Homologous recombination deficiency real-time clinical assays, ready or not?

Fuh, Katherine C.; Mullen, Mary M.; Blachut, Barbara; Stover, Elizabeth H.; Konstantinopoulos, Panagiotis A.; Liu, Joyce F.; Matulonis, Ursula A.; Khabele, Dineo; Mosammaparast, Nima; Vindigni, Alessandro

doi:10.1016/j.ygyno.2020.08.035

Cited by 49 publications

(48 citation statements)

References 70 publications

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“… 56 BRCA1/2 gene defects and HRD cells are characterized by the reduction of, or inability to form RAD51 foci, which is a functional phenotype irrespective of the underlying cause of HRD. 57 Among 39 HGSOC samples on one study, a functional HR assay based on RAD51 foci detection found 26% of samples to be HRD, while ovarian cancers of nonserous histotypes were all HR proficient. 58 Several preclinical and small clinical studies have also described that reduced RAD51 foci is associated with PARPi response in ovarian cancer.…”

Section: Selecting Patients For Parpis: How Can We Best Identify Hrd?mentioning

confidence: 99%

“… 62 Another published retrospective exploratory analysis of BRCA1/2 -mutant tumor samples from the SOLO1 trial showed that 23% of evaluable samples would have been classified as %LOH <16% by FoundationOne CDx, despite the presence of a germline or tumor BRCA1/2 mutation in all enrolled patients. 57 These data underscore the fact that a degree of overlapping sensitivity exists between these two genomic scar detection methods, but that they cannot be considered equivalent in routine clinical practice.…”

Section: Hrd Testing In the Clinic—practical Considerationsmentioning

confidence: 99%

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The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

2021

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The recognition of homologous recombination deficiency (HRD) as a frequent feature of high-grade serous ovarian cancer (HGSOC) has transformed treatment paradigms. Poly(ADP-ribose) polymerase inhibitors (PARPis), developed based on the rationale of synthetic lethality that predicates antitumor efficacy in tumors harboring underlying HRD, now represents an important class of therapy for HGSOC. Recent data have drawn attention to the assessment of homologous recombination DNA repair (HRR) as a prognostic and predictive biomarker in HGSOC, leading to increasing debate on the optimal means of defining and evaluating HRD, both genotypically and phenotypically. At present, clinical-grade assays such as myChoice CDx and FoundationOne CDx are approved companion diagnostics which can identify patients with HRD-positive HGSOC by diagnosing a 'genomic scar' reflecting underlying genomic instability. Yet despite the rapid maturation of this field, tumoral HRD status has been recognized to be dynamic over time and with treatment pressure. In practice, this means that restoration of HRR through mechanisms of platinum and PARPi resistance are not adequately represented by genomic scar assays, and contribute toward discordance with clinical PARPi response, or lack-thereof. It is thus critical that HRD testing is optimized to address the controversies of diverse HRD testing methodology, appropriate thresholds for HRD identification, and relevant timepoints for HRD testing, in order to realize the potential for PARPis to maximally benefit patients with HGSOC. Here, we discuss the premise of HRD testing in HGSOC, current methodologies for HRD identification and their performance in the clinic, highlight upcoming strategies, and discuss the challenges faced in moving this field forward.

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Section: Selecting Patients For Parpis: How Can We Best Identify Hrd?mentioning

confidence: 99%

Section: Hrd Testing In the Clinic—practical Considerationsmentioning

confidence: 99%

The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

2021

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“…RAD51 focus formation or replication fork assays could be used as functional HRD assays. Nevertheless, there are still some challenges to be solved prior to implementing such assays into routine diagnostics, such as the need for fresh tissue and standardization of positivity thresholds [ 38 ].…”

Section: Parp Inhibition and Homologous Recombination Repair Deficiencymentioning

confidence: 99%

Biomarkers for Homologous Recombination Deficiency in Cancer

Wagener‐Ryczek

Merkelbach‐Bruse

Siemanowski

2021

JPM

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DNA double-strand breaks foster tumorigenesis and cell death. Two distinct mechanisms can be activated by the cell for DNA repair: the accurate mechanism of homologous recombination repair or the error-prone non-homologous end joining. Homologous Recombination Deficiency (HRD) is associated with sensitivity towards PARP inhibitors (PARPi) and its determination is used as a biomarker for therapy decision making. Nevertheless, the biology of HRD is rather complex and the application, as well as the benefit of the different HRD biomarker assays, is controversial. Acquiring knowledge of the underlying molecular mechanisms is the main prerequisite for integration of new biomarker tests. This study presents an overview of the major DNA repair mechanisms and defines the concepts of HRR, HRD and BRCAness. Moreover, currently available biomarker assays are described and discussed with respect to their application for routine clinical diagnostics. Since patient stratification for efficient PARP inhibitor therapy requires determination of the BRCA mutation status and genomic instability, both should be established comprehensively. For this purpose, a broad spectrum of distinct assays to determine such combined HRD scores is already available. Nevertheless, all tests require careful validation using clinical samples to meet the criteria for their establishment in clinical testing.

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“…Since p53 is a master regulator of the cell cycle and survival amid DNA damage, we asked whether high-grade TP53 mutant UCs harbor defects in DDR increasing susceptibility to DDR targeted therapies [ 7 , 8 , 9 ], which target defects in repair of double strand DNA breaks (DSB) by HR and protection of stalled replication forks [ 26 ]. Functional assays for HR defects include (1) assessing tumor cell formation of post-damage RAD51 nuclear foci, and (2) challenging cells with DSB inducing agents such as gamma irradiation, PARP inhibitors, and platinum crosslinking agents [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1–AKT–p53 Interactions

Lynch

Liu

Kesten

et al. 2021

Cancers

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Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.

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Homologous recombination deficiency real-time clinical assays, ready or not?

Cited by 49 publications

References 70 publications

The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

Biomarkers for Homologous Recombination Deficiency in Cancer

Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1–AKT–p53 Interactions

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