In her TEDWomen talk, Deborah Rhodes, a physician and researcher at the Mayo Clinic, describes a new technique for screening women for breast tumors, and how innovation can proceed by tailoring the test to individual characteristics — in the case of Rhodes’ MBI, based on the tissue density — and also about the politics that gets in the way of making those innovations. We caught up with her by phone to talk more about the politics of breast cancer and innovation. (This is Part One of our interview; Dr. Rhodes went on to talk about her work at the Panzi Hospital, which serves victims of sexual violence in the Democratic Republic of the Congo, and we felt it deserved a full interview of its own. Read Part Two, “I couldn’t turn away.”)
One of the things that jumped out at the beginning of your talk is when you said, “The breast is the most political organ there is.”
In some ways, being a political organ is a good thing, because it means you have a very strong base of interest, and that can serve a good cause. There is a stronger advocacy group around breast cancer than around any other type of cancer, or in fact any other health issue period. The Susan G. Komen Foundation is a wonderful example of grassroots advocacy becoming extremely powerful in changing the course of breast cancer research, and indeed the lives of women with breast cancer.
So, the advocacy group is powerful, it exerts a lot of political power, but that can also, sometimes, cause a very impassioned topic to be ruled by what people want and hope for, rather than necessarily by the precise science. When the United States Preventative Services task force recommended against mammography in women in their 40s, people were shocked, like “How could this happen? This has never happened before!” Well, in fact, the exact same thing happened in 1997, when the National Cancer Institute convened an independent consensus panel to look at all the mammography data and make recommendations. My medical fellowship director at that time, Leon Gordis, was actually the person appointed to be the chair of this consensus panel. At the end of the analysis the panel announced that the data did not support routine mammography of women in their 40s. He came back and he just looked disheartened, and he said, “It was literally like facing a pack of hungry wolves. ” They were vilified. This panel was vilified. There was a quote in The New York Times that said, this is tantamount to a death sentence for women in their 40s.
The director of the NCI, the very director who had convened the panel in the first place, held a press conference where he said, “It is my hope and expectation that the data will support a routine recommendation for mammography.”
Now that is a shocking statement. Here is a NIH-level scientist — career scientist — saying, “it is my hope and expectation that the data will show X”? The data show what the data show. The data should not be interpreted through the glasses of our hopes and expectations. And yet, this type of thing happens over and over and over again, because nobody wants women to die from breast cancer. But using a test that’s not well suited to discovering breast cancer in young women is not the answer.
What we need to do is find a better test for women with dense breasts. We need to stop debating mammography. Mammography has been debated, debated and debated to the point where the horse is dead. We have spent millions of dollars in this country debating what to do with mammography instead of innovating to find a better test for the women in whom mammography doesn’t work well. There have been six and possibly more meta-analyses of the mammography screening trials that have combined all the data to look for trends in the totality of data that were not evident in the individual studies. What’s fascinating is that each meta-analysis conclusion contradicts the one that came immediately before it in regard to whether we should screen women in their 40s. That’s incredible – analyzing the exact same data and reaching a different conclusion every time. And so what that tells me is that you can re-sift and re-analyze the data a million more times, but the only thing you can say at the end of all this is that the benefit of mammography for women in their 40s is not strong enough. And not just for women in their 40s, but for all women with dense tissue, because that’s what it ultimately boils down to is that mammography can’t reliably find tumors in dense tissue, so if you have dense tissue you need something else.
I hadn’t realized how much money had been spent on debating this. Do you have a theory of why this money hasn’t gone to innovation?
I do. That lies in this conundrum that exists around the mortality issue. When you’re talking about cancer, the only endpoint that matters at the end of the day is, ‘are lives saved?’ or ‘are lives extended?’ To demonstrate that Test A reduces mortality more than Test B requires a tremendously long period of time in the case of breast cancer, because most women don’t die of breast cancer. If you’re looking at a test to evaluate pancreatic cancer, it’s easy, because most people with pancreatic cancer die, and they die quickly. So, it’ll only take you five years to assess whether Test A is better than Test B. It takes twenty, possibly even thirty, years to address that for breast cancer, because most women don’t die, thank God, and some women who do die, die many, many years after their diagnosis. So it takes such a long time to demonstrate a mortality reduction. The shocking thing is that these mammography trials that keep getting debated and debated and debated — most of these trials were started in the 1970s.
So the problem is whenever a new technology comes around, the mammography mafia, as we call them, says, “Your test is no good, because you can’t demonstrate a mortality benefit.” Well, of course we can’t demonstrate a mortality benefit. Mammography’s been around since the 1960s; they’re the only ones who have a prayer of demonstrating a mortality benefit, because it takes that long to demonstrate.
What do you think the solution is?
First, we need to stop debating mammography and put our resources into developing and evaluating alternative screening techniques for women with dense breasts. MBI is certainly a very promising technique, and there are other promising techniques. Second, we need to accept an endpoint for success that is not strictly mortality-based. Although mortality is the most important outcome, there are intermediate outcomes that can serve as acceptable proxies for mortality. For example, instead of insisting that each technique must demonstrate a reduction in mortality from breast cancer, I believe it is acceptable instead to evaluate whether one technique can find tumors at an earlier stage – in other words, small tumors that have not spread to the lymph nodes. Third, there should be a collective effort among radiologists, breast cancer advocacy groups, and government health organizations to promote the implementation of the technique that demonstrates the most success in regard to this intermediate outcome. Right now, implementation of new radiologic techniques is very haphazard. And fourth, we need to choose something that is not only better than mammography in women with dense breasts and as safe as mammography, but also comparable in cost. Medical imaging companies are currently focused on very high-cost imaging techniques, such as MRI, which are these unbelievably complex, enormous, expensive machines; this is not an answer for a screening test. I mean, it’s perfectly good if you have a diagnostic dilemma. where you have a patient and you can’t figure out what’s going on and you can do this beautiful picture of their breast, but it’s not the answer for large-scale screening, for the 40% or higher of women that have dense tissue. It would bankrupt our health-care system. It’s just not a realistic or rational way to apportion our health care dollars. We need to find something that’s as good as MRI, or almost exactly as good, but much less expensive. That’s what I feel that we have developed.
It sounds like it was a personal choice of yours to not receive financial benefit from the discovery? When did you decide that?
Yeah, there are a number of factors. First, I was raised in an academic household. My father is a professor, and a scientist, and a scholar. His life is a tribute to ethical conduct and behavior in every way, in every detail. I wish I could give a TEDTalk on my father, because he is my absolute, uncompromising hero. In his work, he always does the heavy lifting for whatever project is at hand, but he never, ever does it for personal gain or recognition. He taught me that the best way to maintain your objectivity is to avoid even the perception that your judgment could be compromised.Now — and I want to be very clear about this — I’m not saying that the inventor of an innovative scientific device is not entitled to a patent on the invention. Of course they are. But I did not invent MBI. My brilliant collaborators, Drs. Michael O’Connor and Carrie Hruska, deserve the credit for the technical innovation. My role has been to partner with them in defining and developing the clinical uses of MBI, and for that it is best that I do not have a financial interest in the outcome.
The other thing I find fascinating about this is that it came largely out of a chance meeting with a nuclear physicist.
I have to say, my whole life has been a series of serendipitous encounters. Every important decision and outcome that I can point to in my life comes from having an incredibly blessed moment during which somebody shared their wisdom, or a story, or a piece of advice that I deeply listened to. For example, my decision to go to medical school. I was a history and literature major and was utterly lost after college as all my classmates headed into investment banking. I went to a job interview for a job I desperately wanted, with a foundation that provided aid to the elderly in New York, and the interviewer told me – after 2 hours – that he wasn’t going to offer me the job because what I really needed to do was to go to medical school. I was stunned. But he was very persistent, and here I am. After coming to Mayo, I wasn’t initially involved in any research. I told the story of one patient in my talk, but there were many others in a similar situation. I was really troubled about telling young women with very dense breasts, “Good news – your mammogram looks normal – come back in a year,” once I became familiar with the limitations of mammography in dense breasts. So after seeing the patient I mentioned in my talk, I was talking to a radiologist about it, and he said, “You need to meet Michael O’Connor?” So I did.
I’d never met him before. I’d never even heard of him before. And he was a cardiac nuclear physicist, he didn’t have any connection with the breast at all. I started talking to him about this clinical conundrum, and it was a rollerskate/key kind of moment. He really thought we could adapt this new gamma detector, but what was the best thing to adapt it for? And I realized this could be the answer for women with dense breasts. It looked like an erector set when we started. People would walk in the room and go, “You’re kidding me.” In fact, a women who now works for one of the companies that manufactures MBI unitstold us that she was with another imaging company years ago, and she was allowed to go in and take a look at our machine, and she said that their entire team just burst out laughing. And that’s the thing, people thought we were crazy. People were like, “Who do you think you are? The three of you, trying to suggest that you can do better than what we’ve been doing for thirty years.” That was the reception that we got everywhere.
Michael, Carrie and I are mavericks in our own way, and we don’t really spend a lot of time worrying about what other people are saying or thinking. There was never a moment when I said to myself, “Am I wasting my time?” I just had a very strong belief thatit was going to work. While there were certainly skeptics, we also had some powerful advocates. Frank Prendergast, a legendary researcher at Mayo, saw the potential of this from the very start and we would not have succeeded without his tireless voice on our behalf. Some extraordinary Mayo patients contributed funds to support our research – including a practicing attorney in her nineties whose belief in me is all the more inspiring because it is based on a lifetime of her good sense and judgment. The only time that I became discouragedwas was during the last two years when trying to get this work published. It has been frustrating. We endured a lot of rejections, in part because we had a lot to learn about analyzing and meticulously communicating the results of such a large clinical trial. In that, we had some important help from a very experienced radiologist, Wendie Berg. Yet I also feel that the world of medical journals is not set up to recognize and promote early-stage innovation from unknown entities – and, of course, true innovation often does come from outside the well known team of players. As I said in my response back to the medical editor of one of the journals from which we had received a rejection, “I must say that I am frustrated that the big journals don’t think this is worth publishing – a technology that finds 3 times as many cancers as mammography in women with dense breasts is less interesting than yet another epidemiologic study reaffirming an association between a risk factor and an obvious outcome.”
Where do you see this going forward?
The system is FDA approved, and two companies are selling the machines now. Which is good, but I still think that there needs to be some consistency in how we’re going to interpret these images and use these studies and to whom we’re going to offer them. All of these issues need to be worked out, so in one sense the cart is going before the horse a little bit. But it’s good that it’s at least becoming more widely available.
What we need to do, in order of importance, is we need a common lexicon so that all the radiologists worldwide have the same approach to image interpretation and use the same language. We also need to have a standard MBI training module, something the Mayo radiologists are developing which will be ready next month. Dr. Stephen Phillips did the pioneering work on the radiology side for MBI, and that work is now being continued by Drs. Amy Conners, Bobby Maxwell, and Cindy Tortorelli.
Number two is we need to replicate our findings with our very low dose of radiation, which we’re actively in the process of doing now.
Third, we need to do a multi-center trial. We need to show that this is not just a lucky phenomenon unique to Mayo Clinic. We’re working on partnering with a number of radiology centers. But the price tag on doing this trial is going to be somewhere in the range of $15-million. We are hoping that a foundation will support us to do this in partnership with the National Cancer Institute, but we do not have any of these arrangements yet in place. After that — one thing that we’ve discovered, which is just fascinating, is that you can take, say, five women whose mammograms look absolutely identical, with the same degree of density, yet the MBI images might look very different. The MBI imagecould range from almost an inverse negative uptake pattern — where it looks like an absence of any uptake — to increasingdegrees of diffuse or patchy tracer uptake in the breast.
When a tumor is present, it soaks up the tracer like a sponge, and you get this intense, focal white area on the MBI image with very little uptake elsewhere in the breast – that’s why it’s so easy to spot tumors on MBI. But when a tumor is not present, the tracer uptake can range from a very homogenous pattern throughout the breast to areas of patchy or diffuse uptake. We suspect that the women with the highest amounts of this patchy tracer uptake are really the women at highest risk for developing breast cancer. Why? Because the cells that take up the tracer are the ones in a highly metabolic, proliferative state, and this highly proliferative state is what can lead to tumorigenesis. In contrast, the women who have dense tissue on their mammogram, but have this absence of uptake on the MBI, those women may well beat low risk for breast cancer because their tissue is effectively scarred down, inactive, non-proliferative. Two women may appear to have identical density on their mammograms, but if their MBI images look very different, the implications in terms of their breast cancer risk may also be very different. So the upshot is, while mammographic density is known to be a powerful predictor of breast cancer risk, we think MBI density may bea far more powerful predictor. What we might have on our hands is the a precise, individual predictor of breast cancer risk.
Now that is a revolutionary paradigm. I have to be absolutely candid in saying that we do not have proof of this whatsoever, but I think there is promise.
We also use MBI for a lot of diagnostic work. So if you’ve already been diagnosed with breast cancer, then MBI is very useful for looking at the breast tissue to make sure that there aren’t other areas of breast cancer. So, in about 5-10% of patients who do MBI after a diagnosis, we find additional areas of cancer, which often influences their surgical options.
And we’re also using MBI in assessing response to chemotherapy. So, we give chemotherapy, and then we do an MBI, and if the tumor hasn’t significantly shrunk, then we know it probably isn’t responding well to that particular regimen of drugs. It is possible this could be used to tailor individual drugs to individual patients in the future.
That’s a fantastic research program.
Oh, we have a lifetime of work ahead of us. This could and probably should be my full-time job, but only 15% of my time is devoted to this — time that Susan G. Komen supports. The rest of my time I’m trying to maintain a busy clinical practice. So that’s another reason why the research gets done more slowly than I wish.
— Interview by Ben Lillie