Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer

Athie, Alejandro; Arce-Gallego, Sara; González, M.; Morales-Bárrera, Rafael; Suárez, Cristina; Galobart, Teresa Casals; Hernández, Gonzalo; Carles, Joan; Mateo, Joaquín

doi:10.1007/s11912-019-0790-6

Cited by 15 publications

(25 citation statements)

References 82 publications

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“…Recently, this approach has been found to be efficacious even for tumors displaying LOH at BRCA1/BRCA2, but not complete loss of function (presumably because the second hit remains unknown in these tumors) or mutations in genes such as ATM, ATR, PALB2, and FANCA [31,32]. The synthetic lethality approach has also been extended to the use of other chemotherapeutic drugs like platinum [33]. We found that 20 (39%) patients with PCa had prevalent (i.e., >50% mutant) missense or frameshift somatic mutations at both (a) BRCA1 or BRCA2, and (b) POLQ, ATM, ATR, or PARP1.…”

Section: Discussionmentioning

confidence: 99%

“…We conclude that these somatic mutations may be good biomarkers for selecting patients to be treated with a synthetic lethality approach. The fact that 20-25% of metastatic prostate tumors have defects in the DNA repairome, mostly in the HR pathway [33], suggests that synthetic lethality may be an attractive approach for the treatment of advanced and/ or metastatic PCa.…”

Section: Discussionmentioning

confidence: 99%

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Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians

et al. 2020

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Most hereditary tumors show aberrations in DNA repair genes or their regulators. In contrast, only a minority of sporadic tumors show alterations in these genes. As a result, genomic instability is currently considered an enhancer of tumorigenesis rather than an obligatory event in this process. However, tumor heterogeneity presents a significant technical challenge for most cancer genomics studies performed at less than 100× mean resolution depth. To address the importance of genomic instability in prostate carcinogenesis and tumor progression, we performed ultrahigh depth exome sequencing of 124 DNA damage repair/response (repairome) genes in 63 tumors and matched normal tissue samples in African Americans and Caucasians. The average sequence depth was 712-fold for DNA isolated from normal tissue and 368-fold for FFPE tumors. We identified 671 somatic mutations in tumors from African Americans and 762 somatic mutations in tumors in Caucasians. The most frequently mutated DNA repairome genes were EXO1,

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians

et al. 2020

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“…Precision medicine, despite being relatively new, is a concept that has been part of healthcare for decades. 1,17 It takes into account the individual bases of genomics, lifestyle, and environment to precisely tailor personal therapeutic targets to treat disease and stratify patients to guide the best therapeutic approach. 1,4,9,17 Genome instability has been described as one of the hallmarks of urological cancer.…”

Section: Discussion Precision Medicine and Genomic Markersmentioning

confidence: 99%

“…1,17 It takes into account the individual bases of genomics, lifestyle, and environment to precisely tailor personal therapeutic targets to treat disease and stratify patients to guide the best therapeutic approach. 1,4,9,17 Genome instability has been described as one of the hallmarks of urological cancer. In recent years, different DNA damage repair (DDR) pathways have been found to be altered in urothelial carcinoma (UC), renal cell carcinoma (RCC), and metastatic castration-resistant prostate cancer (mCRPC).…”

Section: Discussion Precision Medicine and Genomic Markersmentioning

confidence: 99%

“…In recent years, different DNA damage repair (DDR) pathways have been found to be altered in urothelial carcinoma (UC), renal cell carcinoma (RCC), and metastatic castration-resistant prostate cancer (mCRPC). [1][2][3][4]9,17,18 New targets in urological oncology are emerging at a fast pace in the era of precision medicine. 2,17 Precision medicine is powered by patient data, health records, and genetic codes.…”

Section: Discussion Precision Medicine and Genomic Markersmentioning

confidence: 99%

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Precision Medicine, Artificial Intelligence, and Genomic Markers in Urology. Do we need to Tailor our Clinical Practice?

Chavarriaga

Moreno

2020

Revista Urología Colombiana / Colombian Urology Journal

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Precision medicine plays a key role in urological oncology practice nowadays, with the breakthrough of the poly (ADP-ribose) polymerase inhibitors (PARPi), which play a critical role in different DNA damage repair (DDR) pathways, the immune checkpoint inhibitors, the genomic expression profiles and current genome manipulation-directed targeted therapy. Information and technology (IT) are set to change the way we assess and treat patients and should be reviewed and discussed. The aim of the present article is to demonstrate a detailed revision on precision medicine, including novel therapeutic targets, genomic markers, genomic stratification of urological patients, and the top-notch technological breakthroughs that could change our clinical practiceWe performed a review of the literature in four different databases (PubMed, Embase, Lilacs, and Scielo) on any information concerning prostate, bladder, kidney and urothelial cancer novel treatments with PARPi, immune checkpoint inhibitors (ICIs), targeted therapy with fibroblast growth factor receptor inhibitors (FGFRi), and theranostics with prostate-specific membrane antigen (PSMA) targeted monoclonal antibodies. Artificial intelligence, machine learning, and deep learning algorithm in urological practice were also part of the search. We included all articles written in English, published within the past 7 years, that discussed outstanding therapies and genomics in urological cancer and artificial intelligence applied to urology. Meanwhile, we excluded articles with lack of a clear methodology and written in any other language than English.One-hundred and twenty-six articles of interest were found; of these, 65 articles that presented novel treatments of urological neoplasms, discussed precision medicine, genomic expression profiles and biomarkers in urology, and latest deep learning and machine learning algorithms as well as the use of artificial intelligence in urological practice were selected. A critical review of the literature is presented in the present article.Urology is a constantly changing specialty with a wide range of therapeutic breakthroughs, a huge understanding of the genomic expression profiles for each urological cancer and a tendency to use cutting-edge technology to treat our patients. All of these major developments must be analyzed objectively, taking into account costs to the health systems, risks and benefits to the patients, and the legal background that comes with them. A critical analysis of these new technologies and pharmacological breakthroughs should be made before considering changing our clinical practice. Nowadays, research needs to be strengthened to help us improve results in assessing and treating our patients.

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Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations

et al. 2021

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Background: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).Methods: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA 50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test. Results and Limitations:The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA 50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA 50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data.Conclusions: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.

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Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer

Cited by 15 publications

References 82 publications

Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians

Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians

Precision Medicine, Artificial Intelligence, and Genomic Markers in Urology. Do we need to Tailor our Clinical Practice?

Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations

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