TP53 Gain-of-Function Mutations in Circulating Tumor DNA in Men With Metastatic Castration-Resistant Prostate Cancer

Chapman, Lynne; Ledet, Elisa M.; Barata, Pedro C.; Cotogno, Patrick; Manogue, Charlotte; Moses, Marcus Marie; Christensen, Bryce; Steinwald, Peter; Ranasinghe, Lahiru; Layton, Jodi Lyn; Lewis, Brian

doi:10.1016/j.clgc.2019.10.022

Cited by 7 publications

(9 citation statements)

References 24 publications

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“…In a number of tumor types including lung, ovarian, and colon, specific types of TP53 mutations have been associated with worse outcomes. In patients with metastatic castration‐resistant prostate cancer, TP53 DN mutations have been associated with prior enzalutamide/abiraterone 11 …”

Section: Introductionmentioning

confidence: 99%

“…In patients with metastatic castration-resistant prostate cancer, TP53 DN mutations have been associated with prior enzalutamide/abiraterone. 11 Recently, homologous recombination deficiency (HRD) alterations have become important for understanding treatment options in metastatic prostate cancer. Poly (ADP-ribose) polymerase inhibitors are a potential therapeutic agent for patients that harbor an HRD gene alteration and are thought to work through synthetic lethality in this context.…”

Section: Introductionmentioning

confidence: 99%

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Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone‐sensitive prostate cancer

et al. 2021

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Background Clinical outcomes may differ among patients presenting with primary (de novo) metastatic hormone‐sensitive prostate cancer (mHSPC) versus secondary (metachronous) mHSPC occurring after local therapy. It is unknown what molecular features distinguish these potentially distinct presentations. Methods A single‐center retrospective study of mHSPC patients classified as primary mHSPC (n = 121) or secondary mHSPC (n = 106). A targeted set of genes was analyzed: BRCA2, PTEN, RB1, TP53, SPOP, CDK12, any two out of PTEN/RB1/TP53 alterations, and homologous recombination deficiency mutations. TP53 mutations were categorized as loss‐of‐function (LOF) versus dominant‐negative (DN). The impacts of genetic features on progression‐free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox proportional hazards regression. Results Median PFS was 15 and 30 months for men with primary and secondary mHSPC, respectively (hazard ratio: 0.57, 95% confidence interval: 0.41–0.78; p < .01). OS did not show a significant difference between groups. There were more men with Gleason 8–10 disease in the primary versus secondary mHSPC groups (83% vs. 68%; p < .01). In univariate and multivariate analyses, TP53 DN mutations showed a statistically significant association with OS for the entire mHSPC population. Conversely, SPOP mutations were associated with improved OS. Additionally, TP53 mutations (DN and LOF) were associated with worse OS for secondary mHSPC. A combination of PTEN/RB1/TP53 mutations was associated with worse OS and PFS for secondary mHSPC, while no genomic alteration affected outcomes for primary mHSPC. Conclusions TP53 DN mutations, but not all TP53 alterations, were the strongest predictor of negative outcomes in men with mHSPC, while SPOP mutations were associated with improved outcomes. In subgroup analyses, specific alterations were prognostic of outcomes in secondary, but not primary, mHSPC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone‐sensitive prostate cancer

et al. 2021

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“…In addition, TP53 alterations are also associated with resistance to taxanes and inferior outcome to AA 13,14 . These aberrations accumulate following progression to androgen deprivation and docetaxel 15 . Hence, patients with less advanced disease, or fewer therapeutic regimens, might be more sensitive for AA.…”

Section: Introductionmentioning

confidence: 99%

The effect of chemotherapy on the exposure–response relation of abiraterone in metastatic castration‐resistant prostate cancer

Boerrigter¹,

Benoist²,

Overbeek³

et al. 2021

Brit J Clinical Pharma

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“…In particular, TP53 gain-of-function mutations have been associated with cancer cell survival and chemoresistance. Interestingly, TP53 mutations conferring gain of function were related to disease progression and drug resistance after abiraterone or enzalutamide treatments[ 13 ].…”

Section: Liquid Biopsy In Metastatic Castrate-resistant Prostate Cancmentioning

confidence: 99%

Circulating cell-free nucleic acids as prognostic and therapy predictive tools for metastatic castrate-resistant prostate cancer

Sobhani¹,

Sirico²,

Generali³

et al. 2020

WJCO

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Metastatic castrate-resistant prostate cancer remains a disease hard to cure, and for this reason predictive tools to monitor disease progression and therapy response are an urgent need. In this respect, liquid biopsy on circulating cell-free nucleic acids represents an interesting strategy based on robust data. The low invasiveness and the possibility to target circulating cell-free tumor deoxyribonucleic acid underline the high specificity, sensitivity and clinical usability of the technique. Moreover, it has been observed that the cell-free tumor deoxyribonucleic acid of metastatic castrate-resistant prostate cancer patients can be representative of the tumor heterogeneity. Cell-free tumor deoxyribonucleic acids express the same behaviors as mutations: Variation in gene copy number or the methylation rate of the tumor tissue. Recently, circulating cell-free ribonucleic acid molecules have emerged as interesting markers to stratify the disease. Due to high-throughput technologies, liquid biopsy on circulating cell-free nucleic acids will soon be utilized in the clinical management of metastatic castrate-resistant prostate cancer patients.

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TP53 Gain-of-Function Mutations in Circulating Tumor DNA in Men With Metastatic Castration-Resistant Prostate Cancer

Cited by 7 publications

References 24 publications

Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone‐sensitive prostate cancer

Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone‐sensitive prostate cancer

The effect of chemotherapy on the exposure–response relation of abiraterone in metastatic castration‐resistant prostate cancer

Circulating cell-free nucleic acids as prognostic and therapy predictive tools for metastatic castrate-resistant prostate cancer

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