Mutations and the Risk for Breast Cancer

Transcript:Claudine Isaacs, MD: Individuals who inherit a mutation in BRCA1 and BRCA2, the hallmark cancers that we see, are an increased risk for breast cancer and an increased risk for ovarian cancers. And, typically, the age of onset is shifted downward, so they tend to occur at a younger age than you would see in the general population. There is a range of risks, even for BRCA1 and BRCA2, two genes that we have been studying now for two decades rather intensively. For women who have a BRCA1 mutation, they have somewhere between about a 55% and 85% lifetime risk of developing breast cancer, and around a 40% to 45% risk of developing ovarian cancer over the course of their lifetime. For BRCA2 carriers, the risks are a little bit lower. Again, the range of risk for breast cancer can vary about 40% to upwards to 75% or so, and for ovarian cancer the risk is about 15%.

There are some other cancers that can be seen in BRCA1 and BRCA2 carriers. There’s an increased incidence for male breast cancer. An increased risk for more aggressive, somewhat earlier onset prostate cancer is also part of what we see. And with BRCA2s, you also see pancreatic cancer and melanomas, and a variety of other rare malignancies can be seen with a slightly increased risk.

Harold J. Burstein, MD, PhD: By far, the most common contributor to hereditary breast cancer is BRCA1 and BRCA2. And of all the cases of breast cancer, maybe 5% will have BRCA1 or BRCA2 mutations; and, there’s another 5% or so which certainly look like there is a hereditary component. And amidst that group are several well-known genetic syndromes, which are fortunately quite rare, but are very interesting from a scientific point of view, and are genes that we can specifically look at. So, one of those is the so-called, Li-Fraumeni syndrome, which is a mutation in the tumor suppressor p53 gene. These are families where there’s a dramatic risk of cancers, not just breast cancer, but leukemia, sarcoma, and brain tumors. And, these are typically very early-onset cancers. Usually by age 30, the family members have been affected. One little clinical pearl in the breast cancer space is that there seems to be an enrichment of HER2-positive breast cancers in very young women. So, if you see a 29-year-old who has a HER2-positive breast cancer, that’s a case where you want to look and think about Li-Fraumeni syndrome, again, a very rare syndrome, however.

There are a couple of other well-known syndromes that track with breast cancer, though again they are very rare. And, unless you do a specialized clinic in hereditary breast cancer, you might see only one or two of these cases in your professional lifetime. There’s a syndrome of hereditary diffuse gastric cancer with a mutation in the E-cadherin gene, and those patients sometimes get lobular breast cancer, which also lacks expression of E-cadherin. There’s a mutation in the PTEN gene—which goes along with Cowden’s syndrome, a syndrome where you get multiple hamartomas and other sort of benign growths—and that can also increase the risk of breast cancer. And, there are a couple of other of these syndromes, again extraordinarily rare, but because we know the specific gene that goes along with these rare syndromes, it’s the kind of genetic testing that’s being built into our panels of genetic tests. And, if we find a specific mutation in those syndromes, then it more likely accounts for the breast cancer in that woman.

Adam M. Brufsky, MD, PhD: One of the many ways that proteins can be altered by changes in DNA sequence is that a premature stop code can be inserted or actually change from an existing amino acid. And when these proteins are truncated, they either get degraded very quickly or their function is lost. BRCA1 is a particular example, as well as, PALB2. By truncating the protein, certain regulatory and DNA-binding portions of the protein are lost and, therefore, in some cases, in what’s called a dominant-negative mutation, it is the truncated protein that can sequester the active protein, resulting in both proteins from both alleles of the gene being reduced or made inactive.

Claudine Isaacs, MD: One of the challenges I think for the patient, and also for the provider who is doing this, is that we really don’t have precise risk estimates, especially for the newer genes. The most precise ones are for BRCA1 and BRCA2. And, as you heard, those risks still range fairly broadly. I think we’re all trying to gather knowledge about that so we can be more precise for patients, and we don’t really know what changes the risk. We see these families where we have a known BRCA mutation. I just saw a patient the other day and she was diagnosed at age 35 with breast cancer. She came with her parents, and it was her mom—who was 65 and well, and had not had her ovaries removed—who was the carrier. So, how do we explain that? They have the same gene, they have the same identical mutation. They didn’t have particularly different other factors, that we could tell, but there’s obviously other genes that modify risk, other environmental factors that do as well. I think we’re only going to get so good at our risk estimates, but I think that the clear thing that we’re grappling with as a medical community is how to better give patients estimates for some of these newer genes that we have far less data about.

Transcript Edited for Clarity