TMPRSS2-ERG in Blood and Docetaxel Resistance in Metastatic Castration-resistant Prostate Cancer

Reig, Òscar; Marín-Aguilera, Mercedes; Carrera, G; Jiménez, Natàlia; Paré, Laia; García-Recio, Susana; Gaba, Lydia; Pereira, María Verónica; Fernández, Pedro; Prat, Aleix; Mellado, Begoña

doi:10.1016/j.eururo.2016.02.034

Cited by 71 publications

(57 citation statements)

References 9 publications

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“…This study shows that the detection of blood TMPRSSR2‐ERG mRNA before the start of therapy is associated with a lower response rate and lower PSA‐PFS to taxanes, confirming in a larger series of patients our prior results . However, this was not observed when TMPRSSR2‐ERG mRNA was tested in tumor samples .…”

Section: Discussionsupporting

confidence: 87%

The influence of treatment sequence in the prognostic value of TMPRSS2‐ERG as biomarker of taxane resistance in castration‐resistant prostate cancer

Marín-Aguilera

Reig

Milà-Guasch

et al. 2019

Intl Journal of Cancer

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TMPRSS2‐ERG expression in blood has been correlated with low docetaxel benefit in metastatic castration‐resistant prostate cancer (mCRPC). This multicenter study aimed to prospectively asses its role as a taxane‐resistance biomarker in blood and retrospectively in tumors, exploring also the impact of prior abiraterone/enzalutamide (A/E) in patients and in vitro. TMPRSS2‐ERG was tested by quantitative reverse‐transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2‐ERG expression was correlated with prostate‐specific antigen (PSA)‐progression‐free survival (PFS), radiological‐PFS (RX‐PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. In vitro ERG knockdown and combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Prior A/E (HR 1.8, 95% CI 1.2–2.8) and blood TMPRSS2‐ERG detection (HR 2, 95% CI 1.1–3.7) were independently associated to lower PSA‐PFS. In patients without prior A/E, blood and tumor TMPRSS2‐ERG independently predicted lower PSA‐PFS (HR 3.3, 95% CI 1.4–7.9 and HR 1.8, 95% CI 1.02–3.3, respectively) to taxanes. When prior A/E was administered, TMPRSS2‐ERG was not associated with outcome. There was a significant interaction between blood TMPRSS2‐ERG and prior A/E related to PSA‐PFS (p = 0.032) and RX‐PFS (p = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced the expression of neuroendocrine markers and reduced that of E‐cadherin. We conclude that prior hormone‐therapy may influence taxanes response and TMPRSS2‐ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow‐up evaluation.

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Section: Discussionsupporting

confidence: 87%

The influence of treatment sequence in the prognostic value of TMPRSS2‐ERG as biomarker of taxane resistance in castration‐resistant prostate cancer

Marín-Aguilera

Reig

Milà-Guasch

et al. 2019

Intl Journal of Cancer

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“…It is interesting to note that Reig et al recently has reported that the detection of TMPRSS2-ERG fusion transcripts in the peripheral blood mononuclear cell fraction predicted a lower PSA progression free survival to docetaxel or cabazitaxel treatments (49). Since the TMPRSS2-ERG fusion is driven by AR and unique to PCa cells, we would consider the detection of TMPRSS2-ERG fusion transcript in our future validation studies.…”

Section: Discussionmentioning

confidence: 99%

Association of AR-V7 and Prostate-Specific Antigen RNA Levels in Blood with Efficacy of Abiraterone Acetate and Enzalutamide Treatment in Men with Prostate Cancer

Xie

Nakabayashi

et al. 2017

Clinical Cancer Research

100

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Purpose We evaluated the association of prostate specific antigen (PSA) and androgen receptor splice variant-7 (AR-V7) transcript levels in patients’ blood with time to treatment failure (TTF) and overall survival (OS) with abiraterone acetate (AA) and/or enzalutamide treatment in castration resistant prostate cancer (CRPC) patients. Experimental Design RNA levels of AR-V7 and PSA in peripheral blood collected before treatment were quantified using Droplet Digital-PCR in retrospective cohorts treated with AA (N=81) or enzalutamide (N=51) for CRPC. Multivariable Cox regression adjusted for known prognostic factors was used for analyses. Results PSA-transcripts were detected in 57% of AA-treated patients and in 63% of enzalutamide-treated patients. PSA-positive patients had a shorter TTF than PSA-negative patients (adjusted-HR=2.27 (95%CI: 1.26, 4.10) and 2.60 (95%CI: 1.19, 5.69); p-value=0.006 and 0.017 in AA and enzalutamide cohorts, respectively). Patients with a higher-AR-V7 transcript level had a shorter TTF with AA and enzalutamide in univariate analysis (median 8.0 versus 15.6 months, p=0.046 in AA-cohort and 3.6 versus 5.6 months, p=0.050 in enzalutamide-cohort). In multivariable models, the association with TTF remained significant in the enzalutamide-cohort (adjusted-HR=2.02; 95%CI:1.01, 4.05; p=0.048), but statistically insignificant in the AA-cohort. In both cohorts, we observed potential prognostic value of both PSA and AR-V7 RNA expression on OS; patients with detectable PSA transcripts and high AR-V7 predicted the poorest OS. Conclusions PSA and AR-V7 transcripts in blood potentially serve as biomarkers predicting TTF and OS with AA or enzalutamide treatment. If validated prospectively, their detection could be facilitated without isolation of circulating tumor cells.

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“…86 Additional effects of ERG overexpression interacting with microtubule dynamics leading to taxane resistance was shown, 87 and detection of TMPRSS2/ERG fusion as a biomarker might have clinical potential for the prediction of taxane sensitivity. 88,89 Mutations in the DNA repair pathway are now intensely focused on the field of cancer research. The BRCA2 mutation, for example, is known as a significant predisposition marker for aggressive prostate cancer, 90,91 and defect of BRCA2 might be a predictive biomarker for the exceptional response to DNA-damaging chemotherapeutics, such as cisplatin.…”

Section: Cross-resistance Between Classes Of Agentsmentioning

confidence: 99%

Current treatment strategies for advanced prostate cancer

et al. 2017

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During the past decade, treatment strategies for patients with advanced prostate cancer involving stage IV (T4N0M0, N1M0 or M1) hormone-sensitive prostate cancer and recurrent prostate cancer after treatment with curative intent, as well as castration-resistant prostate cancer, have extensively evolved with the introduction and approval of several new agents including sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, all of which have shown significant improvement on overall survival. The appropriate use of these agents and the proper sequencing of these agents are still not optimized. The results of several recently reported randomized controlled trials and retrospective studies could assist in developing a treatment strategy for advanced prostate cancer. In addition, prospective studies and molecular characterization of tumors to address these issues are ongoing.

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TMPRSS2-ERG in Blood and Docetaxel Resistance in Metastatic Castration-resistant Prostate Cancer

Cited by 71 publications

References 9 publications

The influence of treatment sequence in the prognostic value of TMPRSS2‐ERG as biomarker of taxane resistance in castration‐resistant prostate cancer

The influence of treatment sequence in the prognostic value of TMPRSS2‐ERG as biomarker of taxane resistance in castration‐resistant prostate cancer

Association of AR-V7 and Prostate-Specific Antigen RNA Levels in Blood with Efficacy of Abiraterone Acetate and Enzalutamide Treatment in Men with Prostate Cancer

Current treatment strategies for advanced prostate cancer

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