1. Jenks, Susan

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A large clinical study challenging the idea that screening mammography should take a one-size-fits-all approach to detect early breast cancer will soon end randomized testing, but continue enrolling women into the trial. Now in its sixth year, the WISDOM study-Women Informed to Screen Depending on Measures of Risk-is comparing a personalized screening strategy to traditional mammography to determine which works best at finding early breast cancers before they progress.

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The new approach ties the timing of mammography to a woman's individual risk for developing one of these complex malignancies, while the other relies on screening guidelines endorsed by many health care organizations, which call for annual mammography, usually by age 50. The American College of Radiology recommends women at average risk for breast cancer start routine mammography screening even earlier, by age 40, with most major breast cancer centers following suit.


So far, nearly 50,000 women have enrolled in the study, roughly half of the recruitment goal of 100,000 women between the ages of 40 and 74 who've never had breast cancer. Each of the women already participating in the trial have been randomized to an annual mammography schedule, if they agree, or to comprehensive risk assessments that measure personal risk.


However, because screening guidelines differ and 45,000 women in the United States still die from breast cancer each year, "we have to think about prevention in a very different way," according to Laura Esserman, MD, lead investigator of the WISDOM study and Professor of Surgery and Radiology at the University of California, San Francisco. Although mammography has reduced overall breast cancer mortality since its inception, "I don't think it can be business as usual," she said. "We need to do much better with aggressive cancers" that the technology often misses.


The decision to move into a new phase of the WISDOM study, called WISDOM 2.0, arose from investigators' desire to address additional concerns.


"We wanted to have more time to answer the questions we need answered," Esserman said, such as whether the new screening paradigm is safer, leads to fewer callbacks or biopsies for indolent disease, or if women prefer it. When WISDOM 2.0 begins, she noted that participants will no longer be randomly assigned to a particular study arm, but can choose which one they want to be in for further observation. Each woman will be followed for 5 years.


Women opting for a risk analysis will be tested not only for well-established hereditary risk factors for breast cancer-genetic errors in the BRCA1 and BRCA2 genes-but the cumulative risk posed by specific mutations within nine genes more recently associated with breast cancer's development. Risk profiles also factor in a woman's age, exercise routines, and dietary habits, as well as breast density. A final risk score then determines when a woman should begin screening, how often, and if, or when, she can safely stop.


For women deemed at highest risk for these cancers, screening recommendations will begin at age 40, alternating every 6 months afterward between mammography or magnetic resonance imaging. The expectation going forward is that treatments may start even sooner for some high-risk women, Esserman said, given the trial's increasing diversity and the disproportionate vulnerability of African American women to an aggressive type of breast cancer at a young age.


Traditional mammography's failure to detect some aggressive tumors is attributed, in part, to how rapidly these cancers spread, often between imaging scans. So, researchers are creating imaging systems better able to distinguish between slow-growing and fast-growing tumors, according to Esserman. Other models using artificial intelligence are characterizing density patterns to characterize those with the highest breast cancer risk-another strategy to gain an edge over nascent malignancy.


Not included in a woman's risk analysis-at least for now-is ductal carcinoma in situ (DCIS), the tiny abnormalities seen inside milk ducts that raise the risk for invasive disease, but researchers still remain uncertain as to how much. And women diagnosed with DCIS fall outside the study's eligibility criteria, requiring participants to be cancer-free.


Esserman said these women will be referred to a network of nationwide clinical trials as they open up. "Like breast cancer itself, there are many types of DCIS, "she stressed. "But, because it's not an emergency, you have the opportunity to do something about it, using the right imaging features." As the WISDOM trial continues, any woman in the United States, no matter where they live or where they receive medical care, can sign up online at


"We wanted to make it as easy as possible," Esserman said, referring to the online recruiting process. "The more people that join, obviously, the faster we can generate the data and information we need."


The American Cancer Society's (ACS) newly elected Chief Scientific Officer, William Dahut, MD, praised the WISDOM study's goals to improve personalized screening for breast cancer as admirable and a high priority shared by other scientists in the cancer community. In his own area of expertise, prostate cancer, Dahut noted that polygenic risk scores have proven helpful in identifying patients at high risk for cancer progression. Moreover, small studies on this malignancy have shown lifestyle modifications can reduce the risk of aggressive disease, a tactic that might change clinical outcomes for some breast cancer patients as well.


But Dahut acknowledged predictive tools work better "once you're diagnosed" with breast cancer, while prediagnostic tools have fared less well so far. "Much of the time they're available mostly to the White population," he said, "not for [People of Color]."


As for changing the cancer organization's screening guidelines any time soon, Dahut noted that the ACS will no longer revise its guidelines every 5 years, as it has in the past, opening the door to much quicker responses to scientific advances. "We've decided to make the guidelines a living document," he said, updating it as needed.


Susan Jenks is a contributing writer.