Population-based cancer screening using genetic sequencing technology is an idea worthy of careful consideration, but there are many challenges to implementing such a program.
Mark E. Robson, MD
Population-based cancer screening using genetic sequencing technology is an idea worthy of careful consideration, but there are many challenges to implementing such a program, according to Mark E. Robson, MD, a Miami Breast Cancer Conference faculty member who specializes in the identification and management of people who have inherited an increased risk for cancer.
A gene mutation such as BRCA1/2 that predisposes a woman to breast or ovarian cancer, for example, “may not manifest itself until it causes cancer in a young person,” Robson said in an interview. “So, the argument is that if we test everybody and find those who have mutations, we will potentially be able to intervene early. This now becomes a potential public health benefit.”
Yet Robson, who serves as director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, sees many challenges in population-based testing for BRCA mutations. He explored these considerations in a presentation at the 32nd Annual Miami Breast Cancer Conference, held February 26-March 1 in Miami Beach, Florida.
“There is a conversation that’s taking place right now about whether there should be broader BRCA testing offered to people who don’t necessarily meet any particular criteria, family, or personal history, and the rationale for that is that there are a number of people who have BRCA mutations inherited from their father or who come from families where there is limited information,” Robson said in the interview.
The role of BRCA genetic screening entered the popular imagination in May 2013 when actress and director Angelina Jolie announced that she had undergone a double mastectomy based on the discovery that she had a BRCA1 mutation that significantly increased her likelihood of developing breast and ovarian cancer. Jolie has a family history of ovarian cancer, but many other women with mutations do not have a history that would prompt testing.
Whereas the average woman in the United States has a 12% lifetime risk of breast cancer, BRCA1/2 carriers have at least a 50% to 60% lifetime risk.1 Female carriers of BRCA1/2 mutations have an even higher risk of developing ovarian cancer—over 40% among BRCA1 carriers and nearly 20% among BRCA2 carriers, up from a 1.4% chance in women without the mutations.1 Prophylactic mastectomy reduces the chances of developing breast cancer by over 90%, and preventive salpingo-oophorectomy substantially reduces the risk of ovarian cancer, which is hard to detect by screening.
Screening Selected Populations
Large-scale population-based genetic test screening may not be practical because of issues of cost and complexities of interpretation. But it may be feasible for groups that have an increased chance of carrying a more limited range of mutations, said Robson, noting the Ashkenazi Jewish population (Jewish individuals of Eastern/Central European origin), of whom 1 in 40 carry one of three specific BRCA1/2 mutations.
A study performed in Israel found that population-based testing had merit not merely because of the prevalence of BRCA mutations among Ashkenazi individuals but also because the cancer risk among female carriers in that group increases dramatically with age.2
For Jewish Ashkenazi women, the cumulative risks of developing either breast or ovarian cancer by age 60 and 80 years, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers, according to the study.
“High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the (Ashkenazi) population,” the report said. “General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria.”
The study also suggested that an Ashkenazi population screening could serve as an investigative model for evaluating the genetic predisposition to cancer in other populations.
“It is an interesting step in the evolution of a genetic susceptibility testing from an almost boutique type of analysis with nothing but a personal utility, which was what it was back in the 1990s, now to something that is potentially so clearly clinically useful that it should be offered to everyone,” Robson said.
Prominent Researcher Ignites Debate
A strong advocate for more general screening is Mary-Claire King, PhD, who won the 2014 Lasker- Koshland Special Achievement Award in Medical Science for linking the BRCA1 gene to hereditary breast cancer. “To identify a woman as a carrier only after she develops cancer is a failure of cancer prevention,” King and colleagues wrote in a Journal of the American Medical Association article.3 “It is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care.”
The World Health Organization has supported the use of population-based genetic screening where the disease risk through identifiable genetic mutations is demonstrably high and effective treatments exist.3 The US Preventive Services Task Force has recommended that primary care providers screen women via questionnaire to determine whether they have a family history of breast, ovarian, tubal, or peritoneal cancer, and then recommend those with positive results for BRCA testing.4
Although they endorsed broad screening, King and her fellow researchers said testing for BRCA1/2 mutations should be carefully defined, since there are numerous BRCA mutations that may or may not threaten an individual’s health. “The challenge is not identification, but interpretation, of making sense of what is identified. Thus far, cancer genetic testing has responded poorly to this challenge,” they wrote.
aIncludes fallopian tube and primary peritoneal cancers.
BC indicates breast cancer; NCCN, National Comprehensive Cancer Network; TNBC, triple-negative breast cancer; USPSTF, US Preventive Services Task Force.
1. US Preventive Services Task Force. BRCA-related cancer: risk assessment, genetic counseling, and genetic testing. http://goo.gl/q5PKTU.
Published December 2013. Accessed April 6, 2015. 2. NCCN Clinical Practice Guidelines. Version 1.2015. Published March 30, 2015.
Many Challenges Ahead
A number of challenges require consideration when proposing a broad public health genetic screening for an adult onset disorder, Robson said.
“There are some difficult questions that come up, centered around who is the right target, what is the right test, to whom should it be delivered, should it be full sequencing or should it just be looking for mutations in target populations, and what information do people need to be able to decide whether or not they want to participate?
“Although we do have effective treatments for BRCA1/2-related predispositions, the demonstrably effective treatments are surgical, and can have significant negative impact upon the women who undergo the procedure. Women considering testing need to understand the decisions that will follow if they are found to carry a mutation.
“So, do we as a society want to have this be something that follows the traditional path of informed decision making by an individual after nondirective counseling, or is this something that we should recommend the same way we recommend vaccination? Is this an opt-in or is this an opt-out kind of question?” Robson asked.