IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer

Abstract

Background: Activated type 1 insulin-like growth factor receptors (IGF-1Rs) undergo internalisation and nuclear translocation, promoting cell survival. We previously reported that IGF-1R inhibition delays DNA damage repair, sensitising prostate cancer cells to ionising radiation. Here we tested the clinical relevance of these findings.

Methods: We assessed associations between IGF-1R and clinical outcomes by immunohistochemistry in diagnostic biopsies of 136 men treated with 55-70 Gy external beam radiotherapy for prostate cancer, comparing results with publicly available transcriptional data in surgically treated patients.

Results: Following radiotherapy, overall recurrence-free survival was shorter in patients whose tumours contained high total, cytoplasmic and internalised (nuclear/cytoplasmic) IGF-1R. High total IGF-1R associated with high primary Gleason grade and risk of metastasis, and cytoplasmic and internalised IGF-1R with biochemical recurrence, which includes patients experiencing local recurrence within the radiation field indicating radioresistance. In multivariate analysis, cytoplasmic, internalised and total IGF-1R were independently associated with risk of overall recurrence, and cytoplasmic IGF-1R was an independent predictor of biochemical recurrence post radiotherapy. Insulin-like growth factor receptors expression did not associate with biochemical recurrence after radical prostatectomy.

Conclusions: These data reveal increased risk of post-radiotherapy recurrence in men whose prostate cancers contain high levels of total or cytoplasmic IGF-1R.

Figure 1

Type 1 IGF receptor associates with adverse outcomes in patients treated with radical radiotherapy for prostate cancer. (A) Examples of IGF-1R IHC in diagnostic biopsies of prostate cancer from patients treated with radiotherapy. (a) Gleason 3+4=7 cancer, IGF-1R score membrane 0, cytoplasm 12, nuclear 9; (b) Gleason 4+3=7 cancer, IGF-1R score membrane 6, cytoplasm 3, nuclear 0; (c) Gleason 3+3=6 cancer containing no detectable IGF-1R; (d) Gleason 4+5=9 cancer, IGF-1R score membrane 0, cytoplasm 12, nuclear 0. Scale bar, 20 μm. (B) Total IGF-1R score (bars, mean±s.e.m.) in benign and malignant areas (***P=0.001 by Wilcoxon matched-pairs signed rank test). (C–E) Kaplan–Meier plots with log-rank (Mantel–Cox) tests to assess association of total, cytoplasmic (Cyto) and internalised (Intern) IGF-1R with (C) all recurrences, (D) metastatic recurrence and (E) biochemical recurrence.