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Biologic Understandings of Bone Metastasis in mCRPC

Insights From: Evan Yu, MD, University of Washington; Ulka Vaishampayan, MD, Barbara Ann Karmanos Cancer Institute ; Neeraj Agarwal, MD, Huntsman Cancer Institute
Published: Thursday, Dec 06, 2018



Transcript: 

Neeraj Agarwal, MD: The mechanisms of prostate cancer progression and metastasis in the bones can be many. We know that bones provide a microenvironment that may be similar to prostate and breast cancer, but different from other cancers. The bone microenvironment definitely plays a role in the progression of prostate cancer and breast cancer. Beyond that, I think it’s very difficult to pinpoint a single pathway that is responsible.

Ulka Vaishampayan, MD: Visceral disease tends to behave more aggressively and frequently has a neuroendocrine component that needs to be treated, typically with chemotherapy. The other difference between visceral and bone disease is that visceral disease can exist and can progress even though the PSA [prostate-specific antigen] is very low. Sometimes the PSA may be 0.1 ng/mL, but in visceral disease, there are other metastases that are clearly progressing.

I think for bone disease, most of the time the PSA is a good indicator for telling you of disease progression, but not always. Frequently, you have to look at other components like alkaline phosphatase and anemia. Clearly, the patient’s symptomology plays a large role in determining whether there is disease progression or not.

Bone microenvironment plays a critical role in metastatic prostate cancer. Prostate cancer tends to have a propensity to metastasize to the bone, and the exact reasons for that are currently unknown. There are a number of enzymes that have been reported to be involved, but the exact mechanism has not been deciphered.

The way that bone microenvironment does play a big role is that we know some of the enzymes that produce testosterone—617-alpha for instance—are overexpressed as the patient gets castrate resistant disease. That is one impact the stroma has had, where we’ve been able to double up targets to attack the 617-alpha enzyme and stop testosterone production at the stroma level. Even though serum testosterone is suppressed with androgen deprivation therapy, what we found is that there is a discordance and the tissue testosterone levels are actually going higher as the patient becomes castrate resistant. That interplay between the stroma and osteoclast and osteoblast has played a tremendous role in developing some of the very effective treatments for metastatic CRPC.

In addition, bone targeted therapy is becoming a critical part of prostate cancer therapy, not necessarily because it will improve survival, which studies show [it] doesn’t have an impact on survival, but because it will enhance the health of the patient and delay or prevent bone fractures and things that could play a major role in impacting morbidity and occasionally mortality in these patients.

Metastatic castrate resistant prostate cancer has a number of symptoms that it can present with. I think because it has a propensity to have bone metastases, the typical and most common symptom that springs to mind is bone pain. But clearly, there are a number of other symptoms that are involved in this disease that contribute to tremendous morbidity and mortality in these patients.

One of the things that I would state is that there is a huge constitutional component of fatigue and anemia, even fatigue without anemia, loss of appetite, and generally feeling rundown. Those are symptoms that typically no scan is going to capture and no blood test is going to capture; only seeing the patient, getting a detailed history, will allow the clinician to capture those symptoms and try to correct them. Clearly, they play a large role in the patient’s feeling of wellbeing and overall performance status.

Neeraj Agarwal, MD: The most common cause of morbidity and mortality in prostate cancer patients with metastatic disease is bone pathology. Bone fractures and bone pain remain the most common cause of suffering in these patients. Hence, the diagnosis of bone metastasis early on is important. When we see PSA rising when somebody is being treated with androgen deprivation therapy or other therapies for castration sensitive disease, I think it’s very important to do bone scans in a timely fashion to detect bone metastasis. If metastasis is present, it is very important to treat patients with bone targeted therapies in a timely fashion.

Transcript Edited for Clarity 
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Transcript: 

Neeraj Agarwal, MD: The mechanisms of prostate cancer progression and metastasis in the bones can be many. We know that bones provide a microenvironment that may be similar to prostate and breast cancer, but different from other cancers. The bone microenvironment definitely plays a role in the progression of prostate cancer and breast cancer. Beyond that, I think it’s very difficult to pinpoint a single pathway that is responsible.

Ulka Vaishampayan, MD: Visceral disease tends to behave more aggressively and frequently has a neuroendocrine component that needs to be treated, typically with chemotherapy. The other difference between visceral and bone disease is that visceral disease can exist and can progress even though the PSA [prostate-specific antigen] is very low. Sometimes the PSA may be 0.1 ng/mL, but in visceral disease, there are other metastases that are clearly progressing.

I think for bone disease, most of the time the PSA is a good indicator for telling you of disease progression, but not always. Frequently, you have to look at other components like alkaline phosphatase and anemia. Clearly, the patient’s symptomology plays a large role in determining whether there is disease progression or not.

Bone microenvironment plays a critical role in metastatic prostate cancer. Prostate cancer tends to have a propensity to metastasize to the bone, and the exact reasons for that are currently unknown. There are a number of enzymes that have been reported to be involved, but the exact mechanism has not been deciphered.

The way that bone microenvironment does play a big role is that we know some of the enzymes that produce testosterone—617-alpha for instance—are overexpressed as the patient gets castrate resistant disease. That is one impact the stroma has had, where we’ve been able to double up targets to attack the 617-alpha enzyme and stop testosterone production at the stroma level. Even though serum testosterone is suppressed with androgen deprivation therapy, what we found is that there is a discordance and the tissue testosterone levels are actually going higher as the patient becomes castrate resistant. That interplay between the stroma and osteoclast and osteoblast has played a tremendous role in developing some of the very effective treatments for metastatic CRPC.

In addition, bone targeted therapy is becoming a critical part of prostate cancer therapy, not necessarily because it will improve survival, which studies show [it] doesn’t have an impact on survival, but because it will enhance the health of the patient and delay or prevent bone fractures and things that could play a major role in impacting morbidity and occasionally mortality in these patients.

Metastatic castrate resistant prostate cancer has a number of symptoms that it can present with. I think because it has a propensity to have bone metastases, the typical and most common symptom that springs to mind is bone pain. But clearly, there are a number of other symptoms that are involved in this disease that contribute to tremendous morbidity and mortality in these patients.

One of the things that I would state is that there is a huge constitutional component of fatigue and anemia, even fatigue without anemia, loss of appetite, and generally feeling rundown. Those are symptoms that typically no scan is going to capture and no blood test is going to capture; only seeing the patient, getting a detailed history, will allow the clinician to capture those symptoms and try to correct them. Clearly, they play a large role in the patient’s feeling of wellbeing and overall performance status.

Neeraj Agarwal, MD: The most common cause of morbidity and mortality in prostate cancer patients with metastatic disease is bone pathology. Bone fractures and bone pain remain the most common cause of suffering in these patients. Hence, the diagnosis of bone metastasis early on is important. When we see PSA rising when somebody is being treated with androgen deprivation therapy or other therapies for castration sensitive disease, I think it’s very important to do bone scans in a timely fashion to detect bone metastasis. If metastasis is present, it is very important to treat patients with bone targeted therapies in a timely fashion.

Transcript Edited for Clarity 
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