Controversies in oncology: are genomic tests quantifying homologous recombination repair deficiency (HRD) useful for treatment decision making?

Pellegrino, Benedetta; Mateo, Joaquín; Serra, Violeta; Balmañà, Judith

doi:10.1136/esmoopen-2018-000480

Cited by 57 publications

(49 citation statements)

References 51 publications

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“…PARP inhibition also has the potential to treat other non-BRCA HR-deficient tumors. There are several commercially available HR repair deficiency (HRD) assays that can be used in the clinic that examine tumor samples using biomarkers such loss of heterozygosity (LOH) ( 48 ). Despite these advances, resistance mechanisms to PARPi occur, which has led to the current efforts to make PARPi more efficacious.…”

Section: Rad51 and Genome Stabilitymentioning

confidence: 99%

Regulation and pharmacological targeting of RAD51 in cancer

2020

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Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase cancer incidence, whereas too much HR can drive cancer resistance to therapy. Importantly, therapeutics targeting HR deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly for breast and ovarian cancer. RAD51 is central to DNA damage repair in the HR pathway. As such, understanding the function and regulation of RAD51 is essential for cancer biology. This review will focus on the role of RAD51 in cancer and beyond and how modulation of its function can be exploited as a cancer therapeutic.

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Section: Rad51 and Genome Stabilitymentioning

confidence: 99%

Regulation and pharmacological targeting of RAD51 in cancer

2020

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“…In this latter trial, an additional explanation for genomic scars having less predictive power is that most patients were already pre-treated by other chemotherapy agents. Resistance might already have been occurred in these patients [ 34 ]. Although patients with BRCAness tumors might have benefit from conventional types of DNA-damaging therapy, like FEC, we believe that BRCAness patients will have additional benefit of high-dose DNA-damaging therapies, like the regimen applied in the Dutch high dose trial, as these are in particular highly vulnerable for this kind of tumors [ 6 , 7 ].…”

Section: Discussionmentioning

confidence: 99%

BRCAness digitalMLPA profiling predicts benefit of intensified platinum-based chemotherapy in triple-negative and luminal-type breast cancer

et al. 2020

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Background: We previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could also indicate which patients would benefit from double-strand break inducing chemotherapy. A simple, robust, and reliable assay for clinical use that utilizes limited amounts of formalin-fixed, paraffin-embedded tumor tissue to assess BRCAness status in both ER-positive and ER-negative breast cancer (BC) is currently lacking. Methods: A digital multiplex ligation-dependent probe amplification (digitalMLPA) assay was designed to detect copy number alterations required for the classification of BRCA1-like and BRCA2-like BC. The BRCA1-like classifier was trained on 71 tumors, enriched for triple-negative BC; the BRCA2-like classifier was trained on 55 tumors, enriched for luminal-type BC. A shrunken centroid-based classifier was developed and applied on an independent validation cohort. A total of 114 cases of a randomized controlled trial were analyzed, and the association of the classifier result with intensified platinum-based chemotherapy response was assessed. Results: The digitalMLPA BRCA1-like classifier correctly classified 91% of the BRCA1-like samples and 82% of the BRCA2-like samples. Patients with a BRCA-like tumor derived significant benefit of high-dose chemotherapy (adjusted hazard ratio (HR) 0.12, 95% CI 0.04-0.44) which was not observed in non-BRCA-like patients (HR 0.9, 95% CI 0.37-2.18) (p = 0.01). Analysis stratified for ER status showed borderline significance. Conclusions: The digitalMLPA is a reliable method to detect a BRCA1-and BRCA2-like pattern on clinical samples and predicts platinum-based chemotherapy benefit in both triple-negative and luminal-type BC.

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“…PARP1 and PARP2 catalyze the synthesis of branched poly ADP-ribose long chains, which in turn ribosylate and activate subsequent effectors of the DNA repair process. More specifically, PARP1 binds to the DNA damaged site, which generates allosteric changes in the PARP1 structure and initiate the enzymatic process [33]. Upon activation, poly ADP-ribosylation (PARylation) is catalytic for the recruitment of downstream DNA repair effectors such as DNA ligase III, DNA polymerase β, topoisomerases and XRCC1 and the chromatin structure remodeling [34].…”

Section: Parp Activitymentioning

confidence: 99%

The Landscape of Targeted Therapies in TNBC

Vagia

Mahalingam

Cristofanilli

2020

Cancers

281

198

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Triple negative breast cancer (TNBC) constitutes the most aggressive molecular subtype among breast tumors. Despite progress on the underlying tumor biology, clinical outcomes for TNBC unfortunately remain poor. The median overall survival for patients with metastatic TNBC is approximately eighteen months. Chemotherapy is the mainstay of treatment while there is a growing body of evidence that targeted therapies may be on the horizon with poly-ADP-ribose polymerase (PARP) and immune check-point inhibitors already established in the treatment paradigm of TNBC. A large number of novel therapeutic agents are being evaluated for their efficacy in TNBC. As novel therapeutics are now incorporated into clinical practice, it is clear that tumor heterogeneity and clonal evolution can result to de novo or acquired treatment resistance. As precision medicine and next generation sequencing is part of cancer diagnostics, tailored treatment approaches based on the expression of molecular markers are currently being implemented in clinical practice and clinical trial design. The scope of this review is to highlight the most relevant current knowledge regarding underlying molecular profile of TNBC and its potential application in clinical practice.

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Controversies in oncology: are genomic tests quantifying homologous recombination repair deficiency (HRD) useful for treatment decision making?

Cited by 57 publications

References 51 publications

Regulation and pharmacological targeting of RAD51 in cancer

Regulation and pharmacological targeting of RAD51 in cancer

BRCAness digitalMLPA profiling predicts benefit of intensified platinum-based chemotherapy in triple-negative and luminal-type breast cancer

The Landscape of Targeted Therapies in TNBC

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