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Genetic Polymorphism in EGF Is Associated with Prostate Cancer Aggressiveness and Progression-Free Interval in Androgen Blockade–Treated Patients

Authors' Affiliations: ¹ Molecular Oncology Group-CI, ² Virology Department, and ³ Urology Department, Portuguese Institute of Oncology, Porto Centre; ⁴ Abel Salazar Biomedical Sciences Institute, Porto University; ⁵ Urology Department, Hospital Militar do Porto; ⁶ Urology Department, Hospital S. João, Porto, Portugal and ⁷ Urology Department, Lisbon Medical Centre (Central Region), Lisbon, Portugal

Requests for reprints: Rui Medeiros, Instituto Português de Oncologia do Porto Francisco Gentil, EPE Grupo de Oncologia Molecular-CI, Edifício Laboratórios, 4° piso Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal. Phone: 351-22-508-4000; Fax: 351-22-508-4001; E-mail: ruimedei{at}ipoporto.min-saude.pt.

Purpose: Most prostate cancer patients develop resistance to androgen deprivation treatment, resulting in hormone resistance. Epidermal growth factor (EGF) activates several pro-oncogenic intracellular pathways inducing proliferation, differentiation, and tumorigenesis in epithelial cells. The EGF-EGF receptor pathway seems to be especially relevant in hormone-resistant prostate cancer stage. A single nucleotide polymorphism G>A in +61 locus of EGF gene has been described, in which A homozygous carriers express significantly less EGF protein compared with G allele carriers. Our purpose was to investigate the potential prognostic and predictive role of EGF functional genetic variant +61 G>A in prostate cancer patients submitted to androgen blockade therapy (ABT).

Experimental Design: We conducted a case-control study in prostate cancer patients treated with ABT (n = 123) and in healthy controls without evidence of cancer (n = 152). Cumulatively, a follow-up study (median follow-up, 37 months) was undertaken to evaluate response to ABT therapy in prostate cancer patients. EGF +61 G>A genotypes were detected by PCR-RFLP.

Results: We found increased risk in G carriers, after age-adjusted regression analysis, for being diagnosed with Gleason 7 and with metastatic disease compared with control group (CG; age-adjusted odds ratio, 3.37, P = 0.004 and age-adjusted odds ratio, 2.61, P = 0.043, respectively). Kaplan-Meier survival analysis and log-rank test showed an influence of EGF +61 G>A polymorphism in time to relapse during ABT (P = 0.018).

Conclusions: EGF functional polymorphism may contribute to earlier relapse in ABT patients, supporting the involvement of EGF as an alternative pathway in hormone-resistant prostatic tumors. Furthermore, our results lend support to EGF-EGF receptor pathway as an additional therapeutic target during hormonal treatment.