Editor's Note: In this One-on-One, Eric Topol talks with UCSF breast cancer specialist Laura Esserman about her approach to individualizing patient care at every stage of cancer screening and treatment, which has both made her an iconoclast and occasionally put her at odds with conventional wisdom in the field.
A Vision of Care for Women With Breast Cancer
Eric J. Topol, MD: Hello. I am Eric Topol, editor-in-chief of Medscape. With me today is Dr Laura Esserman, who heads up the Carol Franc Buck Breast Care Center at the University of California, San Francisco (UCSF), and who has really been pioneering a whole different path for breast cancer. Your background is interesting: You were at Harvard for undergrad, you were at Stanford for medicine and for your MBA, and you have been running this breast cancer program for 20 years. Over this period of time, there have been a lot of changes and there is still a lot of controversy over how to manage breast cancer. What is your take on all of this?
Laura J. Esserman, MD, MBA: When I started the program, I had an idea; there were a couple of things that I wanted to create. I wanted to create a place that really served the women who had breast cancer—to create a place that was "one-stop shopping" for breast cancer. That was organized around patients. It would have a very high-touch, patient-centered program where all the different specialties would revolve around the patients and where we would really think about reducing morbidity and complications, improve the specificity of what we were treating, and create a team that was interested in innovation. Some of those things we have been able to do very well. To really drive innovation, however, you need a bigger platform. You need to have a larger, more population-based focus. The lesson of biology is that one size does not fit all. Cancer is not one disease, and, actually, some of what we call cancer is not even cancer. If you really want to make progress, you have to get your denominator right.
Cancer is not one disease, and, actually, some of what we call cancer is not even cancer.
The other thing that I have been pushing for, and it's sad that it has taken me so long to get there, is to make sure that people had feedback on performance. I have always had this idea—now people call it precision medicine—that we should treat people based on biology, patient preference and situation, and clinical performance. If you figure out how to get the resources and the structures in place to allow that to happen, then you are going to do the best with what you have; you will be able to work together to create a better future and be able to create that future by constantly being able to look at and improve your situation.
A Screening-Created 'Cancer'?
Dr Topol: There is no question that you have been emphasizing this individualized approach at multiple levels, but you have also been termed a rebel who is fighting the status quo. Let's go into a very important area—ductal carcinoma in situ (DCIS), which I think you would prefer to have renamed and re-identified.
Dr Esserman: Correct. DCIS is in many ways a disease that we created because of screening. It's important for us to put screening into perspective. It is not a question of whether screening is good or bad. Let's understand what made us think that screening was a good idea. What have we learned with 3 or 4 decades of screening, not just in breast cancer but in breast, prostate, cervical, lung, and colon cancer? What are the lessons we have learned? How do we then apply them? Let's try to take some of the emotion out of it. I think I understand why people react the way they do; I am not for or against anybody. I am trying to create something better for patients and for women.
DCIS is in many ways a disease that we created because of screening.
Back in the 1970s and 1980s, we were looking at this from a population basis. The people who had cancer in stage III and IV did much worse than the people who had stage I cancer. It stands to reason that if we could only find that disease earlier, we would do a much better job—we would prevent death. That assumed, however, that cancer was one disease. That was a long time ago and that is what we thought then. In fact, we have learned so much more. Cancer is very complicated. It is heterogeneous, and if we accept that scientific reality, that has to impact our clinical practice.
What have we learned? We have learned that in fact there is a range of behavior, from indolent to very aggressive.
Dr Topol: And most [of the DCIS] are indolent? That is why you want to call it IDLE?
Dr Esserman: Yes—indolent lesions of epithelial origin. If you screen, you are necessarily going to find this reservoir of indolent disease. The problem is that we see it and go after it. People understand this in prostate cancer, and, actually, screening may have a greater impact on prostate cancer than it does in breast cancer. When you screen you find more indolent disease in prostate cancer, so people understand that. In breast cancer, young women who have more aggressive disease are the faces of breast cancer, and people are very frightened of it. It is not that it is not a serious disease, but you do not help the people with more aggressive or serious disease by overtreating the people who are never going to get there.
DCIS: Just Another Risk Factor
Dr Topol: A lot of women are referred to you who have already been told that they should have a bilateral mastectomy. You say, "Time out."
Dr Esserman: My email is full of this. I get calls and the women themselves seek me out; it's not just referrals. We assumed that DCIS was the obligate precursor. That is how we thought. Think about cervical cancer for a minute. We used to call it "cervical carcinoma in situ," but they changed the name to "cervical intraepithelial neoplasia" (CIN) because it made people pause and not be so aggressive. Where are we now? If you watch CIN1 for a year, 50% of those lesions go away. This is the lesson. It's not, "If you do not do this, your breast is going to come off and you are going to die." We have to stop telling people that because we have no basis in fact for that. All we know is, this might or might not progress. In itself, it's just a risk factor. The reason why the pathologist probably cannot tell the difference between atypia and low-grade DCIS is because biologically they are the same thing. They are a risk factor.
We should ask, "Do you have any other risk factors? Are there things that we can do to reduce your risk?" What about endocrine risk-reducing therapy? We spend hundreds of millions of dollars on prevention research, so why not apply it here? Why not start figuring out who is at risk and who is responding to these features and start thinking about alternative therapies? I also wonder why it is that we are accepting of interventions without data, but we're anxious to withdraw interventions when we have no data to suggest that they are working.
For example, there is no evidence that we make a mortality difference with radiation for DCIS. With the exception of some very high-risk situations, why are we radiating people with DCIS? This is [an intervention for which], even though that risk is very low, the mortality, in fact, is probably not zero. Why are we doing that?
Screening the Right People
Dr Topol: I am glad that you are questioning that. I actually think the questions here go even broader. What you are saying, though, is that the model of breast cancer applies, as you have already asserted, across many other cancers. Prostate is another perfect example. There are many others where we overtreat, we do too much, we overreact, and we do not appreciate the individualized story here. Why do we do mammography routinely? This seems really crazy. The data suggest a net harm that is really profound.
Dr Esserman: You do not necessarily want to throw the baby out with the bathwater. One thing to do is figure out who is at risk for what kind of cancer. Which groups and which populations of people should be screened? Just as today, no medical oncologist and no surgeon would treat everyone with breast cancer the same. Why are we screening everybody the same? That cannot make sense either.
Dr Topol: You are working on a really big cohort of the WISDOM study, with hundreds of thousands of women, to understand this better. Recently, a JAMA Oncology study[1] of 37,000 women with 92 single-nucleotide polymorphisms (SNPs) was published. They could sort out risk for mortality and breast cancer from 3% to 25%. We know that there are better ways than just clinical data to do this.
Dr Esserman: We are doing that. In the WISDOM study we are using 157 SNPs.[2] We are taking the Breast Cancer Surveillance Consortium model, which has been validated in a million people. We have validated it with the SNPs; these are the SNPs that we are talking about—these small variations. There are also probably nine genes—not just BRCA1 and 2—that are associated with significant risk for breast cancer. It's not the majority of the population but that 1%-2% of the population who have the most risk. Let's make sure we get those. Let's add breast density, exposures, and the SNPs and put that into a model and do two things. Let's identify the groups of people who are most at risk. We will make sure that we screen them, make sure that we think about prevention. We should integrate screening and prevention. There are many tools. These SNPs tell us whether you are at risk for ER-negative disease or ER-positive disease.
You can imagine, as we are starting to figure out what is actually working to treat some of these hormone receptor–negative cancers—and many probably have something to do with the immune environment—that if we can understand who is at risk for them, maybe we can start to think about other things. Maybe that is where we start to think about the microbiome and prevention.
We are starting with a framework that is within the US Preventive Services Task Force guidelines because we do not have room to do it differently. We are going to adapt over time. We are going to learn. I am not going to start with a model that, 20 years from now, everyone is going to argue about. The whole idea is to have living learning systems and adaptation.
More Is Just More
Dr Topol: Absolutely. You have been a standout. You are somewhat of a maverick, because the rest of the breast cancer community is much more aggressive. They are not exactly adopting this "less is more" position, wouldn't you say?
Dr Esserman: The funny thing is, I am not a therapeutic nihilist. With my other hat on, I run the I-SPY trial where I am trying to figure out how to do better for the people at most risk. Last time I checked, 40,000 women a year are still dying of breast cancer, and people don't like the treatments that we have to offer. As far as I am concerned, until we get those numbers down and the morbidity of our treatments goes down, we have a long way to go to improve what we are doing. If you keep doing the same thing, how are you going to make it better?
Dr Topol: That is the key point; there has not been a substantive change in the landscape here.
Dr Esserman: I have started to see a sea change. I will tell you another thing that I am working on. More is not better. But people feel that; it is an emotional reaction. "I did everything I could. I am going to fight it. I am going to do everything I can." More is just more. Sometimes more is worse.
Let's talk about the MINDACT study[3] for a minute. They spent 70 million Euros on this trial. They are trying to say, "Look at the people who have the 70-gene test who are low-risk." It does not mean low-risk ever. It just means low early risk. They are trying to say, "Does chemotherapy really help these people?" They set as their primary endpoint that there would be less than a 2% variation in that outcome of 94%; the survival of this group was 94.7%, so with confidence, it was above the 92.5% survival. The maximum benefit you could have from chemotherapy in that group, as they showed, for low-risk patients with up to three positive nodes was 2%. If you want to do chemotherapy for that benefit, have at it. I would bet you that a lot of people would say they did not absolutely prove there was no benefit. My point? Take it to the patients.
If we just stop doing the things that we do every day that actually do not have that much value, there is plenty of room to pay for new things.
Dr Topol: Yes, give them the choice.
Dr Esserman: Here is the thing. We already know that the higher the proliferation, the more the chance that chemotherapy is going to benefit those people. With lower proliferation, it is not that you never have risk, but what is going to help you are endocrine manipulation and other targeted therapies that are coming along. People talk about how expensive all of these new therapies are. I say, honestly, if we just stop doing the things that we do every day that actually do not have that much value, there is plenty of room to pay for new things.
Dr Topol: It sure seems that way.
Dr Esserman: For example, radiation therapy for women over age 55 with luminal A disease or people over 70. I gave a talk to an internal medicine review course yesterday morning, all about screening across all five major cancers. I gave some great examples around DCIS. This woman came up to me afterward and said, "I had this patient who had about a centimeter and a half of DCIS, and she had a little bit of microinvasion, was strongly hormone positive, and they want to radiate her." I said that if she had an invasive cancer that was 2 cm and is strongly hormone positive, there is no indication that radiation will have any improvement in mortality. Why would you do that? I gave the discussion at the American Society of Clinical Oncology (ASCO) meeting in 2005 over these data that were in the New England Journal of Medicine.
Dr Topol: I applaud you for asking these questions.
Dr Esserman: I think people are afraid, and as the physician community, we make them afraid. We are afraid that we will be blamed if they have a recurrence or that something bad will happen. If anything, you cannot prevent bad things from happening. Bad things happen all the time. That is not in our purview.
Dr Topol: What you are getting at is that by having as much information about the individual as possible, you would minimize your chances of doing that. The outcomes would be better by giving choices.
Their Personal Lullaby
Dr Topol: I want to get into something that you do that is unique and goes beyond medicine: singing to your patients. Is that a frequent thing?
Dr Esserman: Every person I operate on.
Dr Topol: Really?
Dr Esserman: If they have a song that they like, they can request it. I tell them that if it is an aria, they have to give me a week; otherwise I can learn it the night before or usually 20 minutes beforehand. I know a lot of songs.
Dr Topol: Have you been singing for a long time?
Dr Esserman: I have been singing for a long time. It is my hobby, it is my avocation. I love to sing. The other day, someone asked me to sing the song "Good Morning Starshine" from the musical Hair. It is such a happy song; it was so great. You could see the mood; it was something that was meaningful to her. I sang it. Actually, a couple of people in the operating room sang it with me. It changes the culture. It changes the dynamic from a scary operation to something where everyone is focused on that patient, and you change it from being a horrible, scary time.
Dr Topol: So the person comes in to the OR, and before they are actually put under, you sing?
Dr Esserman: I am the pre-anesthetic induction. Everybody falls asleep on me.
Dr Topol: Does anybody say, "I do not want you to sing"?
Dr Esserman: No, nobody.
Dr Topol: You have been doing this for all these years.
Dr Esserman: I have. It started when I was an early attending. Someone had a complication, and we were waiting for the anesthesiologist to come in the room. Everyone was just really anxious. I was anxious, the patient was getting more and more anxious, and she was on the blood pressure monitor. I could not think of anything else to do. I had just seen Phantom of the Opera the night before, so I just started singing "All I Ask of You." It's a beautiful song; it starts with "No more talk of darkness..." Her systolic blood pressure dropped about 40 points. I am sure mine did too. She told me afterwards that that was the most incredible thing that had ever happened to her. I thought, now I can blend another skill that I bring to the table and something that I love to do.
Dr Topol: That is fantastic.
Dr Esserman: It creates a connection, that you are doing something for them to take their mind off of what is about to happen. You think about something that is meaningful in this moment. The wonderful thing about medicine is the relationships you create. One of the songs that I particularly love to sing is the song "For Good." It is about how you have been changed for the better because of the people that you know and the experiences that you have had. I think that is true as a physician.
The wonderful thing about medicine is the relationships you create.
Every person you meet changes you and informs you. It is part of your own heuristic about how you can tailor treatments to an individual person. If someone says, "I really do not want to have this," I don't say that someone refused therapy; I say that this person was told what the choices were. If they do not like what we have to offer, that is their choice. If you give someone a choice, you have to allow them to make a choice that you would not make. It is not you; it is not for you. It is for them.
I think that is the essence of what I do. I do not browbeat people into doing what I think they should do. I can advise them and try to explain the outcomes, but they have to make their own choices.
A 'Top 100 Most Influential' Person
Dr Topol: It is really refreshing. You question a lot of the sacred cows in medicine and surgery. Recently you were recognized by Time as one of the 100 most influential people in the world—not just in medicine but in the world. Congratulations on that.
Dr Esserman: Thank you.
Dr Topol: How was that event? Did you meet a lot of interesting people?
Dr Esserman: Yes. I also met Trevor Noah, which was very exciting. He was someone I have admired quite a lot. These are people who say some of the things that should be said and make us think and make us question. Melissa McCarthy said that she thought people were picked because they were iconoclasts.
Dr Topol: They are out there a little bit.
Dr Esserman: Out there, but making people think—making people change. I do not say that I am right; I say, let these ideas have their day in court and let us test them. In the WISDOM study, I am saying that I think personalized screening is the way to go. I do not know that. If the radiologists say, "We think annual screening is right" and primary care says something else, and the people who are paying for it say, "I do not like it," then everyone is fighting and putting people in the middle. Someone is sending a letter saying, "Come back every year." Another physician is sending a letter saying, "Come back every other year."
Women deserve better and we should aspire to better. Why are we arguing about data that are 40 years old? Let's have a real trial and let's learn. More important, let's have something that learns, where we take the data and we can keep improving the model. I did not say I was going to test this model today; I said I am going to keep testing the best risk model that we have at the time and turn it into a living registry. In the same way, in the I-SPY trial, if you give people adjuvant therapy, that means you treat them, you take away the biomarker, which is the tumor, and then you give them therapy. You can figure out for that population of patients what works, but you have no idea how it worked for that individual. While it may not be perfect as an indicator of how well that treatment worked, it is so much better than having no idea. Why would you ever do an adjuvant therapy trial? The order of therapy does not make a difference in outcome. Let's learn. Let's take those data and figure it out.
Here is something that is very interesting; here is our paradigm: If A is better than B, we always go for A. What if A is only a little bit better than B, but B is so much less toxic?
Dr Topol: Also, is A better than B at the population level?
Dr Esserman: Exactly. We just graduated T-DM1, which is a drug with toxins that attach to the antibody that targets HER2-positive breast cancer. It graduated from I-SPY. Strong chance that it is definitely better than paclitaxel/trastuzumab, and it is probably about the same as paclitaxel/trastuzumab/pertuzumab. But it is so much less toxic.
The other thing is, we give everybody [chemotherapy] afterwards. That is the way we have always done it. I think, going forward, for the future, why wouldn't we say, "Wait a minute—if we can get 40%-50% of these people who would have had lethal breast cancers to a complete pathologic response without anything other than this relatively nontoxic regimen, or that plus other biologics, why wouldn't we want to go in that direction?" And then take the people who need more and give them more. To me that is so exciting. Everyone is afraid; how do you know that it is really going to work? It's not perfect and they can still die. Maybe I just think differently.
Dr Topol: Clearly you are passionate about it.
Dr Esserman: Isn't that what women would want?
Dr Topol: You are asking the right questions and doing the right thing for each individual patient. That is why we wanted to recognize you as one of the most interesting people in medicine.
Thank you all at Medscape for tuning in for this One-on-One interview with a rebel who is, in a great way, shaking up medicine and breast cancer, and is much more than that.
