This podcast episode is made possible, in part, by a grant from Lilly.
Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org senior editor Jamie DePolo.
Jamie DePolo: Hello, I'm Jamie DePolo, senior editor at Breastcancer.org. I'm podcasting live from the 2024 American Society of Clinical Oncology Annual Meeting.
I'm joined by Dr. Holly Pederson, professor of medicine and founder of the Medical Breast Program at Cleveland Clinic, and Dr. Elisha Hughes, director of biostatistics at Myriad Genetics. At the conference, Dr. Pederson presented their research on whether a polygenic risk score could help predict early-onset triple-negative breast cancer in Black women. Dr. Pederson, Dr. Hughes, welcome to the podcast.
Dr. Holly Pederson: Thank you, so much, for having us.
Jamie DePolo: Excellent. Now, I'm going to ask you, Dr. Pederson, to please explain, so all of us with non-science backgrounds can understand, exactly what a polygenic risk score is.
Dr. Holly Pederson: I'd be happy to try.
Jamie DePolo: Okay.
Dr. Holly Pederson: So, you know, genetics has become so complex, and I think patients wonder about different genetic tests and what they can reveal. And the polygenic risk score is a newer type of genetic test. So, in just a little over the course of my lifetime, genetics has just exploded. And BRCA1 and BRCA2 were discovered in 1994 and 1995, and by 2013, we had over 12 genes that were felt to be associated with the development of breast cancer and risk and panel testing became available, gene, multi-gene panel testing. And so, with that panel testing, one is tested for the changes in DNA, or mutations, that confer the highest level of risk, like BRCA1 and BRCA2, PALB2, and others.
Then there are the moderate risk genes, like CHEK2 and ATM and others in that category. But 90% of women who have breast cancer don't carry a high-penetrant or moderate-penetrant gene change, or mutation, and we're now looking at a third level of genetic risk involving common genetic variants. Those other ones are very rare, you know, the highly-penetrant and moderate-penetrant mutations are relatively rare.
The SNPs — or single nucleotide polymorphisms — stay with me, are changes in the DNA that occur very commonly, and individually, they confer very small levels of risk, but in combination, and in a weighted way, such that the more significant SNPs are weighted more heavily, and it also depends on ancestry, in terms of the level of risk that a certain allele at that spot might confer.
It will help to estimate someone's lifetime risk, using this array of over 300 breast cancer-related SNPs. And so, in a given family, siblings can have markedly different polygenic risk profiles because you inherit one of — you have two copies of every gene in your body.
And you inherit one from your mother and one from your father. And so, each child gets a different combination of these SNPs, and so, each child may have a different polygenic risk score. Now, this is being done not only with breast cancer, but with other cancers and with other disease types. This is a very, very common next step for further risk stratifying patients in the proactive setting.
Jamie DePolo: All right. Let me just paraphrase that back to you, a little bit, to make sure that I understand.
Dr. Holly Pederson: Yeah.
Jamie DePolo: So, we're talking about not high-risk mutations, lower level, but there could be a lot of them, and so, in combination, that's where the elevation in risk comes from? If somebody has, say, 20 of these SNP mutations, okay, that are bad? Oh, thank you. So, that's very helpful. I never really understood what a polygenic risk score was before. So, that's great.
Now, Dr. Hughes, could you summarize the study and the results for us?
Dr. Elisha Hughes: Sure. So, we previously evaluated this polygenic score as a predictor of overall invasive breast cancer and as a risk factor that explains why many women are genetically susceptible to breast cancer.
In this study, we asked a different question. We asked whether this polygenic score explains triple-negative disease, and specifically whether it explains triple-negative disease in Black women and early-onset triple-negative disease in Black women.
We were able to examine a cohort of over 17,000 Black women, and what we found is that it is indeed a really important risk factor, one of the most important known risk factors for predicting triple-negative breast cancer risk. And importantly, most of the women who got triple-negative breast cancer in this study had no family history. So, here, we have an extra tool that can help identify those women who are at the highest risk.
Jamie DePolo: So, they had no family history, but they had a high polygenic risk score, is what you're saying?
Dr. Elisha Hughes: Right.
Jamie DePolo: Got you. Okay.
Dr. Holly Pederson: About 60% of the women under the age of 40 who developed triple-negative breast cancer.
Jamie DePolo: Interesting, but they had this high score?
Dr. Holly Pederson: Right. Exactly.
Jamie DePolo: Okay.
Dr. Holly Pederson: You know, and so, as you know with screening, 70%, at least, of breast cancers that develop in women are found in women who have no identifiable risk factors and no family history that's known about. Most women are unaware, still, of their breast density, but many more are learning, and it really is, it's an important new tool.
Jamie DePolo: That's great. So, Dr. Pederson, could you put this in context for us? Could me, I'm not a young Black woman, but could I go and get this risk score figured out? Is that is it available now?
Dr. Holly Pederson: So, it is not currently clinically recommended by the National Comprehensive Cancer Network guidelines, NCCN guidelines, which are the common guidelines that most oncology practices and breast centers follow, and the reason for that, is that there's concern about interpretation of polygenic risk scores, and there's concern that since the test was initially developed and validated in European populations, does it have the same discriminatory accuracy and calibration in other ancestries?
And what we found was that early polygenic risk scores were not accurate in other ancestries, but the multiple ancestry polygenic risk score that we're working with is calibrated.
You know, the big issue is there's nothing worse than seeing a young woman come in with breast cancer before the time at which regular screening would begin. And it may be more advanced than it would have been had she been screened.
Sometimes there's family history that would've indicated a hereditary link that should've been investigated. Those are the women that we are trying to address, and what we've found across the board with the polygenic risk scores is that they do perform very well in Black women, but in — particularly Ashkenazi individuals and Hispanic women — it performs a little bit better, the polygenic risk score, and I think that the feeling of a lot of the guidelines committees is that they would like to see that discriminatory accuracy be exactly the same prior to it being released into a clinical setting.
But that is going to be really difficult, mainly because of biology, the genomic diversity in Africa is such that we probably, we're getting closer with that number, but we decided let's not focus on that, but we'll focus on the, you know, the early-onset breast cancer patient to see if they have a high polygenic load, and sure enough, they did.
Jamie DePolo: Okay. So, do you think, as you continue to work on this, if it becomes more accurate, that it would be recommended? I mean is that something you two see happening?
Dr. Holly Pederson: So, yeah. So, it's been validated back to 2015, and in my opinion, hopefully, it will be available, you know, yesterday, clinically.
I think that it will be very helpful for women, it's helpful for women with genetic mutations to stratify their risk. For other women with family history, to know where they are on the bell curve. It actually even helps to predict contralateral, or other side, risk in women who develop breast cancer. And so, it ultimately perhaps it could identify low-risk patients, who may not need to be as vigilant, or you know, may be more comfortable with every-other-year screening, which I'm not currently recommending.
Jamie DePolo: Sure.
Dr. Holly Pederson: Because we can't identify them yet, but it really has profound implications and may even change the way we approach younger women in terms of screening based on genetics and ancestry in addition to just age.
Jamie DePolo: Right. Right. Okay. Dr. Pederson, Dr. Hughes, thank you, so much. This has been really informative. I appreciate it.
Dr. Holly Pederson: Thank you so much. Good to see you.
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