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  • br improved progression free survival

    2019-09-23


    improved progression-free survival was much lower in HR-proficient cancers than in ovarian cancers with a positive HRD score. In contrast, in the present study where the endpoint was tumor shrinkage, responses to ABT-767 were only observed in HR-deficient cancers (Fig. 3A). Even so, the numerical value of the HRD score did not further correlate with per-cent change in tumor area within the HR-deficient subset (Fig. 4A), sug-gesting that factors beyond HRD score must be considered to identify ovarian cancers most likely to respond to PARPi therapy.
    Considering only the HR-deficient ovarian cancers, there was a strong correlation in the present study between low 53BP1 levels and poor carci-noma response (Fig. 4B), consistent with studies in model systems
    Table 1
    Univariate analysis of response with clinical parameters and H-scores.
    HR status
    PARP1 H-score
    XRCC4 H-score
    DNA-PKCS H-score
    The 7th patient who responded had an ovarian cancer harboring RAD51C promoter
    methylation (Fig. S4). 1 Fisher's exact test. 2 Kruskal-Wallis rank sum test. 
    indicating that 53BP1 loss restores HR and confers diminished PARPi sen-sitivity mechanisms in BRCA1-mutant Cytochalasin D [Fig. 5 and refs. 13–16]. Consis-tent with earlier findings that loss of certain NHEJ components also is associated with PARPi resistance [11,12,16], trends were also observed be-tween low KU80 or low DNA-PKCS and poor response (Fig. 4C and D), al-though this association did not reach statistical significance in the present small sample set. Strikingly, these proteins were all expressed at some-what higher levels in ovarian cancers that respond to ABT-767 (Fig. 4E).
    The present analysis was performed on cancer samples harvested at the time of initial diagnosis. While secondary mutations that restore ex-pression of HR proteins can occur between diagnosis and subsequent treatment [5,37,39], it is unclear how frequently expression of repair proteins encoded by nonmutated, nonmethylated genes changes over the course of therapy. Analyses that compare archival versus pretreat-ment biopsies are required to further address this issue, as well as clarify the potential role of low 53BP1 expression in intrinsic versus acquired PARPi resistance in ovarian cancer. Additional studies are also needed to determine whether low 53BP1 expression correlates with poorer PARPi response in other cancers that are being treated with PARPis, in-cluding HR-deficient breast and prostate cancers.
    In summary, the present study suggests a possible role of repair pro-teins in complementary pathways in the response to the PARPi ABT-767 as a single agent in the clinical setting. Among HR-deficient ovarian can-cers, 53BP1 H-score demonstrated a strong correlation with the percent change of tumor volume. These results not only extend previous preclini-cal studies [11–16] into the clinical setting, but also point toward a strategy to identify patients most likely to respond to PARPi therapy. Accordingly, studies to assess the relationship between 53BP1 as well as possibly other repair proteins and response to other PARPis should be considered, as this type of analysis may add value to the HRD score in predicting re-sponse. In view of correlation between PARPi sensitivity and platinum sensitivity [36,40], studies to assess the relationship between platinum re-sponse and expression of these same proteins also appear warranted.
    Acknowledgements
    Fig. 5. Complementary pathways in DNA double strand (ds) break repair and PARP inhibitor response. In the setting of a DNA ds break, HR preferentially restores DNA integrity in an error-free fashion (left column). In the setting of HR-deficiency, however, the error-prone NHEJ pathway and the less error-prone alternative NHEJ (alt-NHEJ) pathways (middle and right columns, respectively) play a larger role in DNA ds break repair. PARP inhibitors inhibit alt-NHEJ and simultaneously facilitate NHEJ, leading to increased chromosomal rearrangements, genetic instability, and cell death. In the setting of 53BP1 downregulation, an inhibitory influence on HR is removed [16] and HR is restored. In the setting of NHEJ protein down-regulation, other DNA repair pathways with higher fidelity repair also appear to be utilized [11,12], although the mechanistic details are incompletely understood.