Evaluation of the methods to identify patients who may benefit from PARP inhibitor use

Abstract

The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating cancers associated with BRCA1/2 mutations hinges upon the concept of synthetic lethality and exemplifies the principles of precision medicine. Currently, most clinical trials are recruiting patients based on pathological subtypes or have included BRCA mutation analysis (germ line and/or somatic) as part of the selection criteria. Mounting evidence, however, suggests that these drugs may also be efficacious in tumors with defects in other genes involved in the homologous recombination repair pathway. Advances in molecular profiling techniques together with increased research efforts have led to a better understanding of the molecular aberrations underlying this BRCA-like phenotype and helped broaden the concept of BRCAness. Hence, it is likely that the list of predictive biomarkers for PARPi therapy will increase in future. There is currently no gold standard method of testing for PARPi response and no universal guidelines are in place on how to incorporate biomarker testing into routine clinical diagnostics. In this review, we explore the concept of BRCAness and highlight the different methods that have been used to identify patients who may benefit from the use of these anticancer agents. The identification of predictive biomarkers is crucial in improving patient selection and expanding the clinical applications of PARPi therapy. 23:6 Review D Lim and J NgeowEvaluating BRCAness for PARP inhibitor use

Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer

“…Our findings suggest that high SLFN11 and low ATM expression levels predict PARP inhibitor response in PDX models and/or cell lines, whereas standard biomarkers of PARP inhibition defined in other cancer types (mutational burden, Myriad HRD score, and mutations in DDR genes) do not [33]. We also report for the first time that EMT score and E-cadherin levels predict response to PARP inhibition, chemotherapy, and other targeted drugs in development for SCLC.…”

Targeting DNA damage in SCLC

“…BRCA mutations are rare in SCLC but scoring systems have been proposed to predict for a 'BRCA like' genomic environment [97,98]. A novel 'DNA repair score' consisting of 17 DNA repair proteins, applied to SCLC cell lines and xenografts established that baseline activation of the PI3K/mTOR pathway is associated with resistance to the PARP inhibitor BMN673 [42].…”

Evaluation of the relative effectiveness of the 2017 updated Manchester scoring system for predicting BRCA1/2 mutations in a Southeast Asian country

“…Additionally, mutation status can guide personalised clinical treatment such as the use of platinum-based neoadjuvant chemotherapy for breast cancers in BRCA1/2 mutations carriers 6. Additionally, poly (ADP-ribose) polymerase inhibitors have been increasingly reported to be an effective means of treating BRCA1/2 mutation tumours through synthetic lethality, thereby exemplifying the concept of precision medicine 7. In terms of preventative care, patients who have a BRCA1/2 mutation are advised to consider risk-reducing mastectomy and bilateral salpingo-oophorectomy once they have completed childbearing—typically around age 40 8…”