Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • br d Abbvie North Chicago IL United States

    2019-09-23


    d Abbvie, North Chicago, IL, United States of America
    e Department of Obstetrics and Gynecology, Univ. of Washington, Seattle, WA, United States of America
    f Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America
    g Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
    h Radboud University Medical Center, Nijmegen, the Netherlands
    i University Medical Center, Groningen, the Netherlands
    • Not all cancers with defects in homologous recombination (HR) demonstrate clinical responses to PARP inhibitors.
    • In a BRCA1-mutant ovarian cancer cell line, 53BP1 loss restores HR and decreases PARP inhibitor sensitivity.
    • Samples from a phase I trial of the PARP inhibitor ABT-767 were stained with validated IHC assays for DNA repair proteins.
    • In HR-deficient ovarian cancer, 53BP1 expression negatively correlated with percent change in tumor size from baseline.
    • Assessment of proteins that modulate DNA repair pathway choice might inform PARP inhibitor response in ovarian cancer.
    Article history:
    Keywords:
    PARP inhibitors
    Ovarian cancer
    DNA damage
    HR-deficiency
    Objective. Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For rea-sons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Pre-clinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity in ovarian cancer models. This has not previously been assessed in the clinical setting.
    Methods. Clonogenic and plasmid-based HR repair assays were performed to compare BRCA1-mutant COV362 ovarian cancer Dihexa (PNB-0408) with or without 53BP1 gene deletion. Archival biopsies from ovarian cancer patients in the phase I, open-label clinical trial of PARPi ABT-767 were stained for PARP1, RAD51, 53BP1 and multiple components of the nonhomologous end-joining (NHEJ) DNA repair pathway. Modified histochemistry- (H-) scores were determined for each repair protein in each sample. HRD score was determined from tumor DNA.
    Results. 53BP1 deletion increased HR in BRCA1-mutant COV362 cells and decreased PARPi sensitivity in vitro. In 36 women with relapsed ovarian cancer, responses to the PARPi ABT-767 were observed exclusively in cancers with HR deficiency. In this subset, 7 of 18 patients (39%) had objective responses. The actual HRD score did not further correlate with change from baseline tumor volume (r = 0.050; p = 0.87). However, in the HR-deficient subset, decreased 53BP1 H-score was associated with decreased antitumor efficacy of ABT-767 (r = −0.69, p = 0.004).
    Corresponding author at: Gonda 19-212, Mayo Clinic, 200 First Street, S.W., Rochester, MN 55905, United States of America. E-mail address: [email protected] (S.H. Kaufmann). 1 Equal contribution as first authors.
    2 Current affiliation: Corcept Therapeutics, Menlo Park, CA, United States of America.
    Conclusion. Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers. © 2019 Elsevier Inc. All rights reserved.
    1. Introduction
    Multiple poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have recently received regulatory approval for the treatment of ovarian cancer and are undergoing extensive clinical testing in additional ho-mologous recombination (HR) deficient cancers, including triple-negative breast, prostate, and pancreatic cancer [1–4]. Among recurrent high grade serous or endometrioid ovarian carcinomas, the response rate to PARPi therapy is highest in BRCA1- or BRCA2-mutant carcinomas, intermediate in BRCA1/2-wildtype carcinomas that show evidence of HR deficiency as manifested by high loss of heterozygosity, and lowest in HR-proficient carcinomas [5]. Given the toxicities of PARPi therapy, including prolonged nausea, myelosuppression and possible risk of myleodysplastic syndrome and acute myeloid leukemia, identifying car-cinomas that are unlikely to respond could spare a subset of ovarian cancer patients unnecessary side effects. How to distinguish HR-deficient ovarian carcinomas that will or will not respond to PARPis re-mains incompletely understood.