#121 - Azra Raza, M.D.: Why we're losing the war on cancer
Dr. Azra Raza, Professor of Medicine and Director of the MDS Center at Columbia University, discusses her book 'The First Cell,' critically examining cancer research's outdated models and poor ROI. She advocates for reconfiguring the system to prioritize early detection and prevention, offering an optimistic outlook for the future.
Deep Dive Analysis
12 Topic Outline
Motivation for Writing 'The First Cell'
Personal Journey into Oncology and Early Experiences
Historical Context and Lack of Progress in Cancer Treatment
Critique of Cancer Mortality Statistics and Treatment Success Metrics
Limitations of Immunotherapies: CAR T-cells and Checkpoint Inhibitors
High Failure Rate of New Cancer Drugs and Economic Burden
Misaligned Incentives and the Flawed Drug Development Model
Critique of Pre-clinical Research Models: Cell Lines and Animal Studies
Proposed Solution: Prioritizing Early Detection and Prevention
The Role of Technology in Future Cancer Screening
Coping with Personal Loss and Maintaining Optimism
The Value of a Longitudinally Collected Tissue Repository
5 Key Concepts
Age-Adjusted Cancer Mortality
This metric measures cancer deaths adjusted for the age distribution of the population. Dr. Raza highlights that the age-adjusted mortality for cancer in 2020 is similar to what it was in 1930, suggesting a lack of fundamental progress in extending life once cancer is established.
Progression-Free Survival
A metric used in clinical trials that measures the length of time a patient lives with cancer without the disease getting worse. Dr. Raza criticizes its use as a primary endpoint for drug approval, arguing that it often doesn't translate to meaningful overall survival benefits for patients.
Tissue Culture Cell Lines
Cancer cells grown in a lab, often immortalized, used for drug testing. Dr. Raza explains that these cell lines undergo a 'transcriptomic drift,' causing them to express genes for survival in vitro rather than genes faithful to their tissue of origin, making them poor models for human cancer.
CAR T-cells
A type of immunotherapy where a patient's own T-cells are engineered to recognize and kill cancer cells. Dr. Raza points out a critical limitation: CAR T-cells often cannot distinguish between normal and cancer cells, leading to the destruction of entire organs unless the targeted antigen is specific to replaceable cells like B cells.
Phase Zero Clinical Trials
A regulatory approach where a very small, sub-therapeutic dose (e.g., 1/500th) of a new drug is given to humans to assess its pharmacokinetics and pharmacodynamics, bypassing extensive animal testing for efficacy and potentially safety.
7 Questions Answered
The age-adjusted mortality for cancer in 2020 is essentially the same as it was in 1930, despite purported advances. The observed 27-30% decline in mortality over the last 30 years primarily parallels the decline in smoking rates, not significant breakthroughs in treatment for advanced disease.
For the 32% of patients who present with advanced disease, current treatments (surgery, radiation, chemotherapy) are largely ineffective. Even targeted therapies and immunotherapies, while successful in rare cancers or specific cases, account for less than 10% of overall cancer types and often offer only marginal survival improvements.
A staggering 95% of new experimental cancer drugs fail because the pre-testing platforms, such as mouse models and tissue culture cell lines, are artificial and do not accurately replicate the complexity of human cancer. These models often develop genetic changes that make them unrepresentative of actual tumors.
Many new cancer drugs are approved based on median survival improvements of only a few months, costing tens of thousands of dollars (e.g., $45,000 for a drug offering 3.7 months improvement compared to $5,000 for standard therapy). This leads to 42% of cancer patients being financially ruined by the second year of diagnosis.
The most successful strategy in cancer has always been early detection. Dr. Raza advocates for shifting significant resources (e.g., 50% instead of 5%) towards developing sophisticated biomarkers and continuous monitoring technologies to detect cancer at its earliest, most curable stages.
Advanced genomics, transcriptomics, proteomics, metabolomics, imaging, and artificial intelligence can be combined to develop numerous tests and devices, like microfluidic chips, that can continuously monitor the human body for early cancer footprints from various compartments like blood, sweat, tears, and urine.
The academic system incentivizes researchers to publish frequently and secure grants, often leading to irreproducible studies and a focus on incremental findings rather than transformative breakthroughs. There's also a pressure for academic institutions to open clinical trials, further intertwining them with the drug development pipeline.
12 Actionable Insights
1. Prioritize Early Cancer Detection
Focus efforts and resources on early cancer detection, as it is the only strategy proven to work in cancer treatment, enabling intervention when the disease is in its earliest, most curable stages.
2. Adopt Continuous Body Monitoring
Leverage cutting-edge technology like microfluidic chips, genomics, proteomics, and AI to continuously monitor the human body for early biomarkers of cancer, moving beyond annual screenings for more timely detection.
3. Embrace Cancer Prevention Lifestyle
Actively understand and implement lifestyle changes related to diet, stress management, and exercise, as these factors can significantly reduce cancer risk by 30-50% and are crucial for prevention.
4. Shift Cancer Research Focus
Redirect a significant portion of cancer research funding and intellectual resources (e.g., 50% instead of 5%) towards prevention and early detection, studying human tissue and biomarkers rather than relying on artificial animal models.
5. Refine Prostate Cancer Screening
Move beyond basic PSA testing for prostate cancer screening by incorporating PSA volume, PSA velocity (rate of change over time), and advanced tests like 4K to get a more nuanced and accurate assessment of risk.
6. Cultivate Radical Acceptance
When facing uncontrollable and devastating circumstances, strive for acceptance, as exemplified by Harvey’s approach to his terminal illness, focusing on what can be handled rather than succumbing to despair.
7. Correct Initial Impressions
Avoid self-delusion in relationships and ideas by being willing to correct your initial impressions when new information or experiences don’t align, rather than trying to change the person or idea to fit your preconceived notion.
8. Teach Truth Gradually
When conveying difficult or overwhelming truths, especially to those new to a field, present information gradually and with kind explanation, allowing understanding to ‘dazzle gradually’ rather than blinding with too much intensity at once.
9. Stimulate Lymphatic System Daily
Incorporate daily physical activity like jumping on a small rebounder (mini-trampoline) for 20-30 minutes, as this can effectively stimulate the lymphatic system.
10. Read ‘The Price We Pay’
Read Marty McCary’s book, ‘The Price We Pay,’ to gain a deeper understanding of the economic obscenities and vulgarity within the healthcare system, particularly regarding drug costs and their impact on patients.
11. Write Only When Compelled
Approach writing a book with the mindset that it should only be undertaken if you feel an absolute, undeniable compulsion to write it, as this indicates a deep-seated need to communicate the ideas.
12. Establish Human Tissue Repositories
For researchers, meticulously collect and save diverse human tissue samples (blood, bone marrow, germ line controls, various cell types) from patients, serially following them over time to create a national treasure for unraveling disease natural history and identifying early biomarkers.
6 Key Quotes
Tell all the truth, but tell it slant. Success in circuit lies. Too bright for our infirm delight, the truth's superb surprise. As lightning to the children, eased with explanation kind, the truth must dazzle gradually or every man be blind.
Azra Raza (quoting Emily Dickinson)
The only good news you can give to a cancer patient is that, oh, we caught it early so we can get rid of it. So we know that cancer itself may not kill. It's the delay in treatment that really kills.
Azra Raza
In this day and age today, 68% of cancers that we diagnose, new cases, 68% are cured. Cured with what, Peter? Slash poison burn, surgery, radiation, and chemo.
Azra Raza
95% of experimental agents that we bring to the bedside today, 95% in cancer fail completely. The 5% that succeed should have failed because they are only prolonging survival for 20 to 30% of patients by a few months.
Azra Raza
No man is an island entire of itself, each a part of a piece of the continent, part of the continent, part of the main. Any man's death diminishes me. That's what you said. What is a human life worth? John Dunn says, any man's death diminishes me because I am for mankind and therefore never sent to know for whom the bell tolls. It tolls for thee.
Azra Raza (quoting John Donne)
I had no time to hate because the grave would hinder me. And life was not so ample. I could finish enmity. Nor had I time to love. But since some industry must be, this little toil of love, I thought, was large enough for me.
Azra Raza (quoting Emily Dickinson)