p53 status in the primary tumor predicts efficacy of subsequent abiraterone and enzalutamide in castration-resistant prostate cancer

Maughan, Benjamin L.; Guedes, Liana B.; Boucher, Kenneth M.; Rajoria, Gaurav; Liu, Zach; Klimek, Szczepan; Zoino, Roberto; Antonarakis, Emmanuel S.; Lotan, Tamara L.

doi:10.1038/s41391-017-0027-4

Cited by 50 publications

(36 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is uncertain how this mechanism may apply to our study since GR expression was decreased in resistant cells. Interestingly, two recent clinical studies in prostate cancer have correlated poor treatment response to enzalutamide with p53 alterations in tumors [28,29]. Our data suggest similar ineffectiveness to anti-androgen therapy should be expected in human endometrial cancers containing p53 alterations.…”

Section: Discussionsupporting

confidence: 64%

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma

Koivisto

Parrish

Bonala

et al. 2019

Preprint

View full text Add to dashboard Cite

Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Pten fl/fl . In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.

show abstract

Section: Discussionsupporting

confidence: 64%

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma

Koivisto

Parrish

Bonala

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…TP53 alterations are linked to poor prognosis and may represent an important variable to capture at initial diagnosis [10,21]. For ADT-naïve patients, over half (9/17) of the non-silent TP53 mutations were missed by either tissue biopsy profiling or cfDNA sequencing, primarily due to failure of one approach to capture any somatic information, as described above (Fig.…”

Section: Ctdna and Tissue Biopsy Provide Complementary Insight To Drimentioning

confidence: 99%

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

et al. 2019

View full text Add to dashboard Cite

Word count abstract: 293Word count text: 2592 This is the accepted manuscript of the article, which has been published in European Urology. 2019, 75(4), 667-675. http://dx. AbstractBackground: Several systemic therapeutic options exist for metastatic castratesensitive prostate cancer (mCSPC). Circulating tumour DNA (ctDNA) can molecularly profile metastatic castration-resistant prostate cancer (mCRPC) and can influence decision-making, but remains untested in mCSPC. Objective:To determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically-relevant information to a prostate biopsy. Design, Setting, and Participants:We collected plasma cell-free DNA (cfDNA) from 53 newly diagnosed patients with mCSPC and, where possible, during treatment.Targeted sequencing was performed on cfDNA and DNA from diagnostic prostate tissue. Results and Limitations:Median ctDNA fraction was 11% (range 0-84) among untreated patients but lower (1.0%, range 0-51) in patients after short term (median 22 days) androgen deprivation therapy (ADT). TP53 mutations and DNA repair defects were identified in 47% and 21% of the cohort, respectively. Concordance for mutation detection in matched samples was 80%. Combined ctDNA and tissue analysis identified potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone was insufficient in 19 cases (36%). Limitations include the use of a narrow gene panel and undersampling of primary disease by prostate biopsy.Conclusions: ctDNA provides additional information to a prostate biopsy in men with de novo mCSPC, but ADT rapidly reduces ctDNA availability. Primary tissue and ctDNA share relevant somatic alterations, suggesting that either are suitable for molecular subtyping in de novo mCSPC. The optimal approach for biomarker development should ! 3 utilize both a tissue and liquid biopsy at diagnosis, as neither captures clinically-relevant somatic alterations in all patients. Patient summary:In men with advanced prostate cancer, tumour DNA shed into the bloodstream can be measured by a blood test. The information from this test provides complementary information to a prostate needle biopsy and could be used to guide management strategies.! 4

show abstract

“…(TP53) are associated with poor prognosis [100,106,107]. TP53 is a tumor suppressor gene of which alterations are frequently observed, up to 50%, in mCRPC patients [103].…”

Section: Tp53 Aberrations Aberrations In Tumor Protein 53mentioning

confidence: 99%

Clinical utility of emerging biomarkers in prostate cancer liquid biopsies

Boerrigter¹,

Groen

Erp³

et al. 2019

Expert Review of Molecular Diagnostics

View full text Add to dashboard Cite

Introduction: Prostate cancer (PCa) is one of the most common malignancies in men and a major cause of cancer deaths among men worldwide. Prostate specific antigen (PSA) monitoring and histopathological examination of tumor biopsies remain gold standards in PCa diagnostics. These clinical parameters are not well suited for patient stratification, predicting and monitoring treatment response. On the other hand, liquid biopsies offer a unique opportunity to easily isolate tumor-derived material for longitudinal clinical assessment. Areas covered: In this review we focus on the clinical application of novel liquid biomarkers that have the potential to monitor and stratify patients in order to achieve better therapeutic effects and improve clinical outcomes. Enumeration and characterization of circulating tumor cells (CTCs), tumor-educated platelets, exosomes, and cell-free nucleic acids have been studied for their clinical utility in PCa diagnostics, prognostics, monitoring treatment response and guiding treatment choice. Expert opinion: Liquid biomarkers have high potential to be used for prognosis, monitoring treatment response and guiding treatment selection. Although there is a remarkable progress in PCa biomarker discovery, their clinical validation is very limited. Research should be focused on biomarker validation and the incorporation of these biomarkers in clinical practice.

show abstract

p53 status in the primary tumor predicts efficacy of subsequent abiraterone and enzalutamide in castration-resistant prostate cancer

Abstract: p53 inactivation in the primary tumor (but not PTEN loss) may be predictive of inferior outcomes to novel hormonal therapies in CRPC.

Cited by 50 publications

References 39 publications

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

Clinical utility of emerging biomarkers in prostate cancer liquid biopsies

Contact Info

Product

Resources

About