The diagnosis of breast cancer is already very intense, but what if you are told that it can also run ‘in the family’? Then an uncertain period follows not only for yourself but also for your immediate loved ones. Clinical geneticists at UMC Utrecht are now working with a new way to determine even more precisely what your own personal risk of breast cancer is with a calculation model.
Do you have family members with breast cancer? This question is often asked by the doctor when you feel a suspicious lump, and also by the specialist. And this mainly concerns female family members in primary and secondary care, so your mother, your daughter(s), your sister(s) and aunts.
If you have breast cancer and heredity may play a role, the specialist can discuss and request DNA testing. Or a referral to a clinical geneticist from the university medical center in your region follows. But referral to the clinical geneticist can also be done through the GP if you have not yet been diagnosed yourself but breast cancer is common in your immediate family.
Mapping family history
Bernadette van Nesselrooij is a clinical geneticist at UMC Utrecht. When is genetic testing important for women with breast cancer or women with breast cancer in the family?
“There are clear criteria for that. For example, if a patient is younger than 40 years old. And even if there are three or more first- and second-degree relatives who have or have had breast cancer, there may be a hereditary predisposition. So just a 60-year-old mother with breast cancer is not enough for DNA testing.”
Bernadette then makes an extensive family tree with her patient. And then, if heredity seems to play a role, an extensive DNA test is done. DNA changes in the PALB2, BRCA-1 and BRCA2 genes give a very greatly increased risk of breast cancer. These are so-called high-risk genes.
Not one but hundreds of genes
Abnormalities in these three better-known genes are rare. Most women with breast cancer have no change in the BRCA or PALB2 gene. Some women have a DNA change in moderately increased risk genes, such as ATM or CHEK2.
If a change in a breast cancer gene is found, immediate family members may be eligible for a genetic test.
“We then give patients a family letter that they can show to their families, and in which we tell them that they can have genetic testing done,” says Bernadette.
But the risk of breast cancer is not only genetically determined by high and moderately increased risk genes. In fact, usually the increased risk of cancer cannot be traced back to one particular gene. The entire genetic risk is spread over hundreds of small DNA variations.
This so-called Polygenic Risk Score (PRS) is a combination of more than 300 small changes in the DNA, each of which slightly affects the risk of breast cancer. This then results in a number that indicates how high the risk of breast cancer is.
Bernadette and her colleagues do not determine the PRS score for every patient by default. This is currently only done in family members who receive a genetic test because a DNA change in a moderately increased risk gene has been detected in a close family member and a few other situations.
Lifestyle also counts heavily
Enough about genes… Because it is not only your genetic material that determines your risk of breast cancer. Factors such as age, lifestyle (smoking, alcohol, sports), weight and density of your breast tissue also weigh in.
These factors can differ enormously, also between sisters, for example. For example, one sister cannot drink alcohol at all and the other three glasses a day. Or a daughter, for example, has much denser breast tissue than her mother.
“So remember: No two sisters are alike.’ There are so many factors that add up to breast cancer. Lifestyle certainly contributes as well,” says Bernadette.
Fortunately, clinical geneticists no longer have to rely solely on their own brain power to weigh up all risk factors. Nowadays, there is the internationally recognized risk prediction model CanRisk for this purpose. This online programme combines personal data, lifestyle factors, breast density and family data, as well as the results of a DNA test and the PRS to calculate the risk of breast cancer individually. In the Netherlands, a project subsidized by the Dutch Cancer Society is currently underway so that CanRisk will be used in the same way nationwide. This project is coordinated by the LUMC.
Of course, we will never say: ‘You won’t get breast cancer’.
Need for extra research?
Together with the patient, Bernadette or one of her colleagues goes through all the risk factors in CanRisk: from family background and known DNA changes to medication (contraceptive pill, for example) and lifestyle. The result: a percentage that indicates whether it is wise to have regular additional check-ups (mammography and/or MRI scans).
“If you exceed 20 percent, something extra is needed, for example more frequent check-ups with a mammogram. Or perhaps an MRI scan is necessary if there is very dense breast tissue and a greatly increased risk of breast cancer. If you fall below that 20 percent, the checks of the breast cancer screening are in principle enough,” says Bernadette.
“Of course, we will never say, even with a low score: ‘You won’t get breast cancer.’ Because we can’t: the CanRisk remains a probability calculation. The chance is never zero. We can only say: ‘Based on your risk compared to other women, it is better to do something extra or it is enough to just follow the population screening.'”
All genes at once
The PRS can also be entered in the CanRisk. This usually does not happen by default, but in specific cases. This is a pity, because the CanRisk result becomes even more precise if PRS is also included. As a result, clinical geneticists can advise women even better whether they are advised of additional screenings. The CanRisk score could be refined just a little more.
Good news: UMC Utrecht is now including the PRS in the CanRisk analysis. “We can now be the first in the Netherlands to do that, because it all fell into place and our lab was able to scale up quickly. We switched to the whole genome sequencing technique and a research route for bioinformatics was set up. The lab team, led by Lars van der Veken together with Joris van Steenbrugge, moved mountains, in the field of bioinformatics, to make the PRS available in the results of DNA research,” Bernadette explains.
In whole genome sequencing, the DNA code is mapped in its entirety. The patient’s DNA from blood or other body material is processed and dripped onto a glass or plastic mini-cartridge. This is shoved into a so-called ‘DNA sequencer’. This device reads millions of DNA fragments at the same time. The data is then analyzed. In this way, DNA changes in genes are detected. For a PRS, bioinformatics is used to automatically map the small DNA variations and determine the score. Bioinformatics is the field that uses the latest computer science innovations, such as machine learning and artificial intelligence (AI), to analyze complex molecular and other biological data.
UMC Utrecht now has enough DNA sequencers and the necessary software to determine the PRS for breast cancer in-house.
“We have worked closely with the LUMC and Radboudumc in particular to make the PRS a strong and reliable test, which we can now offer in diagnostics. This is really a joint effort. They are also working hard to prepare their labs for adding the PRS score,” says Bernadette.
Future dream
What does this mean in practice? Does every woman who reports to a clinical geneticist at UMC Utrecht in connection with breast cancer for herself or an immediate family member now receive a CanRisk calculation including PRS?
“That is really not always necessary, we look at it per person, it remains tailor-made. When a woman has a BRCA abnormality, her deductible is already increased to such an extent that a CanRisk with PRS adds little to her personally,” says Bernadette.
“But the PRS can indeed be important when abnormalities in moderately increased risk genes, such as ATM/CHEK2, have been found. These DNA changes may already pose an increased risk, but with the CanRisk and PRS we can sharpen that risk picture just a little bit for someone, and her first-degree relatives. This allows us to better advise them on possible follow-up policy. Perhaps no additional examinations are needed based on that refinement, and that saves a lot of stress for the women themselves and less burden on healthcare in general.”
And based on the CanRisk including PRS, it may just turn out that you have less chance of breast cancer than your mother or sister, who also has a CHEK2 mutation, but drinks more alcohol than you, for example.
“We ask for the details of the patient himself and first-degree relatives during the interviews, so we can use that to calculate a CanRisk,” Bernadette explains. “In the long term, of course, we would prefer to expand that. The dream for the future is that every woman from the age of 35 can have a CanRisk calculation made every ten years to have the personal risk of breast cancer periodically assessed. Including PRS, of course, based on a blood draw. The DNA data used to calculate the PRS score will remain available, so if there are other PRS scores, we can go back to that data to recalculate the PRS if necessary. Because your genetic data doesn’t change.”
Your genetic data may always remain the same, but there is a lot that you can influence yourself. “You can’t blame everything on genes. Your lifestyle can already make so much difference to your breast cancer risk.”
Also for men?
In this story, we are only talking about women with breast cancer. But men can also get breast cancer, although it is rarer. We focus this story specifically on women because it is not yet possible to make a CanRisk calculation for breast cancer for men.
“The risk of breast cancer for a man may be increased, but does not give rise to a recommendation for screening. So for the purpose for which we use the CanRisk, a CanRisk calculation is not necessary. Moreover, very little data from men are included in the model, so a calculation cannot be made reliably,” Bernadette explains.
From all over the Netherlands?
UMC Utrecht is now the first UMC in the Netherlands to be able to add the PRS to the CanRisk calculation on a larger scale. Does this mean that women from all over the Netherlands can come to Utrecht for this? No, because the umcs have made agreements about this among themselves.
For questions about breast cancer, you will be referred to the clinical geneticists of the umc in your own region. And if a gene change is detected, the DNA tests of family members are carried out in the DNA lab of the umc where a DNA change was first found in the family.
The other UMCs are currently working hard to prepare their own labs, so that the PRS can also be added to the CanRisk on a larger scale.
