Homologous recombination repair deficiency (HRD): From biology to clinical exploitation

González, David

doi:10.1002/gcc.22939

Cited by 20 publications

(19 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A high correlation of HRD scores derived from WES data and from genotyping data has been demonstrated 58 . Further studies evaluating the comparability of different platforms for routine diagnostics of HRD will be necessary 59 …”

Section: Examples Of Biomarker Classificationsmentioning

confidence: 96%

“…58 Further studies evaluating the comparability of different platforms for routine diagnostics of HRD will be necessary. 59 Example: PAOLA-1 was a phase 3 trial that evaluated olaparib in combination with bevacizumab as first-line maintenance treatment for advanced high-grade serous ovarian cancer. 60 The addition of olaparib to bevacizumab provided a significant survival benefit, which was substantial in patients with HRD-positive tumors.…”

Section: Homologous Recombination Deficiencymentioning

confidence: 99%

See 1 more Smart Citation

Assigning evidence to actionability: An introduction to variant interpretation in precision cancer medicine

Horak

Leichsenring

Goldschmid

et al. 2021

Genes Chromosomes & Cancer

Self Cite

View full text Add to dashboard Cite

Modern concepts in precision cancer medicine are based on increasingly complex genomic analyses and require standardized criteria for the functional evaluation and reporting of detected genomic alterations in order to assess their clinical relevance. In this article, we propose and address the necessary steps in systematic variant evaluation consisting of bioinformatic analysis, functional annotation and clinical interpretation, focusing on the latter two aspects. We discuss the role and clinical application of current variant classification systems and point out their scope and limitations. Finally, we highlight the significance of the molecular tumor board as a platform for clinical decision-making based on genomic analyses.

show abstract

Section: Examples Of Biomarker Classificationsmentioning

confidence: 96%

Section: Homologous Recombination Deficiencymentioning

confidence: 99%

Assigning evidence to actionability: An introduction to variant interpretation in precision cancer medicine

Horak

Leichsenring

Goldschmid

et al. 2021

Genes Chromosomes & Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although it is far beyond the scope of this review, we should note that fundamental research on cell lines or mouse models has described several genetic/epigenetic mechanisms (e.g., PARP1 mutations, miRNA-622 overexpression) that explain PARPi resistance, mainly based on HR restoration, DNA replication fork protection, drug efflux through overexpression of multidrug resistance protein (MDR1) and impact of the tumor microenvironment [ 93 , 94 , 95 , 96 ]. Evidence-based in cellulo research has even suggested that the HR process should be viewed on a continuum, including influences of (epi)genetic modulation (through amplification and/or overexpression) between pathway choices concerning DNA repair [ 97 ].…”

Section: Hrd Evaluation In Clinics: Current Limitationsmentioning

confidence: 99%

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer Part 2: Medical Perspectives

Quesada

Fabbro

Solassol

2022

Cancers

View full text Add to dashboard Cite

High-grade serous ovarian cancer (HGSOC) is the most frequent and aggressive form of ovarian cancer, representing an important challenge for clinicians. Half of HGSOC cases have homologous recombination deficiency (HRD), which has specific causes (mainly alterations in BRCA1/2, but also other alterations encompassed by the BRCAness concept) and consequences, both at molecular (e.g., genomic instability) and clinical (e.g., sensitivity to PARP inhibitor) levels. Based on its prevalence and clinical impact, HRD status merits investigation. To date, three PARP inhibitors have received FDA/EMA approval. For some approvals, the presence of specific molecular alterations is required. Three companion diagnostic (CDx) assays based on distinct technical and medical considerations have received FDA approval to date. However, their use remains controversial due to their technical and medical limitations. In this companion and integrated review, we take a “bench-to-bedside” perspective on HRD definition and evaluation in the context of HGSOC. Part 1 of the review adopts a molecular perspective regarding technical considerations and the development of CDx. Part 2 focuses on the clinical impact of HRD evaluation, primarily through currently validated CDx and prescription of PARP inhibitors, outlining achievements, limitations and medical perspectives.

show abstract

“…In parallel with PARPi development, HRD assays have been developed to provide clinicians with accurate estimates of homologous recombination status. As such, PARPis, coupled with HRD assays, led to substantial improvements in HGSOC prognosis [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…The F1-CDx also detects microlesions and macrolesions in 324 genes, selected gene rearrangements, and MSI and TMB 4. In this context, FoundationOne Liquid CDx (performed on a whole blood sample) is also FDA-approved but does not provide LOH evaluation 5. In this context, rucaparib is not biomarker-driven, but a positive HRD status is predictive of its efficacy and indicates improved progression-free survival.…”

mentioning

confidence: 99%

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

Quesada

Fabbro

Solassol

2022

Cancers

View full text Add to dashboard Cite

High-grade serous ovarian cancer (HGSOC), the most frequent and lethal form of ovarian cancer, exhibits homologous recombination deficiency (HRD) in 50% of cases. In addition to mutations in BRCA1 and BRCA2, which are the best known thus far, defects can also be caused by diverse alterations to homologous recombination-related genes or epigenetic patterns. HRD leads to genomic instability (genomic scars) and is associated with PARP inhibitor (PARPi) sensitivity. HRD is currently assessed through BRCA1/2 analysis, which produces a genomic instability score (GIS). However, despite substantial clinical achievements, FDA-approved companion diagnostics (CDx) based on GISs have important limitations. Indeed, despite the use of GIS in clinical practice, the relevance of such assays remains controversial. Although international guidelines include companion diagnostics as part of HGSOC frontline management, they also underscore the need for more powerful and alternative approaches for assessing patient eligibility to PARP inhibitors. In these companion reviews, we review and present evidence to date regarding HRD definitions, achievements and limitations in HGSOC. Part 1 is dedicated to technical considerations and proposed perspectives that could lead to a more comprehensive and dynamic assessment of HR, while Part 2 provides a more integrated approach for clinicians.

show abstract

Homologous recombination repair deficiency (HRD): From biology to clinical exploitation

Cited by 20 publications

References 42 publications

Assigning evidence to actionability: An introduction to variant interpretation in precision cancer medicine

Assigning evidence to actionability: An introduction to variant interpretation in precision cancer medicine

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer Part 2: Medical Perspectives

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

Contact Info

Product

Resources

About