Recurrent Prostate Cancer Genomic Alterations Predict Response to Brachytherapy Treatment

Fontugne, Jacqueline; Lee, Daniel; Cantaloni, Chiara; Barbieri, Christopher E.; Caffo, Orazio; Hanspeter, Esther; Mazzoleni, Guido; Palma, Paolo Dalla; Rubin, Mark A.; Fellin, G.; Mosquera, Juan Miguel; Barbareschi, Mattia; Demichelis, Francesca

doi:10.1158/1055-9965.epi-13-1180

Cited by 27 publications

(19 citation statements)

References 49 publications

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“…We are unable to differentiate whether the clonal heterogeneity we observe is a result of multiple different foci with distinct cells of origin or clones arising from the same cell in which these genomic aberrations have occurred stochastically. Although there is an association between ERG rearrangement and PTEN deletion (28, 29), here we identified a higher prevalence of loss of PTEN and NKX3.1 than reported previously. The detection of coexistent clones, each with a different ERG status, is in contrast to previous studies on metastases obtained at rapid autopsy or CTC data that reported 21q deletion in all CRPC tissue from the same patient (2, 30).…”

Section: Discussioncontrasting

confidence: 87%

Tumor clone dynamics in lethal prostate cancer

et al. 2014

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It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.

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Section: Discussioncontrasting

confidence: 87%

Tumor clone dynamics in lethal prostate cancer

et al. 2014

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“…In a study of 262 patients [40], loss of PTEN protein expression by IHC was more strongly associated with biochemical recurrence among ERG-positive compared to ERG-negative tumors. Similar findings have been reported for a cohort of patients treated with brachytherapy [41]. Only one study has examined the interaction of PTEN and ERG and their association with PCa-specific mortality in a cohort of 308 patients managed conservatively [16].…”

Section: Discussionsupporting

confidence: 78%

“…Indeed, this may be why PTEN loss was not significant in the final multivariate models for ERG-negative tumors, but was significant for ERG-positive tumors. In previous studies, only between five and 19 ERG-negative tumors with PTEN loss were available for follow-up [21,40,41], so the studies may also have been underpowered for observation of an association with outcome in this subgroup. By contrast, the largest FISH-based study that found no effect of ERG status on the association of PTEN loss with progression examined 97 and 356 ERG-negative PTEN-loss tumors in the original and expanded series [17,39].…”

Section: Discussionmentioning

confidence: 99%

PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer

Lotan

Wei

Morais³

et al. 2016

European Urology Focus

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Background PTEN is the most commonly deleted tumor suppressor gene in primary prostate cancer (PCa) and its loss is associated with poor clinical outcomes and ERG gene rearrangement. Objective We tested whether PTEN loss is associated with shorter recurrence-free survival (RFS) in surgically treated PCa patients with known ERG status. Design, setting, and participants A genetically validated, automated PTEN immunohistochemistry (IHC) protocol was used for 1275 primary prostate tumors from the Canary Foundation retrospective PCa tissue microarray cohort to assess homogeneous (in all tumor tissue sampled) or heterogeneous (in a subset of tumor tissue sampled) PTEN loss. ERG status as determined by a genetically validated IHC assay was available for a subset of 938 tumors. Outcome measurements and statistical analysis Associations between PTEN and ERG status were assessed using Fisher’s exact test. Kaplan-Meier and multivariate weighted Cox proportional models for RFS were constructed. Results and limitations When compared to intact PTEN, homogeneous (hazard ratio [HR] 1.66, p = 0.001) but not heterogeneous (HR 1.24, p = 0.14) PTEN loss was significantly associated with shorter RFS in multivariate models. Among ERG-positive tumors, homogeneous (HR 3.07, p < 0.0001) but not heterogeneous (HR 1.46, p = 0.10) PTEN loss was significantly associated with shorter RFS. Among ERG-negative tumors, PTEN did not reach significance for inclusion in the final multivariate models. The interaction term for PTEN and ERG status with respect to RFS did not reach statistical significance (p = 0.11) for the current sample size. Conclusions These data suggest that PTEN is a useful prognostic biomarker and that there is no statistically significant interaction between PTEN and ERG status for RFS. Patient summary We found that loss of the PTEN tumor suppressor gene in prostate tumors as assessed by tissue staining is correlated with shorter time to prostate cancer recurrence after radical prostatectomy.

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“…Although it remains unclear why this enrichment of PTEN loss occurs among ERG‐positive acinar tumors in humans, genetically engineered mouse models have suggested these two genetic alterations may have synergistic effects on tumor cell growth, migration and androgen signaling, leading to selection for ERG‐positive PTEN‐negative tumor clones . However, human studies examining the interaction between PTEN loss and ERG expression for disease outcomes have been mixed . This raises the possibility that ERG rearrangement, which precedes PTEN deletion in most cases, may directly or indirectly predispose tumor cells to PTEN loss.…”

Section: Discussionmentioning

confidence: 99%

PTEN loss and ERG protein expression are infrequent in prostatic ductal adenocarcinomas and concurrent acinar carcinomas

et al. 2015

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Background Prostatic ductal adenocarcinoma is an unusual and aggressive morphologic subtype of prostate cancer. PTEN gene deletion and ERG gene rearrangement are among the most common genomic changes in acinar prostate cancers. Though ductal adenocarcinoma most commonly occurs with synchronous usual-type acinar adenocarcinoma, little is known about the molecular phenotype of these mixed tumors. Methods We used genetically validated immunohistochemistry (IHC) assays to assess PTEN and ERG status in a group of 37 surgically treated ductal adenocarcinomas and 18 synchronous acinar adenocarcinomas where we have previously reported ERG gene rearrangement status by fluorescence in situ hybridization (FISH). A group of 34 stage and grade-matched pure acinar adenocarcinoma cases was studied as a control. Results ERG IHC was highly concordant with ERG FISH results, with 100% (36/36) concordance among ductal adenocarcinomas and 91% (31/34) concordance among 34 pure acinar carcinomas. Similar to previous FISH results, ERG expression by IHC was significantly less common among ductal adenocarcinomas (11% or 4/37) and their synchronous acinar tumors (6% or 1/18) compared to matched pure acinar adenocarcinoma cases (50% or 17/34; p= 0.0005 and 0.002, respectively). PTEN loss by IHC was also less common among ductal adenocarcinomas (18% or 6/34) and their synchronous acinar tumors (22% or 4/18) compared to matched pure acinar carcinomas (50% or 17/34; p = 0.01 and 0.08, respectively). As expected, PTEN loss was enriched among ERG positive compared to ERG-negative tumors in the pure acinar tumor control group (2.5-fold enrichment; p=0.04) however this was not observed among the ductal adenocarcinomas (1.5 fold enrichment; p=NS). Of ductal adenocarcinomas with an evaluable synchronous acinar component, ERG status was concordant in 94% (17/18) and PTEN status was concordant in 94% (16/17). Conclusions Based on PTEN and ERG, ductal adenocarcinomas and their concurrent acinar carcinomas may be clonally related in some cases and show important molecular differences from pure acinar carcinoma.

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Recurrent Prostate Cancer Genomic Alterations Predict Response to Brachytherapy Treatment

Cited by 27 publications

References 49 publications

Tumor clone dynamics in lethal prostate cancer

Tumor clone dynamics in lethal prostate cancer

PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer

PTEN loss and ERG protein expression are infrequent in prostatic ductal adenocarcinomas and concurrent acinar carcinomas

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