):156.

Claus EB. Risk models used to counsel women for breast and ovarian cancer: a guide for clinicians. Fam Cancer. 2001;1(3-4):197-206. doi: 10.1023/a:1021135807900.

Ozanne EM, Annis C, Adduci K, Showstack J, Esserman L. Pilot trial of a computerized decision aid for breast cancer prevention. Breast J. 2007 Mar-Apr;13(2):147-54. doi: 10.1111/j.1524-4741.2007.00395.x.

Darabi H, Czene K, Zhao W, Liu J, Hall P, Humphreys K. Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement. Breast Cancer Res. 2012 Feb 7;14(1):R25. doi: 10.1186/bcr3110.