Researchers and clinicians have a better understanding of who is at risk for recurrence and how to prevent overtreatment thanks to advancements in gene therapy, says Laura J. van’t Veer, PhD.
Laura J. van't Veer, PhD
Laura J. van't Veer, PhD
“We have started to use [genetic testing] to inform screening for breast cancer because the logical thinking is, if somebody has an elevated risk, you want to screen [them] more than if somebody has a very low risk to develop breast cancer,” said van't Veer. “We can assess that by looking into the genetics of a person, whether somebody has a hereditary mutation in a gene as well as looking at other risk factors and combine it in a risk score.”
In an interview during the 2017 OncLive® State of the Science SummitTM on Breast Cancer, van't Veer, director of applied genomics at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, discussed determining more accurate methods of treatment for patients with early- and late-state breast cancer based on advances in genetic testing, specifically the 70-gene prognostic signature.
Can you touch on some of the current guidelines for genetic testing?
If we look [into the] guidelines in genetic testing, for instance, for women who are diagnosed with breast cancer and who have a family history of breast cancer, their recommendation is to get tested if you have 2 first-degree relatives with breast cancer or 1 at a really young age and you’re [young]. Those guidelines for genetic testing are quite clear if it also involves family history, but what is becoming more and more a practice is that the information of genetic risk is relevant for every woman, regardless of her family history.
For every woman, at a given age based on her genetic makeup and risk factors, we can give her an estimate of what [chance] she has of the next 5 years of developing breast cancer. That we use to better guide who needs screening by mammography every year.
Perhaps some women can [do it] every other year; some women who have a very high risk need [a mammography] every 6 months. For women under age 40, more than two-thirds have such a low risk that screening doesn't give any benefit. It does more harm because of false negatives and biopsies. You can much better understand who needs what frequency of screening and the age for somebody to start screening.
Where are we now with testing in late-stage or high-risk disease?
Once somebody is diagnosed, there's another way of using the word "risk" just to make that clear. We look into the biology of the breast cancer. We can recognize if that tumor actually would foretell a high risk of recurrence or a low risk of recurrence. There are a couple of genomic tests available, in which you do your test on the tumor material and you assess whether it is a fast-growing tumor or a slow-growing tumor. That would help determine whether therapy by systemic chemotherapy would be good advice.
These tests, such as Oncotype DX, MammaPrint, and PAM50, can all distinguish these subgroups. It depends how they have been tested in clinical trials. MammaPrint is one I’ve been working on for a long time. We also set out to understand [what it means if] somebody is clinically high risk, but the tumor is biologically low risk. Can we derive enough evidence that maybe such patients do not benefit from chemotherapy? That was a large clinical trial among 7000 patients, where we showed that those women [who are] clinically high risk and biologically low risk do not benefit substantially from chemotherapy.
It actually does more harm than good. We start to learn more and more how to apply biology for screening and frequency of mammography in a healthy woman. We start to understand by looking into the biology of the tumor. If that tumor displays factors of high risk of recurrence or low risk of recurrence, we use [that] to guide and advise “yes” or “no” [to] chemotherapy.
Can you expand on the utility of the 70-gene prognostic signature, or MammaPrint, entails?
[This was] established 15 years ago on patients whom we had the tumor material [from] that was being “banked” as we call it, so it was saved. We knew after their diagnosis what their disease course had been. Some women had developed a distant recurrence in metastases and other women, for the longest time, had remained disease free, so our scientific question was “Can we actually understand why, and can we recognize why some of these tumors have the capacity to metastasize and others do not?”
We actually looked at the 25,000 genes that every cell has and tried to find a pattern of activity of genes that would distinguish the low-risk from the high-risk cancers. We found that 70 genes of the total of 25,000, if they are in the "on" status, display the characteristics of an aggressive tumor that is high likelihood to metastasize. If those 70 genes are in the "off" status, then that means that this is a slow-growing tumor that doesn’t have much capacity to invade in surrounding tissue and is not at the capacity to metastasize elsewhere in the body. That was the initial finding of those patients who had donated their tumor material.
We waited some 10 years so that we had their follow-up and that gave us this 70-gene prognostic signature, and then subsequently repeated that finding in other series. However, ultimately, 7000 women chose to participate in this MINDACT trial where they got the standard clinical assessment as well as the 70-gene prognostic signature. Based on whether they were low-low risk, high-high, or discordant (high-low, low-high), particularly the discordant group then was randomized to use either the 70-gene prognostic signature or their clinical assessment for further treatment.
That showed that, for women [who are] clinically high risk but the biology is low risk, that they can safely forgo chemotherapy. That actually reduces overtreatment if that would be applied to all women with breast cancer diagnosed in the United States today. There are some 35,000 women per year who could actually forgo chemotherapy or at least can be considered to forgo chemotherapy.
Are there any remaining challenges in developing, implementing, or administering these tests that you would like to see addressed in the next 5 to 10 years?
The prognostic tests, as they are called…are now well established; they're in the 2017 ESMO Congress recommendations. It is just realizing that this is a question that can be answered to get it fully used.
The next challenge is, if a patient is at high risk of recurrence, then what is the best treatment? There are many clinical trials addressing this question to subsequently match the therapy with the biology of the tumor that can respond to the therapy. It will be a set of tests that will help determine what therapy is needed and which one will then give the best predicted results.