Expert interview with Daniel Fleming Hayes, MD, on biomarkers for breast cancer

Posted on July 01, 2020 –

Dr. Hayes is Professor of Breast Cancer Research and Internal Medicine at the University of Michigan Rogel Cancer Center, Ann Arbor, MI. He is a world-renowned medical researcher and oncologist in the field of breast cancer. He has been involved in cancer research and treatment since 1982. Dr. Hayes is a specialist in translational research, an area of research that moves pure scientific discoveries from the laboratory to the clinic. He is a pioneer in tumor biomarker research and has largely contributed to the discovery and development of biomarkers currently used to guide the treatment of breast cancer patients. Dr. Hayes has played a critical role in setting up guidelines to standardize diagnostic tests to ensure that every cancer patient can be tested in a consistent manner across the US. His achievements in translational medicine have been recognized by the prestigious Gianni Bonadonna Breast Cancer Award (2007) from the American Society of Clinical Oncology (ASCO). In addition to his research, he plays leadership roles at ASCO and was elected ASCO President for a three-year term from 2015 to 2018. In this interview, Dr. Hayes takes us back to the discovery of the first biomarker for breast cancer. He tells us how combining laboratory discoveries with clinical observations and the development of guidelines can lead to reliable diagnostic tests that help treat breast cancer patients. Then he gives us an outlook on what the future of biomarker discovery holds. Disclosures: Dr. Hayes receives research funding from Menarini Silicon Biosystems and CELLSEARCH®. He is the named investigator on a patent related to circulating tumor cells and receives royalties from CELLSEARCH®.

Could you tell us about your research interests?

My research interests are focused on breast cancer, more specifically on tumor biomarkers and translational medicine. Fundamentally this means identifying, testing and validating things that help us make more precise oncology. Precision medicine and personalized medicine are on track now and you cannot do that without biomarkers.

How would you define biomarkers?

Biomarkers are things in a tumor that help doctors guide the treatment of cancer patients, either by determining prognosis (perhaps a patient does not need therapy) or by determining whether a treatment is likely to work. For example, a drug may work in some people but not in others with the same cancer. Biomarkers can help doctors find out in which people the drug will work or not.

What are some examples of biomarkers for breast cancer?

Estrogen receptor and human epidermal receptor type 2 (HER2) are two good examples. In my opinion, estrogen receptor is the first breast cancer biomarker discovered. And HER2 is a biomarker widely used to treat patients.

How estrogen receptor was identified as a biomarker is an interesting story. It takes us back to the late1890s and to Sir George Beatson who was a surgeon in Glasgow and also raised dairy goats. He had learnt from farmers that dairy animals keep lactating when ovaries are removed. Sir George Beatson also took care of patients with breast cancer and he hypothesized that there must be some connection between the ovary and the breast. He thought that was neurologic because people did not know about hormones at this time. He took the ovaries out of three young women who had breast cancer. He was extraordinary lucky. A) The three women were menstruating. Had he done it in older women it would not have worked. B) At least two of these women had what we know now as estrogen receptor-positive breast cancer, because two of them responded but the third one did not. He monitored what happened to their breasts. He described first of all what we call now, locally advanced breast cancer, and second of all what we call, response. He did not have the semantics in those days. Ovaries removal became the therapy of choice for breast cancer. By the early 1970s, the observation was that ovary surgery was not working in everybody to stop breast cancer. In 1975, Elwood Jensen identified and cloned something called the estrogen receptor, out of a rabbit uterus, not out of a human breast. Then the late Bill McGuire, and also Marc Lippman, suggested using estrogen receptor as a marker to be more precise in the way we treated breast cancer. McGuire demonstrated that patients who had breast cancer negative for estrogen receptor did not respond to the treatment, while patients positive for estrogen receptor had a pretty good chance of experiencing a response. In other words, estrogen receptor is like a mark, a label. Breast cancers with that mark may well respond to treatment, those without do not respond. Doctors can find out which patients will respond to treatment by looking for this mark on the tumor.

How have things changed since you started working in this field? Were there any particular marking moments?

There are two aspects, the technical changes and the standardization of the tests used to detect the biomarkers. The molecular biology revolution started in the 1970s and 80s with the understanding of DNA, RNA, proteins, how to isolate them and how to analyze them. Then 20 years ago, we started to learn how to do high throughput proteomics, genomics, etc. We generated enormous sets of information to develop markers that could be quite helpful to treat cancer patients and breast cancer patients specifically. Over the years we have learnt how to take a molecular biology discovery, make it better with clinical observations and develop guidelines to have standardized tests to help treat breast cancer patients.

If we go back to the original assays for estrogen receptor, estimation of the amount of estrogen receptor in tumor tissue was performed by radioligand-binding tests. These tests are very difficult to do and the results were not as precise as people would have liked. The development of antibody work – monoclonal antibody for which César Milstein won the Nobel price in 1975 – allowed people to do another type of test called immunohistochemistry. Antibody-based tests are now the standard of care.

Nevertheless, for many years, the way biomarker detection tests were done was widely disparate. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) were developing guidelines on how to standardize biomarker detection tests without talking to each other. One of the things I am the most proud of is to have helped put together a joint committee between these two organizations to develop guidelines on how to do the test for the detection of HER2 in breast tumors initially, then for estrogen receptor, about 15 years ago. Now the way the tests are done is standardized, and we have updated those guidelines 2-3 times already. A patient who comes to be treated in Northern Michigan can have the same kind of results as the patient who comes to Ann Arbor because the tests are standardized. That is a fundamental change in the 35 years I have been in the field.

For estrogen receptor, it took 30 years to go from a really good idea, to the molecular biology that allowed us to identify what the marker was, to the technology that allowed us to make the marker better, to the guideline panel that standardize the way the assay is done so that all patients across the US can have the same kind of results.

The same story could be told for HER2 although the timeline is shorter.

What about BRCA1/2 breast cancer patients?

We can exploit abnormalities in the BRCA1/2 genes in terms of treatments. And now it has been pretty well demonstrated that PARP inhibitors work quite nicely in patients with BRCA1/2 mutations, at least in terms of metastatic disease – the adjuvant trials are ongoing. People are working hard to make sure that the tests for the detection of BRCA1/2 are standardized. It is a sequencing test, which is harder to mess up than antibody-based tests. We want to be right about what we tell the patient and we do not want to overtreat or undertreat people. The observation that BRCA1/2 patients respond to PARP inhibitors is leading to better outcomes for breast cancer patients. Again, we have learnt about BRCA molecular biology and the associated clinical outcomes, developed a drug for BRCA-related cancers and a test for the detection of BRCA mutations.

In recent years, we have heard about using liquid biopsies for cancer detection and monitoring. You have done a lot of work in the field of liquid biopsies. Can you tell us more about it?

I started working on circulating biomarkers – biomarkers found in blood – when I was a fellow at the Dana Farber Cancer Institute in the early 1980’s. I was assigned to a laboratory sort of against my will that was doing molecular pharmacology, which I did not like. However, my laboratory chief, Dr. Donald Kufe, put me on a collaborative project on breast cancer with a friend of his, Dr. Jeffrey Schlom, from the National Cancer Institute, and told me “I want you to find circulating markers in breast cancer”. “How do I do that?” I said. Ultimately we discovered circulating MUC1 and developed the CA15-3 assay for it, and it is now used around the world to monitor metastatic breast cancer.

The term “liquid biopsy” was first coined in 2009-2010 by Klaus Plantel from Hamburg to refer to any circulating marker that could be used to help care for patients with cancer, including proteins, nucleic acids, and circulating tumor cells. He is a giant in the field. Anything that comes out of a blood draw or urine is a liquid biopsy. Can we use this for screening healthy people? The closest is the prostate specific antigen (PSA), but it is not perfect.

More recently, the term liquid biopsy has been appropriated mostly to refer to circulating cell-free tumor DNA (ctDNA). There was a study published a month ago that looked at using liquid biopsies for cancer screening. It is a hybrid assay that measures circulating tumor DNA and tumor associated proteins in the blood. They asked all the tough questions and it is a very nice proof-of-principle study, but did not establish the use of ctDNA as a routine strategy for cancer screening. As for now, we do not have a liquid biopsy that tells a woman what to do in terms of treatment. More work is needed.

Where do you see the field going in the future in terms of biomarkers? What are you looking forward to?

Biomarkers from liquid and tissue biopsies should become complementary! Everybody wants one or the other, but the two categories should be complementary. With tissue biopsies, you get information on a lot of cells, in one organ. It is very good statistically but inform only on one place. You do not get information on other organs and it is in practice not feasible to do several organ biopsies or to do them serially. Liquid biopsies should give you information on the entire body and they can be more easily repeated in time in serial blood draws. In the long run, we need to find out which of these will give you a global picture of what is going on in the cancer.

We are trying to design new ways of getting more cells out of the blood for liquid biopsies. We have been working on a wearable device to capture circulating cancer cells to serve as biomarkers to monitor disease status. This is an exciting advance!

Thank you!

Expert Interview with Professor Jack Cuzick, PhD, on medicines for the prevention of breast cancer

Posted June 03, 2020 –

Professor Jack Cuzick is the Director of the Wolfson Institute of Preventive Medicine and Head of the Centre for Cancer Prevention in London, UK. He is a pioneer in the field of cancer prevention. His work has played a vital role in bringing the drugs, tamoxifen and anastrozole to breast cancer prevention. Over the years, he has also perfected mathematical models to measure an individual’s risk of developing cancer. In recognition of his contribution to the field of cancer prevention, he has received multiple distinguished awards and has been elected a Fellow of the Academy of Medical Science, a fellow of the Royal Society and also appointed a Commander of the Order of the British Empire by the Queen. In addition to his research activities, Professor Cuzick dedicates his time to increasing awareness about cancer prevention so that more individuals can benefit from it. In this interview, Professor Cuzick takes CPI’s readers through his professional journey, discusses challenges associated with developing cancer preventives as well as future opportunities in cancer prevention.

 

Professor Cuzick, thank you for being with us today. Please, could you tell our audience about your career path and how you became interested in cancer prevention research?

Although I was trained as a pure mathematician, I have always had an interest in applied activities. My undergraduate degree is in mathematics and my PhD is in theoretical probability theory. After my PhD, I took a job in the Statistics Department at Columbia University in New York. I then went to work with Richard Peto in Oxford, originally for just a year, to do some work on real clinical trials and add more experience to my theoretical work. I liked the challenges in the real clinical trials more than the theoretical ones. So, I stayed on in Oxford for 5 years before coming to London, working on a range of clinical trials and related issues. I always liked to sit at the border between 2 subjects, and here I was between mathematics and medicine. I was also interested in epidemiology. At the boundary between epidemiology and clinical trials, there are prevention trials, which combine a need to understand risk factors for a disease and clinical trials methodology. This is a how I got where I am now.

What was the first clinical trial you were involved with?

The first clinical trial I was involved with was coordinated by the Medical Research Council at the Marsden Hospital in London. We did some of the early trials for the treatment of multiple myeloma, a type of cancer of blood cells like leukaemia. These trials offered a great opportunity to learn more about the natural history and causes of this cancer. We were the first to clarify that radiation is an important risk factor for multiple myeloma, and that this cancer probably also has to do with animal viruses, because those who worked in agriculture had a higher risk. That was one of the early links between clinical trials and epidemiology that stimulated me to continue to work in this area.

What achievements are you most proud of so far?

The one I am the most proud of is the first IBIS trial. Against all odds we got the drug tamoxifen to be used as a treatment for prevention. We had any number of obstacles that almost made it impossible to do this work. There was a study in which researchers had chosen to give tamoxifen at high doses to rats and found that the rats would get liver cancer. Even though millions of women who had taken tamoxifen at standard doses had no increased risk of liver cancer, there was a general reluctance to offer healthy people any kind of preventive therapy. The fact that we pushed through and got this study done and carried on to do the long term follow up was a great achievement. Recently we published that the benefits of taking tamoxifen for 5 years are continuing for at least 20 years. Of course we will continue to follow the subjects for another 10 years to document the extent of long term protection.

What are the challenges associated with running cancer prevention clinical trials?

One of the biggest challenges in running any kind of trials is the extreme bureaucratic complications that are now imposed. For example, when we ran IBIS-1, we were allowed to label the drug for our 7000 patients ourselves. We had a well-defined and controlled procedure. Unfortunately, all the labeling has now to be done by a company that charges £15 (~$20) a label. We have been trying to run big trials to test the cancer preventive effect of aspirin. With the price of the label, it makes drugs like aspirin, where the part of drug is £0.25 ($0.32), really expensive and the trial impossible because of the cost. This is an example of the bureaucratic requirements are inhibiting the ability to run large-scale public health trials of drugs that are not that expensive. An organization based in Oxford, has been set up (MoreTrials – see www.moretrials.net) which now has support from the Gates foundation and Wellcome Trust to address these issues. It lobbies to get good clinical trial practices reformulated, especially for trials that are not commercial and are using readily available inexpensive drugs. It would be a major breakthrough if we could get more rationale regulation of trials. No one is arguing that you don’t need to be careful with trials, but there are silly things that make trials impossible to do and are not in the patient’s benefit, because of the excessive bureaucratic requirements.

How difficult was it to recruit patients for the trials?

Tamoxifen got a bad start in the United States. There was a certain amount of controversy with Bernie Fisher, which had nothing to do directly with tamoxifen but made the legislators concerned about these trials. And tamoxifen got confused in the popular press with taxol, which is highly toxic. There was this widespread belief that tamoxifen is far more toxic than any of the data actually showed. Our trials also showed, and that is still not widely appreciated, that the common side effects, for example, the menopausal symptoms in early post-menopausal women or muscular skeletal aches and pains are extremely common even in the absence of a treatment. An example I like to quote is in IBIS-2 with anastrozole. We offered anastrozole for 5 years and 64% women complained about muscular skeletal aches and pains. This sounds terrible until one looks at the placebo arm, in which participants have no treatment, and yet 58% of the women complained about the same side effects. There was a real increase in side effects but the real increment is about 8% and not 64% as sometimes suggested, esp. by those who don’t realize this is a common event in the general population of postmenopausal women. This has been a real concern, as people believe that the side effects are much worse than they are and in fact most have nothing to do with the drug. These are just symptoms that people have at that age. The expected benefits clearly outweigh the side effects for anyone who would be considered at sufficiently high risk to take it. General Practitioners also need to be made more aware of the facts regarding risks and side effects. In many cases in our trials, women go to the specialist and are recommended to take preventive drugs like tamoxifen or anastrozole. Then they talk with their GPs who are not expert in the subject and the GP convinces them not to do it because of concerns of the side effects, which are largely exaggerated.

How can we communicate better with patients and doctors?

We have been working with a behavioral psychologist trying to figure out to deliver the true message about preventive therapies. Cardiologists have been successful at this for some time now and, but of course, their drugs have very few side effects. There is a general fear to take drugs that prevent these cancers.

Better communication is the key.

Yes, and it is our job to that. I now try to spend more of my time figuring out how to get preventives used than discovering new preventive treatments. There is a lot to be done here.

Prevention trials are long and difficult by nature. What are your thoughts about surrogate endpoints? Is there an ongoing effort to develop biomarkers to predict the drug response earlier within the treatment?

Because of the cost, large trials are not being done as much as they should be. Surrogate endpoints, if they are reliable, are the way to go forward. But good ones are really difficult to identify and validate. Reduction in breast density with tamoxifen seems to be a reasonably good predictor of a lowering of subsequent risk, but some uncertainty remains. Another way of finding out who is likely to respond to preventive treatment is the “no-pain-no-gain result”. Women who have endocrine based symptoms seem to respond better to the drugs. These symptoms may be a measure of activity of the drug for the specific person. Nobody has yet developed this approach well enough so that it can be reliably used. We are desperately looking for markers who can help us monitor response. One of the big additions to improving our ability to assess risk is adding a SNP/polygenic risk score to other markers. That is turning out to be a major biomarker in terms of being able to predict risk. In addition, we are exploring if methylation profiles can provide good information on the risk of getting cervical cancer. Most of our work uses material coming from smears and early biopsies. The methylation profile seems to be a good indicator if the tissue is going to become a lesion or if the body is going to clear it. It is at an early stage and all our work is in cervical cancer but it does appear promising and may be useful for other cancers as well. Biomarkers for response to endocrine agents are highly desirable and people are looking at them but we do not really have anything much more than breast density at the moment. We have not done any real work on methylation but it is something that might work.

What level of risk reduction is meaningful for a drug to be considered preventive?

You have to balance the benefits to the risk profile. Something like aspirin, which has very low toxicity and appears to reduce overall cancers by 10%, making it is a good option for a large part of the population. It appears to reduce colorectal cancer, stomach, and esophageal cancer by as much as 30% and lung breast and prostate by about 10%, and because it is a minimally-toxic, well tolerated drug you can consider it even for those at average risk of these cancers. If you start looking at aromatase inhibitors or tamoxifen, where there are some common side effects, it becomes important to focus prevention on those at highest risk, so that the benefits on average will clearly outweigh any risks.

Do you have any advice for organizations like ours who are interested in developing cancer preventatives?

For breast cancer risk-adapted screening should be implemented for the general population. Everyone should get a risk assessment – ideally at their first screening visit to determine what their risk of getting breast cancer is. Some people will be found to have high enough risk that they should be considering therapeutic preventive treatment upfront, while others will have a lesser increase in risk and would benefit from additional screening. Some will also be found to be at very low risk and may need less or even no screening. So there is a potential to tailor screening and prevention activities to the individual women’s risk and focus efforts on those who stand to gain the most.

What is coming next in the cancer prevention space?

Now that we know that the standard dose of some drugs also work for prevention, we are interested in knowing if lower doses also work, and if side effects can be reduced. Another approach is to look at local topical delivery for tamoxifen like drugs to determine whether a cream or gel could prevent cancer. Finally, we would like to do a big trial to study better how aspirin prevents different cancers, but the bureaucracy is making this difficult. We do not know how aspirin prevents cancer and we are doing a lot of work to find out the mechanism by which this happens. The doses at which it works are too low to act via the known COX2 anti-inflammatory pathway, so there is something very important still to discover. It is a really active research area.

Thank you!

Expert Interview with Joe Miletich, MD, PhD, on vaccines for cancer prevention

Posted May 13, 2020 –

Joe Miletich is the Senior Vice President of Research Sciences at Merck Research Laboratories. He is an expert drug developer whose personal life and career have intersected with HPV. His older sister died of cervical cancer when he was a first year medical student. Twenty-five years later, following a career at Washington University in St. Louis, he joined Merck, a world leading company in vaccine development, and witnessed the development and commercialization of the first HPV vaccine, a vaccine that is used by millions of people over the world and can prevent the type of cancer that killed his own sister more than four and a half decades ago. Here he helps us understand the challenges behind the development of a vaccine that can prevent cancer and how important it is to improve the biological knowledge of human diseases to develop better medicines. He talks about the necessary long-term commitment to conduct thorough and long studies that will ensure a preventative vaccine is safe, tolerable and provide lasting immunity to protect vaccinated people against HPV infections and their consequences. This article reports Dr. Miletich’s personal views as an individual and cannot be attributed to Merck.

 

Tell us about your career.

I am an MD-PhD and trained at Washington University in St Louis. After residency at UCSF, I worked as a professor of Internal Medicine and Pathology at Washington University for 18 years. I conducted basic research, saw patients and for the last half of my time there, I also directed the clinical diagnostic laboratories for the medical center.

Late in 1998, I decided to go to Merck because I was a bit dissatisfied with the unconscious bias in many academic research reports. I hoped to find more satisfaction bringing therapeutics to market because they must actually be proven to work. It was a chance to broaden my horizons and a very important time to me. I subsequently decided in 2002 to move to Amgen. It was a relatively small company at the time and I was given the terrific opportunity to set up and be responsible for all the discovery research, preclinical development and early clinical studies- where we test if the candidate medicine we invented is safe, tolerated, and has enough biological impact to pursue registrational clinical studies. Then in 2014, I left Amgen when the company took a different direction. I thought I might retire because I was in my 60s by then. But a very long-term friend and colleague asked me to return to Merck to reinvigorate its discovery, preclinical and early development and translational medicine efforts. That is what I have been doing for the last 5 and half years!

I got involved in the development of the HPV vaccine because in my first job at Merck I was responsible for toxicology. We were making sure that the vaccine was safe and well tolerated. When I left Merck in 2002, the clinical trials were started and by 2006 there was enough evidence for the vaccine to be approved. At the time, Gardasil was for 4 HPV types. Then, in 2014, the company received approval for Gardasil 9 that covers 9 HPV types and increases protection.

How has your personal experience affected your career choice?

 In my last year as an undergraduate, my sister, who was 9 years older than me, was diagnosed with cervical cancer. At the time I didn’t understand what it was and I didn’t know much about cancer or its treatments. My sister was bright and well educated; she was the chief medical technician in a hospital. I assumed she would get excellent care. Not many treatments were available then; there were radioactive implants to preserve reproductive capacity or surgery. She chose the implants because she wanted to have children. I was not worried because I thought there would be a good outcome and went back to school. I started the MD-PhD program in St Louis. During that summer, my sister visited me a couple of times. She helped me find an apartment and with various other things; she was always a very considerate older sibling and available to me. But late in the year it became clear she was going to die. It was so rapid! The radioactive implants had not worked and the cancer had metastasized widely to her bones and elsewhere. I spent our 3 week vacation taking care of her at home and then returned to school for mid-terms. Shortly after I got back to school I received a phone call that she was back in the hospital. I returned home and it was clear she was going to die soon. When I walked into her hospital room, she sent everyone away, the doctors, etc., and said: “You can all go away now, my brother’s here and he can fix everything, I will be fine.” That haunted me for many years. What I think she really meant was that she was going to die and it was OK since I was there, but those words have stayed with me ever since. Her death had a devastating effect on my life and on my family. I’ve thought about it frequently and realize that there are thousands of people and families ravaged by cancer in every corner of the world. I can’t really say it was my singular driving force – that I chose my career because of that event – but it gave me an intense connection.

Where did the idea to make an HPV vaccine come from?

In the early 80s, there was an idea that HPV might cause some cancers. At this time, we did not understand much about what caused any cancers and the idea that a viral infection might be a cause initiated a vigorous debate. However epidemiologists showed that it was possible to recover HPV types 16 and 18 from early dysplasia and from malignant tumors. Evidence started to be overwhelming that it may be true. I vividly remember many discussions in our department at the time about incorporating tests for evidence of viral infection into screening programs for cervical cancer. Who should get the credit? The world has recognized the German virologist, Harald zur Hausen as the champion for the discovery of a link between HPV and cervical cancer. It was a milestone to recognize what causes these cancers but what do we do about it? The Australians, Ian Frazer and Jian Zhou made the next bigger step with the remarkable observation that a virus-like particle could be assembled from a single protein expressed late in the life cycle of the HPV, the L1 protein. Those observations in turn made it possible to make the vaccine. A lot of work was done in the early 90s to find the right conditions under which the particles form.

How did Merck get involved in the development of the HPV vaccine?

Somewhere in the mid-90s, the vaccine group at Merck started working on the HPV vaccine. I was not at Merck at the time, I was still at Washington University.

Merck has a very long history of making vaccines. So there was a commitment and heritage at Merck for wanting to make the HPV vaccine. Not all companies would embrace it because to make a vaccine with the intent to give it to millions of people requires long studies to ensure that the vaccine is extremely safe and very effective. To actually prove that a vaccine works is very difficult because the things we are most worried about do not happen to everyone who is infected, but when they do it can be horrific. Take HPV for example, almost everyone gets infected with different types of HPV strains during their lifetime. For most people it does not have any consequences. For those it does, the consequences can be catastrophic. So a very large number of people must be vaccinated and watched for an extended period of time to determine that the vaccine is safe and to detect possible side-effects. We also needed to figure out how long the protection lasts, if there is a necessity for revaccination with some periodicity. Development of a vaccine is a very long term commitment.

What were some of the challenges associated with developing Gardasil?

Many people are misinformed about vaccines. Because of the large number of people vaccinated, a subset will have adverse events or diseases that happen to coincide with the time they had the vaccine. Even if there is no evidence for a direct link, some people will blame it on the vaccine. It is an association and not causation.

There was also a lot of resistance to overcome because the cancers we are talking about are caused by strains of papillomavirus that are transmiited during sexual activity. There was a lot of pressure suggesting that instead of benefiting mankind, the vaccine would enable bad behaviors. But that was never the motive. As we know from epidemiology, 1 in 20 cancers worldwide are caused by HPV. Absolutely wonderful people, huge actual or potential contributors to society, are afflicted by these cancers and either their life or the quality of their life is severely limited. We are just trying to change that.

So there were struggles and there were frequent conversations on how to deal with the challenges and how to best engage with partners, official agencies and advocacy groups to help get the messages through. Of course, nothing has helped more than the evidence showing that after a decade of use the vaccine had a dramatic impact on the numbers of cancers and the immunity that it induces is long lasting.

Our biggest challenge now is the increased demand for vaccine. With the epidemiology showing the vaccine prevents these cancers and that the immunity is long lived, suddenly the world wants 10x more Gardasil than it wanted before, and that is a manufacturing challenge. It’s not so easy to go from manufacturing tens of millions of doses a year to hundreds of millions of doses a year in a short time.

What about using single dose vaccination? This is a very complicated problem. A large fraction of people can get demonstrable protection from a single dose, and a larger fraction still from 2 doses. It depends on the age at which people are vaccinated. But the studies we have done were based on 2 or 3 doses, which was what we could do at the time. This is why the 2 and 3 dose schedules are approved in most places. This issue puts us, as a company, in a really tough spot because we don’t think it’s acceptable to say people should go to a reduced number of doses. We don’t know which individuals the one dose schedule will work for or for how long. I put myself in the position of one of the individuals who’s getting the vaccine, not knowing how well or for how long I would be protected.

So we are doing everything we can to increase production as soon as possible. We are also looking to see if we can change the vaccine to be more efficient as a single dose vaccine. But if you think back on everything I said, gaining the evidence through clinical trials that one dose works for most people and for an extended time, is going to take a while. This is a position that companies find themselves in from time to time and it is uncomfortable. Some might argue that we are taking this position because we want to maximize profit but it is not really true. We do worry about making assumptions; we believe it is better to act based on what we know for sure and on what is in the best interest of each individual who gets the vaccine. We are working on it. It takes time.

Many of our readers will be at high risk for the development of inherited cancers (HBOC, Li Fraumeni, Lynch Syndrome etc.). They will want to know how the cancer prevention drug development field may evolve. Are more preventive vaccines and drugs likely to be developed for this in the future?

That is ultimately what we want to do most of all. It is much more desirable to prevent diseases than to try to deal with them when they are established. I can genuinely say that in the companies I have worked at, there is no fear that we would go out of business if we were to make preventatives. It is just harder to develop effective preventative medicines, and it takes a longer period of time and many more people to actually prove they work and are safe.

I have hope that it will become easier. Just think about the logistics. Before, to be enlisted in clinical trials, people had to come in into specialized centers. Now, with new technologies, much of the work can be done remotely. A larger number of people are becoming more knowledgeable; it is going to be easier to obtain true informed consent to participate. So I am optimistic, but that does not make the challenges associated with prevention go away immediately. We will have to work through them over time.

 Then it comes down to the fundamental biology of the diseases and how much of that we understand. There are not that many cases where we truly understand the biological modulation we need to achieve to prevent diseases. We don’t have a whole lot of examples like HPV just yet. But over time, I am hoping we will have more. Nothing happens quite as fast as I wish it could. But it is certainly not going to happen at all if we do not keep working at it. We should keep moving forward at the fastest pace we can.

Could you tell me what the cost for the development of the HPV vaccine was?

It is difficult to estimate because so many people have worked on it. And many individuals contribute to more than one project with their expertise. The capital cost of it over years is well over a billion dollars and then there are the additional costs of the actual production, testing, packaging and and distribution. It has been considerable, and for those who worry about how fast to get return on your money, vaccines and preventatives are not the greatest business because it can take decades. On the other hand, if the vaccine or preventative is quite impactful, people will use it for a long time. They do not draw as much competition as other medicines because they take a long time to test and develop and to replicate all of the evidence. So vaccines tend to endure longer in the market place than other therapeutics but you have to be a company that intends to be a long term player rather than worry about a return on investment in the next 5-7 years. A company like Merck also has a large portfolio of products and has medicines like Keytruda that do generate revenue in a shorter time period, to help balance things out.

George Merck’s philosophy was to focus on where we can do good for people and the profits will follow as long as we don’t lose that focus on good. You can either believe that or not; it’s not just something you can say conveniently when it works. You have to believe it when things are not working, too. And honestly you need a bit of good fortune as well. Without a deep enough understanding about human disease biology, which we still don’t have, it is difficult to put together a low- risk businees strategy that has a high probability of financial and medical success. You simply have to be confident that if you try hard and explore enough things in earnest, that something will turn up, and that it will turn up in time. And that is not easy in our world today where people are interested in how fast they will get a return on investment.

Looking back over time, your work and the work of your colleagues fixed quite a few people, didn’t it?

I do take some satisfaction in that. Going back to one of your earlier questions, I did not set up my life to try to fix a problem about cancers that were caused by HPV. By the good fortune of opportunities that I had, I have been able to intersect with that very well and I’ve added to that effort where I could. It does mean a lot to be able to look back and say I did have some contributory role. I also can’t help but wonder what it would be like if it could have been done decades earlier and my sister was still alive. And mostly I think about what it will mean when no other young women and young men will ever again have to have to go through what she suffered.

Thank you!

Preventing disease to prolong life…

Posted May 04, 2020 –

Preventing disease to prolong life…

Our friend Roger Horchow died on Saturday, May 2, 2020, at 11:36 am.

Roger was obsessed with prevention in a variety of ways. He prevented forgetfulness by keeping records of people’s names and faces (which thereby also prevented him from seeming rude) – as well as by documenting facts and figures he found important. He paid precise attention to his friends and family to prevent them from not knowing how much he loved them. He prevented misunderstandings by stating the truth without saccharine caveats. Roger was pure gold authenticity and generosity.

When I told Roger about this cancer prevention venture, his answer, delivered with a twinkle in his eye was that he’d help us but we should know he already had a very busy day job. He’d just finished his 90th year on this earth.

The reason I bring up Roger Horchow is that when I got the news he’d passed, I felt a shock like no other — even though we’d been warned he was not going to make it.

Loss of loved ones — be they young, less young, or really old — is one of the most profound of human experiences. It reminds us it’s not a bad idea to do all we can to put that day off.

What we hope to do in this series of essays and interviews is to discuss the who, the what, the when, and the there of cancer prevention.

Our first piece will be an interview with Dr. Joe Miletich, a pioneer of cervical cancer prevention. We hope you like it!

Theo Ross