Value of Hereditary Breast Cancer Testing

Transcript:Claudine Isaacs, MD: One of the issues that comes up a lot when you’re evaluating somebody for counseling and for testing is, what’s the most appropriate test to do? Should we be doing just standalone testing for BRCA1 or BRCA2, or should we think about doing one of these multigene panels? And it really goes back to some simple rules, actually. The first thing is to really just look at the individual’s own personal cancer history and their family history, and if the cancers are in the family are very characteristic of a particular syndrome, BRCA1 and BRCA2, for instance. So, if there’s solely breast cancer and lots of ovarian cancer in the family, then it makes sense to just do single gene testing, or BRCA1 and BRCA2—obviously two-gene testing in that situation. If you have a family where it could fit any number of syndromes, so there’s some thyroid cancers thrown in or endometrial cancers that might be suggestive of other syndromes, then it tends to make sense to think about a multigene panel. That’s the first thing that we take into account.

And then the other thing that’s really critically important is to assess the individual that you’re talking to. What’s their tolerance for ambiguity? Because we’re much likelier to get an ambiguous test result—a variant of uncertain significance or a mutation in a more modern penetrance gene where we don’t really fully understand the cancer risks associated with that gene. If you do multigene panel testing and you’re testing for 25, 30 genes at the same time, you’re much likelier to get a result that you don’t know how to interpret clinically for the patient. So, whoever you are talking to, they have to be able to know beforehand that if you’re doing a multigene panel, it is relatively likely that you may end up with a result that you don’t have clear understanding of today. And I like to tell patients that today in 2016 or so, where we are, the technology has outpaced our medical knowledge right now. I’m quite confident that our medical knowledge will catch up. But at this point, it’s possible when you do multigene testing that you might get a result that you don’t know. And many people are perfectly fine with that and they understand that.

And then the final thing that can come in is, just how quickly do they need the test result? If you need it more quickly, you often want to do single gene testing to start with. And then the finances are involved. Insurances cover differently and that could impact things. The one other scenario that’s important to think about is you don’t necessarily have to make the decision. The decision you make at that point in time doesn’t have to hold. You could tell a patient your family is very characteristic of BRCA1 and BRCA2. Let’s do that first and then with different companies, you can reflex to broader multigene panel testing. So, it allows you to do it in a more paced way.

Adam Brufsky, MD, PhD: Next-generation sequencing has really changed everything. When I was a post-doctor, or Fellow, back in the 1990s, it took almost 2 months, if not longer, to do sequencing of various genes. And I remember when BRCA1 and BRCA2 were cloned, it took several years to actually clone those two genes.

I think they can get sequenced now within 2 days, and probably get the analysis done in about a week or two. And the number of genes that you can sequence at once has gone up dramatically. I think that this really has changed everything because in a week to 2 weeks, we can now sequence multiple genes at once and get the results back in about 3. And some of these multigene panels are now 25 to 30 different genes that can be done, and I think that it gives us an enormous amount of information, which is good and bad that we can do this.

Harold Burstein, MD, PhD: The challenges in state-of-the-art testing for hereditary breast cancer mostly relate to access to the testing, and then they also relate to the identification of so-called variants of unknown significance. So, there are different kinds of testing that are now available. We have narrow panels where we just do BRCA1 and BRCA2 genes, and then we have larger panels typically on the order of about two dozen genes, which are potential contributors to hereditary breast cancer risk. And our genetics team uses these in different ways, depending on the clinical situation. If mom has a BRCA1 mutation and the daughter wants to know if she has it, all you need to do is test for one gene. But, in most situations, you’re casting a broader net, and you want to look around a little bit more. And that has led to widespread adoption of the multigene panels.

The biggest issue that you run across in these multigene panels is a 21st century problem, one that clinicians are going to have to get used to in all sorts of ways of thinking about genetic information. There’s a lot of variation in the human population. If you go into a movie theater and sequence everybody’s genes, you find out that 10% to 20% have little mutations all over every gene you look at. That is the human species, that’s what we all carry with us. Most of those mutations are not clinically significant. So, sorting out the wheat and the chaff, which mutations are really important ones? Which are telling you something very critical about hereditary risk of cancer or other illnesses, and which ones are just genetic noise is a problem? And the way to handle that problem is to create large databases where you collect the information and you correlate these genetic variants with clinical outcomes. And, over time, you enrich that database so that at the end you know that if you have this weird mutation and you have a single point mutation of that gene, and you know that’s just noise, versus this one is something to be concerned about. And you do that in a way that’s publicly accessible. So, the researchers and the companies are moving towards that. There’s been a big push for this kind of repository of information. Several of the companies have huge repositories already, and there’s discussion about how to make that information publicly available. And breast cancer has really been in the forefront of this, because it’s one of the first cancers for which we had good hereditary testing. But this is going to be something that more and more patients are going to see testing for, not just in breast cancer but as we broaden it.

Then the other thing is that the likelihood of these variants being important goes down as the family history goes down. If you’re talking about a family and you say, ‘Well, my gosh, every generation of people seems to have these linked cancers, there’s got to be something going on.’ And you do your basic testing and it’s negative, and then you do a variant testing and you find something, you're thinking, ‘Well, that might really be important.’ But if you’re taking just an average woman who doesn’t really have a family history and there’s a mutation, again, the probability that that’s concerning goes way down. Ultimately, we need the repository and that collected experience to help guide patients.

Transcript Edited for Clarity