Biomarkers for Homologous Recombination Deficiency in Cancer

Abstract

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.

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

“…Recent clinical studies using olaparib monotherapy for TNBC showed promising response in HRD high patients [ 58 ]. Among the current HRD screening tests in clinic only two (Myriad’s myChoice ® CDx and HRD Focus Panel) screen for TAI in patient samples to account for HRD [ 59 ].…”

PARP Inhibitor Applicability: Detailed Assays for Homologous Recombination Repair Pathway Components

“…Separately, both preclinical and preliminary clinical data have shown that patients who have mutations in HR repair genes other than BRCA1/2 can benefit from PARPi therapy. 42 , 91 , 92 The prevalence of these mutations across non-reproductive solid tumors has been reported to be less than 20%, 93 and the rarity of these alterations makes developing clinical trials with sufficient statistical power to demonstrate the benefit of PARPi in these populations a challenge. Multiple companies have off-the-shelf targeted sequencing panels that include HR repair genes “beyond” BRCA1/2 , and Table 1 summarizes the use of these non- BRCA1/2 HR repair genes as eligibility criteria in currently recruiting PARPi clinical trials listed on clinicaltrials.gov.…”

“…Ultimately, interpreting the relevance of HR-related mutations is likely still to be dependent on the clinical and histological context of a patient, as few of these mutations predict for PARPi benefit outside of reproductive cancers. 34 , 92 …”

AKT Isoforms Interplay in High-Grade Serous Ovarian Cancer Prognosis and Characterization

“…Another emerging point of our results was the relationship between the tumor morphology, AKT isoforms and HR status. Considering the incompleteness of the HR status by BRCA1/BRCA2 genetic testing [ 33 ] as well as the expensiveness of current multigene panels for HRD testing, the prediction of homologous recombination proficiency/deficiency by means of AKT ratios, SET and BRCA1 expression could be of particular interest as a possible surrogate. Despite the small sample size, our logistic regression analysis suggested that the simultaneous assessment of the abovementioned features could be useful at least in discriminating tumors with somatic pathologic mutations on BRCA1 or BRCA2 genes, also resulting in a good level of sensitivity and specificity (0.75; 0.97 − AUC = 0.88).…”