Skip to main content
Premium Trial:

Request an Annual Quote

UC Launches Framingham-Like Study to Inform Personalized Breast Cancer Screening Guidelines


NEW YORK (GenomeWeb) – Researchers within the University of California system have received a $14 million grant from the non-profit Patient-Centered Outcomes Research Institute for a large, longitudinal study that they hope will quash the debate over how often to screen women for breast cancer and spur personalized guidelines that incorporate current knowledge of genetic risk factors.

The Women Informed to Screen Depending on Measures of Risk (WISDOM) study will take place within the Athena Breast Health Network, where approximately 150,000 women receive care across five UC medical centers and Sanford Health in the Midwest.

Led by Laura Esserman, director of the breast cancer center at the University of California, San Francisco, researchers will enroll 100,000 women into either a group that receives standard annual mammogram screenings starting at age 40 or one that receives screenings on a personalized schedule based on their risk for breast cancer after factoring in family and medical history, breast density measurements by mammograms, and results from genetic tests.

Researchers will test more than half of the 100,000 WISDOM participants for genetic markers associated with breast cancer risk using tests from Color Genomics. Blue Shield of California has agreed to pay for the genetic testing performed in the study under coverage with evidence development.  

Laura van 't Veer, who is leading the UCSF research site, believes WISDOM has the potential to inform breast cancer diagnoses and treatment in the way that the Framingham Heart Study defined cardiovascular disease risk factors.

Over the last three years, study investigators have already gathered data on the cohort of 100,000 women on their clinical risk factors, such as breast density. "What we're starting to do now is include their genetic risk factors," Van 't Veer, associate director of applied genomics at UCSF's Helen Diller Family Comprehensive Cancer Center, told GenomeWeb.

In the next five years of the study, researchers will explore how individualized guidance influences women's perceptions of breast cancer risk. For example, how anxious will low-risk women who receive less-frequent screenings be about breast cancer? Will women who find out they are at high risk for breast cancer using the personalized screening modality be more inclined to take preventative measures than low-risk women? 

But it will take likely a decade or more to assess whether a personalized screening strategy leads to fewer false-positive results and reins in overdiagnosis but also lowers breast cancer incidence compared to standard screening. For many years, the accepted standard has been to begin annual mammography screenings for women at age 40. But guidelines bodies in the US are moving away from this and advocating for beginning mammograms in older women and doing it every two years.

Members of the radiology community who want to stay the course with annual mammograms beginning at age 40 say this approach has reduced breast cancer deaths by 21 percent. Detractors argue that the benefits of annual screening are modest compared to the increased anxiety and needless procedures that women will have to undergo due to false-positive results. Studies suggest that after a decade of annual screenings more than half the women will receive a false-positive result and up to 9 percent will have to undergo an unnecessary biopsy.

The US Preventive Services Task Force now recommends mammograms for women every other year starting at age 50, while leaving open the option to offer screening to women in the 40s based on individual patient's factors. The ACS last week increased the age at which to start mammograms for women from 40 to 45 years, but, like USPSTF, noted that women between ages 40 and 44 should have the choice start screenings earlier. 

Although these recommendations allow healthcare providers to adjust the frequency of mammograms based on a woman's specific risk factors, Van 't Veer noted there isn't clear guidance on how to administer individualized screenings and this has caused confusion. In WISDOM, researchers want to define personalized screening parameters by seeing what happens when using their risk algorithm when high-risk women get earlier and more frequent monitoring for breast cancer and the lowest-risk women begin screening later and receive less of it. 

Women's risk for breast cancer increases with age. According to the Centers for Disease Control and Prevention, around one out of 100 women at age 40 will get breast cancer in 10 years. The incidence increases to two out of 100 women at age 50 and nearly four out of 100 by the time women reach 70. In advancing screening guidelines, Van 't Veer observed that insurers and government payors have to balance, for example, how much they want to pay to prevent one out of 100 breast cancers versus taking the risk that they might miss one out of 100 breast cancers.

Economic modeling by her group suggests that by conducting targeting screening using its breast cancer risk algorithm, incorporating clinical and genetic risk factors, the US healthcare system can shave off a significant portion of the $4 billion it spends yearly as a result of overdiagnosis and false-positive results from breast cancer screenings. "As a country and as healthcare professionals, we can and should do better," wrote WISDOM lead investigator Esserman in a recent piece in the American Journal of Hematology/Oncology.

In the article, Esserman suggested that advances in breast cancer genomic knowledge and testing technology has made it possible to conduct "a modern-era screening trial" that considers women's traditional risk factors, like family history and breast density, but also a range of genetic markers known to heighten women's predisposition for the disease.

Van 't Veer, who co-founded the breast cancer-focused molecular diagnostics company Agendia and had a leading role in developing hereditary cancer screening guidelines at the Netherlands Cancer Institute, moved stateside to UCSF a few years ago to build the WISDOM cohort and set up the genetic testing component of the study.

Guidelines in the US currently recommend testing for high-risk BRCA1 and BRCA2 genetic mutations in women with a strong family history of breast and ovarian cancer. But within the WISDOM study, researchers will genetically test 65,000 women for high-risk genes, like BRCA1 and BRCA2; moderate-risk genes, such as CHECK2 and ATM; and around 80 breast cancer susceptibility SNPs that individually confer a small portion of the disease risk, but when assessed as part of the larger algorithm may nudge up a person's risk higher than in the average woman.

After evaluating different firms, Van 't Veer decided to enlist Burlingame, California-based Color Genomics to perform the genetic testing for WISDOM, using its 19-gene next-generation sequencing panel. Color has also agreed to test study participants for the 80 SNPs that are part of the risk assessment, although the firm doesn't offer such testing commercially.

Testing accuracy was a big consideration for Van 't Veer in deciding which company to go with. She gave Color patients' samples with and without markers associated with breast cancer risk, and the firm was able to detect the markers and interpret their links to disease with 100 percent accuracy, Van 't Veer said.

Having to test 65,000 women, Van 't Veer also couldn't afford hereditary cancer predisposition tests with a $4,000 price tag. Color offers its 19-gene panel for around $250, which includes a genetic counseling session. Traditionally, hereditary cancer testing has cost several thousand dollars, but prices have dramatically come down since a US Supreme Court decision restricted patenting isolated gene sequences. A handful of companies are now selling genetic tests for breast and ovarian cancer risk at the consumer-friendly price of a few hundred bucks.

"The price level is really important for us," Van 't Veer said, particularly since WISDOM has piqued the interest of insurers. Van 't Veer could disclose only one such arrangement: Blue Shield of California has agreed to reimburse for the genetic testing, as well as counseling for those with cancer-linked markers, under a coverage with evidence development scheme.

In the future, there will be opportunities within WISDOM for conducting prevention trials. Although the focus of the trial is to derive a more precise breast cancer screening approach, the end goal from a public health standpoint is to identify women at risk of getting the disease and prevent it.

Research has shown that certain low-dose, anti-hormone therapies may prevent breast cancer, but Van 't Veer noted these treatments also have side effects. "So, you wouldn't want to do that for everybody," she said. "But if we now better understand risk levels, you can better target the population for whom [these treatments] might be beneficial."