#267 ‒ The latest in cancer therapeutics, diagnostics, and early detection | Keith Flaherty, M.D.
Dr. Keith Flaherty, Director of Clinical Research at Mass General Cancer Center, discusses cancer's increasing prevalence with age and significant therapeutic advancements. He highlights the impact of immunotherapy and targeted therapies, the promise of liquid biopsies for early detection, and future strategies for combating cancer.
Deep Dive Analysis
16 Topic Outline
Introduction to Dr. Keith Flaherty and Cancer Research Focus
Cancer Prevalence and Mortality Across Decades of Life
Hormone-Driven Cancers: Breast and Prostate Cancer
Obesity as a Carcinogen and its Metabolic Links
Progress in Metastatic Epithelial Cancer Treatment (2000-Present)
Understanding Immunotherapy: Immune System vs. Cancer
Cancer's Evasive Tactics and Immune Checkpoint Inhibitors
Neoantigens and the Potential for Engineered T-Cell Therapy
Challenges and Specificity in Cell-Based Immunotherapy
Limitations of TIL Therapy and Multimodal Treatment
Future of Cancer Therapy: Next Five Years
Targeting Cancer Metabolism and DNA Damage Repair
The Importance of Early Detection: Microscopic vs. Macroscopic Disease
Advances in Liquid Biopsies for Early Cancer Detection
Commercially Available Cancer Screening Tests and Challenges
Addressing Disparity in Cancer Care and Future Outlook
8 Key Concepts
Anthropomorphizing Cancer
This is a useful mindset in therapeutic development, thinking about how cancers 'solve' problems to become cancers. It helps in conceptualizing how to reverse or intercept these processes, despite being a scary way to describe it.
Antigen
An antigen refers to a difference, typically a protein fragment, that is presented by a cell and seen as distinct by the immune system. These can be various types, including developmental markers or mutated proteins.
Immune Surveillance
This concept describes the immune system's role in detecting and eliminating forming cancers or proto-cancers before they become clinically overt. Evidence suggests that if this system is compromised, cancers are more likely to arise.
PD-1/PD-L1 Pathway
PD-1 is a 'brake' receptor on immune cells (like T lymphocytes) that, when activated by PD-L1 (often expressed by cancer cells), tells the immune cell to shut down. Blocking this interaction with antibodies like Keytruda unleashes the immune system against the cancer.
Neoantigen
These are mutated proteins or altered protein fragments within cancer cells that can be recognized by the immune system as 'different.' The presence of these neoantigens explains why certain cancers, like melanoma, respond well to immunotherapy.
Clonal Heterogeneity
As cancers evolve, they accumulate more mutations, leading to the establishment of subclones within a tumor. This heterogeneity means that a therapy might kill the dominant clone but leave resistant subclones, explaining why therapies are less effective against large, established tumors.
Immunogenic Cell Death
This refers to the process where cancer therapies not only kill cancer cells directly but also trigger immune recognition. The immune system then performs the 'mop-up work' of eradicating every last cell, especially in cases of microscopic residual disease.
Fragmentomics
This is a field that studies the different fragment sizes of circulating DNA in the bloodstream. Cancer cells shed DNA fragments that differ in size from normal cell DNA, a characteristic that can be used to improve the sensitivity of liquid biopsies.
9 Questions Answered
Cancer consistently ranks as a top three cause of death across all adult age decades, from 25-34 up to over 85, unlike cardiovascular or neurodegenerative diseases which become dominant later in life.
Cancers that grow without their respective hormones (e.g., ERPR negative breast cancer or prostate cancer in low testosterone) tend to be more aggressive because the cancer cells have evolved to be autonomous or independent of those ligands, making them harder to target directly.
From 1970 to 2000, there was virtually no progress in 10-year survival for metastatic epithelial cancers. Since 2000, the 10-year survival rate has increased to an estimated 15-20%, with half of this advance attributed to PD-1 antibody-based immunotherapy and the other half to molecularly targeted therapies.
The immune system identifies cancer cells by recognizing 'differences' (antigens) presented on their surface, such as altered proteins resulting from mutations or developmental markers. If these differences are detected, immune cells can eliminate the cancer cells, a process known as immune surveillance.
Cancers develop evasive tactics, such as expressing PD-L1 on their surface to activate the PD-1 'brake' on immune cells, or recruiting suppressive immune cells into their microenvironment. They can also alter intracellular pathways to resist immune-mediated cell death.
By identifying specific mutated antigens in a patient's cancer, immune cells can be genetically engineered to recognize and target only those cancer cells. This approach, exemplified by CAR T-cell therapy, aims to create highly specific and potent anti-cancer immune responses.
Microscopic disease has less clonal heterogeneity, meaning fewer resistant subclones, and the tumor has less capacity to create a hostile microenvironment that impairs the immune system. This allows the immune system to perform the 'mop-up' work after direct cell killing by drugs.
Liquid biopsies detect circulating tumor DNA (ctDNA) in the bloodstream, allowing for earlier cancer detection than traditional methods. They can also identify methylation patterns on the ctDNA to suggest the tissue of origin, helping to direct further diagnostic imaging or procedures.
While promising, current tests may lead to anxiety if a positive result doesn't immediately reveal a detectable cancer via standard imaging. The medical community needs to establish clear protocols for managing positive results and guiding patients through subsequent surveillance.
11 Actionable Insights
1. Manage Obesity to Reduce Cancer Risk
Recognize obesity as a significant carcinogen, comparable to UV radiation and smoking, due to its systemic effects like inflammation and altered metabolic signaling (e.g., high insulin, IGF-1 levels) that drive cancer. Actively manage obesity to reduce your cancer risk.
2. Utilize Current Cancer Screening
Regularly engage in established cancer screening protocols such as mammography and colonoscopy to detect cancers earlier, acknowledging that while not perfect, these methods can significantly reduce the risk of cancer death, especially when combined with other diagnostic tools.
3. Secure Expert Guidance for Liquid Biopsy
If you opt for advanced blood-based cancer screening, ensure you have access to a medical professional or a network of specialists who can expertly manage a positive test result, as the medical community is still developing standardized protocols for follow-up and diagnosis in these early detection scenarios.
4. Seek Expert Navigation for Cancer Care
When facing a cancer diagnosis, actively seek expert opinions and leverage specialized resources (e.g., N of One, Xcures, or similar platforms) to navigate complex cases, understand all available treatment options, and identify promising clinical trials, as access to specialized knowledge significantly impacts care quality.
5. Explore Advanced Blood-Based Cancer Screening
Consider advanced blood-based cancer screening tests (e.g., from Grail, Exact, Delphi) if you are an early adopter and understand the current limitations. These tests aim to find cancers at earlier, microscopic stages, but their adoption requires careful consideration.
6. Maintain Immune Surveillance Against Cancer
Understand that a healthy immune system plays a critical role in identifying and eliminating pre-cancerous cells. Support your immune system through general health practices, recognizing that profound immunosuppression can increase cancer risk.
7. Understand Age-Related Cancer Risks
Familiarize yourself with the varying prevalence of different cancer types across age groups (e.g., certain aggressive cancers in younger individuals, smoking-related and hormone-driven cancers in older populations) to better understand personal and population-level risks.
8. Embrace Multimodality Cancer Therapy
For future cancer treatment, be aware that the most effective strategies will likely involve a combination of therapies, targeting different aspects of cancer biology (e.g., cancer cell mechanisms, metabolic environment, immune cells, microenvironment) in a personalized approach, rather than relying on single-drug regimens.
9. Understand Cancer Metabolism Targeting
Recognize that new therapies are being developed to target cancer’s unique metabolic dysregulation, specifically focusing on regulators outside the mitochondria and mitochondrial biogenesis. These approaches aim to potentiate existing treatments and overcome resistance, offering significant promise for improved long-term survival.
10. Understand Mutation-Inducing Therapies
Be aware that some conventional chemotherapies (e.g., platinum-based, alkylating agents) can be strategically used to induce more mutations in cancer cells. This can push them past a survival threshold and enhance their recognition by the immune system, potentially making them more susceptible to immunotherapy.
11. Subscribe for Advanced Longevity Knowledge
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8 Key Quotes
There is no other disease that always ranks in the top three cause of death for every age. That's it. Full stop, period. It's cancer.
Peter Attia
The outcomes of those patients just continue to be distanced from cancers like pancreatic cancer, where first off, the lethality of pancreatic cancer per case diagnosed, the case fatality rate so-called, is far higher than these other cancers.
Keith Flaherty
If you look back over the past 30 years, we have basically made no progress in the long-term management of metastatic epithelial cancers.
Steve Rosenberg (quoted by Peter Attia)
Half of that advance has come from one therapeutic modality, PD-1 antibody-based immunotherapy. A single approach has accounted for half that number. It's astounding.
Keith Flaherty
Basically, people have to understand that by the time they're diagnosed with cancer, something's gone wrong. The system didn't work to detect, you know, in this surveillance mode, the forming cancer. It didn't eliminate it.
Keith Flaherty
You've got to take out the moon that generates the force field around the Death Star before you send in your fighters to actually try to destroy it.
Keith Flaherty
If you solve this problem, you win the game.
Peter Attia
It's the crossing of those wires [diagnostics and therapeutics] that's what's really going to massively get us towards the path of having many, much, much higher percentage of patients who are 10-year survivors.
Keith Flaherty