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Cancer research beset by a Gordian Knot of problems

Turn him to any cause of policy,
The Gordian Knot of it he will unloose,
Familiar as his garter

—Shakespeare, Henry V, Act 1 Scene 1

It’s been a hot summer all over the world, but our work doesn’t stop as our problems need solutions. 

There’s a war in Ukraine, we are continuing this summer to work with colleagues in the U.S. from Ukraine to help Ukrainian physicians and scientists find opportunities, and we’re emerging out of a COVID pandemic that may always be with us, according to some sources. 

Academic oncology forges ahead with numerous challenges, but a new day lies ahead. 

There are champions for the importance of cancer research and care in the White House in President Joe Biden and First Lady Dr. Jill Biden, a respected new leader Dr. Monica Bertagnolli on the way to direct the NCI, a re-energized ACS with Dr. Karen Knudsen, important cancer research and advocacy initiatives by AACR through amazing leadership by Drs. Margaret Foti, David Tuveson, Lisa Coussens, Phil Greenberg, and others, and ASCO’s role in education, invigorating the oncology workforce, and bringing forward practice-changing advances.

I’ll get right to the point as what I’m going to say won’t surprise many, but the problems just aren’t going away. This makes me ask whether the problems are bigger than all of us combined? 

Maybe they are, but a constellation of factors above makes me hopeful that we can at least try to chip away at some root causes to make progress.

What are the major problems facing our field in the summer of 2022? 

The basic and clinical research enterprise is stymied at many levels, including insufficient funding and too much bureaucracy. 

Clinical care faces increasing challenges from poorly functional electronic records that’s three-decades-(plus) into clinical use (I wrote about this five years ago, but nothing has changed), interference from insurers, health systems that are led by business people looking for revenue, far less than optimal working relationships with pharmaceutical companies, over-regulation by IRB’s, IACUC’s, COI committees, and risk-averse administrators and lawyers who have infiltrated academia and academic medicine. 

Passwords and IT have not made our lives better in any area of biomedical science or clinical practice. 

Some, including me, may be suffering from Chronic Password Fatigue Syndrome (CPFS would be the acronym). Scientific publishing, peer review and paywalls are a very problematic area that contributes to disparities around the world, among other disparities in research and clinical oncology that I have previously pointed out. Irreproducibility of scientific results has gotten lots of attention, although real solutions have yet to address the problem.

As one thinks about how we got here, it helps to have lived through the evolution and to have a foot in both medicine and science. Actually, more than a foot. What follows is opinion but maybe it will help connect some dots.

In the mid- to late-1990s, HIPAA privacy rules came on the scene, due to efforts by Hillary Clinton and others. Having completed medical school in Miami, medicine and oncology training at Johns Hopkins, and having started a faculty position at University of Pennsylvania before HIPAA, I can assure anyone reading this that there was no major deluge of privacy violations. 

There were some anecdotes where some nosy people looked at health records of celebrities, and there was some concern by the early- to mid-1990’s that genetic information may be used against people who would be discriminated against by employers or insurance companies. But there has been a law against genetic discrimination, and it’s a good law, separate from HIPAA. Hillary meant well, but no one anticipated the downside of HIPAA.

HIPAA has ruined medical research. For what reason? 

A big problem has been obstruction of biomedical research due to restricted access to medical records and prohibitions against data sharing. Before HIPAA, any faculty, fellow, resident, medical student, or other researcher could access any medical record at their institution for research with much less burdensome regulatory oversight. 

Researchers are not rogue criminals out to spread confidential information about people’s private lives. Physicians and scientists are professionals who have dedicated decades of their lives and talents to serve others, and are capable, as they have for centuries, of professional conduct and of maintaining confidentiality as appropriate. They are the people who study and discover patterns at our hospitals, laboratories and universities, and they are exactly whom we need to empower to help save lives. 

The lack of easy access to clinical records (or clinical specimens) has led many to give up, and has led to a gigantic problem where a lot of research is simply not being done, or, when done, it is extremely difficult and inefficient. 

Much data is now in big databases owned by companies with restricted access. There’s a lot of politics (a whole lot) of who has access to what data and when. HIPAA has not prevented numerous data breaches. 

Also, I have not read about someone’s privacy being actively violated by researchers and how that led to anyone being harmed. I’m not suggesting we get rid of HIPAA, but only to recognize the negative impact its purportedly needed protections have led to.

Insurance companies have come between physicians and patients. 

There is a sacred, thousands-of-years-old, bond and relationship between physicians and patients. This has been disturbed in recent years to a point of violating that relationship. Practice guidelines and money to be saved to increase profits are part of the equation, good or bad.

Guidelines are great, but they are “guidelines.” 

This brings up a question about where the “art of medicine” and the judgement of individual physicians will be over the next few decades and what will the role of physicians be? 

I have felt for years that AI has been far from prime time for replacing oncologists, and would argue and hope on ethical grounds that no algorithm ever makes life-death decisions in the absence of personal and compassionate physician presence.

There are impressive things AI can do, and here’s an example with AlphaFold that represents a valuable resource.

So, we stay open-mined about exactly how it helps or may help.

I’d love to read more about what the experts, who are colleagues, are saying about the impact of AI on research, but it’s behind a paywall.

Administrators have had a profound effect on the practice of medicine in recent decades. as they, too, have invaded and, in many settings, now make the rules. It is well documented that there are at least 10x administrators versus physicians within health systems and academia now as there were a few decades ago. 

How has this helped? 

It has increased costs and has not improved mortality or life expectancy in the United States. It has also led to vast increases in regulatory burdens at the institutional level with overreach by IRBs, COI committees and expectations of physicians. 

Quality of life and salaries for physicians have not been a major contributor to health care costs as some might imagine. Another impact has been on morale and job satisfaction. Action should be taken to address the need for salaries to be more competitive at academic centers and hospitals to attract faculty and staff who move to industry. 

This is important for clinical research infrastructure and clinical trial offices where I’ve seen turnover and instability at multiple institutions.

The funding issue for biomedical research has been very problematic. 

With the exception of those who have career funding from HHMI, Ludwig, intramural programs at NIH, or support from SU2C, the rest of academia depends on grant support from the government (e.g. NIH, DoD, CDC), private foundations, industry or philanthropy. 

The government NIH paylines have been more or less flat for 20 years. I’ve lived (and suffered) through it, and have also seen and led several study sections from the review side. 

Most of what I know is very well known, including that grants between the 10th and 20th percentile are indistinguishable from the top 10% of grants; and on any given day with a different review group, the opinions could be reversed. 

Industry funds what’s of interest to industry’s profits and business development plans, not necessarily what is the most logical, reasonable, or needed experimentation to advance the field. Some important scientific questions will simply not be funded by industry.

The lack of easy access to clinical records (or clinical specimens) has led many to give up, and has led to a gigantic problem where a lot of research is simply not being done, or, when done, it is extremely difficult and inefficient.

There has been more money from the government, but it was for the most part used to impact programs other than the investigator-initiated NIH R01 grant that has been the engine of discovery for many decades. 

It is acknowledged that there has been a larger pool of applicants for NIH R01 grants, but it is worth arguing that there should have been a better plan to deal with the consequences of the NIH budget doubling that occurred 20 years ago. 

Everyone knows we need discovery for translation. Without fundamental discoveries there is no pipeline of new drugs or innovative clinical trials. The limited funding has affected new investigators, trainees, mid-career as well as senior investigators. For the older generation, it’s pretty safe to say that no one expected that viability in science would mean spending enormous amounts of time writing grants—most of which never get funded. 

We grew up in the “publish or perish” environment and that seemed to be the major challenge. The HHMI model I experienced earlier in my career supports research programs of investigators, which frees them to focus on making scientific advances and provides them with the resources to do so. 

Unfortunately, that is a very exclusive club, and, sadly, other billionaires of our time have not followed in the footsteps of Howard Hughes.

What is the role of government? 

Is it to support special projects and interests and/or to support the workforce? Is government responsible for the whole workforce? What about universities? Should certain activities be more for the intramural NIH program that can do things no one else can do? How has that evolved over time? 

Whose responsibility is it to make sure the investment in careers and those who have dedicated their lives with decades of experience ultimately doesn’t end up going to waste when they leave for other careers or retire after being fed up with medicine and science?

There is a lot of me-too drug development going on. It interests me to see how cyclin-dependent kinase inhibitors have been used to treat breast cancer since drug approvals going back seven or more years ago and after decades of study where it is clear the class of drugs was not uniquely discovered for breast cancer. 

With thousands of trials combining immune checkpoint therapy with everything else, there is a point of diminishing returns, loss of innovation and lack of human subjects/patients who could be enrolled in other perhaps more innovative trials. 

But there is big money to be made with approved CDK inhibitors or immunotherapy, and for the latter, maybe some of the Kaplan-Meier curves can be bent with some of the combinations under study. 

But wouldn’t more predictive biology help prioritize those numerous ‘early phase’ trials that have flooded clinical trial portfolios and become incredibly complex, often with numerous treatment arms and hundreds of patients each?

Why have most clinical trials now come under the control of pharmaceutical industry, where investigators at sites in the U.S. or abroad enroll patients, and very few people know what’s going on? Academia is where the trials are conducted, but the trials emerge from industry to serve industry. 

Industry has its priorities and doesn’t support science to the extent one would expect for the several orders of magnitude more of resources versus what is available in academia. It is somewhat shocking what was recently reported in JAMA Oncologythat over 90% of individual clinical trial participant data from among the most common cancer medicine (nivolumab, pembrolizumab, pomalidomide) were “not eligible” for sharing.

Why have things come to this point in terms of how our national cancer research agenda is prioritized and how the research is conducted? 

I think a major problem is lack of real accountability for how our national resources have been and are being deployed to address the cancer problem.

I remind you of what ACS disseminated a couple of years ago, that ~50% of cancers are preventable by lifestyle, vaccinations, screening, and early detection. 

Of course, we need to address disparities and get people to stop smoking. A lot of progress has been made and is celebrated. But many have also already died, as my colleague Dr. Jas Ahluwalia just point out in an article entitled “Nicotine is not the devil, cigarettes are.”

But where did the advances come from? Where does the credit go? Do we need billions of dollars and new entities to do what is obvious to detect cancer early, when it’s curable in most cases, or to prevent cancer altogether by adopting existing recommendations? 

Does progress, the credit for which is possibly usurped, justify a snowball effect of more big science and special interests while the basic discovery engine atrophies away? Does everything or most things going forward need to involve big data and big science? 

Has little science failed us? Why has the NIH payline remained mostly flat for the last two decades and made my life very difficult and the lives of so many of my colleagues so difficult as well? 

I’ve been watching resources being siphoned to so many programs at an unbelievable level for many years now. 

Who is minding the store, and objectively assessing the fruits of the national investment and tax dollars? Why isn’t there more money in the system with President Biden in office? 

And why is ARPA-H external to NCI? 

Why? Why aren’t the resources for cancer research under the NCI director’s authority and vision? Why would anyone think reinventing a new system will do any good? 

It brings to mind that we always spend more money and achieve less; healthcare is a great example. Why does my CTEP Investigator ID keep expiring? Don’t we have better, more important work to do?

With regard to science, technology, tools and capabilities (things we can do because we can), should cell line research be deemed obsolete and replaced with 3-D cultures, organoids, PDX models or other expensive transgenics? 

Should old technologies be abandoned and replaced by more expensive new technologies? Are we looking at a future of solid-state science where everything is exported to companies that own technologies (developed in academia)? 

Will academic labs of the future be able to make innovative discoveries in the tradition of the last century? Will single cell profiling in the tumor microenvironment or from blood improve patient survival? Will universal germline testing in colorectal or other cancer improve outcomes? 

Should we have a gigantic database that has everything in it with multi-dimensional analysis capabilities? What will the quality of the data be, will we learn things we would have never dreamed of, and will they impact meaningfully on patients’ lives or public health in general?

Listening to a White House webinar moderated by John Dickson on July 26, where Catharine Young, senior director of policy for the Biden Cancer Initiative spoke, it was interesting to learn more about the national Cancer Moonshot and Cancer Cabinet priorities and directions including reducing mortality from cancer by 50% over the next 25 years and improving quality of life for patients and caregivers. 

I think reducing mortality by 50% should be achievable if we just follow current ACS recommendations for cancer screening, diet, exercise, avoiding tobacco, alcohol, use of vaccination to prevent HPV and avoid choices that lead to infections with other viruses that cause cancer. 

Why should that take 25 years and cost billions? 

Shouldn’t we spend more on discovery science to fuel the pipeline of new strategies and therapeutics?

The White House Moonshot strategy described by Catharine Young has five priority areas to accelerate solutions, including: 

  1. Closing the screening gap where 10 million screenings were missed due to COVID, 
  2. Studying and addressing environmental and toxic exposures with involvement from EPA
  3. Reducing the impact of preventable cancers such as liver cancer from Hepatitis C, 
  4. Accelerating cutting-edge research through the pipeline with focus on rare cancers, childhood cancers and the deadliest cancers, and
  5. Better support for patients and caregivers. 

More details can be found here

These are great goals, and certainly states, including Rhode Island, where the Legorreta Cancer Center and Brown University are located, and where we have higher rates of a number of cancers, stand to benefit from more focus on environmental and toxic exposures as possible underlying causes. 

The priorities highlight lifestyle factors, such as diet and nutrition, physical activity, smoking cessation or avoiding other exposures that contribute to the burden of cancer, which is good, but really shouldn’t cost more billions of dollars or take such resources away from discovery research. 

Implementation science is promising, but why isn’t medical care executing on what is already or should be standard of care? 

The moonshot goals and Cancer Cabinet priorities focused on research do not highlight the central role and importance of fundamental discoveries across the spectrum of cancer as hundreds of diseases. 

There is an emphasis on precision therapies, which, of course, is very important and an emphasis on the deadliest cancers is important. I would say all malignant cancers are deadly, and for a national agenda we can’t pick and choose. Studying different populations is very important as is delivering treatment innovations to all. 

All cancer research should strive for that as agreed upon, just like we now have a focus on scientific rigor, reproducibility, and biological variables in all NIH funded research. It is time, however, to address the burden of many unfunded across-the-board mandates, and those that will come in the future. 

This is particularly important when cost of living has gone up while the magnitude of a modular budget has not changed in decades. I have previously suggested considering an Earth Shot Program.

Disparities are a major problem, and some in the field have publicly condemned AAMC recommendations and anticipated actions in medical education curricula. 

I disagree with those views. I think there needs to be a balance, because both biological and social determinants of health are relevant to clinical outcomes and patient mortality. 

Maybe instead of arguing that we need to choose between learning about mRNA or history of oppression, perhaps medical education should last longer and maybe include more didactics and research requirements in biology, environment and disparities.

There is a responsibility to prioritize our national investments in cancer research, but also a need for accountability at the level of those investments, by those who are not conflicted. We know what real impact looks like and it should be straightforward to trace it back to its origins and to specific investments.

Some things shouldn’t cost as much as they seem to be costing. 

This is not to diminish the great importance or acuteness of the societal problems, but we can certainly learn from other countries and be smarter with execution. 

There is waste and there are also missed opportunities to gain back funds from government-funded research that gets commercialized. Some would say that much has been invested already and why haven’t we made more progress. 

An answer is that cancer is complex and that much progress has been made, but there are also many challenges outlined in this article, including waste of time and money, as to why more progress hasn’t been or isn’t being done.

Where do great impactful (towards human health) discoveries come from? Historically, work in biochemistry, lower organisms such as worms, flies, yeast, viruses, and bacteria revolutionized our knowledge. 

In some ways, we have gotten so far away from that with big science and big data. 

Pure basic science for the sake of science without expectation of translation has not been a failure. My view is to support innovative science while always thinking about translational opportunities. 

For the older generation, it’s pretty safe to say that no one expected that viability in science would mean spending enormous amounts of time writing grants most of which never get funded.

Collaboration is great to solve difficult scientific and societal problems when the collaborators bring meaningful substance to the table. Forcing collaboration or feeling good that the answer is we would solve problems if we just got the scientists to collaborate is not the answer. 

This comment should not be taken out of context, because collaboration can be very impactful. There are many mandates these days, and grand programs that allocate major resources away from the mainstream scientific community that are not evidence-based as far as likelihood to deliver and solve real problems. 

Power and politics are at play here when one sees who the beneficiaries are of various national awards involving big science. And maybe that’s just how it is and something good will come of it, but as decades go by, one has to revisit accountability as cycles repeat themselves.

A new day lies ahead—if we find ways to address long-standing challenges that have made things worse. Reforms are needed. 

Accountability in use of resources is needed, and more grassroots, as well as leadership input, into prioritization. 

Workforce issues go beyond how any specific research projects are supported. 

It’s high time we pay attention to support of scientific careers, physician-scientist careers and academic clinician researchers and educators. Salary support and protected time for academic careers has to be addressed by institutions and at a society/government level. 

I have said that physicians, scientists, and especially practicing physician-scientists, should be valued more and helped by everyone in the system to achieve goals that benefit society. 

How the Gordian Knot of current problems is addressed will surely impact on the makeup of our workforce in the future, who will undertake the noble profession, and the pace of impact on science and our community. 

Perhaps ancient Greece has some solutions.

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