New Genetic Findings Should Revolutionize Cancer Screening

Zosia Chustecka

March 27, 2013

LONDON, United Kingdom — Newly identified genetic variants could revolutionize cancer screening by distinguishing people at highest risk for certain cancers from people at lowest risk. The largest study of its kind to date has identified 80 genetic variants, mostly single-nucleotide polymorphisms (SNPs), that substantially raise the risk for breast and prostate cancer and, to a lesser extent, ovarian cancer.

These variants will eventually allow "a greater level of discrimination to target screening to those at greatest risk, and will help reduce overdiagnosis and overtreatment," said Hamal Kumar, PhD, chief executive of Cancer Research UK. The charity funded the work, along with the Wellcome Trust, and hosted a press conference to unveil the results.

The massive project, led by researchers from Cambridge University and the Institute of Cancer Research, involved more than 1000 scientists in 100 international research groups working together for 4 years. More than 200,000 individual samples (100,000 from cancer patients, 100,000 from control subjects) underwent DNA analysis; most of the samples were blood, but some were saliva.

The work is detailed in a collection of 13 papers published today in Nature Genetics, Nature Communications, PLOS Genetics, the American Journal of Human Genetics, and Human Molecular Genetics.

A clinical test developed on the basis of this research will likely be available in 4 to 5 years, predicted coauthor Ros Eeles, MA, MBBS, PhD, professor of oncogenetics at the Institute of Cancer Research, at the press conference. The technology is relatively straightforward and not expensive (about £30 per test), she added.

The test would identify people who have genetic variants that increase their risk for breast, prostate, and ovarian cancer. However, this information would have to be put into the wider context of an individual's health and lifestyle, so "the best place for it would be within primary care," she explained.

Biggest Impact on Prostate Cancer

The biggest impact of the test will likely be on prostate cancer, Dr. Eeles said, because there is currently no screening for this cancer in the United Kingdom (or in many European countries). Even in countries such as the United States, where there is screening for prostate cancer, there would still be benefits, because the prostate-specific antigen (PSA) test currently used is indiscriminate. The current data on PSA screening suggest that 12 to 48 men need to be treated to save 1 life, she said. In addition, about two thirds of men treated have indolent disease that would not have been discovered without screening, and would likely not affect survival.

Of the genetic variants identified, 30 increase the risk for prostate cancer, and 16 of these are associated with aggressive disease. "We can use this information to refine the risk profiles," she noted.

In the general population, prostate cancer will affect about 1 in 11 men, Dr. Eeles explained. Among men whose father died of prostate cancer before the age of 60, the risk is about 1 in 4.

The genetic variants can identify the 1 man in 100 who has a very high risk for prostate cancer. In this group, the risk of developing prostate cancer is increased to 1 in 2, she said.

Men at very high risk would benefit from close surveillance, but exactly what this would involve is not clear at the moment, she said. It could be a combination of PSA tests and/or biopsy and/or magnetic resonance imaging (MRI) scans. The ongoing PROFILE study is currently addressing this surveillance issue, and "we should have answers in 2 to 3 years," Dr. Eeles explained.

"These results are the single biggest leap forward in finding the genetic causes of prostate cancer yet made," she said in a statement. "They allow us, for the first time, to identify men who have a very high risk of developing prostate cancer during their lifetime through inheritance of multiple-risk genetic variants. If we can show from further studies that such men benefit from regular screening, we could have a big impact on the number of people dying from this disease."

Fine-tuning Breast Cancer Screening

For breast cancer, a new test to identify genetic variants could help to fine-tune current screening programs, said coauthor Per Hall, MD, PhD, a medical oncologist at the Breakthrough Breast Cancer Research Center at the Institute of Cancer Research in Sutton, United Kingdom (formerly from the Karolinska Institute in Stockholm, Sweden).

Currently, mammography is offered to women on the basis of age, he explained, but there is concern that this results in overdiagnosis and overtreatment.

In the general population, breast cancer will affect about 1 in 9 women, he said. The new genetic variants identify higher-risk women, in whom the risk is 1 in 3.

These higher-risk women could be offered extra screening, perhaps with MRI or ultrasound scans, Dr. Hall explained. Other factors would also need to be taken into consideration, including breast density and reproductive history.

This research will also help stratify risk in women who carry BRCA mutations, which confer a very high risk for breast and ovarian cancer. The researchers found that in women with BRCA mutations who had many of the newly identified SNPs associated with an increased risk for breast cancer, the likelihood of developing the disease before the age of 80 was more than 80%. In women with BRCA mutations who had very few of the new SNPs, the likelihood was 20% to 50%.

"This difference could influence a woman's decision to opt for prophylactic interventions," Dr. Hall noted. For women at very high risk, such options include prophylactic mastectomy or chemoprevention with drugs such as tamoxifen and aromatase inhibitors.

The new genetic variants also identify people at very low risk for breast cancer, Dr. Hall said. For these women, it might be possible to increase the screening interval to every 5 or 10 years.

This research "will allow us to focus screening on high-risk women and to reduce it in low-risk women, for whom we merely induce anxiety," Dr. Hall said. However, "there are huge ethical, clinical, and healthcare implications to this work," he noted.

Other Cancers

Genetic variants that increase the risk for ovarian cancer were also found, but the magnitude of the increase was much lower — only 4% — compared with 30% for breast cancer and 50% for prostate cancer. "We have much further to go," said coauthor Paul Pharoah, MD, PhD, from the Department of Oncology at Cambridge University in the United Kingdom. "This is probably not sufficient to have clinical relevance," he said.

He speculated that other common cancers that have large inheritable components, such as colorectal cancer, might benefit from this research.

Dr. Pharoah also works at the Department of Public Health and Primary Care, Institute of Public Health, Cambridge University, and was one of the coauthors on a commentary that accompanies the special collection.

The 5 research articles in the collection are "the output of a massive international scientific collaboration," he and his colleagues write. They go on to discuss how these emerging findings could enhance disease prevention by "enabling the stratification of risk and fine tuning of current screening programs according to risk."

"By understanding why some people seem to be at greater risk of developing cancer, we can look forward to an era in which we can identify them and take steps to reduce their chances of getting cancer or pick up the disease in its earliest stages," Dr. Kumar added at the press conference.

Nat Genet. 2013;45:349-351. Commentary