Investigating the role of the IGF axis as a predictor of biochemical recurrence in prostate cancer patients post-surgery

Between 20% and 35% of prostate cancer (PCa) patients who undergo treatment with curative intent (ie, surgery or radiation therapy) for localized disease will experience biochemical recurrence (BCR). Alterations in the insulin-like growth factor (IGF) axis and PTEN expression have been implicated in the development and progression of several human tumors including PCa. We examined the expression of the insulin receptor (INSR), IGF-1 receptor (IGF-1R), PTEN, and AKT in radical prostatectomy tissue of patients who developed BCR post-surgery.

Tissue microarrays (TMA) of 130 patients post-radical prostatectomy (65 = BCR, 65 = non-BCR) were stained by immunohistochemistry for INSR, IGF-1R, PTEN, and AKT using optimized antibody protocols. INSR, IGF1-R, PTEN, and AKT expression between benign and cancerous tissue, and different Gleason grades was assessed. Kaplan-Meier survival curves were used to examine the relationship between proteins expression and BCR.

INSR (P < 0.001), IGF-1R (P < 0.001), and AKT (P < 0.05) expression was significantly increased and PTEN (P < 0.001) was significantly decreased in cancerous versus benign tissue. There was no significant difference in INSR, IGF-1R, or AKT expression in the cancerous tissue of non-BCR versus BCR patients (P = 0.149, P = 0.990, P = 0.399, respectively). There was a significant decrease in PTEN expression in the malignant tissue of BCR versus non-BCR patients (P = 0.011). Combinational analysis of the tissue proteins identified a combination of decreased PTEN and increased AKT or increased INSR was associated with worst outcome. We found that in each case, our hypothesized worst group was most likely to experience BCR and this was significant for combinations of PTEN+INSR and PTEN+AKT but not PTEN+IGF-1R (P = 0.023, P = 0.028, P = 0.078, respectively).

Low PTEN is associated with BCR and this association is strongly modified by high INSR and high AKT expression. Measurement of these proteins could help inform appropriate patient selection for postoperative adjuvant therapy and prevent BCR.

The Prostate. 2017 Jul 20 [Epub ahead of print]

Kieran J Breen, Amanda O'Neill, Lisa Murphy, Yue Fan, Susie Boyce, Noel Fitzgerald, Emma Dorris, Lauren Brady, Stephen P Finn, Brian D Hayes, Ann Treacy, Ciara Barrett, Mardiana Abdul Aziz, Elaine W Kay, John M Fitzpatrick, R William G Watson

UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland., Department of Histopathology and Morbid Anatomy, Trinity Translational Medicine Institute, Trinity College, Dublin, Ireland., Department of Histopathology, Mater Misericordiae University Hospital, Dublin, Ireland., Department of Pathology, RCSI Education and Research Centre, Beaumont Hospital, Dublin, Ireland.