Short summary

We hope that a future use of bone biomarkers can improve the diagnostic precision regarding metastases in prostate cancer. Several studies have demonstrated that they can predict a worsening of bone disease as well as mortality. But in praxis it has proven difficult to put this into daily use in the clinic because most studies report on averages or medians of a cohort, which cannot be implemented into daily clinical practice. Therefore, in our study we will focus on the absolute or delta values for CTX and PINP of the individual patient to find the cut-off values or delta-values that show progression in disease, poor response to treatment and/or risk of early death.

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Rationale

Background

Prostate cancer is the most common cancer and the second most common cause of cancer related deaths amongst men in Denmark in 2016. In Denmark there were 4,519 new cases of prostate cancer in 2016. Already at the time of diagnosis  about 15% debut with bone metastases and more than 80% will during their remaining lifetime develop bone metastases. The survival of prostate cancer patients drops significantly when they get bone metastasis and it is worsened if they also have a bone fracture or severe damage to their bones. The metastasized cancer cells trigger a so called "vicious cycle" in the bone marrow, where they affect the bone-forming osteoblasts and the bone resorbing osteoclasts in such a way that there is an early elevated bone resorption, which quickly is followed by a massive overproduction of immature chaotic bone. This combination of some bone resorption and a massive overproduction of bone can result in anemia and deformities/fractures resulting in for example paralysis. The elevated activity of the bone cells makes the cancer cells grow even more and become resistant to treatment. In return, the activity of the bone cells is further elevated and a self-reinforcing vicious cycle is initiated. 

PSA (enzyme prostate specific antigen) has proven to be an important tool and has improved diagnostics and monitoring of prostate cancer considerably. But PSA is not specific for the pathologic condition since it can also be elevated under benign conditions. Apart from elevated PSA levels a biopsy is also required in order to diagnose prostate cancer. For diagnosing and monitoring of bone metastases, bone scintigraphy is the main diagnostic tool used. It is a well-established technique, but its major limitation is that many signals are too blurry or weak to allow a diagnostic conclusion for example in the case of renewed progression in bone disease. More recently NaF PET has to some extent replaced bone scintigraphy. This method has improved the image quality considerably but you still have the same elementary limitations as for scintigraphy.

The initial choice of treatment for metastatic prostate cancer is surgical or medical castration. This treatment will bring most patients into remission for a while, but the cancer will eventually become castration-resistant. In order to diagnose the progression of castration resistant cancer the testosterone levels should forth on be low and either PSA should be elevated by at least 50% for 3 consecutive measurements or a bone scintigraphy/NaF PET should show at least two new focal lesions. Patients only receive medication (bisphosphonates or denosumab) to prevent or reduce the damage on their bones by the bone disease when their cancer has become castration resistant.     

It is a widespread perception and frustration amongst the treatment-responsible urologists and oncologists that they often suspect that a patient has bone metastases or that existing bone metastases have become active again, but that the diagnostic tools are not good enough to allow them this conclusion. Sometimes they have to wait for several months for the disease to progress so much that the diagnostic tools allow a new diagnosis and an alteration in the treatment of the patient. It is precisely in these situations we hope that a future use of bone biomarkers can enable a much earlier and better treatment of the patient than it is possible now.  

Hypotheses/aims

1. The combination of PINP and CTX-I can at the time-point of the initial diagnosis (together with PSA, biopsy and bone scintigraphy/PET) be used to identify patients that have bone metastases.
2. The combination of PINP and CTX-I can enable an earlier and more precise detection of resistance to castration treatment.
3. The use of PINP and CTX-I can predict who the chosen treatment will and will not work on.

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Description of the cohort

Newly diagnosed prostate cancer patients

Group 1: 100 newly diagnosed PCa at the Department of Urology, Lillebaelt Hospital will be recruited when they are informed of their diagnosis.

• Upon accepting participation, patients will be asked to have "fasting" blood samples taken (2x 4 ml) to measure CTX (bone resorption marker) and PINP (bone formation marker). This visit will be coordinated with a scheduled visit according to the program for this patient group and before any treatment is initiated.
• Patients will only have a blood sample taken once.
• It is expected that some of these patients already at this point will have metastases to bone. If this is the case they will continue into Group 2 (see below) and will continue to have blood samples taken as described below (Group 2)

Group 2: PCa patients under suspicion of having bone metastases at the Department of Urology, Lillebaelt Hospital. 

• PCa patients under suspicion of having bone metastases will have fasting blood samples taken once before the bone scintigraphy or NaF PET/CT result is known.
• Those, who despite the suspicion, do not have a positive bone scintigraphy or NaF PET/CT will not have further protocol-related blood samples taken.
• Those who have the suspicion confirmed, and have a positive bone scintigraphy or NaF PET/CT meaning that they have bone metastases, will stay in the protocol. They will have fasting blood samples collected approximately every 3 months for the following 3 years and will take place at routine visits so they will not have extra visits.
• Once 50 mPCa patients with bone metastases have been included in the protocol, recruiting to Group 2 will stop! It is expected that around 200 PCa patients will be recruited to Group 2 before 50 mPCa have been found.

Metastatic castration resistant prostate cancer patients with bone metastases

Group 3: 50 mCRPCa patients newly transferred to the Department of Oncology, Lillebaelt Hospital.

• Fasting blood sample (2x 4 ml) will be collected before new treatments are initiated to measure CTX and PINP.
• Subsequently fasting blood samples will be collected approximately every month for the following 2 years and will take place at routine visits so patients will not have extra visits.

Data and biological material

At baseline

The following basic information about the patient will be registered at baseline:

• Age
• Weight
• Height
• Any previous fractures? When?
• Smoker/non-smoker.
• Date of primary diagnosis
• Date of identification of bone metastasis
• Co-morbidities
• Current medication
• If dexa-scans have been made earlier their result will be noted 

Group 1

6 months after they had their blood samples taken their clinical status will be evaluated (by accessing the patient chart) to see if their disease has progressed

Group 2

Patients where bone metastases were NOT diagnosed

6 months after they had their blood samples taken their clinical status will be evaluated (by accessing the patient charts) to see if their disease has progressed

Information about the types and duration of treatments

Information about surgical intervention or similar

Access to images from bone scintigraphy, NaF PET/CT, CT-/MR-scans and/or X-rays and evaluations of these by nuclear and X-ray specialists

Access to results from blood samples obtained during the inclusion in the protocol. Here it is particularly the measurements of PSA that are important

General information about fitness, co-morbidities and general performance status

Patients where bone metastases WERE diagnosed

Information about the types and duration of treatments

Information about surgical intervention or similar

Access to images from bone scintigraphy, NaF PET/CT, CT-/MR-scans and/or X-rays and evaluations of these by nuclear and X-ray specialists

Access to results from blood samples during the inclusion in the protocol. Here it is particularly the measurements of PSA that are important

General information about fitness, co-morbidities and general performance status

Group 3        

Information about the types and duration of treatments

Information about surgical intervention or similar

Access to images from bone scintigraphy, NaF PET/CT, CT-/MR-scans and/or X-rays and evaluations of these by nuclear and X-ray specialists

Access to results from blood samples during the inclusion in the protocol. Here it is particularly the measurements of PSA that are important

General information about fitness, co-morbidities and general performance status

Measurement of bone biomarkers

CTX and PINP will be determined using an accredited automated procedure that is part of the routine analyses performed in the Department of Biochemistry at Lillebaelt Hospital.

The samples will be stored appropriately and will be measured regularly approximately once a month.

A few patients will be offered to have to their blood samples taken at the Department of Clinical Diagnostics at Esbjerg Hospital in case they live closer to this location. The samples will be labeled with patient ID and be coordinated by the project nurses at Vejle Hospital. The samples will sent to Vejle Hospital for measurement and long term storage

Collaborating researchers and departments

Department of Clinical Cell Biology, Lillebaelt Hospital, University of Southern Denmark

• Associate Professor Kent Søe, PhD, MSc
• Professor Jean-Marie Delaissé, PhD, MSc

Department of Urology, Lillebaelt Hospital

• Professor Palle Osther, PhD, MD
• Chief Consultant/head of department  Bettina Nørby, PhD, MD

Department of Oncology, Lillebaelt Hospital

• Staff specialist Lone Volmer, MD
• Consultant Inge Mejlholm, MD
• Specialist registrar Ahmed Zedan, MD

Department of Immunology and Biochemistry, Lillebaelt Hospital

• Chief Consultant/head of department Jonna Madsen, PhD, MD