Ask the expert: Triple-negative breast cancer

During this webinar, oncologist Rita Nanda, MD, answers questions about early stage and metastatic triple-negative breast cancer. This program was entirely dedicated to Q&A and addresses questions about symptoms, side-effects, treatment options and more.

Janine Guglielmino (00:00:02):

As we’re polling for questions, I’m just going to start with a couple of questions that we’ve gotten ahead of time, and then I’ll jump right into the question. We usually start this program by talking a little bit about what triple-negative breast cancer is, because it’s obviously defined by something that it is not. What have we learned recently about whether triple-negative breast cancer is a single disease?

Rita Nanda, MD (00:00:28):

I think that’s a great question and triple-negative breast cancer, in fact, all different types of breast cancers, but specifically triple-negative breast cancer, is very heterogeneous. And by that, I mean, there are lot different subtypes of triple-negative breast cancer, and a bunch of different groups have studied triple-negative breast cancers in different ways and have different categorizations for triple-negative breast cancers. So, triple-negative breast cancer is not one disease. It is a mix of many different types of cancers, and we are starting to identify certain subtypes of triple-negative breast cancer that we can target with certain types of therapies. For example, pembrolizumab or Keytruda. Pembrolizumab (I call it pembro for short) is immunotherapy. And we have that now approved for a subtype of triple-negative breast cancer that expresses a protein called PD-L1, at least in the metastatic setting. for early-stage breast cancer, pembrolizumab is approved for all stage II and III, triple-negative breast cancers. That’s just one example of how we’ve identified that there are different types of triple-negative breast cancers that can potentially respond to different therapies in different ways.

Janine Guglielmino (00:02:14):

Thank you, Dr. Nanda. There have been so many developments over the past 12 to 18 months, both in early-stage and metastatic triple-negative breast cancer. Would you mind just reviewing two or three of the most significant developments that we’ve seen?

Rita Nanda, MD (00:02:38):

Absolutely. After spending 10 years looking for newer therapies for triple-negative breast cancer, to finally see some of that work come to fruition has been really exciting. For advanced triple-negative breast cancer that arises in the setting of a germline mutation in BRCA1 or BRCA2. We now have two PARP inhibitors that are FDA approved for advanced triple-negative breast cancer. Olaparib and talazoparib are both approved, and olaparib was just approved. last year for early-stage, triple-negative breast cancer in the setting of a BRCA1 or BRCA2 mutation for women who are at high risk for recurrence. That was really exciting. And that’s typical for what we see happen in clinical trials and drug development. We see drugs that are first approved for advanced cancer, and then when they show a lot of promise there, we move them up into the early-stage setting.

Rita Nanda, MD (00:03:53):

And that’s definitely what’s happened with PARP inhibitors for those women who have BRCA1 and BRCA2 mutations. That was a big advance. We also now have immunotherapy, and that was that first example I used of pembrolizumab, also called Keytruda, that is now FDA approved for advanced triple-negative breast cancer that expresses a protein called PD-L1, and it’s also approved for early-stage, triple-negative breast cancer, for stage II and III, triple-negative breast cancer, and it’s approved to be given in combination with chemotherapy prior to surgery. So, that was a really big advance in the middle of last year. We’re already seeing more and more drugs that are showing promise in the advanced cancer setting, moving up. And then I would say the third big advance has been the approval of a drug called sacituzumab, which is also called Trodelvy.

Rita Nanda, MD (00:04:58):

Sacituzumab — I call it sassy for short, because it’s so much easier to say — is now FDA approved for all patients with triple-negative advanced breast cancer. There’s no special marker that you have to have or express. And sacituzumab is a new kind of treatment. It’s what we call an antibody drug conjugate. And that’s basically a fancy term for what I consider targeted chemotherapy: chemotherapy that really is targeting those cancer cells selectively. And so, a lot has happened over the last 3 to 4 years, and there are more drugs coming. There are a lot of other drugs that are being developed specifically for triple-negative breast cancer. More of these antibody drug conjugates or these targeted chemotherapies are showing a lot of promise in early-stage trials, and I suspect will be approved in the next few years.

Janine Guglielmino (00:06:12):

Thanks so much for reviewing those, Dr. Nanda, because I can see, even in the Q&A, a couple of our participants expressing some frustration that most clinical trials seem to not be in triple-negative breast cancer. Can you talk a little bit about what clinical trials are most exciting to you that are ongoing in triple-negative breast cancer and that people might be able to get involved with?

Rita Nanda, MD (00:06:39):

So, we have these great approvals now — things like the PARP inhibitors, but those target a small proportion of individuals with triple-negative breast cancer, the immunotherapy, which also targets a select group of patients with triple-negative of breast cancer, probably about 40 percent of triple-negative breast cancers express that PD-L1 protein that is important in the metastatic setting. Sacituzumab fortunately is a drug that’s available to all different types of triple-negative breast cancer. And then there are a number of trials that are ongoing or soon to start. There’s another antibody drug conjugate calleddatopotamab, which is somewhat similar to sacituzumab in that it targets the same protein, but at least in phase I studies, it looks like it can be effective even after sacituzumab stops working.

Rita Nanda, MD (00:07:49):

So, I think there is hope for some newer targeted chemotherapies down the line. There are also trials of drugs that have been done, and some are ongoing, and we’re waiting for results from some of them, looking at reusing or repurposing some of the HER2 therapies for segments of patients who have tumors that have a very low level of HER2 expression. So, triple-negative breast cancer is a cancer that’s negative for the estrogen receptor, the progesterone receptor, and the HER2 receptor at a high level of expression, but at a low level of expression, we can actually see probably about 30 percent or so of triple-negative breast cancers have a low level of HER2 expression, and so there are trials that are focused at looking at some of these targeted chemotherapies that target HER2. And we have some data already that those drugs are looking interesting.

Rita Nanda, MD (00:08:52):

We are also going to be looking again at the androgen receptor-positive form of triple-negative breast cancer. There were some trials that were going on a number of years ago, and then there was a pause, but now there’s a trial that Tiffany Traina at Memorial Sloan Kettering and I are going to be co-leading that hopefully will open up in the next few months looking at using some drugs that we use to treat prostate cancer, because most prostate cancers are positive for the androgen receptor. We would use a drug called enzalutamide, to treat androgen receptor-positive, triple-negative breast cancer. I’m pretty excited about that. Although full disclosure, I am co-leading that trial, but I think those are two areas that are really moving forward, the antibody drug conjugates. These targeted chemotherapies targeting the androgen receptor and then a number of immunotherapy combinations. Nobody really knows if there’s a good combination of a drug like pembrolizumab with other immunotherapy drugs, but there are a whole host of trials ongoing trying to add drugs like pembrolizumab or cousin drugs to pembrolizumab, to other chemotherapies, targeted therapies, and immunotherapies to see if we can help more individuals with triple-negative breast cancer benefit from immunotherapy.

Janine Guglielmino (00:10:33):

Thanks for sharing that, Dr. Nanda. I have a good mix of questions about early-stage and metastatic breast cancer. So, I’m just going to jump into some of these. We have a couple specifically about Keytruda. Our first question is for someone who had a stage III, triple-negative breast cancer in 2021. So a person who is at high risk for recurrence who was wondering if it’s possible, after having been treated starting in January 2021, to get Keytruda now, even though she’s done with her initial treatment.

Rita Nanda, MD (00:11:12):

That’s a great question and a question I don’t have the answer to. Keytruda is not approved to be given in that way, and we don’t even know if it’s effective, if it’s given by itself. The trial that was done combined it with chemotherapy, so it’s unclear if there’s a role for Keytruda in that setting. There was a trial that looked at individuals with triple-negative breast cancer who didn’t have all of their cancer go away with chemotherapy prior to surgery — so, they had chemotherapy, then they went to surgery. There was still some cancer that was removed at the time of surgery, but there was still some cancer in the surgery specimen. And there was a trial that randomized individuals to observation or a year of Keytruda or pembrolizumab, and we’re still waiting for the results of that trial.

Rita Nanda, MD (00:12:13):

It’s hard to recommend that treatment. Immunotherapy can come with side effects. And so, I think until we know that it’s effective in that way to be given by itself after chemotherapy, it’s not something we generally recommend. It’s not impossible to have your physician try to contact Merck, which is the manufacturer, to see if they’ll give compassionate use approval. I have seen that done in certain situations, and the company has provided the drug, so that is certainly possible. But right now, I would say the standard of care, if there’s not a complete response to therapy prior to surgery in individuals who didn’t have immunotherapy as part of their treatment, is to get a pill chemotherapy called capecitabine or Xeloda afterwards for about 6 months.

Janine Guglielmino (00:13:13):

Great. Thanks for addressing that. And it’s also good to hear that it’s a question that’s being looked at in a clinical trial, because I think that’s a very common question that we do hear from people now that that medication is available in the early-stage setting. A follow-up question about Keytruda is: Why is it approved only for people who test a 10 percent or higher for PD-L1? And if you could just explain all of that, that would be helpful.

Rita Nanda, MD (00:13:47):

PD-L1 is a protein, and it can be expressed on tumor cells and on immune cells that live in the tumor. The tumor isn’t just a bunch of cancer cells. There are other cells in that tumor; the cancer-fighting cells and cancer-promoting cells, all different kinds of things go into making up a tumor. And there are different ways to look at PD-L1 status. Some trials have only looked at the immune cells and whether or not they’re positive. And 1 percent was used as a cutoff. If 1 percent of those immune cells are positive, that was considered positive for some trials. For the pembrolizumab trials, they looked at what’s called a combined positive score or a CPS. And it’s actually not a percent. It’s just a number. What the trial found was that for those individuals who had a combined positive score greater than 10, that is used as the cut point, because those are the people who benefit from getting pembrolizumab. There was just an update of the trial that was presented at San Antonio in December. They went back and they looked at those individuals who had a combined positive score of less than one, between one and nine, greater than 10 but less than 20, and then greater than 20. And it was only those individuals who had a combined positive score of more than 10 who benefited from adding the pembrolizumab. For people under that, pembrolizumab didn’t do anything. If they had a response, it was only because of the chemotherapy and adding pembrolizumab didn’t improve the effectiveness, but it did expose people to side effects. And so that’s why we use that 10 as a cut point. It’s not to leave anyone out. It’s just to give the drug to the people who are going to benefit and not give it to the people who aren’t, but who could have some severe side effects from it.

Janine Guglielmino (00:16:15):

Thanks for addressing that. In the last question, you talked a little bit about the importance of pathologic complete response. Could you just explain what it is you’re looking for with PCR and how that’s associated with the risk for recurrence? We’ve got lots of questions about how you determine if someone’s at high risk for the cancer returning versus low or medium risk.

Rita Nanda, MD (00:16:44):

That’s a great question. It comes up all the time. I would say that the standard of care way to treat a stage II or III, triple-negative breast cancer in 2022 is to give what we call neoadjuvant therapy, treatment prior to surgery, and the reason we do that is number one, it lets us see how the tumor’s responding to a treatment. We can make some adjustments in real time. If somebody’s not responding to a particular type of treatment, we have the opportunity to change it to something else. But the most important part of this is that we use how someone’s tumor responds to treatment that we give to determine what we do after surgery. As of late last year, the standard of care for stage II and III, triple-negative breast cancer is chemotherapy plus a year of pembrolizumab or Keytruda.

Rita Nanda, MD (00:17:49):

If patients have their therapy upfront and they don’t get what we call a pathologic complete response. And by that, I mean, when the surgeon goes in to do the surgery, they remove the area where the cancer was. If all the cancer’s dead and there’s nothing that’s living remaining, we call that a pathologic complete response. So, if there’s no cancer left in the breast area or the lymph node area, that’s called a pathologic complete response. There are ways, it’s called a residual cancer burden, where we can quantify the amount of residual cancer there is left. How big is the tumor that’s left in the breast? What percent of the tumor are cancer cells? Are the lymph nodes involved with cancer or not? And if so, how many? So, this residual cancer burden is something that we’ve really adopted because it helps us figure out how much risk someone is at for recurrence.

Rita Nanda, MD (00:18:53):

If you have a pathologic complete response, which is a residual cancer burden of 0, that means there’s no cancer left. The risk of recurrence is very low. We can’t say it’s 0, but it’s very low. If it’s I, the risk is a little bit higher. It’s pretty close to 0. And residual cancer burden of I is a little bit of cancer left in the breast, but not much. And then residual cancer burden II and III. It’s a scale of 0 to III. That risk of recurrence increases as the residual cancer burden goes up. And so, if there’s no cancer left, the recurrence risk is very low. If there’s a little bit left, it’s also still very low. If there’s a lot left in a bunch of lymph nodes, then the risk of recurrence is higher, but it’s not absolute. It’s not that if you didn’t have a complete response that your cancer is definitely going to come back still, even if there’s cancer left, that gets removed at the time of surgery.

Rita Nanda, MD (00:19:53):

We don’t leave it in there. It comes out. But if when the pathologist looks at what was removed, and there’s still some cancer there, it doesn’t mean that your cancer’s definitely going to recur. Most women are cured, still with the chemo, the surgery, radiation, if they need it, the Xeloda, or capecitabine is the generic name, if they need it after. I think that’s just important to remember, because I think a lot of people think if there’s cancer left, “That’s it, my life is over. I’m just going to lie in bed and wait for my cancer to recur.” That’s actually not the case at all.

Janine Guglielmino (00:20:32):

Thank you for explaining that Dr. Nanda. And there are a lot of questions about how a person should be followed and screened after they’re done with treatment. Can you talk a little bit just about what are the screening standards after a person’s done with initial treatment? Are there any differences if you have residual disease versus if you don’t have residual disease?

Rita Nanda, MD (00:20:59):

That’s a great question because I see patients in my practice who maybe come for a second opinion or something, and their local doctors are doing all kinds of bloodwork and scans and all of this. Outside of a routine physical exam, mammograms, if women still have breast tissue. Some women, obviously if they have a bilateral mastectomy or something, don’t need mammograms. Some women are getting MRIs, if they have a cancer that wasn’t picked up on a mammogram, for example, sometimes we follow them with MRIs. But for the most part, aside from just a routine exam and breast imaging, whatever the appropriate test is, there’s not any special bloodwork or scanning that we do. It’s all based on history, taking a physical examination. If someone has a symptom or something that is concerning that, “Hey, maybe this could be the cancer coming back.”

Rita Nanda, MD (00:22:00):

Then the doctor will order the appropriate test, either bloodwork or scans or whatever, based on someone’s symptom. But we do not generally scan people from head to toe constantly in the absence of symptoms. Sometimes, when somebody first is diagnosed with an early-stage breast cancer, if they’ve got lymph nodes that are positive, sometimes we’ll do scans. And if we find something, but we don’t really think it’s cancer, but we found something, we’re obligated to check on later on, but there’s not routine scanning or blood testing or tumor markers or anything that we do for women with early-stage breast cancer. Scanning is really reserved for those individuals who’ve had a recurrence and we’re trying to make sure that the treatment we’re giving is working.

Janine Guglielmino (00:22:56):

Thanks for answering that. And we also know that it can feel very frustrating sometimes, when you want to be able to get more information. We really appreciate that question. Are there other things that people can be doing once their medical treatment for triple-negative breast cancer has ended?

Rita Nanda, MD (00:23:19):

Absolutely. I mean, everyone should feel empowered to live a healthy lifestyle. There are lots of things that, that people can do to keep themselves healthy: being active, so exercising, which I am not so good at in the pandemic days, but I think to get up and to get your heart rate up, to move for 30 minutes a day, four to five times a week; to eat healthful foods — a heart-healthy diet is generally what we recommend. There are a lot of myths out there about what you can’ eat and what you can’t eat. You need to have a plant-based diet, you shouldn’t have sugar, you didn’t do this, or you should juice, or you should do that. I mean, there’s no substitute for eating a well-balanced, nutritious diet.

Rita Nanda, MD (00:24:13):

So, low fat, high fiber, plenty of lean sources of protein: chicken, fish, turkey (grains, if you don’t eat meat), that are lean, not baked, not fried, alcohol in moderation. Generally, we like patients to limit their alcohol consumption to on average three alcoholic beverages a week, some weeks can be more some weeks, maybe less. So, that is an important part of survivorship care and what people should feel empowered to do to reduce their risk of recurrence. So, healthy diet, active lifestyle, limiting alcohol consumption, and just being in tune with their own bodies and knowing if something doesn’t feel right and letting their doctor know as soon as they suspect something.

Janine Guglielmino (00:25:09):

Thanks for answering that question. And I think we’ll have some more questions about that later in the program. I want to turn to some of our attendees with stage four triple-negative breast cancer. We have a question from someone who does not have a BRCA mutation and wants to know what’s the standard of treatment or what the next line of treatment would be after progression with Keytruda or Trodelvy. What would typically be recommended?

Rita Nanda, MD (00:25:47):

I would say sacituzumab is usually my go-to after first-line treatment. I’m assuming you received the Keytruda in the frontline setting with chemotherapy. That’s generally how it’s given, although not always, because sometimes we don’t know people are PD-L1 positive and they’ve had other things, but my go-to generally in that second-line setting is sacituzumab, or Trodelvy is the trade name, is generally what I go for. And that’s because Trodelvy has been shown to be very effective and actually helps people live longer. And so, we definitely want to make sure that everybody has access to that medication. Now I know, unfortunately I am not really following the chat, but I see “I’m from New Zealand” and “I’m from other parts of the world.” And I will say Trodelvy is not approved everywhere yet. My hope is that it will be, but right now in the United States it is available and is generally that go-to.

Janine Guglielmino (00:26:53):

Thanks for sharing that. And our next question is from someone who has had a number of different lines of treatment for metastatic triple-negative breast cancer has participated in clinical trials, and she’s interested in understanding because she’s heavily treated: would she still be eligible for clinical trials? Also, would you ever repeat treatments that may have worked in the past?

Rita Nanda, MD (00:27:22):

That’s a great couple of questions there. A lot of clinical trials will limit how many prior treatments you can have had. However, phase I trials, which are generally trials of newer drugs or trials of new combinations of old drugs, a lot of will allow people who’ve had other therapies and even similar types of treatments in the past. Some phase I trials are new drugs that have never been tested in humans, but some of them are combinations of drugs that are approved, for example. There are’ all different kinds of phase I trials out there, but absolutely, some of these trials will allow patients regardless of how many treatments they’ve had provided, their labs look good, and they fulfill the other criteria to qualify for the trial. So absolutely, there could be other options.

Janine Guglielmino (00:28:28):

Great. That’s really good to hear. And we have someone who’s asking about a specific clinical trial, that is looking at pembrolizumab, gemcitabine, and carboplatin in metastatic triple-negative breast cancer. This trial does not require PD-L1 positivity. Could you talk a little bit about what’s being looked at in that trial, what the researchers think they are looking for?

Rita Nanda, MD (00:28:57):

I will tell you I’m not familiar with that trial. Carboplatin plus gemcitabine plus pembrolizumab is FDA approved for PD-L1 positive breast cancer. I’m assuming that they’re testing it in PD-L1 negative breast cancer, but I’m not sure why, because it’s been shown already in a large, randomized phase III trial to not necessarily help people with PD-L1triple-negative breast cancer. I’m sorry, I’m not familiar with the trial. I’m not sure what the investigators are looking for, but it’s already been shown to not necessarily be an effective strategy in PD-L1 negative breast cancer.

Janine Guglielmino (00:29:44):

OK. Thank you. My next question is about brain mets. We know that sometimes in metastatic triple-negative breast cancer people develop brain mets. What progress is being made in medications and in clinical trials for people who do develop brain metastasis or CNS tumors?

Rita Nanda, MD (00:30:06):

That is a great question. And we have participated in, and people have designed and studied a variety of different strategies for brain mets, specifically on triple-negative breast cancer, even other forms of breast cancer. Unfortunately, many of our drugs that we give what we call systemically, in your arm and kind of circulate throughout the body, don’t necessarily get up to the brain in a high enough concentration to have an effect. So, that’s what’s limited some of the development in this space, and that is why the standard of care therapy is radiation for brain metastases. Whether it’s focused radiation, gamma knife, stereotactic radiosurgery, there are a lot of different names for focused radiation, or what we call whole brain radiation. If there are lots of spots all over, then sometimes we just radiate all of them all at once in the whole brain. There are going to be some trials coming out, looking at newer agents. There is also some evidence that sacituzumab may be effective in the brain, and some of these other new targeted chemotherapies that are coming down the line. As of right now, we don’t have a specific treatment that is approved for brain mets outside of radiation, but there is a lot of interest in trying to identify new strategies that can be effective in this space.

Janine Guglielmino (00:31:46):

Great. Thanks for sharing that. That’s really good to hear. Our next question is whether it’s possible for triple-negative metastatic breast cancer to ever change receptor status and become HER2-positive, or hormone receptor-positive.

Rita Nanda, MD (00:32:08):

Breast cancers, when they’re early-stage and then when they recur, we always recommend biopsying them. If someone has early-stage breast cancer and then, down the road, they develop metastatic breast cancer, we always recommend repeating the receptors at that time of initial diagnosis. Sometimes estrogen receptor-positive breast cancers become estrogen receptor-negative or triple-negative. Sometimes HER2-positive breast cancers become HER2-negative. It’s not common, but not impossible because tumors can be what we call heterogeneous. Not every single cell within a tumor is like the cell right next to it. It’s always possible things can change, but in general, once cancers are triple-negative, they don’t generally change to become estrogen receptor-positive or HER2-positive. If when someone had early-stage breast cancer and they’re biopsied at the time of recurrence and things are a little different, it’s probably because the tumor that they had from the get-go was a mix of different kinds of breast cancers. But absolutely, if someone recurs, we 100 percent recommend that tumor should always be biopsied and the receptors repeated. For my triple-negative patients, if they stop responding to a treatment, I don’t always just biopsy them over and over again to figure it out, because generally it does not change.

Janine Guglielmino (00:33:47):

Thank you. And then we sort of have that the opposite question, which is a more common situation we hear about, which is people who had a hormone receptor-positive, early-stage breast cancer and their metastatic tumor tests triple-negative. Is that treated any differently? Are there any strategies where you might look at this differently than something that starts out as a triple-negative breast cancer?

Rita Nanda, MD (00:34:16):

It doesn’t matter if it was hormone receptor-positive or estrogen receptor-positive when someone was first diagnosed; if it’s triple-negative when they are found to have a recurrence, we treat it like triple-negative, and we offer them all those same therapies that we use for triple-negative breast cancer.

Janine Guglielmino (00:34:37):

Great. Thank you. We have a couple of questions specific to side effects of some of these treatments. The first one is about Keytruda, and if you could talk about what some of the common side effects are of that medication and how you manage those.

Rita Nanda, MD (00:34:57):

Pembro is immunotherapy. It’s not chemotherapy; it’s an immunotherapy. The way pembro works is by stimulating the body’s immune system to attack the cancer. And so, the main side effect that we see is an overstimulation of the immune system, where then it attacks normal tissues. Any organ in the body, any tissue in the body can potentially be attacked by an overstimulated immune system. The most common side effects we see with Keytruda (pembrolizumab) are generally pretty mild and easily managed. It’s less common to see severe side effects in the metastatic setting, but it’s actually a little bit more common to see some of these more serious side effects in the early-stage setting. And we think that is because women with early-stage breast cancer have a more intact immune system because they haven’t had a bunch of chemo.

Rita Nanda, MD (00:36:00):

And so, it’s easier to rev it up and have it attack normal tissues. The most common side effects we see are things like fever; a rash; attacking the normal tissues that are part of the lungs, so it can cause something called an pneumonitis, or it can cause a cough or some difficulty breathing; attacking the liver, so it can cause what we call a hepatitis, not because of a viral issue, not because of hepatitis B or C or A, but because of an overstimulation of the immune system that attacks the normal cells in the liver. So, really any organ in the body can be involved. If you’re on Keytruda (pembrolizumab), you should let your doctor know if you’re having symptoms that are unusual because it’s not going to be like chemo. It’s not going to be hair loss or fatigue, or other things; it’s going to be these kinds of autoimmune things.

Rita Nanda, MD (00:37:00):

And probably the most common irreversible autoimmune reaction from pembrolizumab is developing an underactive thyroid. Probably about 15 to 20 percent of people who are treated with immunotherapy will develop an underactive thyroid — it’s called hypothyroidism — and they would need to be on a pill to replace what their thyroid gland doesn’t make. One such popular pill is Synthroid. About 20 percent of the population has an underactive thyroid. It’s unclear if the immunotherapy’s causing it or just kind of bringing it out a little bit earlier than somebody might go on to develop it any way. But diarrhea, shortness of breath, cough, liver enzyme numbers on a blood test — those are probably the most common.

Janine Guglielmino (00:37:50):

Thanks for reviewing those with us because a lot of folks are not really familiar with the side effects of these immunotherapy medications. Our next question is about a side effect of Trodelvy. This person is having very difficult diarrhea, has tried over-the-counter medicines, and has been prescribed some other types of medications. What else would you suggest for diarrhea related to that treatment?

Rita Nanda, MD (00:38:21):

Diarrhea and neutropenia, which is a low white blood cell count, are two of the most common side effects from Trodelvy. And there’s a small proportion of people who have the side effect more severely than most. And it’s probably because of not a mutation, but a gene that helps to process the drug. And so, 10 percent of people probably have an alteration in a gene that processes Trodelvy and it makes them have more side effects from it, low white blood cell count and diarrhea, the two most common. Absolutely they can use Imodium or other prescription-strength antidiarrhea agents, but sometimes you just need to reduce the dose, because what’s happening is your body is seeing more than we intend it to. And so, reducing the dose a lot of times can be helpful — not always — but I would generally say that’s what I have a tendency to do.

Janine Guglielmino (00:39:31):

And Dr. Nanda, for people who do reduce dose, and people are frightened to do that, particularly if the treatment is working for them, can you speak to the safety of that?

Rita Nanda, MD (00:39:44):

All clinical trials, whether it’s for early-stage, triple-negative breast cancer or advanced-stage, triple-negative breast cancer, in fact, any kind of trial for any kind of drug or cancer always has modifications that we can make because it’s not just a one-size-fits-all approach. Different people are different; their bodies process drug differently. They may be more or less susceptible to some side effects than other people. We have to make the drug more tolerable, right? We want to make it effective. And we want people to have a response, but it is very natural and typical that we reduce the dose and most trials that are reported included a large proportion of people who didn’t actually get their starting dose. And so, when trials allow it, then the results of the trials are broadly applicable to people, whether they stayed on the starting dose or they had a couple of reductions in dose. That, I think, should be reassuring to people, because we have to have a good quality of life as we’re also trying to treat the cancer, and there needs to be a balance there.

Janine Guglielmino (00:41:00):

Thanks for explaining that. I noticed a question in the Q&A. I’ve been speaking about early-stage and metastatic. Can you just explain what is considered an early-stage, triple-negative breast cancer versus a metastatic diagnosis?

Rita Nanda, MD (00:41:20):

That’s great. Because my, my intake team, a lot of times gets it mixed up, and these are healthcare professionals. Sometimes it can be really challenging to figure it out. In general, we consider early-stage breast cancer to be breast cancer that is confined to the breast and the lymph nodes underneath the arm, which are called axillary lymph nodes. So, you can have what we call metastatic disease of lymph nodes under the arm, but that’s not considered metastatic disease; that is considered locally advanced breast cancer or local breast cancer or early-stage disease. When breast cancer is in the breast or in the breast and the lymph nodes, early-stage. If it’s spread to another part of the body — so, to the liver, to the lungs, to the brain, to the bones, some other place — that’s considered metastatic and/or stage IV disease. Or lymph nodes outside of the lymph nodes under the arm. Sometimes we see lymph nodes in the lung area that can be involved, and that’s considered metastatic.

Janine Guglielmino (00:42:38):

Thank you for explaining that. The next question I have is whether someone who’s taking immunotherapy such as Keytruda would be considered immune compromised.

Rita Nanda, MD (00:42:52):

No, I would say most of the chemotherapy drugs we use for breast cancer, whether it’s early-stage or advanced cancer, really don’t compromise the immune system. I think a lot of people think, “Oh, well, I’m on chemotherapy, I’m in an immunocompromised state.” But really, most of the therapies that we use don’t dramatically drop the white blood cell count, which are the infection-fighting cells and make people immunocompromised. When I think of severe immunocompromised individuals, I think of people undergoing a bone marrow transplant, where we wipe out their whole bone marrow and look to replace it with new bone marrow, or things like that. I would say for the most part breast cancer patients are maybe a little bit immunocompromised, depending on what they’re on, but not dramatically so. And so, in that sense, Keytruda absolutely is not considered chemotherapy; it’s immunotherapy. So, definitely not immunocompromised.

Janine Guglielmino (00:43:55):

Thanks for answering that. There are a number of questions about how likely triple-negative breast cancer is to return after periods of time. After 5 years, after 6 years, after 8 years — is there kind of a rule of thumb about when you can feel more comfortable that the cancer may not recur?

Rita Nanda, MD (00:44:24):

I would say that most early-stage, triple-negative breast cancers, if they’re going to recur, recur within 3 to 4 years of diagnosis. So not from the completion of therapy, but from the time of diagnosis. And so, I think a lot of people out there think, “Oh, 5 years, I’ve made it 5 years. I’m cured. My cancer’s never coming back.” Well, it differs by the different types of breast cancer. Triple-negative breast cancers, HER2-positive breast cancers that are ER-negative, have a tendency to recur earlier. And the peak incidence of recurrences is between 3 and 4 years from diagnosis; after that, the risk of recurrence very low. I can’t say zero because cancers don’t read our textbooks and listen to me. But for the most part after 4 years, the likelihood of a recurrence is really low. For hormone receptor-positive breast cancer, obviously a different type, people think, “Oh, 5 years, my cancer’s never coming back.” That’s not the case because hormone receptor-positive breast cancers can recur much later; that peak incidence of recurrence is 5 to 6 years from diagnosis. And I’ve even had patients recur 20 years out. That is not something we see with triple-negative breast cancer. Generally, 3 to 4 years from diagnosis is kind of the peak. And after that, it really drops off to about as close to zero as we can get.

Janine Guglielmino (00:45:51):

Thank you. And for folks who are really concerned about this or who are coping with fears of recurrence, which are extremely common, I would invite you to visit lbbc.org and look at our From coping to thriving video series. We actually have a video that’s specific to people with triple-negative breast cancer and where you might be able to find some support and some tips about ways to cope with that concern.

Rita Nanda, MD (00:46:21):

I just noticed a little thing in the chat that popped up. I want to be clear: I’m talking about a recurrence of the cancer. I’m not talking about the likelihood of developing a new primary, which is’ completely different. If you have another breast cancer, that’s different than a recurrence of the initial cancer. And sometimes when a long time has passed for certain types of breast cancer, it’s hard to figure out if it’s a new cancer or a recurrence, but for triple-negative breast cancer, I’m really talking about a recurrence of the initial cancer, not developing a new cancer.

Janine Guglielmino (00:47:02):

Thanks, Dr. Nanda. And are there types of triple-negative breast cancer where a new primary breast cancer would be where you might want to get more screening because of the potential for a new primary cancer?

Rita Nanda, MD (00:47:16):

You mean a new primary breast cancer?

Janine Guglielmino (00:47:19):

Yes.

Rita Nanda, MD (00:47:20):

All women who, who have their breasts should be getting annual mammograms. So, we’re still screening for a new cancer. Just because someone has one triple-negative breast cancer doesn’t mean if they develop another breast cancer that it’s going to be triple-negative. I certainly have patients who’ve been triple-negative in one and then ER-positive in another or HER2-positive. But I think anytime we think about more than one breast cancer, we always want to think about, is there a family history? Or even if there isn’t, with one person and two breast cancers, genetic testing is definitely in order, because it’s important to know if there’s a genetic predisposition. And we talk a lot about BRCA1 or BRCA2, but now there are these really large panels. There are genes out there or collection of genes we still don’t understand yet. So, anytime we see two breast cancers in one person or breast cancer; ovarian cancer; or family history of breast, ovarian, pancreatic, or prostate cancer, those can be suggestive of a BRCA1 or BRCA2.

Janine Guglielmino (00:48:37):

Thanks for answering that. We have a couple of questions about the use of Xeloda or capecitabine. One person is asking whether capecitabine would be needed if you had a complete response to chemotherapy. Would it be recommended in a situation like that?

Rita Nanda, MD (00:48:59):

I would not recommend it if someone has had what we call a pathologic complete response to their therapy before surgery, we know that the risk of recurrence is very low. The trial that was done, the CREATE-X trial — and then there was an ECOG [Eastern Cooperative Oncology Group] trial that compared Xeloda to carboplatin — were only done in individuals who didn’t have a complete response. So, it is not something I recommend in people who have had a complete response. And I also don’t use it for the other types of breast cancers. There’s no role for hormone receptor-positive or HER2-positive disease. It’s really reserved for triple-negative breast cancer and for tumors that did not completely respond to the therapy that a patient got prior to surgery.

Janine Guglielmino (00:49:55):

Great. Thanks for answering that question. I have a question about who gets triple-negative breast cancer. Triple-negative breast cancer can affect anyone, but it’s more likely to show up in those who are younger than age 50 or who are Black or Latinx. And I’m wondering if you can talk about the drivers of some of the disparities that we see with triple-negative breast cancer.

Rita Nanda, MD (00:50:23):

Yeah. Do you mean drivers in terms of why some groups get triple-negative breast cancer?

Janine Guglielmino (00:50:31):

Yes. I think the person is asking: Is it lifestyle factors, genetic factors, metabolic factors?

Rita Nanda, MD (00:50:40):

I think there’s just so much we don’t know. I mean, what we do know from epidemiologic data is that Black women don’t do as well as white women who are diagnosed with breast cancer across the board, not just triple-negative breast cancer. And so, there are lots of different explanations or what we think can contribute, but there’s also a lot we don’t know. There can be things like genetic factors. There can be socioeconomic factors. There can be systemic and institutional biases that go into how people are treated, access to care, access to good care, access to insurance to get the care that they need. There are’ so many different things that contribute to disparities. And I think we need to recognize that it’s multifactorial. It’s not just one thing. There are lots of different things that go into the disparities that we see. And there’s a lot of work that we need to do as a community to help attack those disparities so that we can see equal outcomes for individuals with breast cancer, regardless of their race, their ethnicity, their socioeconomic status, their level of education. There’s just so much that work that needs to be done.

Janine Guglielmino (00:52:03):

Thank you. I appreciate you speaking to that. There are a few questions of about how it’s decided whether chemo is given before surgery or after surgery. Could you speak to how that’s determined?

Rita Nanda, MD (00:52:20):

I would argue that anybody with stage II and III, triple-negative breast cancer should have chemotherapy and immunotherapy first, if they’re a candidate for those strategies. Obviously, there are people have autoimmune disorders that may make them not candidates for immunotherapy, or heart issues, and maybe they’re not eligible for certain types of chemotherapy. But I would argue that it is standard practice in individuals with stage II to III, triple-negative breast cancer that these individuals should get therapy prior to surgery. And the reason for that is because what we do after surgery is different. If somebody has a complete response, we don’t give them capecitabine. If they don’t have a complete response, we do give capecitabine. And we know that capecitabine and individuals who don’t have a complete response improves outcomes; it decreases the risk of recurrence by 13 percent.

Rita Nanda, MD (00:53:21):

So absolutely we need to make sure that our patients with triple-negative breast cancer are getting therapy earlier. Now, in those individuals who have small tumors, it’s a little bit of a gray zone. We probably do surgery first because sometimes it’s hard to know how big is the tumor really, because we don’t want to overtreat people with a whole lot of chemo that they don’t need. In stage I, triple-negative breast cancer, I would say outside of a trial, it’s probably more standard practice to have surgery first and then base the decision for what to do after surgery — what type of chemo to give, how much to give — on how big the cancer is and if the lymph nodes are involved or not. That’s kind of where we stand.

Janine Guglielmino (00:54:10):

Great. Thank you. Our next question is whether there is any higher occurrence of triple-negative breast cancer after a recent pregnancy or during pregnancy.

Rita Nanda, MD (00:54:25):

Not that I am aware of. I will say that we are seeing more pregnancy-associated breast cancers now because women are having families at a later stage in their lives because women are going to college, getting advanced degrees, they’re out in the workforce. So, definitely we’re seeing women delaying childbearing for their careers. And so, we are seeing the average age of women who become pregnant is higher now than it was 10, 20, or 30 years ago. We are definitely seeing more pregnancy-associated breast cancers. And the definition of that is breast cancer diagnosed within 2 years of a pregnancy. But there is no evidence that a pregnancy itself increases the risk of developing breast cancer.

Janine Guglielmino (00:55:25):

Thanks for answering that. We had a question, and I would just love for you to speak to it. One of our participants said she was in her eighties, very healthy, always exercised, is a white woman. “Why did I get triple-negative breast cancer?” Can you just talk for a moment about in general who gets triple-negative breast cancer?

Rita Nanda, MD (00:55:48):

Anybody can get triple-negative breast cancer. It’s more common in younger women — women under 40. It’s more common in women of African and Hispanic ancestry. But if you look at the numbers of individuals who get triple-negative breast cancer, the numbers are actually higher in white women, because white women — at least older white women — are more likely to develop breast cancer for example, than younger Black women. So, when you look at the numbers of people out there with triple-negative breast cancer, the actual numbers are probably higher in white women. It’s interesting. I saw a patient who told me that her doctor said, “Oh, you’re a 50-year-old white woman. Well, this is a cancer of young Black women.” And that is absolutely not the case. Anybody can get triple-negative breast cancer.

Rita Nanda, MD (00:56:43):

We know that the risk of breast cancer increases as we get older, and 15 percent of all breast cancers are triple-negative. I think as we get older our risk of breast cancer goes up and 15 percent of breast cancers are triple-negative. Now, absolutely, in those of African and Hispanic ancestry, it’s probably higher than 15 percent. In individuals who are under 40 it’s higher than 15 percent if they develop breast cancer. But anybody can develop triple-negative breast cancer. It is more common in certain populations. It’s more common in young women. It’s more common in individuals who have BRCA1 mutations. Probably about 80 percent of those individuals who have of a BRCA1 germline mutation who go on to develop breast cancer — and not all of them will, but many will — it’s generally triple-negative.

Janine Guglielmino (00:57:36):

Thanks for addressing that. And we have a question from someone who was diagnosed at age 55 with no family history and didn’t have BRCA testing or genetic testing done and is asking, should she reconsider now?

Rita Nanda, MD (00:57:56):

I don’t know if there’s a family history, but in general we do recommend genetic testing in anyone who is diagnosed with triple-negative breast cancer regardless of age. And so, I definitely think if that might inform preventative surgeries or other family members that may want to get tested as well, it’s certainly something to talk to your oncologist about and see if somebody would qualify for genetic testing. But yes, I think if somebody’s diagnosed at the age of 55 with triple-negative breast cancer, I do think that person could very likely qualify for genetic testing.

Janine Guglielmino (00:58:38):

Thanks for addressing that. We have a couple of participants with us who are saying they developed adrenal insufficiency from taking Keytruda, and I was wondering if you could talk a little bit more about why that happens and what can be done about it.

Rita Nanda, MD (00:58:58):

No, that’s a great question. I, too, have a patient who has developed adrenal insufficiency from Keytruda. I don’t know if the folks who talked about this here have early-stage or metastatic triple-negative breast cancer, but a lot of times in the early-stage setting, we see a higher incidence of immunotherapy-related side effects than we do in the advanced cancer setting. And specifically in the early trials of Keytruda or pembrolizumab, with chemo prior to surgery, in the neoadjuvant setting, that is something that we’ve seen, and about 5 percent of individuals will develop either primary or secondary adrenal insufficiency.

Most of the side effects from immunotherapy are reversible just with steroids, but there are some side effects that are irreversible, and the three that we call endocrine abnormalities or endocrinopathies are first, the thyroid abnormalities.

Rita Nanda, MD (01:00:12):

I talked about where people are on lifelong replacement for their thyroid gland. Adrenal insufficiency is the second, and people need to take replacement hormones for what their adrenal glands don’t produce. The adrenal glands sit right on top of the kidneys, and they’re glands that produce hormones that help regulate blood pressure, so they’re really important for us. And then diabetes unfortunately the third, very severe, potential side effect from immunotherapy. All of these three things are irreversible and require treatment. The adrenal insufficiency occurs in about 5 percent of individuals with early-stage, triple-negative breast cancer who get Keytruda or an immunotherapy as part of their treatment regimen. It’s not as common in individuals with metastatic disease; it’s under 1 percent. But it is because of the autoimmune response; it’s the immune system revving up and attacking normal tissues.

Janine Guglielmino (01:01:20):

Thank you. There are a couple of questions about the relationship between stress and developing triple-negative breast cancer. Can you speak to what we know and what we don’t know about the impact of stress on developing cancer?

Rita Nanda, MD (01:01:40):

Again, it’s just such a hard thing to study. If things were easy, we probably would’ve figured them out by now, but how do we categorize stress? How do we monitor stress, and how what’s stressful for one person translate to another? This is an area that’s been of a lot of interest: there’s stress, like we’re stressed as people, and then there’s stress in the breast tissue or on cancer cells or on the immune system locally in that environment where tumors may form. And there’s just a lot we don’t know about all of that. I don’t think I could speak eloquently to that question, but obviously stress in general is not good for us, but it’s a balance because we all need a little bit of stress, right? I need deadlines sometimes to get my work done, but if I have so much on my plate, then I just get overwhelmed and shut down. I think, life is not ever going to be stress free. There’s always going to be stress. And absolutely people have developed animal models to look at stress and social isolation, and how that could impact the likelihood of developing cancers, specifically breast cancers. I don’t know that anybody’s really figured out exactly what translates into an increased risk. It’s a great question, but I don’t have a great answer.

Janine Guglielmino (01:03:11):

Thanks for trying to answer that question. And it’s a really, really common question. We have an attendee who is asking: if you do not experience a pathologic complete response from your chemotherapy, what are the best questions to ask your oncologist when you’re trying to decide next steps?

Rita Nanda, MD (01:03:35):

That’s a great question. And you know, what I would say is that someone’s oncologist will likely say: “Look, here is the pathology report from the surgery. Here’s the response that you had.” And whether or not there’s a role for additional therapy, whether there’s a clinical trial that somebody could enroll in, or whether there’s a role for capecitabine — it’s a collaborative discussion between the provider and the patient. They can talk about “What is my risk? What can I do to reduce my risk? Do I need capecitabine or not? And is there a trial that I’m eligible for or not?” There are other trials ongoing out there. There are trials looking at vaccines to see if we can stimulate an immune response to attack any residual cancer cells and prevent them from causing problems down the road.

Rita Nanda, MD (01:04:37):

There are trials of other therapies outside of capecitabine therapies that might be targeted towards something that was going on in an individual’s tumor. There are lots of options potentially. Now, I know not everybody has easy access to trials or lives somewhere where a trial is ongoing, and capecitabine is considered the standard approach and is available anywhere. There’s always something someone can do and someone can access. And I would argue also in this era of the pandemic, it’s much easier to get a second opinion than it used to be because now I do a lot of virtual second opinions for people who don’t want to travel to where I’m located, but can easily get me through a virtual visit. And certain states don’t allow virtual visits outside of the state, but every state has someone that someone can see for a second opinion. Lots of options. And I would encourage everyone to consider exploring all their options and not to be scared to get a second opinion. As a provider whose patients sometimes go get second opinions, I encourage it because at the end of the day, want my patients to feel like they’ve had access to everything possible available to them and have a second opinion. Even if they come back or they switch, it’s all about a patient and what makes them happy and makes them feel like they’re doing the best for themselves.

Janine Guglielmino (01:06:08):

Thank you, Dr. Nanda. And, to follow up with that for someone who wants to keep up with the progress of clinical trials and the news about triple-negative breast cancer: where are the places that you typically send your patients to get that kind of information?

Rita Nanda, MD (01:06:28):

There are reputable websites. There’s a lot of stuff out on the internet that isn’t maybe the best source of information, because anybody can post anything on the internet these days and it doesn’t mean that it’s’ true. And so, I always recommend if somebody is interested in exploring a trial to see if there’s anything close to them or close to a family member, or somewhere where they have friends, clinicaltrials.gov — that’s all one word: clinicaltrials.gov — is a website where you can go and look or ask your physician to look for trials that you may be eligible for. All the trials that are done are listed there and can be searched. The other that I recommend, and, disclosure here: I am on the board of directors of the foundation for the Triple Negative Breast Cancer Foundation. The Triple Negative Breast Cancer Foundation is a very credible and reputable source for information specifically on triple-negative breast cancer. That is a place you can always go and if need help, someone can help you, you can reach out to them. And they have a lot of programming around the needs specifically of women with triple-negative breast cancer, both early-stage and advanced. That’s an easy go-to place, and they’ve got great resources for patients and caregivers. So, I’d encourage you to check it out.

Janine Guglielmino (01:08:04):

Thanks Dr. Nanda. And certainly the Triple Negative Breast Cancer Foundation is a great partner of Living Beyond Breast Cancer. We encourage you to check them out, and to check out our updates that we have on lbbc.org as well. So, unfortunately that was our last question. And I want to first thank you, Dr. Nanda, for covering so much ground over the past hour. And I’d like to just give you a moment if there are any closing thoughts that you’d like to share.

Rita Nanda, MD (01:08:36):

The last few years have been really exciting for me. I’ve spent 15 years doing research on triple-negative breast cancer, and so, it’s really exciting to see all of the advances that we’ve made in the last few years and many more to come. For those who have access to trials, I encourage you to consider participating because that is how we move the field forward. Make sure that you advocate for yourself and go out there. And if you don’t feel like your provider knows as much as you want them to know about triple-negative breast cancer, there are resources that you can access, where you can get additional information because it’s not that all providers don’t want to help. But if you think about a lot of doctors out there, they have to treat everything. You have to treat all different kinds of cancers and all different types of breast cancers. They just may not have as much experience with it. There are places out there they can have access to CME to learn more about triple-negative breast cancer, and places where you should feel empowered to learn about triple-negative breast cancer and advocate for yourself.