Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage

Marshall, Catherine Handy; Fu, Wei; Wang, Hao; Baras, Alexander S.; Lotan, Tamara L.; Antonarakis, Emmanuel S.

doi:10.1038/s41391-018-0086-1

Cited by 76 publications

(68 citation statements)

References 23 publications

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“…The observed DDR pathway alterations rate in localized prostate cancer was significantly higher than expected based on the reported range of 8-20% [8,9]. Previously, DDR pathway has been reported to be altered in the 30% range in men with mCRPC.…”

Section: Discussioncontrasting

confidence: 57%

“…To test this possibility we are currently designing an adjuvant trial that will assess the effect of a PARP inhibitor in prostate cancer patients with high-risk features post-operatively. It should be noted that a recent manuscript also investigated the DDR pathway in localized prostate cancer using the same TCGA database [9]. However, there were two significant differences between the present and the aforementioned study.…”

Section: Discussionmentioning

confidence: 73%

“…However, the full extent and prevalence of DDR pathway alterations has not been extensively analyzed in localized disease. Thus far two prior studies suggested the incidence to range 8-20% [8,9]. Therefore, in the present study, we analyzed the largest publically available version of The Cancer Genome Atlas (TCGA) to assess the rate of altered DNA damage repair machinery in localized prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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Similar incidence of DNA damage response pathway alterations between clinically localized and metastatic prostate cancer

Kim

Srivastava

et al. 2019

BMC Urol

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Background: In this era of precision medicine, the DNA damage response (DDR) pathway has been shown to be a viable target of intervention in metastatic castration-resistant prostate cancer (CRPC) as approximately one-third of CRPC patients harbor DDR pathway mutations. To determine whether DDR pathway is a potential therapeutic target in localized disease, we analyzed The Cancer Genome Atlas (TCGA) in the present study. Methods: TCGA is a publically available cancer genome database that is sponsored by the United States National Cancer Institute. Total of 455 cases were available in the database at the time of this analysis. Results: DDR pathway gene mutations or copy number alterations were present in 136 (29.9%) of the 455 cases. On a univariate analysis, DDR pathway status did not correlate with serum prostate specific antigen, tumor stage or grade. However, among patients with high-risk features post-operatively (pathologic stage ≥ T3, Gleason score ≥ 8, or PSA > 20 ng/ml), DDR pathway alteration was associated with a lower overall survival (p = 0.0291). Conclusions: Collectively these results suggest that DDR pathway alterations may also be significant in localized prostate cancer and agents such as PARP inhibitors should be considered in patients with a high-risk disease.

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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Similar incidence of DNA damage response pathway alterations between clinically localized and metastatic prostate cancer

Kim

Srivastava

et al. 2019

BMC Urol

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“…In our case, the Gleason grade group was 5, with an expected poor prognosis. A previous study reported that the prevalence of DNA repair mutation involving FANCA was higher in prostate cancer cases with high Gleason grade groups than in cases with low Gleason grade groups [16].…”

Section: Discussionmentioning

confidence: 90%

Aggressive prostate cancer with somatic loss of the homologous recombination repair gene FANCA: a case report

et al. 2020

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Background: Precision medicine based on genomic analysis of germline or tumor tissue is attracting attention. However, there is no consensus on how to apply the results of genomic analysis to treatment. Case presentation: A 59-year-old man diagnosed with metastatic prostate cancer was diagnosed with castrationresistant prostate cancer. Although he was sequentially treated with enzalutamide and abiraterone, bone metastasis progression was identified by skeletal scintigraphy. Therefore, we sequentially performed docetaxel therapy followed by cabazitaxel. After the third cycle of cabazitaxel, his prostate-specific antigen level was stable at < 10 ng/mL, and no radiological progression was detected. The patient's formalin-fixed paraffin-embedded tumor biopsy specimen underwent multiple-gene testing by next-generation sequencing, which identified a FANCA homodeletion. No significant germline mutation was observed. Conclusions: We describe a case of aggressive, castration-resistant prostate cancer with FANCA homodeletion. Genomic analysis of prostate cancer tissue can be useful to determine optimal treatment of such cancers.

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“…Homologous repair deficiency (HRD) genes (particularly BRCA1/2) are found in 20-25% of all patients with metastatic CRPC [11]. Although the 2019 National Comprehensive Cancer Network guidelines recommend germline testing for all prostate cancer patients, treatment based on molecular characterization is still not commonly practiced [8].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Personalized Treatment Approach to Metastatic Castration-Resistant Prostate Cancer with BRCA2 and PTEN Mutations: A Case Report

Julka¹,

Verma²,

Gupta³

2020

Case Rep Oncol

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DNA repair mutations (BRCA1 and BRCA2) are found in metastatic castration-resistant prostate cancer (CRPC) patients. Here, we report a case of a 71-year-old male patient with metastatic CRPC along with BRCA2 and PTEN mutations. As per the genomic findings of the Foundation One report, FDA-approved therapies were available for other tumor types, such as olaparib for the loss of BRCA2 and everolimus for the loss of PTEN exons 2-9. These findings were confirmed in another novel phenotypic assay that revealed the sensitivity of olaparib and carboplatin combination therapy. After 4 cycles, our patient achieved a partial response along with a good performance status.overall response rate of 50% with median progression-free and overall survival durations of 7.2 and 18.4 months, respectively. These results are consistent with our observations; however, our patient had only been followed up for 9 months at the time of writing this report.So far, olaparib and carboplatin combination therapy has never been studied among CRPC patients; we report the first case on this chemotherapy and targeted therapy combination. This case demonstrates the clinical utility of olaparib and carboplatin combination therapy in patients with metastatic CRPC with BRCA2 loss. Further, the good partial response achieved in this case establishes the importance of germline testing for homologous recombination genes (BRCA1, BRCA2, ATM, PALB2, and CHEK2) using NGS among patients with metastatic CRPC.Olaparib and carboplatin combination therapy holds promise for the management of metastatic CRPC patients with BRCA2 loss. The administration of olaparib and carboplatin combination therapy can demonstrate a good response along with prolonged survival in patients with metastatic CRPC associated with DNA-repair defects.

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Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage

Cited by 76 publications

References 23 publications

Similar incidence of DNA damage response pathway alterations between clinically localized and metastatic prostate cancer

Similar incidence of DNA damage response pathway alterations between clinically localized and metastatic prostate cancer

Aggressive prostate cancer with somatic loss of the homologous recombination repair gene FANCA: a case report

Personalized Treatment Approach to Metastatic Castration-Resistant Prostate Cancer with BRCA2 and PTEN Mutations: A Case Report

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