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

Conditions:Breast Cancer, Cancer
Therapuetic Areas:Oncology
Age Range:40 - 74
Start Date:August 31, 2016
End Date:December 2020
Contact:Allison Fiscalini, MPH
Phone:(415) 476-0267

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

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 proposal 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

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

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.

Inclusion Criteria:

- Female

- Age 40 years old to 74 years old

- Reside in California or receive care at a Sanford Health site

Exclusion Criteria:

- Prior breast cancer or DCIS diagnosis

- Non-English proficiency (plans to expand to Spanish by year 2)
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