• 2019-07
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  • br Preclinical studies have suggested several pathways that


    Preclinical studies have suggested several pathways that might modulate sensitivity of HR-deficient cancers to PARPis [6–8]. In particu-lar, the PARP trapping model [9,10] suggests that cancers with dimin-ished PARP1 Paxilline might be less sensitive to PARPis. Studies in ovarian cancer cell lines [11,12] and BRCA1 mutation-associated murine breast cancers [13] have also indicated that downregulation of compo-nents of the nonhomologous end-joining (NHEJ) DNA repair pathway, including KU70, KU80 and Artemis, or diminished levels of the 53BP1 protein that regulates engagement of the NHEJ pathway are associated with PARPi resistance. In the case of 53BP1 loss, this PARPi resistance has been attributed to restoration of HR despite the continued absence of BRCA1 [14–16]. The pertinence of these findings to clinical PARPi re-sponses is currently unknown.
    ABT-767 is a potent orally bioavailable small molecule inhibitor of PARP1 and PARP2 (Ki = 0.47 and 0.85 nM, respectively) that demon-strated anticancer activity in preclinical models [17]. A recent phase I study (NCT01339650) evaluated ABT-767 in subjects with advanced solid tumors harboring deleterious BRCA1 or BRCA2 mutations or sub-jects with recurrent ovarian, fallopian tube, or peritoneal cancer [17]. In the present study we examined the relationship between HRD score, BRCA1 and BRCA2 mutation status, expression of repair proteins, and response of ovarian cancers treated with ABT-767 on this trial.
    2. Methods
    2.1. Patient population and study design
    NCT01339650, a Phase I, open-label, multicenter study of the PARPi ABT-767, included dose escalation and safety expansion cohorts [17]. ABT-767 was administered orally on Days 1–28 of 28-day cycles until patients experienced progressive disease (PD) or unacceptable toxicity. From an initial dose level of 20 mg once daily, ABT-767 was escalated to 500 mg twice daily (BID) using a 3 + 3 trial design. At the recom-mended phase 2 dose of 400 mg BID, an expansion cohort with BRCA1/BRCA2-mutated advanced solid tumors and another cohort with advanced ovarian, fallopian tube or primary peritoneal carcinoma (hereafter collectively called “ovarian cancer”) were enrolled. The pres-ent analysis focused exclusively on ovarian cancer patients enrolled in this trial. When available, archival tissue was submitted for biomarker analysis. Objective response rate (ORR: confirmed complete response [CR] and partial response [PR]) was measured by Response Evaluation 
    Criteria in Solid Tumors (RECIST) version 1.1 in patients who had mea-surable disease at baseline [18]. As defined by RECIST, CR indicates dis-appearance of all target lesions with pathologic lymph nodes reduced to b10 mm on the short axis, PR required ≥30% decrease in sum of the di-ameters of target lesions, and non-responders included both progres-sive disease (PD, ≥20% increase in sum of diameters of target lesions) and stable disease (SD). CA-125 response was measured by Gynecologic Cancer Intergroup criteria [19].
    2.2. Homologous Recombination Deficiency (HRD) score and BROCA analysis
    HRD score, which is a weighted sum of LOH, telomeric allelic imbal-ance and large scale transitions, was assayed at Myriad Genetics as de-scribed by Telli et al. [20]. Samples were considered HR-deficient if the HRD score was ≥42. Tumor mutation status of BRCA1 and BRCA2 was si-multaneously determined at Myriad Genetics. Mutations were consid-ered deleterious only if they were nonsense mutations or missense mutations known previously to be associated with altered function or strongly correlated with disease penetrance [21]. In the sample set, HR deficiency was defined as an HRD score ≥ 42 and/or the presence of a deleterious BRCA1 or BRCA2 mutation.