Dataset Information

Docetaxel Treatment in PTEN- and ERG-aberrant Metastatic Prostate Cancers.

ABSTRACT:

Background

Loss of PTEN is a common genomic aberration in castration-resistant prostate cancer (CRPC) and is frequently concurrent with ERG rearrangements, causing resistance to next-generation hormonal treatment (NGHT) including abiraterone. The relationship between PTEN loss and docetaxel sensitivity remains uncertain.

Objective

To study the antitumor activity of docetaxel in metastatic CRPC in relation to PTEN and ERG aberrations.

Design setting and participants

Single-centre, retrospective analysis of PTEN loss and ERG expression using a previously described immunohistochemistry (IHC) binary classification system. Patients received docetaxel between January 1, 2006 and July 31, 2016.

Outcome measurements and statistical analysis

Response correlations were analyzed using Pearson's χ² tests and independent-sample t tests. Overall (OS) and progression-free survival (PFS) were analyzed using univariate and multivariate (MVA) Cox regression and Kaplan-Meier methods.

Results and limitations

Overall, 215 patients were eligible. Established metastatic CRPC prognostic factors were well balanced between PTEN loss (39%) and normal patients (61%). PTEN loss was associated with shorter median OS (25.4 vs 34.7 mo; hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.18-2.13; p = 0.001). There were no differences in median PFS (8.0 vs 9.1 mo; univariate HR 1.20, 95% CI 0.86-1.68; p = 0.28) and PSA response (53.4% vs 50.6%; p = 0.74). PTEN loss was an independent prognostics factor in MVA. ERG status was available for 100 patients. ERG positivity was not associated with OS or PFS. Limitations include the retrospective nature and the single-centre analysis.

Conclusions

Our findings suggest that metastatic CRPC with PTEN loss might benefit more from docetaxel than from NGHT.

Patient summary

In this study we found that metastatic prostate cancer with loss of the PTEN switch may benefit more from docetaxel than from abiraterone.

SUBMITTER: Rescigno P

PROVIDER: S-EPMC5995869 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Docetaxel Treatment in PTEN- and ERG-aberrant Metastatic Prostate Cancers.

Rescigno Pasquale P Lorente David D Dolling David D Ferraldeschi Roberta R Rodrigues Daniel Nava DN Riisnaes Ruth R Miranda Susana S Bianchini Diletta D Zafeiriou Zafeiris Z Sideris Spyridon S Ferreira Ana A Figueiredo Ines I Sumanasuriya Semini S Mateo Joaquin J Perez-Lopez Raquel R Sharp Adam A Tunariu Nina N de Bono Johann S JS

European urology oncology 20180501 1

<h4>Background</h4>Loss of PTEN is a common genomic aberration in castration-resistant prostate cancer (CRPC) and is frequently concurrent with ERG rearrangements, causing resistance to next-generation hormonal treatment (NGHT) including abiraterone. The relationship between PTEN loss and docetaxel sensitivity remains uncertain.<h4>Objective</h4>To study the antitumor activity of docetaxel in metastatic CRPC in relation to PTEN and ERG aberrations.<h4>Design setting and participants</h4>Single-c ...[more]

PMID: 29911685

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Project description:Abstract Objectives To assess cabazitaxel versus docetaxel re‐challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy. Patients and Methods The CANTATA trial was a prospective, two‐arm, open‐label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0–2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression‐free survival (PFS) as defined by either date of pain progression, date of a cancer‐related skeletal‐related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012‐003835‐40 Results Between 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54–76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported. Conclusion Due to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy.

Project description:Identification of new molecular markers has led to the molecular classification of prostate cancer based on driving genetic lesions. The translation of these discoveries for clinical use necessitates the development of simple, reliable and rapid detection systems to screen patients for specific molecular aberrations. We developed two dual-color immunohistochemistry-based assays for the simultaneous assessment of ERG-PTEN and ERG-SPINK1 in prostate cancer. A total of 232 cases from 184 localized and 48 metastatic prostate cancers were evaluated for ERG-PTEN and 284 cases from 228 localized and 56 metastatic prostate cancers were evaluated for ERG-SPINK1. Of the 232 cases evaluated for ERG-PTEN, 81 (35%) ERG-positive and 77 (33%) PTEN-deleted cases were identified. Of the 81 ERG-positive cases, PTEN loss was confirmed in 35 (15%) cases by fluorescence in situ hybridization (FISH). PTEN status was concordant in 203 cases (sensitivity 90% and specificity 87%; P<0.0001) by both immunohistochemisty and FISH; however, immunohistochemisty could not distinguish between heterozygous and homozygous deletion status of PTEN. Of the 284 cases evaluated for ERG-SPINK1, 111 (39%) cases were positive for ERG. In the remaining 173 ERG-negative cases, SPINK1 was positive in 26 (9%) cases. SPINK1 expression was found to be mutually exclusive with ERG expression; however, we identified two cases, of which one showed concomitant expression of ERG and SPINK1 in the same tumor foci, and in the second case ERG and SPINK1 were seen in two independent foci of the same tumor nodule. Unlike the homogenous ERG staining in cancer tissues, heterogeneous SPINK1 staining was observed in the majority of the cases. Further studies are required to understand the molecular heterogeneity of cases with concomitant ERG-SPINK1 expression. Automated dual ERG-PTEN and ERG-SPINK1 immunohistochemisty assays are simple, reliable and portable across study sites for the simultaneous assessment of these proteins in prostate cancer.

Dataset Information

Docetaxel Treatment in PTEN- and ERG-aberrant Metastatic Prostate Cancers.

Background

Objective

Design setting and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Publications

Docetaxel Treatment in PTEN- and ERG-aberrant Metastatic Prostate Cancers.

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