PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate - PubMed (original) (raw)

. 2015 Apr;67(4):795-802.

doi: 10.1016/j.eururo.2014.10.027. Epub 2014 Nov 4.

Daniel Nava Rodrigues 1, Ruth Riisnaes 1, Susana Miranda 1, Ines Figueiredo 1, Pasquale Rescigno 1, Praful Ravi 1, Carmel Pezaro 1, Aurelius Omlin 1, David Lorente 1, Zafeiris Zafeiriou 1, Joaquin Mateo 1, Amelia Altavilla 1, Spyridon Sideris 1, Diletta Bianchini 1, Emily Grist 1, Khin Thway 1, Raquel Perez Lopez 1, Nina Tunariu 1, Chris Parker 2, David Dearnaley 2, Alison Reid 1, Gerhardt Attard 1, Johann de Bono 3

Affiliations

PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate

Roberta Ferraldeschi et al. Eur Urol. 2015 Apr.

Abstract

Background: Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer.

Objective: To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression.

Design, setting, and participants: We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis.

Outcome measurements and statistical analysis: The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses.

Results and limitations: A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19-2.55; p=0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12-2.28; p=0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis.

Conclusions: Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted.

Patient summary: PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression.

Keywords: Abiraterone acetate; Immunohistochemistry; PTEN; Prostate cancer.

Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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Figures

Fig. 1

Fig. 1

Cytoplasmic (right) and nuclear (left) PTEN H-score in specimens with no somatic cell deletion of PTEN by fluorescent in situ hybridization (FISH) (no deletion); heterozygous somatic PTEN loss by FISH (heterozygous loss); and homozygous (biallelic) somatic PTEN loss by FISH (homozygous loss). Staining intensity in prostate cancer cells was scored 0–3 (negative; weak; moderate; intense), and this value was multiplied by the percentage of cancer cells staining positively to generate an H-score (0–300). PTEN protein loss was defined as an H-score ≤10 (red line). FISH = fluorescent in situ hybridization.

Fig. 2

Fig. 2

Micrographs show PTEN expression by diaminobenzidine immunohistochemistry method in six samples. (A) Column A displays three micrographs of primary prostate adenocarcinoma. (A1) Needle biopsy with moderate nuclear and cytoplasmic PTEN protein expression (×100 magnification). (A2) Prostatectomy specimen with extensive PTEN protein negative adenocarcinoma infiltration. In the upper right-hand corner, cytoplasmic PTEN protein–positive benign glands are adjacent to invasive carcinoma (×50 magnification). (A3) Prostatectomy specimen showing heterogeneous PTEN protein expression (×50 magnification). Two inserted photographs at ×200 magnification demonstrate cytoplasmic positivity (upper right: short dashes square) and negativity (bottom left: long dashes square). Nuclear staining was predominantly negative in both areas. (B) Column B shows three matched metastatic castration-resistant prostate cancer samples acquired at a later time point from the same patients as the respective diagnostic samples in column A. (B1, B2) PTEN negativity has been verified in bone marrow and liver metastases, respectively (×200 magnification). (B3) PTEN nuclear and cytoplasmic positivity is demonstrated in tumor nests of a lymph node biopsy (×200 magnification). CRPC = castration-resistant prostate cancer.

Fig. 3

Fig. 3

Kaplan-Meier survival curves from initiation of abiraterone treatment according to PTEN expression status demonstrating a significantly shorter overall survival for patients with PTEN protein loss. CI = confidence interval; HR = hazard ratio.

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