Venture Partner Perspectives: Dr. Avrum Bluming & Dr. Carol Tavris (Co-Authors of ‘Estrogen Matters’)
Welcome back to FundRx Venture Partner Perspectives, created to share the knowledge and opinions of a diverse array of healthcare clinical and industry experts. We hope these interviews spur further thought and potential innovation.
Today we’re featuring two distinguished guests, Avrum Bluming, M.D., and Carol Tavris, Ph.D. Dr. Bluming is a hematologist, medical oncologist, and emeritus clinical professor at USC. Dr. Tavris is a social psychologist, a contributor to the WSJ, NYT, and LA Times, and the co-author (with Elliot Aronson) of Mistakes Were Made (But Not By Me).
They recently co-authored Estrogen Matters, evaluating and presenting evidence on why taking hormones in menopause can improve women’s well-being and lengthen their lives — without raising the risk of breast cancer. For additional resources, check out their excellent long-form interview on Dr. Peter Attia’s ‘The Drive’ podcast, and their interview with genneve CEO Jill Angelo and genneve Director of Health and Ob/Gyn Dr. Rebecca Dunsmoor-Su.
**This interview has been edited and condensed for clarity.**
Dr. Chris Duff: After the release of Estrogen Matters, can you describe the process of promoting a book with content deemed as belonging to the ‘medical minority’? How are you working through the challenges associated with that?
Dr. Avrum Bluming: You would have to know that Estrogen Matters wasn’t the start of this campaign. It evolved after 25 years of working with symptomatic postmenopausal women who had been treated for breast cancer. Since 1993, I have been publishing articles dealing with the benefits and risks of administering postmenopausal hormone replacement therapy (HRT). I have reported results of a study we did giving HRT to women with a history of breast cancer annually for 14 years and presented results of that study at the 1997 plenary session of the American Society of Clinical Oncology annual meeting in front of 8,500 oncologists.
Carol and I have been publishing articles on HRT since 2009 in peer-reviewed medical journals. After the book was published, I spoke to the Royal Society in England about our findings and overall conclusions.
Dr. Carol Tavris: Avrum’s work in trying to understand the benefits of estrogen — and in particular his efforts to overturn the deeply entrenched paradigm that estrogen causes breast cancer — has been a persistent effort for many years, as he has gathered empirical evidence from decades of studies around the world, as well as doing his own studies.
But in 2002, the Women’s Health Initiative (WHI) — which seemed to many to be the gold standard, scientifically best method of research — claimed that they had found that estrogen causes breast cancer. They reported this in advance of the JAMA publication, with a press conference that generated alarmist headlines — naturally frightening millions of women and their physicians.
Up until 2002, the consensus was that HRT was safe and beneficial for the great majority of women, but the WHI brought that idea to a screeching halt. Ever since, Avrum has been working hard to explain what was wrong with the WHI — scientifically and medically. That’s been the uphill battle.
Chris: The last chapter of Estrogen Matters eloquently states the inherent bias natural to human beings and the difficulty in shaking beliefs inherent to ingrained thought processes. Even with what appears to be a recent relaxing of the anti-HRT rhetoric, do you have a rough estimate of the pro/anti-split of clinicians regarding HRT use in the U.S., or in other countries?
Dr. Bluming: I think you have to determine first who’s casting ballots. Our book has been endorsed by a powerful cadre of opinion leaders, including a former director of the National Cancer Institute, former editor-in-chief of The New England Journal of Medicine, and a former president of the Royal College of Physicians. The North American Menopause Society, and national menopause societies in 31 other nations from Thailand to Israel, have issued position papers in support of the benefits of HRT throughout a woman’s life span, concluding that there is no evidence for the current advice that if a woman must take estrogen, it should be “the smallest dose for the shortest time.” That’s a heartening development.
There are many gynecologists around the world who have never doubted what we wrote in the book. But most doctors, as you are well aware, are bombarded with confusing and sometimes misleading information. Over 2,200 English-language medical journals are published every week. There’s just no way one can often do more than read the conclusions as summarized in the abstract and accept them uncritically. That’s why I think the majority of physicians take the WHI’s claims as gospel, concluding that HRT is too dangerous to prescribe to their patients. Even the Cochrane Database analysis, which is usually a superb assessment of research on a particular subject, came out against hormones — but they based that conclusion almost exclusively on the flawed WHI study. That is why we spent so much time challenging WHI’s methods and claims.
Dr. Tavris: Avrum has been getting a steady stream of emails and messages from women who have read the book or heard our podcasts, saying, “My doctor won’t prescribe HRT for me anymore, even though I’ve been on it for years.” One woman said her doctor wouldn’t renew her prescription because HRT could cause dementia. She said, “I’m 78 years old; I’m running a company! But it’s going to cause dementia?” We’re getting many responses from women who are immensely grateful for the information that validates their personal experiences — the benefits of HRT — but the subtext of their message is, “My doctor is afraid of HRT. My doctor won’t prescribe it.”
Dr. Bluming: And these letters are coming from all across the United States, from many countries in Europe, and as far east as Chiang Mai, Thailand.
Chris: What would you recommend to women in a more rural environment, or where there are just not many choices in providers, or where there is a pervasive cultural, anti-HRT viewpoint? Is it possible to order HRT online? How might they possibly receive treatment that may be indicated for them?
Dr. Bluming: To be clear, we are not recommending that women order HRT online and take it simply because we say so. As a note, when you walk into the Royal Society, the mantra on the archway over the front entrance is nullius in verba, which means, “Take nobody’s word for it.” And that includes us.
We want women to be empowered to talk about this issue with knowledgeable physicians to decide on what’s best for them and not simply to order it online. One of the projects that we’d like to see done is the creation of an international list of physician consultants whom women can see. We have letters from women in Manhattan (which isn’t exactly an under-represented medical community) who say they can’t find a doctor willing to prescribe HRT. Well, we know doctors in Manhattan and we refer them there. Clearly, it’s harder in some other communities.
We’d love to see an interactive database of physicians we can identify and vet who would be legitimate consultants on HRT. We were contacted by Jill Angelo, who successfully marketed the XBOX for Microsoft. Jill has set up a website called genneve, where she’s trying to do just that — create a network of physician experts who can be contacted around the world.
Chris: It’s one thing for scientifically-adept clinicians to be led astray, but in cases where there aren’t books like yours available, what do you recommend to patients who are overwhelmed by conflicting reports and anxiety-producing headlines?
Dr. Tavris: That’s an important question: how does a patient know that his/her physician is up-to-date on what the latest research shows? Many physicians don’t have time to read to keep up with the latest evidence, just like all of us in our everyday lives. We can’t stop to check everything we believe and make sure it’s still empirically supported. And physicians already have so many time constraints and pressures on them.
When the WHI first came out, I was delighted to learn that my gynecologist had actually bothered to read the published study in JAMA — not just the press release that scared everyone — and he saw that the findings weren’t statistically significant. But he was one of few. Most gynecologists, he said, got their information the way everybody else does: from headlines and the newspaper reports and brief medical updates. So what patients have to do is to become better advocates for their own health. They need to get second and maybe even third opinions. They need to make sure that their physician is up to date on what the most current research suggests for their particular problem. I say this knowing this process can be difficult and anxiety-producing for patients.
Dr. Bluming: There is an online service called UpToDate, which can be used by physicians and patients. It is regularly updated by respected experts. It is very expensive, but it can be accessed through institutions, and that’s at least something patients can consider.
Chris: What are 2–3 additional studies you’d most like to see done in the HRT space?
Dr. Bluming: Unfortunately, it is unlikely that the government or industry will ever fund another costly WHI. Epidemiological studies are often flawed and subject to “uncovering” correlations that are spurious or simply not strong. So I am looking for leads that can shed better light on how estrogen works at a fundamental biological level.
One lead that we’re following — and it’s still early in its development — is work by Dr. Joanne Weidhaas at UCLA who, in 2008, identified a gene that she called the KRAS-variant. This gene is an inborn, congenital abnormality, and appears to be much more common than the BRCA gene, which is more well known. Joanne has found that mice that carry this gene develop breast cancer when their normal level of estrogen declines. And so she looked at human studies and found that breast cancer appears to develop most often in perimenopausal and early menopausal women when estrogen levels decline. “Decline” is too subtle a word. Testosterone in men declines at a slow rate, but estrogen in menopausal women rapidly plummets to one percent of the normal circulating level. If a fall in estrogen is going to be associated with the development or progression of breast cancer, that would be the time you would see it.
We are going to be working with Joanne because I have a large database of patients with breast cancer who subsequently were given HRT. Some of them had a recurrence of breast cancer, though not at a higher rate than similarly treated women who didn’t get HRT. We’re getting tissue from these women and Joanne is going to run analyses on them and to look particularly at the women who stopped HRT because of anxiety (caused by the WHI’s claims) and subsequently relapsed, to see whether or not they carry this KRAS gene.
Chris: What does each of your current day to day’s look like, and what’s most exciting to each of you right now?
Dr. Tavris: We are reaching out to other experts and interested parties, writing op-eds, giving lectures, and doing podcasts. Our website has been doing well. Because we did not get the reviews from major media that we expected, getting the word out about this book is becoming a ground-up, woman-to-woman, doctor-to-doctor kind of news network. Websites have picked up the book and have been advertising, recommending, and promoting it.
Dr. Bluming: We cheer each other up by recognizing first that we’re trying to light small fires around the world. We would like women to acquire the best information available in making medical decisions, share that information, be informed about what we all know and what physicians should know, and not simply be put off by dismissive statements on the part of doctors. The message we seek to convey is that the more you know, the better a proponent you will be for your own optimal health care, and more importantly, the more you know, the less you fear.
Dr. Tavris: Of course, we both recognize that if a woman goes in to see her gynecologist or oncologist waving our book and saying, “’Look! Don’t take my word for it! These authors even conveniently summarize the 10 major points about the WHI that show how flawed it was!’ is the doctor going to say, ‘Why thank you so much, Ms. Annoying Patient, for this information that I don’t agree with?’” Probably not, unless Ms. Patient happens to have an open-minded physician who is willing to reconsider what he or she thinks they know. We realize that’s a challenge. Most physicians don’t want to hear from their patients with questions that are provocative or counter to what they believe. That’s why our book is written both for physicians and for patients.
Dr. Bluming: I’ve debated opponents before we wrote the book. One highly regarded epidemiologist and I debated in front of both a medical audience and in front of a lay audience. As I always do, I laid out the extensive evidence of HRT’s benefits and waited for his response. In frustration, he turned to the lay audience and said, “Look, if all you care about is looking good, feeling good, and living a long time, then take estrogen.”
Chris: What else are each of you most excited about in terms of the pipeline of innovation in your fields?
Dr. Bluming: Clearly, AI is exciting for all of us. The problem in medicine is that if AI, like the Cochrane analysis, is based on flawed data, or a flawed belief in what causes cancer — or what the disease even is — the result may not be valid. I’ve been a medical oncologist for over 50 years, I’m an emeritus clinical professor of medicine at USC, and I still don’t know what cancer is. I’ve treated tens of thousands of patients and most of the data we use to treat are based on trial-and-error studies, which don’t require a basic understanding of what cancer is. That’s why I am especially fascinated by creative new directions in medical oncology.
One of the most exciting areas is the use of CAR T-cells to help immunize an individual against his or her own tumor, especially in lymphomas. Unfortunately, a CAR T-cell treatment- where you take out the patient’s T-cells, incubate them with tumor antigens, and reinfuse them- is running something like $350,000-$425,000 a treatment. And while you are clearly curing some people who would not be cured, the exact mechanism by which this is working isn’t completely clear.
What I find most interesting about that work is some patients who are now immunized against their tumors go into remission and then develop a biopsy-proven recurrence. Sometimes the biopsy-proven recurrence disappears without additional treatment, suggesting that you truly have done something to make this person relatively immune against their cancer. But the whole field of tumor immunotherapy, suggesting that cancer is a foreign invader that has to be cut out, or radiated out, or poisoned out of existence, is fallible. We need better, more creative ways to approach these problems, which probably are different from tumor to tumor.
Another good example of where the field is starting to go is the treatment of acute promyelocytic leukemia (APL). As you may know, this is one of the hardest malignancies to treat. Chemotherapy for this disease is responsible for perhaps a two-percent response rate and almost never a complete response rate.
Years ago, several investigators found that immature cells multiply rapidly. The more mature a cell is, the less rapidly it multiplies. With APL, where the cells fill the bone marrow and populate the bloodstream, what was identified was a maturation arrest, so that the cells were blocked from progressing beyond the promyeloblastic phase; like all immature cells, they continued to multiply rapidly. That maturation arrest was found to be removed by administering trans retinoic acid. If you add trans retinoic acid to promyeloblastic cells in culture or inject it into a patient with the disease, you remove the maturation arrest, the cells mature into normal myelocytes, and then granulocytes… and the disease evaporates.
That kind of research is where we’re starting to go. APL is only one example of malignancy, but that kind of understanding of what causes it is going to propel advances in this field that we haven’t dreamt of until recently.
There are findings in the medical literature that are not mainstream but are accepted by respected investigators. For example, if you take a toad bladder cancer cell and implant it in a toad embryo, the cancer cell takes over the embryo and the embryo dies. If you take that same cell and implant it into the same identical embryo but a half centimeter closer to the yolk sac, that same cancer cell is incorporated into the embryo and the embryo is born as a normal toad and never develops cancer.
Likewise, if you take patients with infectious mononucleosis and biopsy their lymph nodes and give them to 10 different pathologists to read, the pathologists will identify all of the criteria that allow you to say this is a malignant lymphoma. But it’s not a malignant lymphoma, it’s infectious mono. And in almost every case, these people get better.
Findings like these aren’t being adequately investigated because they don’t fit into most researchers’ paradigms of what cancer is. But they are leading us into a much more exciting direction in oncology.
Dr. Tavris: I would add, as the social psychologist partner here, that my interest has been on what it takes to get people to give up entrenched beliefs, including their paradigms of what cancer is and how to treat it. If ever there were an area where it is essential for researchers to be open-minded and accept evidence that disputes their beliefs, this would be it. But social psychologists have identified the cognitive mechanisms that make it difficult for people to change their minds. In fact, the smarter that people are and the more self-assured they are of their competence, the harder it is for them to say, “I was wrong; time to change directions.”
For example, Ignaz Semmelweis’ fellow physicians thought he was an idiot for suggesting that they should wash their hands before delivering babies — a simple intervention that would keep women from dying of childbed fever. Semmelweis didn’t know about germs, but he observed that the doctors were attending their patients straight after conducting autopsies on their patients who had died the day before, and hypothesized that they were carrying a “morbid poison” on their hands from the morgue to bedside. Ergo, just wash your hands! Did the doctors thank him? No, they said, in effect, “Get lost, Ignaz. You’re crazy. You think we are causing the deaths of our patients in labor?”
These physicians were not stupid, foolish, or cruel. On the contrary, it was precisely because they saw themselves as good, competent, compassionate physicians that they didn’t want to believe they had been doing something to harm their own patients.
That phenomenon continues. The doctors who were continuing to do radical mastectomies long after it was known that lumpectomy was as effective, and certainly not disfiguring, likewise just found it hard to give up a deeply felt belief that removing a woman’s entire breast was the right thing to do to save her life. So we have both a medical challenge and a psychological challenge, if you will, in getting physicians to give up old ways of thinking and be open to new methods and ideas.
Chris: What are your go-to resources to stay up to date about your field and healthcare in general?
Dr. Bluming: I get newsletters from the American Society of Clinical Oncology, and I get Oncology Times, which is a throw-away journal that wonderfully summarizes research that I can then follow up on when I come across something that’s particularly interesting. If I read anything that’s a clue, I go to the National Library of Medicine. UpToDate is useful when I need a quick summary of a disease with which I’m not familiar.
Dr. Tavris: As a psychological scientist, I read the journals of the Association for Psychological Science, many of which have sections on health communication, cognitive dissonance, biases in thinking and perception, communication, and so forth. In my book with Elliot Aronson, Mistakes Were Made (But Not By Me), we draw on research on persuasion and influence to show how to avoid communicating in a way that makes the other person feel ignorant, stupid and wrong, but in ways that might get them to be more open to change. In today’s polarized culture, of course, this is a special challenge!
Chris: What is the most rewarding aspect of your current role, and what advice might you give young people interested in science, or even mid-career scientists, to gain a leg up and contribute in a meaningful way?
Dr. Tavris: We love what research has to offer toward improving human health and well-being in our respective fields. Of course, both of us have discovered over the years that, unsurprisingly, it is not often the case that people say, “Why, thank you so much for this information which disconfirms everything I have believed for the last 22 years.” That is why I advise young researchers that while it is a great time to be a scientist today, it is also a difficult time: Scientists have to battle issues arising from the blurring of industry and independent research, including conflicts of interest, funding constraints, and external pressures, all of which can taint the questions you ask and the answers you get. Doing good, creative, quality science — where an investigator gets to go in the direction that he or she wants — is in some ways harder to do, and more important to do.
I can’t make this point strongly enough. It can be difficult for young scholars to take the road not commonly traveled — to ask critical questions of establishment assumptions, to investigate possible causes of cancer formerly unthinkable — yet the process can be so exciting, and the results, like the simple discovery of trans retinoic acid for APL, astonishing and unexpected.
Dr. Bluming: I’d like to add two points. First, on the important matter of conflicts of interest, we get absolutely no support or money from the pharmaceutical industry. Estrogen Matters was written out of conviction, not for any profit motive.
Second, as a physician you go to bed every single night with the knowledge that in some small way, you have made a difference; you’ve helped countless lives and you’ve saved lives. That is an incredibly rewarding feeling. In addition, you are constantly challenging yourself and other people, which is also an exhilarating (and sometimes frustrating) way to spend your time.
When I spoke at the Royal Society in England, I quoted Theodore Dalrymple, who said, “Information without perspective is just a higher level of ignorance.” And providing perspective is what we physicians try to do. We belong to a fraternity of people holding hands around the world, working together, regardless of political bias, to make a difference. I can’t think of a more satisfying way to spend time.
Chris: Where can people stay up to date about your latest work or potentially connect?
Dr. Tavris: You’ll be able to contact us at estrogenmatters.com, and you can find the latest information about our podcasts, reviews, forthcoming lectures, and updated research.
Dr. Bluming: The updates are important since there are advances in the HRT field all the time and we don’t want to be limited by a publication date on the book. We welcome comments from physicians and laypeople alike.