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Keywords:

  • Prostate;
  • adenocarcinoma;
  • insulin-like growth factor-1;
  • prostatic biopsies;
  • prostate specific antigen

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objective

To determine whether the use of serum insulin-like growth factor 1 (IGF-1) levels is more efficient than serum prostate specific antigen (PSA) levels in predicting prostate cancer in patients undergoing prostatic biopsy.

Patients and methods

The study included 94 consecutive patients who required transrectal ultrasonography (TRUS)-guided biopsies of their prostate and who had blood samples taken before their biopsies. These samples were then analysed for IGF-1 and PSA concentrations. Six prostatic biopsies were taken from each patient; they were assessed and a diagnosis made of prostate cancer or no malignancy.

Results

Thirty-seven patients were found to have prostate cancer and 57 had no evidence of malignancy. There was no statistical difference in serum IGF-1 levels between these groups. The PSA level and age of the patients differed significantly between the groups (both P<0.001). There was no correlation between IGF-1 and PSA levels, and even when the age difference in the groups was considered, there was still no significant relationship between IGF-1 levels and the incidence of prostate cancer. In patients with a PSA level of 4–20 μg/L there was no statistically significant difference in IGF-1 levels between the groups.

Conclusion

Serum IGF-1 as a tumour marker does not help to predict patients with prostate cancer. PSA level and even age were better predictors of the presence of prostate cancer than were serum IGF-1 levels.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

IGF-1 is a peptide hormone that is structurally and functionally related to insulin [ 1]. It induces cell proliferation, inhibits apoptosis [ 2] and has been implicated in the development of various malignancies, including lung cancer, breast cancer and several embryonal tumours [ 3]. However, the role of serum IGF-1 in the aetiology and diagnosis of prostatic cancer is unclear. There is evidence that immortal prostate cancer cell lines produce IGF-1 and possess the IGF type 1 receptor (IGF-1R) [ 4, 5]. Malignant prostate cells taken from patients and established immortal prostate cancer cell lines are stimulated to grow and proliferate by IGF-1 [ 6, 7].

Early studies were unable to confirm any correlation between serum IGF-1 levels and the presence of prostate cancer [ 8[9]–10]. However, a recent study showed that serum IGF-1 levels are higher in patients with prostate cancer than in patients with BPH or in healthy controls [ 11]. It was also reported that there is an association between an elevated serum IGF-1 level and an increased risk of later developing prostate cancer [ 12]. PSA is a useful marker of prostate cancer but is not specific and may be elevated in benign conditions of the prostate, e.g. BPH and prostatitis. Thus we investigated patients undergoing prostatic biopsy to determine whether levels of serum IGF-1 alone, or IGF-1 with PSA, improved the prediction of cancer compared with PSA alone.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The study included 94 consecutive patients who attended the urology clinic at our hospital and required a TRUS-guided prostatic biopsy. The criteria for this investigation was a total PSA level of > 4 μg/L or a DRE suspicious of malignancy. Before biopsy, all patients had a clotted blood sample taken for analysis of PSA and IGF-1. Serum was stored at −20 °C on the day of collection until analysis. Serum PSA was measured using an equimolar PSA kit on the AutoDelfia system (Wallac Berthold UK, EG&G Ltd) and serum IGF-1 using an immunoradiometric assay kit supplied by Nichols Institute, UK. Six TRUS-guided biopsies were taken from each patient and a diagnosis made of prostate cancer or no malignancy. Patients with prostate cancer were compared with those without. Means were compared using the two sample t-test, logistic regression was used to predict cancer status, and all tests of significance, correlation and multiple regression used logarithmically transformed data.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

From the biopsy, 37 patients had prostate cancer and 57 had no evidence of malignancy ( Table 1); the mean age of patients with cancer was significantly higher than that of those without. The mean total PSA values were also significantly higher in those with cancer ( Table 1) but IGF-1 levels were similar in both groups. Both PSA and IGF-1 level were significantly correlated with age (r=0.36, P<0.001, and r =−0.21, P=0.04, respectively). However, there was no significant correlation between IGF-1 and PSA levels when the values from both groups were combined (r=0.13, P=0.22 (Fig. 1). Table 1 also shows the odds ratios derived for age, PSA and IGF-1 level. These data indicate that in these patients, PSA level was the most significant test in distinguishing patients with cancer from those without; IGF-1 did not add significantly to the separation achieved with PSA.

Table 1.  Age, and PSA and IGF-1 levels in distinguishing patients with prostate cancer from those without Thumbnail image of
image

Figure 1. A comparison of IGF-1 and PSA values in patients with (green) and without (red) prostate cancer.

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In the PSA range of particular clinical interest (4–20 μg/L) there were 17 patients with prostate cancer and 37 patients with no evidence of malignancy. The mean age of patients with cancer was 71.8 years and was 68.4 years in those without (sd 8.7). The mean IGF-1 level in both groups is shown in Table 1; the difference in the IGF-1 levels was not statistically significant (P=0.08, two sample t-test on log-transformed data).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study showed that there was no clear association between IGF-1 levels and positive prostatic biopsies. PSA level and even age were better at predicting biopsy results than was IGF-1 level. That the IGF-1 level decreases and the risk of prostate cancer increases with age may partly account for this lack of correlation. However, even when age was considered using multiple logistic regression analysis, IGF-1 was still unhelpful in distinguishing patients diagnosed with cancer from those who were not.

In patients with a PSA level of 4–20 μg/L the mean IGF-1 level was higher in those found to have prostate cancer than in those with no evidence of cancer. This was partly caused by one spuriously high IGF-1 value in the cancer group (Table 1), but even when this result was included there was still no statistically significant difference in the mean IGF-1-values of the two groups (P=0.08).

Chan et al. [ 12] examined serum IGF-1 levels in patients who later went on to develop prostate cancer. They found that those with higher IGF-1 levels were more at risk of later being diagnosed as having prostate cancer than were those with lower IGF-1 levels. In their study, IGF-1 was measured using an ELISA rather than a radioimmunoassay, as in all the other studies, and the IGF-1 was measured in serum samples which had been stored for 15 years. That study did not show that IGF-1 was a marker of the presence of prostate cancer, but rather showed that a raised serum IGF-1 level may be predictive of the later development of prostate cancer. The present study did not confirm a definite aetiological link between IGF-1 and prostate cancer, and this new information does not assist significantly in the management of patients.

Previous studies showed that there was no significant difference in serum IGF-1 levels between patients with prostate cancer and healthy controls [ 8[9]–10]; all these studies had very few patients. More recently Mantzaros et al. [ 11] conducted a case-control study examining serum IGF-1 levels in 52 patients with newly diagnosed prostate cancer, compared with age-matched patients with BPH and with healthy controls. The patients with prostate cancer had a significantly higher concentration of IGF-1. However, it is not clear from that report how the patients with prostate cancer were diagnosed. There was no mention of prostate biopsies or PSA values and the authors did not clarify whether they had specifically excluded a diagnosis of prostate cancer in both of the comparison groups.

IGF-1 is known to have metabolic effects as well as growth promotion effects, and causes an increase in DNA synthesis, cell proliferation and cell differentiation [ 13]. It is also thought to inhibit apoptosis [ 2]. There are binding proteins that regulate the availability of the free, biologically active IGF-1. There are also various proteases that cleave the binding proteins, releasing the free IGF-1. The most abundant binding protein in the circulation is IGFBP-3, and this is split by a protease allowing the release of free IGF-1; this specific protease has been identified as PSA [ 14].

Prostate cancer cells grown in culture possess abundant IGF-1R and IGF-1 acts as a mitogen when added to them [ 6]. IGF-1 therefore plays an important role in the growth and proliferation of prostate cancer cells in vitro, but whether this is significant in the development of prostate cancer in vivo is still unconfirmed.

There are many variables that can alter IGF-1 levels. Serum levels of IGF-1 are reasonably constant during waking hours but fall significantly during sleep, and take until late morning to rise to a stable level. It is well established that IGF-1 in the circulation decreases with age after puberty [ 15[16]–17]. Serum IGF-1 has also been found to be a useful marker of nutritional status, and decreases in both protein and energy malnutrition [ 18, 19]. Fasting also causes a significant decrease in circulating IGF-1 [ 20]. Epidemiological studies have shown that smoking is associated with a lower [ 21] and drinking alcohol with a higher serum IGF-1 level [ 17]. Decreased exercise is also thought to correspond to lower levels of IGF-1 [ 22]. Height and weight do not seem to be linked with serum IGF-1 concentrations in adults [ 17]. In addition, numerous disease states affect circulating IGF-1 levels; inflammatory bowel disease [ 23], coeliac disease [ 24], and anorexia nervosa [ 25] all lower IGF-1 serum levels, but this may be a reflection of nutritional status. Liver disease [ 26] and endocrine disorders such as diabetes mellitus [ 27], acromegaly [ 28] and hypopituitary disease, all affect serum IGF-1 levels.

As many different factors can alter circulating concentrations of IGF-1, IGF-1 alone is unlikely to be a useful marker in a specific disease state such as prostate cancer. IGF-1 may well have an important role in the pathogenesis of prostate cancer, but the present study shows that it does not have a useful role as a serum marker for the presence of prostate cancer.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We are grateful to Dr C.M. Corbishley, Consultant Histopathologist, and Dr U. Patel, Consultant Radiologist, for allowing us access to the radiology and histology database at St George’s Hospital.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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