Adam M. Brufsky, MD, PhD, FACP, professor of medicine, University of Pittsburgh School of Medicine (UPMC), associate chief, Division of Hematology/Oncology, Department of Medicine, medical director, Magee-Women’s Cancer Program of UPMC Hillman Cancer Center, associate director of Clinical Investigations, UPMC Hillman Cancer Center, codirector, Comprehensive Breast Cancer Center, discusses efficacy data with enobosarm in metastatic estrogen receptor (ER)–positive, androgen receptor (AR)–positive, HER2-negative breast cancer.

Several clinical trials explored the utility of enobosarm as a treatment for patients with breast cancers, including AR-positive triple-negative breast cancer, says Brufsky. ​Findings from a phase 2 clinical trial (NCT02463032) evaluated enobosarm in patients with progressive ER-positive, AR-positive metastatic breast cancer and demonstrated a reasonable response rate with the agent, Brufsky says. 

It was discovered that if a patient had greater than 40% staining of the AR, the response rate with enobosarm was about was 34% with a clinical benefit rate (CBR) of about 52%, Brufsky continues. Moreover, the median progression-free survival (PFS) was over 5.5 months and was improved compared with the median PFS in patients with under 40% staining of the AR, Brufsky explains. The CBR with those patients was 14%, with almost no responses observed, Brufsky concludes.

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Adam M. Brufsky, MD, PhD, FACP, discusses efficacy data with enobosarm in metastatic estrogen receptor–positive, androgen receptor–positive, HER2-negative breast cancer. 


Dr. Brufsky on the Efficacy of Enobosarm in ER+/AR+ Breast Cancer 

 Great. This has been great. We had a great hour. The time just flew. Do you have any final remarks about oral therapy or chemotherapy more generally that you want to make? George, you can start first.

Chemotherapy is going to persist for a long time because it is efficient at killing cancer cells. It will persist until we get agents that are more effective at killing cancer cells. I do not know when those will come, and I do not know whether those will come. In the meantime, of course, doctors and patients in the clinic make decisions through shared decision-making if they are smart.

I always tell my patients something that Cliff Hudis, MD, told me once upon a time: when you have an oncologist and a patient in the room, there are 2 experts in the room. One is an expert on the disease and the other is an expert on the patient. Those 2 experts should agree with each other. The advantage of the oral therapeutics, of course, is that it makes that shared decision-making a whole lot easier in most cases.

 I agree with everything George said. The only thing I would add is that, as we talked about, if you ask patients about their preference if you say you are going to get a treatment that works equally well, they will pick oral therapy most of the time. It is convenient, and it may have less toxicity in the those we have been talking about. That is a big win for patients who are struggling with metastatic breast cancer. It is an exciting time to have these new options for patients when we sit down and talk to them about what all their options are.

 Thank you both very much. This is fabulous. Thanks for your time. This concludes our program for this evening, and on behalf of the 

, I would like to thank both of you very much. Everybody, have a good evening.

Using Oral Therapies to Advance Care in MBC

 The nice thing I like about oral therapy is the ability to adjust. Clearly, we all recognized, and most oncologists recognized, pretty quickly after the original stuff came out about the 2 weeks on, 1 week off regimen that it was overdosed. George, you know this better than me because you were the discussant, but my understanding is that they had to pick a dose that 5% of the United States would be able to metabolize. Is that what it was? Was that due to the metabolism of it or something?

 You were apparently overdosing 95% of the United States with the drug. Is that right, with capecitabine?

I do not remember the exact numbers, but it was something along those lines, yeah.

 Yes. We all realized it pretty quickly, and we reduced the dose. Then Tiffany Traina, MD, at Memorial Sloan Kettering Cancer Center came out with a 1 week on, 1 week off regimen, and some of us use that. I use that, too. We do not know. I do not think that there has ever been any formal testing back and forth about whether that is as efficacious. We do not know, but we still use it anyway for the toxicity issue. That brings me back to tesetaxel, and then we will talk generally again. Were dose reductions allowed in the CONTESSA trial? Can you dose-reduce it?

 Yes, absolutely. There were 2 dose reductions. There was a substantial minority of patients who had dose reductions in both the capecitabine and in tesetaxel. The capecitabine could be reduced pretty much once you saw anything, any grade 2 toxicity. To George's point, why are you doing the 2 drugs here? Let’s get it down for the toxicity. Yes, 27 mg/m

, which is the starting dose that was used, is a reasonable dose to start. As we gain more experience, there might be certain populations who can start a little lower.

 That gets me to this point: when we get this to be a single agent, what a lot of us are going to do, especially in the elderly people for right or for wrong, is that we are going to dose-reduce quickly to avoid the use of growth factors. That is where I think this may go. I am trying to predict the future, and I may be wrong, but I suspect that a lot of people are going to start doing that. They are going to say, “Listen, I want to give this to you. It is an easy drug to take. It is 1 pill every 3 weeks. We are going to check your white blood cell count. Instead of giving you pegylated filgrastim or whatever, we will just dose-reduce you and try to treat you that way.” I do not know. Do you think that this is where this is probably going to go at some point? We do not know because it is so far in the future.

 We will get some good experience with the monotherapy with a couple hundred more patients now at that dose, both those over 65 years of age and those below. Those will be helpful data.

Oral Therapies and Dose Reductions in MBC

 There is the other one, before we talk a bit more and go back to generally summing everything up. The other one, we just saw the CONTESSA trial data, and Lee, you know these data backward and forward. You are on the abstract in the paper. What do you think of it?

 I am reasonably excited about what we have seen with tesetaxel. First of all, if you look just at what we have been talking about with the pill burden, it is given once every 3 weeks because of the pharmacokinetics. Like we were talking about, it has a low C

 [peak plasma concentration], and it has an 8-day half-life, so it lasts a long time.

For the toxicity, in our hands at West Cancer Center & Research Institute, we did phase 2 a few years ago. Andy Seidman, MD, and I basically ran that one. We treated a bunch of patients either as monotherapy or in combination with capecitabine, and we found it well tolerated. As a monotherapy, it clearly had less alopecia, and it seemed to have less neuropathy as well. Admittedly, the numbers are small, so we need a larger number of patients. In the phase 3 CONTESSA trial, there was also a small amount of grade 3 neuropathy, and there was a 3-month improvement in progression-free survival and a 30% improvement in hazard ratio.

For that combination, other than neutropenia, which was well managed once we learned about it in the first cycle in the combination with capecitabine, it is going to be a good regimen. Personally, I would initially give the every 3 week dosing in the office to make sure the patient took it because it is just once. After the patient has then taken a couple of cycles, a well-educated, compliant patient can certainly continue it at home without difficulty, certainly as monotherapy, and with capecitabine too once they got used to it.

 The only thing that concerned me about it was the fever neutropenia rate. I am trying to figure that out from the abstract. What was it, 6% or 8%? I could not figure it out.

 It was a little higher than that: about 11%.

 That was without growth factors, so in a palliative setting, I am curious because I know George has been pounding at this very topic many years. In the palliative setting, we are now going to give people growth factors.

 We’ve got another drug that also causes a lot of neutropenia: sacituzumab.

Here is a bit of a different question: why the combination as opposed to giving these 2 drugs sequentially?

 That is the million-dollar question, is it not?

 All of us asked that question to Odonate Therapeutics. They all came to us at Miami Breast Cancer Conference 2020; we said that we are doing this, and we asked why. I am sure that you had the same thing, right Lee? We said why? Why are you doing this design? They only did it because they wanted to compare it to an existing regimen. I do not know.

From an FDA standpoint, from an agency standpoint, you have to demonstrate benefit above and beyond an approved therapy. Capecitabine is a standard therapy in patients who’ve had had prior anthracycline, prior taxane, so it is entirely reasonable from an FDA-approval standpoint.

I like the drug, but I hate the trial. I see no particular reason to give the drugs in combination, which requires you to give 2 drugs until progression. There is no evidence whatsoever that there is a true synergy such that you have to give the drugs together to see the benefit. You probably buy increased toxicity. You certainly buy increased costs to the health care system and probably to the patient as well.

I do not see it. Does a 3-month improvement of progression-free survival give you a significant improvement in overall survival? We will have to wait and see, but you would be surprised if there is a huge improvement in overall survival. This is E1193: it is a trial that we started in 1993. If I were king of the world, I would have run this trial with a sequential arm.

 Right. That will be the next trial that they do.

Can I ask you both a related question? The trial, because they were trying to get FDA approval, used the FDA-mandated overdose of capecitabine: 2 two weeks on, 1 week off. In my clinic, Stanford Cancer Center, if I am giving a patient capecitabine, I am typically going to be giving 1 week on, 1 week off.

 This has significantly less in the way of hand-foot syndrome. Again, this is another reason I am not a big fan of the trial: it is not just that it has a problem with the combination, but there is a problem with the capecitabine that is used in the combination.

 I would counter one thing that George said, which is this: if a lower dose had been used, then the trial could be criticized by saying, “Well, you compared 2 agents against the lower dose of capecitabine.” Those who want to criticize it that way could, but I agree. It was completely regulatory in nature, the design of the control arm. It had to be against a standard.

I have the advantage of having been the primary discussant for capecitabine approval in 1998 at ODAC [the Oncologic Drugs Advisory Committee], which I will remind you was not done based on a phase 3 trial.

 It was phase 2, right? It was Joanne Blum, MD, PhD, FACP’s phase 2 trial, right?

 Yes, I remember that. We could never do that now. We would never get that trial passed. It would never get through.

MBC Therapy: Tesetaxel/Capecitabine

 I want to spend a bit of time, maybe another 15 minutes, talking specifically about some oral therapies for metastatic breast cancer because it is important to understand and put all of this in context and get some generalities out of it. We have 1 that is a bit further along: that is the Athenex Inc product, OPE [oral paclitaxel and encequidar]. I do not know what it is called. Is there even a name yet? I do not even know what it is called, but we have that.

We now have the CONTESSA trial with tesetaxel. It was just presented at San Antonio Breast Cancer Virtual Symposium 2020, and I am curious to hear what you guys think of these particular agents. We can start with what we call OPE: it is oral paclitaxel and encequidar. Did you guys participate in those? I think Lee, you did. You are on those papers, are you not?

 No. I have a lot of experience with tesetaxel. The other one is called Oraxol [oral paclitaxel and encequidar].

 Oraxol [oral paclitaxel and encequidar]. George, were you involved in any of that?

No, I was not involved with the OPE [oral paclitaxel and encequidar], but our institution, Stanford Cancer Center, did participate in the CONTESSA trial.

 Let's start with OPE [oral paclitaxel and encequidar]. What do you think of it? It is interesting. When you think about it, it is like a trade-off. You have a drug that was compared to every 3 week paclitaxel, which is a problem, but we can let that go for a minute. We can assume for a minute that that is OK.

It is then, basically, a complicated scenario where you have to be fasting at night and then wake up, you take the encequidar, and you then wait an hour. You then have to take all the paclitaxel pills, that can be up to 15 based on your body surface area, within 30 minutes. Then you cannot eat for 2 more hours. You have to do that for 3 weeks on 3 days out of 7. That is the good part.

It looks like it has a decent PFS [progression-free survival] and a decent response rate: what you expect from those taxanes or maybe a bit better, but it is hard to know because they compared it to Q3 [every 3 week] therapy. What you get is this: you get an all oral therapy, No. 1, but you also do not get much neuropathy, at least theoretically in the trials.

This is the issue: let’s get back to the trade-offs you have to make. As a general idea, would women go for this, do you think? Would doctors go for it? Would they say, “Your neuropathy is less. You do not have to come into clinic, but you have this complicated regimen that you have to remember to do 3 days out of 7.” Do you think people would go for that?

 It is going to be a challenge. The efficacy data look good from what we saw, with the caveat that we compared it to an old regimen that we do not typically use, so it is hard to know against weekly paclitaxel. I am concerned about the pill burden, Adam. It is huge. Many of the patients who I see in a community setting will have a challenge with the directions and with doing it correctly. That could go in 2 directions: 1, many will skip doses, and 2, some will take doses incorrectly, which may lead to more toxicity. Of course, if you have 1 bad toxicity with an oral therapy, those patients do not like to take it again. That has been my experience. You have to be careful.

 And then the doctors do not like to give it.

 The doctors do not like to give it, exactly. It is a challenge with the way it is formulated. Hopefully, the company is working on making a somewhat simpler formulation. We have seen that in a few other oral drugs like some of the PARP inhibitors, which have gotten to less of a pill burden over time as they have improved their formulations. Hopefully, we can do that here. It is a big pill burden and a complicated schedule, which is going to limit its use, even though it does seem to be effective.

 The neuropathy is the trade-off. You could tell people. That is my problem: that is a dose-limiting toxicity, most of the time. I have people, as you guys probably do too, who have been on weekly paclitaxel for a year or more.

It eventually gets to the point where they cannot button their clothes. That is usually when I stop. For me, that is grade 3: when they cannot button their clothes during the morning. I ask them that every time they come in. I say, “Can you button your clothes?” They never want to stop because they are responding to it. I say, “Listen, alright, enough is enough. We have to either cut you, give you a couple of weeks off, or stop.” George, what do you think about this? To be able to potentially not have neuropathy for continuous use but to have all of this tough pill burden, there is always that trade-off that you have. What do you think?

You are reminding me of my mother who, as soon as she looked at a pill in a bottle, would start gagging. I am trying to imagine her taking that dose. You obviously need a compliant, well-educated, and well-instructed patient. That is an issue.

Anything that allows you to get away from peripheral neuropathy, of course, is a positive. I am always skeptical about peripheral neuropathy early on because I remember the nab-paclitaxel where we were repeatedly told that it had less peripheral neuropathy than paclitaxel by people who should have known better. I would like to wait and see more data on that, but if it indeed has less peripheral neuropathy, then it will certainly be embraced by physicians and patients.

Metastatic Breast Cancer Therapy: OPE

 I was struck, for example, to have the PrefHER trial. This is in Europe: they did a trial of subcutaneous vs IV [intravenous] trastuzumab, and they found that, 9:1, patients preferred the subcutaneous delivery. Is it because they spend less time in the chair? They are there for 20 minutes and they leave, so they do not have to spend several hours there. Do you think that is the reason behind it?

They do not even have to be in the chair. It is eminently possible to give those therapies at home. You can have a visiting nurse come out and give it in 5 minutes.

 Have you started to do that at Stanford Cancer Center, by the way? I know Mark Pegram, MD has been talking about it for quite a while.

We are part of a larger Genentech trial that is doing subcutaneous delivery for both trastuzumab and pertuzumab.

 Can you do it at home? You get a visiting nurse to give it to people at home?

Yes. As I recall, they have a contracted visiting nurse who gives it.

 Do they have to be chemotherapy certified, I'm assuming, to give it, or can a general nurse give it?

That I do not know. One would imagine they have to have some sort of certification.

 Lee, are you doing the same thing? I am curious.

 We have not done it at home yet. We want to make sure that the custody of care and delivery is right. In the office, we are doing it. I know that my colleagues in hematology are doing it a lot with rituximab now, which has subcutaneous technology, as well as Darzalex [daratumumab]. These are drugs that take hours and hours, and anti-HER2 antibodies are the same.

 I will take the last 15 minutes to talk about specific agents that we have now have seen both at ESMO [the European Society for Medical Oncology Virtual Congress 2020] and San Antonio Breast Cancer Virtual Symposium 2020, as well as at San Antonio in 2019.

I want to talk a bit about the concept of toxicity. Do you believe that it is a C

 [peak plasma concentration] sort of thing? Is it a peak that determines toxicity to the agents, or is it more chronic? I am curious to hear what both of you think about that topic. It influences oral agents, right? I do not know if that is true, but supposedly, oral agents are more chronic, so you do not get as high of a C

. I am curious to hear what you think about that.

It depends on the drug, and it depends on the toxicity. For most agents we are talking about a C

sort of thing. But if I think of something like taxane neuropathy, weekly low-dose paclitaxel does not have a lower rate of taxane neuropathy than every 3 week taxane.

 issue. It is probably more of a time above threshold issue.

 Fair enough. Same thing, Lee? Do you think it is the same kind of thing?

 Yes, I agree. It is specific for the types of toxicity that you are looking at.

At-Home Administration of Therapies to Treat MBC

 We should probably turn for the next 20 minutes of this presentation to talk about delivery because ADCs [antibody-drug conjugates] are just 1 form of delivery. Something that has become pretty important over the last many years in breast cancer is that we are trying—at least I am in my practice at the University of Pittsburg Medical Center, Hillman Cancer Center, and women appreciate it—to stay on all oral therapy.

I am curious to hear your thoughts about this mainly because, the perfect example is now the CDK4/6 [cycline-dependent kinases 4 and 6] inhibitors. You have someone on a CDK4/6 inhibitor for 2 years, 3 years, or 4 years. They are used to being on it, and then all of a sudden, they progress. Then you try out alpelisib or everolimus with some other antihormonal therapy. You are then 2, 3 regimens into it, and it is now time for some sort of cytotoxic chemotherapy.

The default for all of us has been capecitabine because you are used to it, and the patients want to do it. Patients are now coming to me and they think that they are in big trouble. They get depressed, and they say, “Dr Brufsky, I have got to go on IV [intravenous] therapy now. Is this the end? Should I be talking to my family about hospice?” I am curious to hear your thoughts about this. Is that where we are going, toward trying to keep oral agents as long as we can? Is that something you guys consider? Go ahead, Lee. You go first.

 I have the same experience you do, Adam. It is disconcerting for a patient with HR+ [hormone receptor-positive] breast cancer who has been doing well for 2, 3, or 4 years on oral therapies, or even if they have to come in for fulvestrant. It is not that much, but they do not have hair loss, they do not have neuropathy, and they do not have neutropenia. It is tough for them when they hear that their cancer is getting worse, and they are now going to have to go to IV therapy as well.

That is a big inducement for capecitabine. If we assume that, since we do not have the biomarkers, patients are going to do as well with capecitabine as they would with other single agents, even though we know taxanes and anthracyclines probably have the most activity of single agents, at least in nonexposed patients. The idea to that is this: you are not going to lose your hair, and you are not going to get really sick. In fact, it is just your hands and feet that we have to worry about. We can modulate the dose. We can do that remotely. You can call me in 10 days if you are having a problem. I can look at it on your cell phone and say, “Yes, let's adjust the dose.” They like that; it gives them a bit more empowerment, and it keeps them free. It is not that, “I am getting near the end. I am now coming to the clinic every 3 weeks for IV chemotherapy.”

When we at Stanford Cancer Center studied this, I was co-author on a paper several years ago that was looking at patient preferences in the metastatic setting. What we discovered, of course, is that patients differ considerably in terms of what sort of therapies they are willing to accept. It is a trade-off between toxicity and benefit. In general, patients are more focused on the benefit than they are on toxicity, particularly in younger women, our studies showed.

The younger you were, the more likely you were to accept significant toxicity for even fairly modest benefits in terms of treatment. At the end of the day, patients want to live longer first and foremost, of course. Secondly, they want to live well. Thirdly, this gets to both of your points, they would like to spend as much time with their family and friends and as little time in the hospital as possible. As much as we think that we bond with our patients, my patients would by far rather be with their spouse than with me, depending on the spouse of course.

One of the huge advantages of oral therapy is that it significantly cuts down on what has been called time toxicity. A wonderful paper I saw recently looked at how much time patients with metastatic breast cancer spent attached to the health care system. If you are an average patient with metastatic breast cancer, something like 10% of your waking hours are spent attached to the healthcare system in some way, shape, or form. That time toxicity is huge.

It is increased if you have to come in; it is not just that you are spending an hour or hour and a half sitting in the chair getting an infusion. You may have to drive a couple of hours. You have to pay a parking fee. You have to walk in. You have to wait at the reception area. You have to get a blood count. Then, you sit in the chair. Then you wait a while longer after that. Then you have to go back and get to your car. You probably had a doctor’s visit that day because it is common for us to attach those to IV treatment days. Before you know it, you have burned through a fair amount of your day. The great advantage of oral therapeutics is that they minimize time toxicity to a significant degree.

 We at West Cancer Center & Research Institute did a study years ago in the context of long-acting growth factors and in both white blood cell and red blood cell growth factors. It was a time motion study that showed exactly what George is talking about with the amount of time that not only the patient by the way, but the caregiver in many cases as well, had to spend just coming to the office. Whether you are in an urban environment and have to get on a subway or if you live 100 miles away as many of the patients do around Memphis, it is a huge amount of time, with the waiting and then everything.

Doctors look through it in the filter of 15 minutes with the patient, which is not so bad, and then they go up to infusion. We do not realize that it is 3 or more hours there. It is a big deal, and it impacts their lifestyle. It is hard to work, and it can sometimes be their caregiver who it also affects. It is huge, particularly for disadvantaged populations, which we have a lot of, unfortunately, as well. It is difficult; they often do not have transportation, so they sometimes have to take 3 buses or wait for the special Uber driver who is contracted to come get them.

 That is an interesting idea. You have an Uber driver that you contract with to bring patients into the clinic?

 That is cool. I never thought of that. How do you pay for that, is it through a foundation or something?

 We did it with Lyft. We had a grant for it.

 That is great. That is a good idea. That is pretty cool.

Advantages of Oral Therapy for Metastatic Breast Cancer

 Let’s turn it a bit and talk about some innovations in chemotherapy that have happened. I would love to talk to you guys about ADCs [antibody-drug conjugates] because a lot of us are saying that this is the decade of the ADC and that sort of thing. Clearly, we started with Kadcyla [ado-trastuzumab emtansine]. At least in breast cancer, that was 1 of the first, but we now have trastuzumab-deruxtecan. I would like to know what you guys think of trastuzumab deruxtecan. Not only is this 1 where it will apparently work anywhere you have a target and deliver a chemotherapy payload to it, but all you need to do is have a certain percentage of the target for it to work.

What do you guys think of the data, especially in the San Antonio Breast Cancer Symposium. In the most recent update, it was 19.4 months. It was admittedly in phase 2, ready for phase 3, but that is a 19.4-month progression-free survival [PFS] in people who have had a median of 6 regimens. What you guys think of that?

Yes, it is pretty stunning, is it not? When we talk about drugs like TDXD [trastuzumab deruxtecan], T-DM1 [ado-trastuzumab emtansine], or sacituzumab govitecan—all the ADCs that have come along in the last few years—the payloads are, in essence, chemotherapy. Ultimately then, the drug resistance is going to be chemotherapy drug resistance.

Whether these will represent cures for metastatic breast cancer, I would say that is unlikely. They have certainly changed the field in a special way, and we have the opportunity to prolong life fairly hugely. Because there is no limit to the number of payloads that you can add to an antibody, we can expect further advances in this field going forward.

 I would completely agree. We have gotten better even since T-DM1 [ado-trastuzumab emtansine], which is arguably the first ADC that we were using in breast cancer. We have gotten better in terms of technology: the linking technology and the payloads. The future is bright for this, and it is interesting work.

For example, with sacituzumab, the target is present on almost every cell, so we are not using it so specifically as a targeted therapy like we do in the 

 [human epidermal growth factor receptor 2] area. That may also be true for TDXD [trastuzumab deruxtecan]. You may not need a lot of expression of 

, and many cells have some. We will wait to see those results. It is another method of getting chemotherapy in. What is interesting, though, is at about the 19 months. To George’s point, I am struggling to understand how you do not get resistance from 19 months.

 It may be back to what we started talking about, because there may be mechanisms there that we are not understanding. It may be an immune mechanism that is unique to that drug because even if it is just chemotherapy, if you deliver it effectively.

Some combination of chemotherapy plus ADC.

 I would agree. It is interesting. When you look, there is an interesting abstract. I do not know if they published it yet. They looked at the genes that were associated with trastuzumab deruxtecan resistance. I do not remember who presented this. It was at ASCO [American Society of Clinical Oncology Annual Meeting] about 6 months ago, and they had the usual ones: If you had apparently circulating levels of 

, then you would do better after a couple of months.

What was interesting was this: If you looked carefully at that abstract and looked at the other genes that came out, a lot of them had to do with all these weird immune genes like endosomal transport genes. It was weird. I agree. Something else is probably going on besides that, because I agree. Who gets a 16- or 19-month PFS without resistance to the underlying chemotherapy? That was the weird thing about it. That struck me.

Chemotherapy to Treat MBC: Drug Developments

One of the failures in our field is that, after 2 or 3 generations of using chemotherapy for metastatic breast cancer, we are still bad at predicting which patients benefit from which drugs. If you think about it, long after HER2 [human epidermal growth factor receptor 2]–targeted therapy picked out a population and long after the estrogen receptor [ER] status picked out which patients would not benefit from an endocrine agent, if I walk into a clinic to this day, I cannot tell Mrs. Jones whether her cancer will respond to paclitaxel or capecitabine.

I do not have any clinically useful predictors for doing that. That represents a huge challenge to our field. If one thinks about it, the tragedy is not that chemotherapy causes adverse effects. The tragedy is that chemotherapy costs so much in the way of toxicity while providing so little in the way of targeted benefit. That is clearly what we need to change.

 I know, and what has struck me is this: Lee, you are a big participant in this with Caris Life Sciences and the idea of doing ctDNA [circulating tumor DNA] sequencing or even tumor sequencing and trying to correlate mutations with response. Have you been disappointed by that, to a degree? I thought this would be a great effort. You got Caris and 200,000 or 300,000 people in sequence. You got Tempest Therapeutics, Inc. You have the big companies. You got all the academic centers doing the same thing, yet no one has come out with something that says, “You have this profile of your tumor, so you respond to paclitaxel. You have this profile, so you respond to capecitabine.” At least I have not seen it. What do you think? Why haven’t we been better at this?

 We are just starting to get the data, so it is a glass-half-full type of thing. We are starting to see that it is more complex than single-gene alterations, single-driver alterations, unless where they are important like 

. When you have a good target like imatinib 

, it is reasonable to say that you have a good target in breast cancer that is a driver target that remains active throughout the course of cancer.

You can do a lot of great things with that. We have new therapies that are exciting, but that is not the way. George gave a lecture that I remember well, talking about dumb cancers and smart cancers. CML [chronic myeloid leukemia] was the dumb cancer because you have only 1 alteration, and we know how to take care of that. It does not change. Breast cancer is a little smarter, and it has outsmarted us to date.

It will get there, Adam. We are starting to get AI [artificial intelligence] use, and this may be a bit of hand-waving. AI put together patterns of both gene expressions and alterations, and it put them together to try to see if we can discern who will respond to traditional chemotherapy, for example. We are at the beginning of it. We will make some progress, but I do not think it is going to be the be-all and end-all.

That would be an interesting question. I agree with everything you just said. When I think of biomarkers, by and large, biomarkers are negative predictors rather than positive predictors. They tell you whom not to treat, so if you are estrogen receptor negative, you do not get hormonal therapy. If you are HER2-, you do not get Herceptin [trastuzumab]. We do not have anything like that for any chemotherapy agent. You do not have to have a 100% success rate to have a positive biomarker. You just need to eliminate the patients who are not going to benefit from contention for that agent.

 Remember: We had a few false alarms there. We thought ERCC might work for platinum for a while with immunized chemistry. We went down that blind alley, so you are right.

 AL for paclitaxel—I remember that 1. Why is that? I have always wondered why that is. Why? We clearly understand the mechanism of what some of these things do: Certain drugs are antimetabolites, and certain drugs are DNA methylating, or demethylating agents. I am curious. For how many years of work—30, 40, or 50 years—have we have not found a biomarker.

Is it because we are not sophisticated enough? We do not have the systems biology, the computing power, or the AI to do it? May it be that there just is none? I do not know. I am raising a question to you guys. You guys have been doing this for a long time, so from what I am hearing from Lee, it sounds like we are just not there. We do not have AI powerful enough. George, you are saying the same thing. Is that what I am hearing?

I guess, but perhaps in addition, the biology of the estrogen receptor is straightforward in a way, and the biology of 

 is straightforward in a way. I am not sure the biology of chemotherapy response and chemotherapy resistance is straightforward. It may not have the uniformity that we see in ER or 

. There is no particular fluorouracil receptor that we can measure. There is no platinum receptor that we can measure. Platinum’s receptor is called DNA.

 That is the key: A lot of these end up working on DNA damage. There are so many evolutionary redundancies in DNA repair that cancer cells find their way around it, I think. It is going to be hard to identify that chemotherapy because whether you are an antimetabolite, you cause single-stranded breaks, or you have some other mechanism, most of the chemotherapy drugs are at least in some way working on DNA repair and replication. That is a complicated and redundant area.

Predicting Response to Chemotherapy in Metastatic Breast Cancer

 Let’s turn it a bit to some more practical kinds of things. What factors do you consider when you select chemotherapy for somebody? What is going through your mind in metastatic disease? That’s a huge thing, obviously. I will let you guys answer that. It is an incredibly general question.

I will start with Lee: What do you think? What goes through your mind? You have a woman coming in the door who has metastatic breast cancer. Let’s make it incredibly generic. What would make you do chemotherapy over hormonal therapy as an example?

Today we are going to subdivide the patients into at least 3 groups: 

+ [human epidermal growth factor receptor 2 positive], HR+ [hormone receptor positive]/

2-, and triple-negative. We start from that when we are thinking about the disease.

We also then think about patient factors. The patient’s prior therapy is increasingly more important in my mind because we have tended to get more appropriately aggressive in the adjuvant setting. Therefore, we may see a different pattern of response to therapies that traditionally were used in the metastatic setting without prior exposure. That is true for taxanes, for example, depending on when the patients were previously exposed.

Patient factors are important, as we all know, for patients with metastatic breast cancer. We cannot tell them that, on the 1 hand, we are going to make them a patient with chronic disease, and their quality of life is going to be great and then give them therapy that is going to have them, in the worst cases, end up in the hospital. That is not doing a favor for patients. In the hormone receptor–positive group, we are all excited about the vast majority of women receiving CDK4/6 inhibitors in therapy to start.

In the other groups, at least at the moment, it is chemotherapy with or without HER2 therapy, or it is chemotherapy alone in the triple-negative population in the first-line setting. That is how I think about it. When patients with hormone receptor–positive disease finish their endocrine therapy—however many lines that is, and it is increasingly longer—at that point, they behave not-too-dissimilarly in terms of response and length of life to patients with triple-negative disease who are de novo

It is usually a couple of years, or it may be a bit longer than patients with triple-negative disease. They are responding to the same types of therapies.

Metastatic Breast Cancer: Chemotherapy Selection

 I want to focus on something George said about the paradigm shift: We had that huge paradigm shift when Bernard Fisher and everybody else—not only Bernie, but a lot of people—said breast cancer is a systemic disease. That was the big shift; that was the first huge shift. 

What about a shift that would say, “What are our cytotoxic agents? What are they really doing?” Yeah, they are debulking the cancer. We get it, but the question we always asked was more of a philosophical 1, which is to say, “We debulked the cancer. Where is it going? When we kill cells off, and they apoptose, where do they go? Who gets rid of the garbage? How does a body react to it?” This gets into the immune system business.

There has been a crazy paradigm that has been floating around for a while, saying that what chemotherapy may be doing in some cases is manipulating the host tumor microenvironment in combination with treating the cancer. Have you guys ever thought of that or even considered it as something? I know it is crazy; I am just bringing that up as something out there.

 It is absolutely sensible. I read somewhere that basically every cell in your body is touched by a macrophage every day of your life.

 If those big eaters see something abnormal, if they see some funny set of antigens since these are antigen-presenting cells, then they are going to do something to that cell. It is absolutely likely.

Of course, I said that chemotherapy is an efficient inducer of apoptosis, but if you look at what chemotherapy actually does, it does a lot of things. In killing cancer cells, it is releasing lots of antigens that are probably activating the immune system. Many chemotherapy agents are antiangiogenic in preclinical model systems and indeed in some clinical model systems. Rather than saying that we are just pounding cancer cells, when we give chemotherapy, we are doing several things at once.

 It is interesting. We would all agree that we do cure breast cancer, but we cure it only in the micrometastatic situation for now. 

 We would agree on that. I believe that is true, and that is what adjuvant therapy does, but we do not know exactly how it does it. Is it a volume issue? Is it immune stimulation in a more intact immune system? 

We now have some early clues from checkpoint inhibitors: They work better the earlier you use them. We are less dependent on our not-so-great biomarkers right now, like PD-L1 in the neoadjuvant setting, than we are in the first-line setting or in the late-line setting in metastatic cancer. We are going to make progress, and we may still use chemotherapy, particularly in the early stages to increase cure rate. It is going to be hard to cure metastatic cancer without chemotherapy, which is probably benefiting because it is not discrete in terms of 1 single target. It is difficult to cure with 1 target.

 Otherwise, I still remember something important that I am always going to remember, George. This must have been in 2003 or 2004. We were probably talking about how there was some trial. I am trying to remember what it was. I was doing something with Gemzar [gemcitabine], and I was at a meeting with you. We were talking about it, and I will always remember this. You said, “Gemzar [gemcitabine] is a targeted agent. Chemotherapy is targeted therapy.” It is a more general target; it is not a specific 1. I always remember that. 

I want to comment on the thing that I am interested in. What is going to make me turned on about this is that this is the exact thing that we are seeing in the neoadjuvant checkpoint trials: If you are PD-L1 positive, you benefit from chemotherapy regardless of whether you get the checkpoint inhibitor. Your pCR [pathologic complete response] rate is higher, but if you are PD-L1 negative, the absence of checkpoint inhibitor—what is that telling us?

 Similarly, if you are in the adjuvant setting, you have a large number of TILs [tumor-infiltrating lymphocytes], and you have triple-negative breast cancer, then you have a higher cure rate in the absence of checkpoint inhibitors with just chemotherapy.

 It tells us that we have always been giving immunotherapy. We just called it chemotherapy.

 That is right. These are the things that the generation beyond you guys and I may be thinking about. I agree. This is going to be a long-term project, but it is cool that we are starting to see this when people are talking about signatures of response and survival even in metastatic disease and involving the immune system. It is getting interesting.

Assessing Response to Chemotherapy in Metastatic Breast Cancer

 Is this going to be a chronic disease that we take care of for long time? As both of you know, having been intimately involved and doing this over many years, chemotherapy remains. Despite the fact that we have a lot of targeted agents, with the latest being CDK4/6 inhibitors in breast cancer, we still need chemotherapy. Let me start at the beginning. Do you think we are ever going to be at a point where we are not going to need it at all? I will start with George: Do you think we will ever be at the point that we will never need cytotoxic chemotherapy for this disease?

 I do not know. Chemotherapy is good at inducing apoptosis.

 That is its saving grace. It kills cancer cells, and it does so relatively efficiently in many patients. It is going to depend to a great extent on how well we understand the biology of drug resistance for endocrine agents, for HER2 [human epidermal growth factor receptor]–targeting agents, and everything else that we have brought along over the last couple of decades.

Because cancers tend to be heterogeneous, because they frequently have mutations that confer resistance, and because we are dealing with relatively large-volume disease where the play of chance allows you to develop mutations on a large scale that will make you resistant, it is hard to imagine that chemotherapy goes away anytime soon unless we have some major changes in the field. One could imagine, for instance, a more effective immune approach allowing you to better control the cancer or to wipe out cancer. But not any time soon, I suspect.

 Lee, what do you think? Same kinds of thoughts?

 I still tell my fellows that they will be giving chemotherapy through their careers, most likely. I get a bit less emphatic about it every year. If we have a couple of paradigm shifts that we do not see coming—it is hard to predict the future, as Yogi Berra once said—it could happen that we could diminish or get away from chemotherapy. 

What I see happening is that chemotherapy administration is getting smarter through the use of antibody-drug conjugates, for example. That is clearly, in my opinion, the next generation of the way we will be giving chemotherapy over the next decade or 2, as well as other potential delivery systems that are more sophisticated and cause less toxicity.

Cytotoxic Chemotherapy for Metastatic Breast Cancer

Lee, the next question related to that is this: We have all these things, so what are the goals when we treat someone with metastatic breast cancer? What are we trying to do right now? What is realistic? Is it to cure? Probably not. Is it more survival or progression-free survival and the avoidance of symptoms? What are the goals when we try to treat somebody, either through a clinical trial or in practice?

 I am a few years behind George, and I agree: The change over the last 3½ decades has been incredible, and it is so exciting. I come to work believing that there has never been a better time to be a medical oncologist and take care of patients with cancer. We are optimistic about the future. But with that said, Adam, we still do not talk in terms of cure for metastatic breast cancer. There is a small percentage of patients, a growing percentage in some of the subgroups, who live a decade or more with metastatic disease.


It is fair to call metastatic breast cancer a chronic disease today, which we could not do in the 1980s or 1990s when some subgroups of people lived just a few months, and some lived a couple of years. Now we can anticipate most of our patients will live at least a few years. Quality of life is important too, so that is the other thing: extending life and maintaining quality of life when you are dealing with hopefully a chronic disease.

I want to push that a bit more because I am interested in trying to figure it out. We always say that there is going to be a cure. I am not as old as you guys—maybe 15 or 20 years, younger. I am older than I look, though. My hair never turned gray. I am trying to determine what the parameters are when we sit down and say “We have cured this.” Are we ever going to say that, or are we going to say that we have turned it into something chronic?

Something like coronary artery disease is a perfect example. Think about it: 50 years ago, everybody dropped dead at their desk, and we now have all these things. People are living, but they are living with it. We do not get rid of every plaque in somebody. My thought is this: You guys have been around a long time. I am curious what you think of this formulation. It is more like we are trying to turn this into something you can live with.

You are probably going to die, just like with coronary artery disease. Eventually as part of a whole panoply of things, you will eventually die of something. To me, the cure to this—not the cure but the control of it—will look like this: You get this, and we give you a bunch of things just like in coronary artery disease. We treat you systemically and medically, and we keep you going for as long as we can. What do you guys think of that? Is that where you think we are going with this?

 The model I think of is what we have seen in CML [chronic myeloid leukemia] with BCR-ABL targeting agents, which is to say that we have a life span that, in essence, approximates that of the general population, if one looks at age of the patient. The overall survival curves are basically parallel to that of the general population. We have not reached that for any subtype of breast cancer. We have gotten better at all the subtypes of breast cancer, but we are nowhere close to what you would say about a Gleevec [imatinib mesylate]–type definition.

It is a good analogy in another way, which is to say this: If you stop your imatinib, your cancer will come back. A true chronic disease, I would argue, would be 1 in which you do not stop your imatinib, and the disease does not come back. We are not there yet.

 I agree. I usually use the analogy of diabetes, which all our patients are familiar with 1 way or another. We think of diabetes as a disease that you are not going to cure, but you probably know at least 1 or maybe many people living with diabetes. They can often live a perfectly normal life. It depends on how they get controlled and what medications we need to use for that. 

Of course, it would be great to talk about a normal life span, but we do not do that. We are moving the conversation from cure, which is what patients are thinking about—“Am I cured or not?”—and moving it from a dichotomous variable to say, “No. It is a chronic disease. We can keep you alive and well for a long time.”

Long-Term Disease Control in Metastatic Breast Cancer

® webcast titled, “The Role and Rationale for Oral Options in the Treatment of Metastatic Breast Cancer.” My name is Dr Adam Brufsky. I am a professor at the University of Pittsburgh School of Medicine, and I am a codirector of the comprehensive breast cancer center at UPMC [The University of Pittsburgh Medical Center] Hillman Cancer Center in Pittsburgh, Pennsylvania. Joining me for this 60-minute discussion are Dr Lee Schwartzberg, the chief medical officer of West Cancer Center in Memphis, Tennessee, and Dr George Sledge Jr., a medical oncologist at Stanford Women’s Cancer Center in Palo Alto, California.

Today we will explore the standards of care and unmet treatment needs associated with metastatic breast cancer, focusing on the role of chemotherapy. We will identify emerging chemotherapy options for metastatic breast cancer with an emphasis on the rationale for oral therapy. Finally, we will discuss the shift in treatment paradigm based on the use of oral oncolytics, including the impact of COVID-19 [coronavirus disease 2019] on the uptake. We will also discuss approaches to ensure successful treatment with such oral agents.

Let’s start with the beginning. We are here to talk about metastatic breast cancer, something that all of us have treated, and we have observed dramatic changes in how we do this. These are general questions but I will start with George. How have things changed since you started practicing metastatic breast cancer? You have been involved in just about everything that happened in this business in the last 35 to 40 years. I do not know if you can even encompass it in a statement, but if you could encompass this in any kind of way, how have things changed since we started many years ago?

 Thanks, Adam. The biggest change is simply the tools we have available. During the first decade of my career, I became a brand-new assistant professor in 1983. During the first decade of my career, there were 0—I repeat, 0—new drugs approved by the FDA for the treatment of metastatic breast cancer. If you look at that in contrast to the last decade, there has been more than 1 new drug approved for the treatment of metastatic breast cancer per year. The sheer volume of what we have available to us has changed.

Secondly, above and beyond the volume of course, there is a huge profusion of new biology-based treatments. Most of the treatments that we had available to us 2 or 3 decades ago were relatively nonspecific agents. We had the first targeted therapy, which is to say endocrine therapy, in perhaps all of oncology, but beyond that, most of our agents were relatively nontargeted. It’s the profusion of new agents, and these new agents are incorporating what we have learned about the biology of breast cancer over the last 2 or 3 decades.

Adam M. Brufsky, MD, PhD, University of Pittsburgh/UPMC Hillman Cancer Center

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