| PSA-NEGATIVE PROSTATE CANCER
Dr Alison Birtle, Clinical Research Fellow Institute of Urology and Nephrology, Royal Free Hospital Medical School |
Prostate cancer is the most frequently diagnosed cancer in men and kills over 10,000 men every year in the UK. One in 10 men over 50 will be diagnosed with prostate cancer and if a man lives long enough, he will almost certainly develop prostate cancer.
The management of prostate cancer has been helped by a blood test called the PSA test (prostate specific antigen). This is of limited use for diagnosis, but is very useful for following the progress of the disease if the PSA level falls or is absent then the cancer is responding, whereas if the PSA level rises then the cancer is growing.
So PSA is informative, but there is one group of unfortunate men whose cancers do not produce PSA. They tend to have highly aggressive cancers. It is very difficult to tell whether the cancer is responding to therapy because of the lack of any marker to follow the disease. Conventional treatments tend to fail and these men usually have a difficult and painful period of ineffective treatment followed by death due to the cancer. It is this group of men that Dr Alison Birtle set out to study. Her goals were
1. To define the natural history of PSA negative cancer (with the aim of defining better ways of managing these cancers). 2. To look for alternative markers that could be used to follow the progress of the disease (so that response to therapy can be monitored). 3. To understand why some cancers do not produce PSA.
Until Dr Birtles work, very little had been published on men presenting with metastatic PSA-negative prostate cancer, other than a few case reports (reports on one or a handful of cases).
Report
The first tasks were to obtain ethical approval and identify men presenting with metastatic prostate cancer with negative or inappropriately low serum levels (less than 10ng/ml) of P SA. The British Association of Urological Surgeons have a database of UK men with prostate cancer, from which 60 men were identified who were diagnosed in 2000 or 2001 and appeared to fit the criteria.
From these 60 cases, consent was obtained and tissue was obtained from 33 cases. It should be stressed that this was an enormous administrative task, necessitating visits to hospitals around the UK and liaison with ethical committees, patients, urologists and histopathologists in order to access the medical notes and stored tissue, and that Dr Birtle has managed to collect by far the largest series of these cases.
Natural history
All the clinical information on these cases was collected. This series of patients had a very poor outcome. The period of survival following diagnosis was approximately half that of PSA-positive cancers and the period of response to hormone therapy was very short. The indications are that these men should be treated with more aggressive chemotherapy to try to prolong survival. Dr Birtle's findings were published in a leading cancer journal (Birtle et al, 2003).
Tumour markers for PSA negative prostate cancer
In order to look for alternative markers, sections of the cancers were cut and stained for other proteins that are found in the prostate, including PSMA (prostate specific membrane antigen), PAP (prostatic acid phosphatase) and AR (androgen receptor). All these markers were found in the majority of the PSA negative cancers, indicating that they could be used as aids in differential diagnosis and might also be found in the serum (further experiments would be needed to test this possibility). This work has been written up and submitted to a leading urological journal (Birtle et al, 2004).
Why are some prostate cancers PSA negative?
Using a PSA negative prostate cancer cell line, it was found that PSA production could be switched back on by a drug that removes methyl groups from DNA. Methylation is one of the processes by which genes are switched on and off. This preliminary work is included in Dr Birtle's MD thesis.
Future work
This has been a very successful and productive project. Dr Birtle has undertaken a large body of work and published original papers providing guidance for doctors treating these cancers. Dr Birtle has also written up the work for a higher degree (MD), which has been submitted to the University of London and will be examined early in 2005. Dr Birtle has recently been appointed a consultant in clinical oncology, and plans to pursue some of the leads identified in this project.
References
Birtle AJ, Freeman A, Payne HA, Masters JRW, Harland SJ. Neuroendocrine differentiation in prostate cancer: is it detectable and treatable? BJU Int 92: 490,2003.
Birtle AJ, Freeman A, Masters JRW, Payne HA, Harland SJ and contributors to the BAUS section of oncology cancer registry. Clinical features of patients who present with metastatic prostate carcinoma and serum prostate specific antigen (PSA) levels <10ng/inL. Cancer 98: 2362 2367, 2003.
Birtle AJ, Freeman A, Masters JR, Payne HA, Harland SJ and Contributors to the BAUS Section of Oncology Cancer Registry. Potential new markers in the diagnosis of PSA negative prostate cancer. Brit J Urology Int, submitted, 2004.
Birtle AJ. PSA negative prostate cancer. MD thesis, University of London, submitted 2004.
Research summary dated 01 December 2004
Project 2001/10