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A Conversation About Genetics and Cancer

Experts at Rush discuss latest advances in prevention, care

Melody Cobleigh, MD, with an image of the BRCA gene

Advances in genetics are transforming cancer care, enabling doctors to identify patients at heightened risk for developing cancer and to take action to protect them from the disease. Recently, Rush University Medical Center hosted an event during which cancer experts at Rush discussed the role of genetics in the prevention, detection and treatment of cancer. An edited transcript of that discussion — which focused on breast cancer but also encompassed ovarian cancer, prostate cancer and other cancers — appears below.

Moderating the discussion was Melody Cobleigh, MD, the Brian Piccolo Chair of cancer research at Rush University, head of the Section of Medical Oncology in Rush’s Department of Internal Medicine, and medical director of the cancer and clinical trials component of the Rush University Cancer Center. The panelists included Abde Abukhdeir, PhD, assistant professor of internal medicine; Kelly Burgess, MS, a genetic counselor in the Rush University Cancer Center; Peter Jokich, MD, director of the Rush Division of Breast Imaging; and Lydia Usha, MD, associate professor of medical oncology.

Melody Cobleigh: Each member of our panel is going to subtly try and get a few points across to the audience. I want to start by getting one point across, and that is that medicine is a team sport. There’s just no way that we can do it alone. And these are five fantastic members, certainly not the whole team, but five fantastic members of the team. Can each of you tell our audience a little about the work you do here at Rush?

Peter Jokich: I’m a radiologist, and our job in breast imaging is to find cancer, if women have breast cancer, and to find it at its earliest stage and smallest size.

Abde Abukhdeir: I’m a scientist. My research is trying to identify biomarkers that can predict which therapies will work best in certain breast cancer patients. I work very closely with the physicians here to try to do that.

Kelly Burgess: As a genetic counselor, I see patients that have strong personal and/or family histories of cancer. I do a lot of education with the patients and help them decide if genetic testing is something that is right for them, and we talk about kind of just all the implications of that testing. Then we can help coordinate that genetic testing, as well as discuss the results with them in detail and what our recommendations are, based on what we found or didn’t find.

Lydia Usha: Like Dr. Cobleigh, I’m a medical oncologist. I treat women with breast cancer, as well as women with gynecologic cancers. I also work really closely with Kelly around the clinical genetic predisposition to cancer.

Cobleigh: I’m going to start with Kelly. I’ve heard patients say, “I have that gene.” Kelly, what exactly does that mean?

Burgess: That’s a bit of a pet peeve of ours in genetics. We all have these BRCA genes among all the genes that we are testing for. It is a mutation in one of those genes that actually causes this increased risk for cancer.

BRCA, or as a lot of people refer to them, the BRCA genes, are actually good genes helping protect our bodies from cancer, they’re called tumor suppressor genes. But when someone has a mutation, which is essentially just a change in the gene that causes it not to work right, that’s when we have this increased risk for cancer. And that’s when we can change the patient’s management and their surveillance. Our goals are to prevent a cancer if possible, or to detect something early on, when it’s more easily treated.

Cobleigh: Dr. Jokich, women are confused these days. Should I have a mammogram? Should I start at 40? Should I start at 50? What difference does it make if I have a BRCA mutation or not? If I have it, how does that affect my screening for breast cancer?

First of all, let’s talk about women at normal, average risk, should they have mammograms? If so, how often and when should they start? Then I want you to talk specifically about someone with a deleterious mutation in the BRCA1 or 2.

Jokich: The gold standard for screening for breast cancer is still mammography. It is the proven test that we’ve had around for many decades. Many randomized control studies and even real life experience around the world shows that this test works. It’s fairly cheap. It’s fairly easy to do. Every woman after 40 who is average risk should have a screening mammogram every year.

When to quit is debatable. I still have my mother do it at 90. She just had it a couple weeks ago. If you’re in good health, you probably should not quit having a mammogram until maybe five years before you think you might die. If you keep doing mammography, find these small little cancers, even in women in their 80s and 90s, you can almost cure them essentially with a small outpatient lumpectomy.

There are people at higher risk that should actually start earlier than 40. And those are people with certain family histories. So we actually recommend that women whose mother or sister have breast cancer start screening 10 years earlier than when their mother or sister got diagnosed, but no earlier than age 30. We never do mammography under the age of 30. It’s because the radiation, even though it’s very low dose radiation, we don’t want to radiate breast tissue when the glandular tissue is still very active.

When we talk about the really, really high-risk women, the patients with BRCA and some of the other gene mutations, the best test we have for breast cancer, the absolute most sensitive test we have is breast MRI. For BRCA mutation patients and all patients with deleterious mutations that are high risk, we recommend that they have yearly mammograms and yearly breast MRIs, and we alternate them at six month intervals. So we are screening that woman or watching her breasts every six months with some test. The problem with MRI is that it’s very expensive, but for high risk women, it’s absolutely really the best test we have.

Cobleigh: So the difference that MRI has made is that screening mammography wasn’t really able to diagnose these patients at very high risk at an early stage. Now with the use of screening MRI, they’re all stage 1 or less, right? It’s a fantastic advance. In addition to surgery as an option for patients who have a mutation, there certainly are other options, as well. Dr. Usha, do you want to talk about the options that are available for someone with a mutation in BRCA1 or 2?

Usha: As far as the sure thing to prevent cancer, unfortunately it still is removal of the breast, but excellent cosmetic results now are available. At least for some mutation carriers and specifically for BRCA mutation carriers, treatment includes the removal of the ovaries, because ovarian cancer is a more silent killer than breast cancer. That surgery is performed after the age of 50 and has been also shown to decrease by 50 percent the risk of breast cancer. It’s certainly still the gold standard.

For women who don’t want to do prophylactic mastectomy or removal of the breast, we recommend intensive surveillance screening like Dr. Jokich described. In addition, some women can benefit from taking a medication to decrease the risk of breast cancer. Those are antiestrogen medications. They certainly can be used in addition to intensive surveillance.

For women with BRCA mutations who unfortunately did develop ovarian cancer, there is a new class of medications, FDA approved, to treat ovarian cancer in BRCA mutation carriers. They are called PARP inhibitors, and they have been really successful in advanced ovarian cancer and currently in clinical trials for early stage ovarian cancer.

Cobleigh: Dr. Abukhdeir, tell us what a biomarker is and what does that have to do with helping us treat patients better.

Abukhdeir: We have 3 billion DNA bases in our genome, and any one of them can be mutated, can be diseased. It can happen when we’re born and it can happen throughout our life. As we see with BRCA1, this can be predictive of your likelihood of developing breast cancer or ovarian cancer throughout your life. We take five, 10, 15, 20 genes and look at their levels in cancer to predict outcomes of a certain therapy, and we can use them to predict sensitivity to new drugs. That’s the focus of research in my lab right now. I’m doing those two things.

Up to 5, 6 percent of all breast cancer patients and maybe up to 10 percent of ovarian cancer patients harbor or carry mutations in those two genes. Those people were born with this mutation. The idea is to identify BRCA carriers or people who were born with this mutation before they develop cancer.

Cobleigh: Some people are reluctant to go for genetic counseling or genetic testing because they’re afraid of discrimination. Kelly, would you like to comment on that? What protections exist, at least in the United States? How do you counsel patients who have not yet had a cancer, in terms of maximizing their insurance before they have genetic testing?

Burgess: Here in the United States, we actually have a federal law. It’s called the Genetic Information Nondiscrimination Act, or we call it here, GINA for short. It was passed in 2008. This law says that health insurers, as well as employers, are not allowed to use genetic information against us.

One caveat that we always mention with patients is that the GINA law does not cover things like life, long-term care or disability insurance. Now, it’s not something we usually hear about patients getting discriminated against for a life insurance policy. But legally, they can ask those questions and they can use that information against us. Sometimes people feel most comfortable getting all their policies set in place before they proceed with the genetic testing, just to be on the safe side, to make sure it isn’t used against them for those certain types of insurance.

Cobleigh: Dr. Usha, beyond BRCA1 and 2, are there other genes that we know about that predispose toward cancer, breast cancer and otherwise?

Usha: Yes. The last several years have seen an explosion of knowledge in this area. In the United States, Myriad Genetic Laboratories used to have a patent for BRCA testing. They lost the patent in June of 2013. Then other laboratories immediately were able to offer gene panels for testing for genetic predisposition to cancer, actually different cancers, including those BRCA genes.

Nowadays, essentially we almost never use just BRCA testing, unless we know that there is a family member with a known BRCA mutation. We always use the panel of genes. Panels are different. They can be targeted to a certain type of cancer, such as breast cancer, or they can be a pan-cancer panel, which could analyze up to 40 and more genes associated with predisposition to different cancers.

We do bring back patients who previously tested negative for BRCA mutations for additional genetic testing. Sometimes we discover mutations in other genes, and we are able to prevent other cancers for these women and men, too, and their family members using this knowledge. All of this became possible with the new technology, next generation sequencing, which essentially allows sequencing a number of genes at the same time, as opposed to one by one gene.

Cobleigh: What percentage of breast cancers is due to hereditary predisposition that’s identifiable?

Usha: The numbers are different, depending on the population studied and the number of genes included. But in some studies, up to 20 percent of patients with breast cancer actually harbor germ line genetic mutations that they were born with that predisposed them to cancer. As far as women who previously tested negative for BRCA mutations, then a mutation in another gene that predisposed them to breast cancer can be found in 6 to 11 percent of those BRCA-negative patients.

Burgess: If I could just elaborate on something you mentioned. You know, we do see patients and families that come to us who definitely seem to have that family history, where there’s something hereditary going on, but we do the gamut of testing we have and they come back negative for everything. It’s not the most common situation we come across, but it does happen.

It just goes to show, we have come a very far way, but we also still have a very far way to go. Right now, there’s around 16 or 17 genes that we have well defined as having an association with an increased risk for breast cancer, but there’s definitely more genes out there that we just don’t know about yet. I can think of a couple families off the top of my head that we’ve seen that fit that description. They're definitely not the majority of the patients, but people who come in, they seem like they have hereditary risk, but they don’t test for anything, that does still happen.

Cobleigh: Which other cancers other than breast are associated with pathogenic mutations in BRCA1 or 2? Dr. Usha?

Usha: We didn’t know this before, because we could only essentially test patients who meet the established criteria for genetic testing. Until recently, we could not offer patients with prostate cancer genetic testing for cancer predisposition, because the national guidelines didn’t include them.

Now we do know that men BRCA carriers can have up to 16, 20 percent, especially BRCA2 carriers, the risk of prostate cancer. Moreover, we know that often this prostate cancer is much more aggressive than just garden variety prostate cancer. This new class of drugs that I mentioned before, PARP inhibitors — which is currently approved only for the treatment of ovarian cancer mostly in BRCA carrier — has been shown in clinical trials to work also in prostate cancer in men who have again those BRCA mutations.

I would say that the next generation sequencing essentially opened the door to identify kind of more clinical manifestations of these mutations. Like you said, it’s not only even prostate cancer, we’re learning more about melanoma. We learn more about other genes and their possible clinical manifestations. It really has been an explosion of knowledge in our understanding of biology of mutations, as well as their clinical presentation.

Cobleigh: I’d like to thank the members of the panel. Now you understand why it’s a team sport. No one can know all of this stuff.

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