In an Era of Precision Medicine, Testing New Approaches to Breast Cancer Screening
A goal of precision medicine for cancer is to match patients with the most appropriate treatments based on information about the genetic and molecular changes in their tumors. This approach can also help patients avoid treatments that would be unlikely to help and could cause harm.
In the field of cancer screening, individualized approaches could help doctors identify individuals at risk of cancer who need to be screened with tests and testing intervals that are appropriate for each person's level of risk. Those who are not at risk could avoid the potential harms of screening, such as false-positive test results and overdiagnosis.
Interest in bringing precision to cancer screening has increased in recent years, particularly in the area of breast cancer.
Last year, for example, researchers in California launched a clinical trial to test a new approach to breast cancer screening. The Women Informed to Screen Depending on Measures of Risk (WISDOM) clinical trial is using several measures, such as safety, to compare annual mammography with a more individualized approach called risk-based screening.
We are trying to bring precision medicine into the arena of screening. The idea is to learn how we can do a better job of screening for breast cancer.
For participants in the risk-based group, researchers will recommend the age to start (and stop) screening and the screening interval based on each woman’s risk score, which is determined by analyzing factors such as certain genetic alterations, family medical history, and breast density.
"We are trying to bring precision medicine into the arena of screening," said Laura Esserman, M.D., who directs the Carol Franc Buck Breast Care Center at the University of California, San Francisco (UCSF), and is co-leading the WISDOM trial. "The idea is to learn how we can do a better job of screening for breast cancer."
Moving toward Precision Cancer Prevention
The trial aims to recruit 100,000 women. Women in the study are encouraged to be randomly assigned to receive annual mammograms or risk-based screening. Recognizing that some participants would join only if they could choose annual mammograms or choose risk-based screening, the researchers give all participants the option of joining the group they prefer.
Women who are assigned to the risk-based screening arm will receive a risk assessment that includes the sequencing of 9 genes strongly associated with breast cancer and the evaluation of more than 80 other genetic markers of breast cancer risk. For those with the highest risk scores, such as women who have harmful mutations in the BRCA genes, the researchers will recommend annual mammography and annual MRI beginning at age 40.
"By design, everyone in the trial is at least 40 years old, so we would start screening the women at highest risk immediately," said Jeffrey Tice, M.D., of the Division of General Internal Medicine at UCSF and one of the leaders of the study. Under the ideal scheduling of mammography and breast MRI, these women would have one of the imaging tests every 6 months, he added.
For women in the risk-based screening arm with the lowest risk scores, the researchers would recommend screening with mammography every 2 years beginning at age 50.
"Many of us involved in this trial feel that the one-size-fits-all approach to breast cancer screening is not optimal for patients, and it's not an optimal use of resources," said Dr. Tice. "But we need to test the risk-based approach in a clinical trial so that we can evaluate the evidence."
Many of us involved in this trial feel that the one-size-fits-all approach to breast cancer screening is not optimal for patients, and it's not an optimal use of resources. But we need to test the risk-based approach in a clinical trial so that we can evaluate the evidence.
The goal of the WISDOM trial is to determine whether risk-based screening is as safe as annual screening (that is, no increase in advanced-stage breast cancers compared with the annual screening group) and less morbid (that is, involves fewer mammograms and biopsies).
Another question is whether risk-based screening helps to reduce false-positive results and the detection of indolent or slow-growing tumors that would not have caused harm in the woman's lifetime, a phenomenon known as overdiagnosis. The researchers will also determine which approach is preferred by women based on feedback about satisfaction and anxiety.
The study could also yield insights into questions about the psychosocial effects of clinical DNA testing. Currently, the trial is sequencing 9 genes and using data on about 80 genetic markers associated with breast cancer risk to help in calculating the participants' risk level, but in the coming months that number should exceed 100, according to Dr. Tice.
Focusing on High-Risk Individuals
As the WISDOM trial was getting under way, a working group of the Cancer MoonshotSM Blue Ribbon Panel recommended that NCI launch two demonstration projects in cancer screening that focus on inherited syndromes that put individuals at high risk of developing cancer: Lynch syndrome and hereditary breast and ovarian cancer syndrome (HBOC).
By screening individuals who may have one of these syndromes—all patients with colorectal cancer, in the case of Lynch syndrome, and breast and ovarian cancer patients whose family histories suggest a hereditary syndrome, in the case of HBOC—for genetic alterations known to cause them, doctors could identify candidates, including family members, for increased surveillance. These individuals could then be monitored closely for early signs of cancer, according to the report.
Targeting individuals at high risk for cancer, whether or not they have an inherited predisposition, is "a major component of precision cancer prevention," noted the authors of a recent commentary on cancer prevention in the era of precision medicine.
Eva Szabo, M.D., of NCI's Division of Cancer Prevention and Nina Brahme, Ph.D., of the Food and Drug Administration, wrote that more information about the early molecular changes associated with the development of cancer is needed to realize the promise of individualized approaches to cancer prevention and early detection.
"To make progress in precision prevention, we really need a better understanding of the early phases of cancer development," Dr. Szabo said in an interview. This will require multidisciplinary studies involving experts in fields such as genomics, epigenetics, immunology, and the microbiome, she added.
We have a golden opportunity. The technology for conducting these kinds of studies has improved dramatically, and we know so much more about how to do these kinds of analyses than we did a decade ago.
A proposed project called the Pre-Cancer Genome Atlas could potentially help, Dr. Szabo noted. This collaborative effort would involve profiling the genomes of premalignant lesions and associated changes in nearby tissues over time; these results would be analyzed along with clinical data.
"We have a golden opportunity," Dr. Szabo said. "The technology for conducting these kinds of studies has improved dramatically, and we know so much more about how to do these kinds of analyses than we did a decade ago."
Investigating Risk Factors
Tools that can reliably assess an individual's risk of developing cancer are essential for the success of risk-based screening strategies. "Health care providers need accurate risk-prediction models so they can identify individuals who are at risk for the disease," said Karla Kerlikowske, M.D., of the UCSF Helen Diller Family Comprehensive Cancer Center.
In the case of breast cancer, most women with the disease have at least one known risk factor (such as dense breasts or high body mass index) that is easily assessed at the time of diagnosis, according to a recent study led by Dr. Kerlikowske. In the study, more than 90% of women had at least one risk factor when diagnosed with breast cancer.
This information could potentially be used to inform risk-based screening in the future, noted Dr. Kerlikowske.
"In our study, the most prevalent and strongest risk factor among women developing breast cancer was breast density," said Natalie Engmann, a Ph.D. candidate at UCSF and the study's first author.
The study authors concluded that to individualize breast cancer prevention, risk models need to include breast density. The Breast Cancer Surveillance Consortium Risk Calculator is the only risk prediction model that incorporates a clinical measure of breast density.
Improving Screening Methods
For Dr. Esserman, the falling costs of sequencing DNA have created an opportunity to explore new approaches to screening that incorporate genetic information.
There's no reason we can't improve on the model we have today. Women should demand and expect changes in how we screen for this disease.
"There's no reason we can't improve on the model we have today," she said, noting that the seminal clinical trials that led to the current guidelines were conducted decades ago, long before the introduction of current tools such as tests for estrogen, progesterone, and HER2 receptors. "Women should demand and expect changes in how we screen for this disease."
As the tools and methods for screening improve, Dr. Esserman predicted, doctors can start to do less screening for people who are at lower risk. "This is the way the field is going to evolve—toward putting resources to the people who need them the most," she added.