A University of Cambridge study has prompted its researchers to suggest that genetically testing all women for a set of common breast cancer risk alleles may improve the efficiency of government-funded breast cancer-prevention programs.
Paul Pharoah of the University of Cambridge and colleagues have found that a combination of seven commonly occurring breast cancer susceptibility alleles suggests that adopting a polygenic approach to risk stratification may help identify women at high risk for developing the disease and allow cancer screening prevention programs to target those most in need.
“Our analysis suggests that the risk profile generated by the known, common, moderate-risk alleles does not provide sufficient discrimination to warrant individualized prevention,” the researchers write in a paper published in the June 26 issue of the New England Journal of Medicine. “However, useful risk stratification may be possible in the context of programs for disease prevention in the general population.
“The clinical use of single, common, low-penetrance genes is limited, but a few susceptibility alleles may distinguish women who are at high risk for breast cancer from those who are at low risk, particularly in the context of population screening,” the authors conclude.
Although this research has caused industry observers to speculate on the economic impact of population-wide genetic screening programs, the UK’s National Health Service, which pays for the vast majority of healthcare costs in the country, still needs convincing before it invests in such a broad program.
“The best way to communicate personal risk, and the contribution that such discussions make to informed decision making, is not yet clear,” the NHS wrote in a review of the study. “It is likely that considerable public and professional education will be required before the general understanding of the complexities of genetic testing for common variations such as these is sufficient for honest, informed consent.
“More research into the harms associated with this sort of pre-screening in addition to the costs involved, will be required before it is possible to be sure that this test is good enough to be offered to women,” the NHS determined.
The study’s lead author, Pharoah, who is a senior clinical research fellow at the University of Cambridge and has an NHS honorary contract, told Pharmacogenomics Reporter this week that he has not discussed with the government agency “how this research might be taken forward in any formal way.”
Regardless, the research still may lead to the development of a commercially available diagnostic test. “I have been approached by a local company that wishes to discuss a possible commercial application,” Pharoah said. He did not elaborate.
In the study, researchers determined that the combination of seven risk alleles — FGFR2 rs2981582; TNRC9, LOC643714 rs3803662; MAP3K1 rs889312; LSP1 rs3817198; rs13281615 in chromosome 8q; rs13387042 in chromosome 2q; and CASP8 rs1053485 — could help determine an individual’s cancer risk, or could focus screening programs to concentrate on those at higher risk.
The researchers gleaned data on risk alleles from four different genome-wide association studies that discussed the seven SNPs. According to the researchers, 56 out of every 10 million women in the UK, or approximately 3,300 individuals, carry two copies of all seven low-risk SNPs, which confers a 4.2-percent lifetime risk of developing breast cancer compared to a 9.4-percent risk in the overall population.
However, around seven in 10 million women, have high-risk variations at the seven gene sites, which confers a 23-percent lifetime risk of developing breast cancer — more than double the risk seen in the general population.
“The cost of a genetic test for [the] purposes of risk profiling would be minimal as compared with the costs of a lifetime screening program.”
While this research does not make a strong case for using these common alleles to test individual patients for their cancer risk, the study authors concluded that the combination of the seven alleles might be a useful tool for stratifying women in the general population into high-risk and low-risk breast cancer groups. This, in turn, may help personalize prevention programs for those who really need it, they claim.
“The risk profile generated by these common moderate-risk alleles apparently does not provide sufficient discrimination to warrant individualized prevention,” the study authors state in the paper. “Useful risk stratification may be possible, however, in prevention programs for a population.”
The NHS currently offers mammography screening for all women 50 years and older, regardless of family history and risk factors. For women as young as 30 years of age, who have a very strong family history of breast cancer associated with the BRCA1 and BRCA2 risk genes, the NHS also offers MRI screening.
However, the researchers suggest that the NHS can provide more targeted breast cancer screening. According to the study, a 50-year-old woman in the UK has a 2.3-percent risk of developing breast cancer over the next 10 years.
“If we assume that 2.3 percent is the threshold at which the screening program has a net benefit, it makes sense to offer screening to all women with that level of risk, irrespective of age,” the authors state. Using this method, women of any age with a lower risk of developing breast cancer would not receive screening, while a 40-year-old woman who has a 10-year risk of 2.3 percent would be eligible for screening.
“If such a strategy were implemented, the efficiency of the screening program would increase because it would be targeted at women at highest risk,” the authors conclude. “The cost of a genetic test for purposes of risk profiling would be minimal as compared with the costs of a lifetime screening program” for all women.
The NHS’ annual budget for the breast cancer screening program, including the actual cost of screening, is approximately £52 million.
The UK’s National Institute for Health and Clinical Excellence recommends that women aged 40 years and older with a family history of breast cancer undergo mammographic screening if their 10-year risk is more than 3 percent on the basis of family history alone.
However, the study authors point out that this moderate-risk group of women comprises less than 5 percent of the population in the UK.
“It would be possible to genotype every woman at all known susceptibility loci and, on the basis of her breast-cancer risk profile, offer a personalized screening program in which the starting age would vary,” the study authors state.
NHS Needs More Proof
Although NHS felt that Pharoah’s study demonstrates the “potential for genetic tests in disease prevention,” the agency said it needed to see more clinical data about the potential harms and costs of such a screening strategy before it can approve and pay for such an option.
The NHS pointed out several assumptions made by researchers in the study “that may not be robust.” For instance, the researchers assumed that the risks attributable to single allele variations can be combined, and that the benefit of mammography depended solely on risk reduction.
“It is likely that there may be some interaction between the function of single alleles found in the genome and also that the benefits of mammography might depend on both the risk reduction and the age of the patient (a factor that is known to determine the sensitivity of the screening procedure),” the NHS noted in its review.
“Any added benefit of this sort of testing, if it is confirmed in further trials, will need to be balanced against the added complexity and costs of adjusting population screening programs to take into account individual genetic profiles,” the agency stated, adding that “this added complexity might … reduce the program’s efficiency.”
Still, the agency determined that the study on the whole “is reliable and highlights the potential of this sort of ‘pre-screening.’”
Pharoah and colleagues did not provide an economic estimate for their approach.
“We have done no [pharmacoeconomic] analysis, which would be a substantial piece of work,” Pharoah told Pharmacogenomics Reporter. However, he noted that the University of Cambridge has recently obtained European Union funding to hire a research fellow to look into the economic impact of this research.