Breast Cancer Podcast

The Impact of BRCA Status on Therapy Choices

Lidia Schapira, MD; Nadine Tung, MD


April 12, 2022

This transcript has been edited for clarity.

Lidia Schapira, MD: Hello. I'm Dr Lidia Schapira, and welcome to Medscape InDiscussion Breast Cancer. Today we're talking about how BRCA status impacts choices of therapy for patients with early-stage breast cancer. Since genetic testing has become widely available and we now understand that BRCAness impacts response to treatment, I'm delighted that my guest today will help us understand how we can apply this new knowledge to our clinical practice. My guest today is Dr Nadine Tung, professor of medicine at Harvard Medical School and director of the Cancer Risk and Prevention Program at Beth Israel Deaconess Medical Center. Welcome, Nadine.

Nadine Tung, MD: Hi, Lidia. Thank you so much for this invitation.

Schapira: Such a great opportunity for us to chat about a topic that I know you've been studying for your entire career. In fact, you were one of the earliest translational researchers to really think about treatment choices for patients who have BRCA-positive tumors. Tell us a little bit about how you think that having a BRCA mutation affects the way we should approach the treatment of breast cancer.

Tung: Well, it is very exciting because for so many years we did the genetic testing for BRCA1 and -2 simply to identify cancers that the individual was at risk for in the future. And now it's actually impacting treatment itself. So how does BRCAness affect our treatment? I think I'll just start by saying the very first decision the patient often has to make is what surgery to undertake. And of course, because of the increased risk for both ipsilateral and contralateral breast cancers, many BRCA carriers are really facing right away the decision as to whether to have bilateral mastectomies. And if they don't, because of those risks, they really should be having an annual breast MRI in addition to a mammogram. So, the one thing, Lidia, that I always do like to remind clinicians about is that when they're talking to their BRCA carriers newly diagnosed with breast cancer, it's really important to remember that the strongest predictor for whether that BRCA carrier is going to develop another breast cancer is the age of that first breast cancer. For example, if you're talking to a BRCA2 carrier who's been diagnosed before age 40, that woman has a 68% chance of getting another breast cancer in the next 20, 25 years. Whereas if she's diagnosed over the age of 50, the risk is more like 25%, 28%. So, I think starting the conversation with really accurate risk estimates helps the woman to make the decision that's right for her for surgery.

Schapira: How do you recommend having those conversations and what is the role of a genetic counselor in both the testing and providing information that's actionable not just for the patient, but also for her family members?

Tung: I think it's just really important to have access to someone with expertise in genetics. This information is really complicated, and sometimes you get an answer which is very clear. But sometimes you get a change that's not as clear. You know, it's not really clear whether this acts in the same way as a BRCA mutation. And of course, now our patients don't just get BRCA1 and -2 testing; they get tested for many genes. Some of these panels have 80 genes or more. Changes come back in these genes, in some of the genes that can increase risk for cancer and in some genes we're hardly familiar with. So helping a woman not to panic, but to understand the information and how it impacts the decisions she needs to make, is really important. I can't say enough about the importance of genetic counselors or experts that can simply help interpret the information.

Schapira: I was talking just a couple of hours ago to a woman who was diagnosed with breast cancer, whose mother had breast cancer. And it turns out that both have mutation in BRCA. She was talking a little bit about how a person is to understand that there are differences even among the tests that are available. And she was talking about the enormous direct-to-consumer advertising that's also taking place from multiple companies. Can you tell us the salient points that general physicians seeing patients and cancer specialists need to know about the different tests?

Tung: I'm not a huge fan of direct-to-consumer genetic testing; I don't think recreational genetic testing is appropriate. It's one thing if you want to find out whether you're a sprinter or marathoner genetically, but it's quite different when you have risk for a disease like cancer. So when an individual is trying to figure out which panel or which genes to test for, I always say there are two main decision points: Does a woman, or any individual, want to test for genes that are associated with the cancers in their family, that they can see in their family (and they're looking for an explanation for those cancers); Or do they want one-stop shopping or for the same price to have as many genes tested as possible, even those that are associated with cancer that they can't see represented in their family? And then the other decision is, does someone want to test for just those genes for which an abnormality or a mutation really confers a very high risk of that cancer? So that the recommendations about what to do are more established, we call those high-risk or high-penetrance genes, like BRCA1 and -2. Or does an individual want to also test for genes for which, if there is a change or mutation, there may be a risk for cancer, but the risk is not as high? We call those the moderate-risk genes in breast cancer. We have some: ATM, CHEK2. And for those, some of the recommendations are not quite as clear-cut as for BRCA1 and -2. So I always think that's the main decision point: genes that are related to the cancers in the family or not, those that are more established, or those that are a little bit newer. That's the way I would think about it.

Schapira: Let's come back to a hypothetical clinical scenario. You're now seeing a patient who's just been diagnosed with breast cancer. She is a carrier of a BRCA mutation that we know is associated with cancer and has a family history. How do you approach treatment recommendations other than the choice of surgery, the systemic therapy?

Tung: I think we know that the breast cancers that occur in the BRCA carriers, in general, tend to be more sensitive to chemotherapy than breast cancers that are not in BRCA carriers. So in some ways, ironically, that is helpful because it makes the tumor more sensitive to standard chemo. Many people think about platinum chemotherapy, and certainly the BRCA-related breast cancers are very sensitive to platinum, but it's not uniquely to platinum; it's to any what we call DNA-damaging chemotherapy. We actually did a study in BRCA carriers. It was called the INFORM trial and we used upfront chemotherapy. Neoadjuvant chemotherapy compared platinum with the more standard Adriamycin/Cytoxan (AC). And really, platinum was no better. So I think the concept is, if you have chemotherapy that damages the DNA, those tumors are particularly sensitive, so it doesn't influence the choice of chemotherapy very much. The question does come up about the added value of platinum. Let's talk about triple-negative breast cancer. A couple of studies have shown that there is less added value when you add platinum to the standard, let's say AC-Taxol chemotherapy, probably because the tumors are already more sensitive to the standard chemo. But nevertheless, there is value.

Schapira: It's interesting to hear that there is another class of drugs that has now entered the conversation, and that's the PARP inhibitors. We just learned a few days ago that FDA has approved olaparib based on the results of the OlympiA study for adjuvant treatment. Talk a little bit about that.

Tung: The OlympiA trial results mean that 1 year of adjuvant olaparib, which is a PARP inhibitor, is now approved for BRCA carriers with early-stage, high-risk, HER2-negative breast cancer after surgery, chemotherapy, and radiation are all completed. And for the BRCA carriers that have ER-positive disease, it can be given concurrently with the endocrine therapy. So it's probably worth reviewing which BRCA carriers are eligible. We said high risk. What does that really mean? For the BRCA carrier with triple-negative breast cancer, usually we use neoadjuvant chemotherapy. And if there's any residual disease after the neoadjuvant chemotherapy, then the patient is eligible for olaparib. Or if the BRCA carrier went to surgery first, and again, the triple-negative breast cancer was larger than 2 cm or had nodal involvement, that again qualifies the patient for a year of adjuvant olaparib. It's a little trickier for ER-positive disease and the bar is higher. For a BRCA carrier with ER-positive, HER2-negative disease, if she goes to surgery first, the requirement is four or more involved lymph nodes to qualify for adjuvant olaparib. If neoadjuvant chemotherapy is given, this is where it gets tricky. There needs to be what's called a CPS and EG score of 3 or higher. What does that mean? CP means clinical and pathologic stage, and then the E is the estrogen receptor. Here, it’s positive. And G is grade. So essentially, this is a measure of how much disease was there at the start, the clinical stage; and how much disease was left at surgery after chemotherapy, the pathologic stage. And the grade, with a point given for more disease — higher grade. There is a table one can look at. If the score is 3 or higher, then the patient qualifies for adjuvant olaparib.

Schapira: And by that, you mean we can assume it will be covered by the patient's insurance.

Tung: Yes, absolutely. I have a patient right now, ER-positive, went to surgery first, has a larger tumor and has three positive nodes, and I don't know if that will be covered. But it's a little frustrating because one thinks that it might be a helpful treatment in a patient like that. I think there are a couple of situations worth highlighting where the clinician is still left with a choice and a little bit where data are not there. So, for example, in a patient — I just mentioned a BRCA carrier, ER-positive disease — sometimes we're choosing between abemaciclib, the CDK4/6 inhibitor per the monarchE trial, or olaparib. So to break that down, if the patient has four or more lymph nodes, particularly if the ki67 is high, there's a choice there about which agent, and there's no direct comparison. But if the patient doesn't qualify for the PARP inhibitor, then obviously abemaciclib may still be an option. I think the same choice and decisions are coming up with triple-negative disease. So, let's say you have a BRCA carrier, you give neoadjuvant chemo, and there’s residual disease, I think a lot of us used to use capecitabine. And now we ask, "Well, which should we use?" I think many of us in the field have admitted that there are no direct data. But in the metastatic setting, the PARP inhibitors were compared with chemo and with capecitabine, and the PARP inhibitors were superior and with better quality of life. So I think in that situation, I choose the olaparib. There are lots of safety data that it can be combined with pembrolizumab and other immune therapy. So, if that patient is supposed to get pembro, that's okay to combine. Those are the kinds of decisions we're facing in our BRCA carriers with early-stage disease.

Schapira: You're probably one of the people with the most experience prescribing the drug. So tell us a little bit about tolerance of the drugs and tolerance of the drug if you are going to combine it, say, with hormonally active therapies for adjuvant therapy.

Tung: Olaparib generally is very well tolerated. I would say probably the most common side effect, if it happens, is nausea. I've been impressed that it often goes away with time. But you use the standard antinausea medications if you need to. I think the lab value one needs to watch for the most is anemia, and it can happen suddenly. I think you know that monitoring the hemoglobin or the hematocrit frequently, every 3-4 weeks, is really important. And if the hemoglobin were to go below 8, or whatever your threshold is for that patient, a transfusion, a dose reduction often takes care of the problem. I would say those are the two side effects that one would encounter probably most, but it's generally well tolerated. There's no hair loss, which is really very important to all of us. Not a problem when combining with endocrine therapy. I haven't found any synergistic or unexpected side effects, and I haven't given it enough. I have a few patients with immune therapy, but there should be no interaction there that one could anticipate.

Schapira: In the studies of PARP inhibitors, how often did you need to dose-reduce?

Tung: I know that very, very few, 5% or less, have to discontinue it due to side effects. I think it's a healthy amount. You know, I wouldn't be surprised if it's 20%-30% that wind up needing a dose reduction or two. And in most of the studies, there were only two dose reductions and only 5% couldn't tolerate beyond that. Most people will be fine with one or two dose reductions.

Schapira: You're such an experienced and compassionate oncologist. I imagine that for patients who qualify to get this drug, it must be reassuring also to know that you're doing something that addresses their particular genetic risk in the particular cancer. Can you talk a little bit about how the recommendation to take adjuvant olaparib is received by patients?

Tung: I think you've hit the nail on the head. I think patients are really excited that there is a therapy that is targeted to their cancer that is so effective and decreases the chance of recurrence significantly. And not just recurrence — distant recurrence.

Schapira: I know you have been a key participant in writing the ASCO guidelines on managing patients with hereditary breast cancer. So can you give us the highlights of the guideline, and tell us why you wrote it and what the message is for the community of practicing oncologists?

Tung: We wrote it because we thought there was a lot of confusion, both for treating BRCA carriers and for treating patients with some of the other genes. So we focused on the five main genes that are related to breast cancer, that for which an inherited abnormality can increase the risk for breast cancer. There's BRCA1 and -2, which are high-risk genes that we've been speaking about in this discussion. There is a gene called PALB2, which is another pretty high-risk gene that a lot of people are thinking about as a BRCA3, almost. And then there are two lower-risk genes called CHEK2 and ATM. We felt like there was a lot of confusion about these five genes. So for the highlights and the main take-home messages… I would say we've covered BRCA1 and -2. PALB2 is a high enough–risk gene that the discussion about bilateral mastectomies is not unreasonable. It always should be had in the context of looking at the family history or the age of the patient, and many other factors. They are not yet approved to receive PARP inhibitors. But we've been doing studies in the metastatic setting, and these PARP inhibitors really seem to work very well in patients who have PALB2 mutations. I think PALB2, which is being thought of sort of like BRCA3, will more and more be treated like BRCA mutations. ATM and CHEK2 are lower-risk genes. I think they shouldn't be thought of like BRCA1 and -2; they shouldn't be thought of like PALB2. For a patient with breast cancer who's found to have one of those mutations, there shouldn't be an automatic response to be doing bilateral mastectomies. These are lower-risk genes; they are risk factors.

I think that was an important message — when there is a lack of data about what the second or contralateral breast cancer risk is. But we really did feel that the literature did not support automatic mastectomies and that this is something that really should not happen automatically. In terms of systemic therapy, it's really the same. There are a couple other points I would make in regard to local therapy. There had been a lot of fear about administering radiation therapy to a breast cancer patient who was found to have an inherited mutation in the gene ATM. And there is reason. Because if a patient were to inherit two of those genes, there would be a more serious illness. But that's not what we're talking about, and a lot of patients were only being offered mastectomy. After we reviewed the literature, we really felt that the data did not support that. So patients with ATM mutations should be offered breast-conserving therapy, including radiation, if they're otherwise appropriate. I'd finish by saying, as a reminder, that the only gene for which radiation should be avoided, if at all possible, is the p53 gene. If someone inherits a mutation in that gene and has breast cancer, a mastectomy would be preferred to lumpectomy and radiation. So, I would say those were the highlights.

Schapira: Thank you so much. That was so clear. So, to finish our conversation, are there any studies that are now ongoing that you think will help us understand and refine our approach to BRCA-positive breast cancer?

Tung: Looking even more at the PARP inhibitors will be interesting. Right now, they are being added to a lot of therapy in the high-risk patients to better their outcomes and their survival. But the question arises in the patients with lower risk. Might the PARP inhibitors, which are tolerated so well in their oral therapy, replace chemotherapy or allow a de-escalation of chemotherapy so that for lower-risk breast cancer, the PARP inhibitors are an alternative, a better tolerated therapy than chemotherapy? There was an interesting study from Jennifer Litton at MD Anderson, who used it in the neoadjuvant setting and got a 45%, almost 50%, pathologic complete response rate using the PARP inhibitor talazoparib alone. So I think there's more to do with the PARP inhibitors as a start.

Schapira: Thank you, Nadine, for all your work and for a wonderful conversation. It's been a real pleasure.

Tung: My pleasure. Thanks so much for inviting me.


TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial)

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer

Validation of a Novel Staging System for Disease-Specific Survival in Patients With Breast Cancer Treated With Neoadjuvant Chemotherapy

Table 1 from Validation of a Novel Staging System for Disease-Specific Survival in Patients With Breast Cancer Treated With Neoadjuvant Chemotherapy

Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2−, Node-Positive, High-Risk, Early Breast Cancer (monarchE)

Evaluation of Efficacy and Safety of PARP Inhibitors in Breast Cancer: A Systematic Review and Meta-analysis

LYNPARZA® (olaparib) Prescribing Information. AstraZeneca; 2020.

Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline

A Population-Based Study of Genes Previously Implicated in Breast Cancer

TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes

Cancer Risks and Mortality in Heterozygous ATM Mutation Carriers

Neoadjuvant Talazoparib in Patients With Germline BRCA1/2 (gBRCA1/2) Mutation-Positive, Early HER2-Negative Breast Cancer (BC): Results of a Phase 2 study

Follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.