Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study

Mateo, Joaquín; Cheng, Heather H.; Beltran, Himisha; Dolling, David; Xu, Wen; Pritchard, Colin C.; Mossop, Helen; Rescigno, Pasquale; Pérez-López, Raquel; Sailer, Verena; Kolinsky, Michael; Balasopoulou, Ada; Bertan, Claudia; Nanus, David M.; Tagawa, Scott T.; Thorne, Heather; Montgomery, Bruce; Carreira, Suzanne; Sandhu, Shahneen; Rubin, Mark A.; Nelson, Peter S.; Bono, Johann S. de

doi:10.1016/j.eururo.2018.01.010

Cited by 112 publications

(87 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We demonstrate that ctDNA can be applied to comprehensively profile AR and identify alterations in genes associated with DNA repair deficiency. Although these two biomarkers are considered promising for clinical decision making, recent data question the association between DNA-repair germline variants and response to PARP inhibitors [65] and the independent association between AR amplifications and response to abiraterone and enzalutamide treatment in mCRPC [55]. In the light of the controversy over AR-V7 [24], the only possible conclusion is the urgent need for efficient biomarker-driven clinical trials to identify in detail which patients may benefit from each therapy option.…”

Section: Discussionmentioning

confidence: 99%

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Mayrhofer

Laere

Whitington

et al. 2018

Preprint

View full text Add to dashboard Cite

Background: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. Methods:A combination of targeted-and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients.Results: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first line mCRPC therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%).Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥0.1 ctDNA fraction). Sequencing of non-repetitive intronic-and exonic regions of PTEN, RB1and TP53 detected biallelic inactivation in 47.5%, 20.3% and 44.1% of samples with ≥0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays.Conclusions: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenge the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Mayrhofer

Laere

Whitington

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…35 However, it should be noted that the response of patients with metastatic CRPC and homologous recombination repair gene mutations respond to standard therapies is similar to the response of patients without mutations. 226,227 The panel recommends clinical trial enrollment for men with prostate cancer and DNA repair gene mutations.…”

Section: Treatment Implications For Patients With Dna Repair Gene Mutmentioning

confidence: 99%

Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

Mohler

Antonarakis

Armstrong

et al. 2019

Journal of the National Comprehensive Cancer Network

1,063

841

View full text Add to dashboard Cite

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

show abstract

“…Germline mutations in BRCA2 are a well‐defined aspect of hereditary breast and ovarian cancer , but were underappreciated as a driver of hereditary prostate cancer as only 1–3% of unselected localized diagnoses harbour BRCA2 germline mutations . In the metastatic setting, however, germline BRCA2 mutations are common, with a prevalence of 3–6% (Table ); when combined with somatic mutations and homozygous deletions, up to 19% of metastatic CRPC (mCRPC) cases exhibit deleterious BRCA2 defects . The exact prevalence varies by patient ethnicity and geographic distribution; germline BRCA2 mutations were more common in a recent cohort of patients enriched for Ashkenazi Jewish ancestry (because of common founder mutations in that population) .…”

Section: High Prevalence Of Pathogenic Brca2 Mutationsmentioning

confidence: 99%

“…While both the Annala et al and Castro et al studies were prospective clinical trials, the numbers of patients with BRCA2 mutations were small and the patient populations (Canada, Spain, respectively) may not be generalizable to all other countries or healthcare systems. Indeed, a recent retrospective analysis of patients from the landmark publication by Pritchard et al in 2016 reported no significant difference in overall survival or PSA progression‐free survival (PFS) for patients with DDR germline mutations receiving AR signalling axis inhibitors (abiraterone or enzalutamide) . Additionally, data from Johns Hopkins reported that patients with CRPC carrying germline BRCA2 mutations ( n = 5), ATM mutations ( n = 3), and rare mutations in other DDR genes experienced a better outcome on AR axis inhibitors with regard to PFS and overall survival .…”

Section: Dna Damage Repair‐deficient Tumours Treated With Standard Ofmentioning

confidence: 99%

DNA repair defects in prostate cancer: impact for screening, prognostication and treatment

Warner

Yip

et al. 2018

BJU International

View full text Add to dashboard Cite

Failure of effective DNA damage repair is a hallmark of cancer, but was previously underappreciated as a driver of aggressive prostate cancer. However, recent international sequencing efforts have revealed that both germline and somatic alterations within the homologous recombination and mismatch repair pathways are relatively common in lethal metastatic disease. BRCA2 gene alterations are particularly prevalent and are linked to poor prognosis as well as poor responses to systemic therapy for castrationresistant prostate cancer, although there is conflicting support for the latter. Defective DNA repair contributes to tumour heterogeneity, evolution and progression, but there are high hopes that management of this aggressive subset will be transformed by biomarker-driven use of poly-ADP ribose polymerase (PARP) inhibitors and platinum-based chemotherapy. In this review, we detail the relationship between DNA repair defects and prostate cancer, highlighting the prevalence of mutations in key genes and their controversial association with clinical outcomes.

show abstract

Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study

Abstract: Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients.

Cited by 112 publications

References 17 publications

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

DNA repair defects in prostate cancer: impact for screening, prognostication and treatment

Contact Info

Product

Resources

About