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July 22, 2024 • 47min
#310 - The relationship between testosterone and prostate cancer, testosterone replacement therapy, and tools for predicting cancer aggressiveness and guiding therapy | Ted Schaeffer, M.D., Ph.D.
The Peter Attia Drive
In this episode, Dr. Peter Attia interviews Dr. Ted Schaeffer, an internationally recognized urologist specializing in prostate cancer. They discuss recent findings on the relationship between testosterone and prostate cancer, including insights from the TRAVERSE trial. The conversation covers the molecular nature of prostate cancer, advancements in assessing tumor aggressiveness, and implications for testosterone replacement therapy in men with and without prostate cancer.
#310 - The relationship between testosterone and prostate cancer, testosterone replacement therapy, and tools for predicting cancer aggressiveness and guiding therapy | Ted Schaeffer, M.D., Ph.D.
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Key Takeaways
- The TRAVERSE trial showed no increased risk of prostate cancer in men receiving testosterone replacement therapy (TRT) compared to placebo
- The androgen receptor saturation theory suggests there is a threshold level of testosterone beyond which additional testosterone has limited effects on prostate tissue
- More aggressive prostate tumors tend to have lower androgen receptor activity and rely on different growth mechanisms than testosterone
- The Decipher test can assess prostate cancer aggressiveness at a molecular level to guide treatment decisions
- For men with low-grade prostate cancer, TRT can often be safely continued under proper monitoring
- Advances in prostate cancer therapies are allowing for more targeted treatments based on tumor characteristics, potentially reducing the need for broad androgen deprivation therapy
- Having a sensitive biomarker like PSA allows for more precise monitoring and targeted interventions for prostate cancer compared to other cancers like breast cancer
Introduction
In this episode, Dr. Peter Attia interviews Dr. Ted Schaeffer, an internationally recognized urologist specializing in prostate cancer. They discuss recent findings on the relationship between testosterone and prostate cancer, including insights from the TRAVERSE trial. The conversation covers the molecular nature of prostate cancer, advancements in assessing tumor aggressiveness, and implications for testosterone replacement therapy in men with and without prostate cancer.
Topics Discussed
The TRAVERSE Trial: Testosterone and Prostate Cancer Risk (3:00)
Dr. Schaeffer provides background on the TRAVERSE trial, which examined whether exogenous testosterone increased cardiovascular and prostate cancer risk in hypogonadal men:
- The trial showed no increased risk of prostate cancer diagnosis in men receiving testosterone replacement compared to placebo
- The study population had relatively low baseline PSA levels (median ~0.9) and were considered low-risk
- Men diagnosed with prostate cancer during the trial tended to have higher baseline PSAs and larger PSA increases than those not diagnosed
- The overall incidence of prostate cancer was very low (23 cases out of over 5,300 men)
Dr. Schaeffer notes the results are reassuring, showing PSA can still be used to monitor risk in men on testosterone replacement therapy.
The Androgen Receptor Saturation Theory (10:30)
Dr. Schaeffer explains the androgen receptor saturation theory and how different organs respond to varying testosterone levels:
- The theory suggests there is a threshold level of testosterone beyond which additional testosterone has limited effects on a given tissue
- For prostate tissue, receptor saturation likely occurs around serum testosterone levels of 200-250 ng/dL
- Hair follicles may have similar saturation levels to prostate tissue
- Muscle tissue requires higher testosterone levels to reach saturation and see anabolic effects
- Prostate and hair follicles have high levels of 5-alpha reductase, which converts testosterone to the more potent DHT
This theory helps explain why increasing testosterone levels beyond a certain point may not significantly impact prostate growth or cancer risk.
Testosterone Levels and Prostate Cancer Aggressiveness (16:15)
Dr. Schaeffer discusses research showing that more aggressive prostate tumors often have lower androgen receptor activity:
- A landmark study in the early 2000s found lower testosterone levels associated with higher-grade prostate cancers
- Dr. Schaeffer's lab developed an androgen receptor activity (ARA) signature to assess tumor reliance on androgen signaling
- More aggressive tumors tend to have lower ARA scores, indicating less reliance on traditional androgen-driven growth pathways
- These aggressive tumors likely rely on alternative growth mechanisms and may have different vulnerabilities to treatment
This counterintuitive finding challenges the traditional view that higher testosterone always promotes more aggressive prostate cancer growth.
The Decipher Test for Assessing Prostate Cancer Aggressiveness (23:45)
Dr. Schaeffer explains how the Decipher test can be used to assess prostate cancer aggressiveness and guide treatment:
- Decipher is a CLIA-approved mRNA-based assay that analyzes gene expression in prostate tumor samples
- It provides a single score indicating how aggressive a tumor is likely to be
- The test also includes the ARA signature and other molecular features to characterize the tumor
- For low-grade cancers, only about 7% have aggressive molecular features on Decipher testing
- For higher-grade cancers, Decipher results may help guide treatment intensity, particularly for radiation therapy
Ongoing clinical trials are evaluating how to best use Decipher results to personalize prostate cancer treatment approaches.
Considerations for Testosterone Replacement Therapy (31:15)
Dr. Schaeffer discusses how he counsels patients regarding testosterone replacement therapy (TRT), including in men with low-grade prostate cancer:
- For symptomatic hypogonadal men without cancer, Dr. Schaeffer rarely advises against TRT due to its many potential health benefits
- For men with low-grade prostate cancer (e.g. Gleason 3+3) on active surveillance, TRT can often be safely continued
- He notes there's no evidence that exogenous testosterone accelerates existing low-grade prostate cancer
- For higher-grade cancers requiring treatment, TRT considerations differ based on treatment approach:
- For radiation, androgen deprivation is typically needed, requiring TRT cessation
- For surgery, TRT can often be continued (perhaps at a lower dose) if pathology is favorable
- Dr. Schaeffer emphasizes considering the whole-body health impacts of testosterone levels in decision-making
This nuanced approach challenges older dogma that TRT must always be stopped in men with any grade of prostate cancer.
Advancements in Prostate Cancer Therapies and PSA as a Biomarker (38:30)
Dr. Schaeffer highlights how PSA allows for more precise prostate cancer monitoring and treatment compared to other cancers:
- PSA is an extremely sensitive biomarker that can detect recurrence when only 100-200 cancer cells are present
- This allows for a more targeted "sniper" approach rather than "bazooka" approach to adjuvant therapy
- Unlike breast cancer, where women often receive years of adjuvant anti-estrogen therapy, prostate cancer treatment can be more tailored
- Ongoing trials are evaluating how to use genomic testing to further personalize treatment intensity, potentially sparing some men from unnecessary androgen deprivation
Dr. Schaeffer expresses hope that other cancers may eventually benefit from similar sensitive biomarkers to allow more precise treatment approaches.
Conclusion
This episode provides valuable insights into the complex relationship between testosterone and prostate cancer. Key takeaways include:
- Recent evidence suggests testosterone replacement therapy does not significantly increase prostate cancer risk in most men
- More aggressive prostate cancers often have lower androgen receptor activity, challenging older assumptions about testosterone always fueling cancer growth
- Molecular testing like the Decipher assay can provide additional information to guide prostate cancer treatment decisions
- For many men with low-grade prostate cancer, testosterone replacement can often be safely continued under proper monitoring
- Having PSA as a sensitive biomarker allows for more precise and targeted approaches to prostate cancer treatment compared to some other cancers
Overall, the discussion highlights how our understanding of prostate cancer biology is evolving, allowing for more nuanced and personalized approaches to both cancer treatment and testosterone replacement therapy in men with and without prostate cancer.