#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.
Dr. Ted Schaeffer, an internationally recognized urologist and prostate cancer oncologist, discusses the complex relationship between testosterone and prostate cancer, including findings from the TRAVERSE trial. He delves into the androgen receptor saturation theory and how to counsel patients on testosterone replacement therapy (TRT) safely, even with low-grade prostate cancer.
Deep Dive Analysis
11 Topic Outline
Introduction to TRAVERSE trial and prostate cancer focus
TRAVERSE trial findings on prostate cancer risk
Limitations and interpretation of TRAVERSE trial data
Androgen receptor saturation theory in different organs
Relationship between low testosterone and aggressive prostate cancer
Androgen Receptor Activity (ARA) signature and its application
Decipher assay for assessing prostate cancer aggressiveness
Using molecular profiling for higher-grade prostate cancer treatment
Counseling patients on TRT with low-grade prostate cancer
Comparing surgery vs. radiation for higher-grade prostate cancer
Role of PSA as a biomarker in prostate cancer management
4 Key Concepts
TRAVERSE Trial
A study designed to determine if exogenous testosterone increases the risk of cardiovascular disease (ASCVD) in hypogonadal men, with a secondary analysis on prostate cancer risk. It found no increased risk of prostate cancer in men with low PSAs who were brought to a barely eugonadal state.
Androgen Receptor Saturation Theory
This theory posits that once androgen receptors in a specific end organ, such as the prostate or hair follicle, reach a certain level of saturation with androgens (testosterone or DHT), providing additional androgen levels will not lead to further augmented effects or growth in that organ.
Androgen Receptor Activity (ARA) Signature
A molecular signature derived from gene expression analysis of prostate cancer tissue, which indicates the level of canonical androgen receptor engagement and output within a tumor. Tumors with lower ARA signatures are generally associated with a more aggressive phenotype.
Decipher Assay
A CLIA-approved mRNA-based assay that analyzes the expression of approximately 20-22 genes in a prostate cancer biopsy. It provides a single score (Decipher score) to assess the aggressiveness of the tumor and can also provide access to the AR activity (ARA signature).
7 Questions Answered
The TRAVERSE trial, a large cohort study, found no increased risk of prostate cancer diagnosis in hypogonadal men supplemented to a eugonadal state, especially in those with low baseline PSAs.
Prostate cells and hair follicles contain 5-alpha reductase, which converts testosterone to the more potent DHT. Their androgen receptors can reach saturation at relatively low serum testosterone levels (around 200-250 ng/dL), meaning higher levels may not cause further growth, unlike muscle which requires higher levels for anabolic effects.
More aggressive prostate tumors tend to be less reliant on canonical androgen receptor activity and are often found in men with lower testosterone levels, suggesting they utilize alternative growth pathways.
These assays can assess tumor aggressiveness and androgen receptor activity, which may inform decisions on whether to intensify or de-intensify androgen deprivation therapy alongside radiation for higher-grade localized cancers, or to favor surgery to avoid systemic ADT.
No, there is no evidence to suggest that exogenous TRT accelerates or propagates low-grade prostate cancer. Patients with low-grade cancer on TRT can often continue their therapy under careful monitoring, similar to men with naturally high testosterone levels.
Surgery allows patients to potentially maintain their testosterone levels post-treatment, thereby avoiding the significant morbidity associated with systemic androgen suppression, which is frequently required with radiation therapy for higher-grade cancers.
Prostate cancer benefits from the highly sensitive PSA biomarker, which allows for early detection of recurrence and the use of targeted 'sniper' salvage therapies, in contrast to the broader 'bazooka' adjuvant hormonal therapy often used in breast cancer due to the lack of a similar sensitive biomarker.
13 Actionable Insights
1. Consider TRT for Health
If you are symptomatic and hypogonadal, consider testosterone replacement therapy (TRT) to maintain cardiovascular health, bone health, muscle mass, and cognitive function, as the benefits often outweigh the risk of prostate cancer development or detection.
2. Continue TRT with Low-Grade Cancer
If you have a low-grade prostate cancer (e.g., Gleason 3+3) and are on testosterone replacement therapy (TRT), you may continue TRT, as there is no evidence it accelerates or propagates low-grade prostate cancer. This applies even if your testosterone levels are high but within the normal distribution.
3. Surgery to Avoid ADT Morbidity
For higher-grade prostate cancers requiring treatment, consider surgery as a primary option to potentially avoid systemic androgen deprivation therapy (ADT) and maintain testosterone levels for overall health, provided post-surgical pathology is favorable. This is a critical factor when deciding between radiation and surgery.
4. ARA Score for Radiation Therapy
If you have a high-grade prostate cancer and are considering radiation therapy, inquire about your tumor’s ARA score, as a low ARA score may indicate enhanced sensitivity to intensified androgen deprivation therapy (ADT) with newer agents.
5. Decipher for Low-Grade Outliers
If you have a low-grade prostate cancer (e.g., Gleason 3+3) typically managed with surveillance, consider a Decipher score to identify if your tumor is one of the rare aggressive outliers (about 7% of cases).
6. Low T & Aggressive Cancer
Be aware that prostate cancers developing in a low testosterone environment may be more aggressive and less dependent on androgens, making them potentially more challenging to treat if they progress.
7. Monitor PSA on TRT
If you are supplementing with exogenous testosterone, monitor your PSA and its changes, as this can still indicate risk for prostate cancer. Men with low PSAs (around 0.9 ng/mL) generally have a low risk.
8. Radiation Requires Aggressive ADT
If you have a higher-grade prostate cancer (Gleason 7 or higher) and opt for radiation therapy, expect to undergo aggressive androgen suppression as part of the treatment, which will reduce your testosterone to zero.
9. TRT May Worsen BPH
If you are a eugonadal man considering testosterone supplementation, be aware that it may worsen benign prostatic hyperplasia (BPH) or urinary symptoms due to the greater sensitivity of benign prostate cells to exogenous testosterone.
10. Post-Radiation TRT Challenges
If you undergo radiation therapy for prostate cancer, be aware that restarting testosterone replacement therapy afterward may be challenging due to residual benign prostate tissue, which could lead to false positive PSA readings for recurrence.
11. Utilize PSA Biomarker
If you have prostate cancer, understand that PSA is an exquisitely sensitive biomarker that allows for precise monitoring of treatment efficacy and early detection of recurrence, enabling targeted salvage therapies rather than broad adjuvant treatments.
12. Advocate for Liquid Biopsies
If you are a woman with breast cancer, advocate for or stay informed about the development of liquid biopsies and cell-free DNA monitoring, which could enable more targeted therapies and potentially reduce the need for widespread adjuvant anti-estrogen therapy.
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5 Key Quotes
The lower a person's testosterone, the greater the risk of high-grade prostate cancer.
Peter Attia
There's no evidence that says exogenous T replacement causes acceleration or propagation of someone's prostate cancer.
Ted Schaefer
In my mind, it's no different than anybody else who's within that normal distribution.
Ted Schaefer
One of the big benefits that we have in the prostate cancer space is we have this exquisitely sensitive biomarker, the PSA.
Ted Schaefer
So instead of just taking this bazooka approach, you can be a sniper.
Peter Attia