53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer

Rachel M. Hurley, Andrea E Wahner Hendrickson, Daniel W Visscher, Peter Ansell, Maria I. Harrell, Jill M. Wagner, Vivian Negron, Krista M. Goergen, Matthew J. Maurer, Ann L Oberg, X. Wei Meng, Karen S. Flatten, Maja J.A. De Jonge, Carla D. Van Herpen, Jourik A. Gietema, Rutger H.T. Koornstra, Agnes Jager, Martha W. den Hollander, Matthew Dudley, Stacie P. ShepherdElizabeth M. Swisher, Scott H Kaufmann

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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 reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical 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 cells 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). Conclusion: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.

Original languageEnglish (US)
JournalGynecologic Oncology
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Homologous Recombination
Ovarian Neoplasms
DNA End-Joining Repair
Neoplasms
Gene Deletion
Tumor Burden
DNA Repair
Poly(ADP-ribose) Polymerase Inhibitors
Plasmids
Clinical Trials
Biopsy
DNA
Proteins

Keywords

  • 53BP1
  • DNA damage
  • HR-deficiency
  • Ovarian cancer
  • PARP inhibitors

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer. / Hurley, Rachel M.; Wahner Hendrickson, Andrea E; Visscher, Daniel W; Ansell, Peter; Harrell, Maria I.; Wagner, Jill M.; Negron, Vivian; Goergen, Krista M.; Maurer, Matthew J.; Oberg, Ann L; Meng, X. Wei; Flatten, Karen S.; De Jonge, Maja J.A.; Van Herpen, Carla D.; Gietema, Jourik A.; Koornstra, Rutger H.T.; Jager, Agnes; den Hollander, Martha W.; Dudley, Matthew; Shepherd, Stacie P.; Swisher, Elizabeth M.; Kaufmann, Scott H.

In: Gynecologic Oncology, 01.01.2019.

Research output: Contribution to journalArticle

Hurley, RM, Wahner Hendrickson, AE, Visscher, DW, Ansell, P, Harrell, MI, Wagner, JM, Negron, V, Goergen, KM, Maurer, MJ, Oberg, AL, Meng, XW, Flatten, KS, De Jonge, MJA, Van Herpen, CD, Gietema, JA, Koornstra, RHT, Jager, A, den Hollander, MW, Dudley, M, Shepherd, SP, Swisher, EM & Kaufmann, SH 2019, '53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer', Gynecologic Oncology. https://doi.org/10.1016/j.ygyno.2019.01.015
Hurley, Rachel M. ; Wahner Hendrickson, Andrea E ; Visscher, Daniel W ; Ansell, Peter ; Harrell, Maria I. ; Wagner, Jill M. ; Negron, Vivian ; Goergen, Krista M. ; Maurer, Matthew J. ; Oberg, Ann L ; Meng, X. Wei ; Flatten, Karen S. ; De Jonge, Maja J.A. ; Van Herpen, Carla D. ; Gietema, Jourik A. ; Koornstra, Rutger H.T. ; Jager, Agnes ; den Hollander, Martha W. ; Dudley, Matthew ; Shepherd, Stacie P. ; Swisher, Elizabeth M. ; Kaufmann, Scott H. / 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer. In: Gynecologic Oncology. 2019.
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abstract = "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 reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical 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 cells 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). Conclusion: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.",
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T1 - 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer

AU - Hurley, Rachel M.

AU - Wahner Hendrickson, Andrea E

AU - Visscher, Daniel W

AU - Ansell, Peter

AU - Harrell, Maria I.

AU - Wagner, Jill M.

AU - Negron, Vivian

AU - Goergen, Krista M.

AU - Maurer, Matthew J.

AU - Oberg, Ann L

AU - Meng, X. Wei

AU - Flatten, Karen S.

AU - De Jonge, Maja J.A.

AU - Van Herpen, Carla D.

AU - Gietema, Jourik A.

AU - Koornstra, Rutger H.T.

AU - Jager, Agnes

AU - den Hollander, Martha W.

AU - Dudley, Matthew

AU - Shepherd, Stacie P.

AU - Swisher, Elizabeth M.

AU - Kaufmann, Scott H

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical 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 cells 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). Conclusion: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.

AB - 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 reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical 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 cells 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). Conclusion: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.

KW - 53BP1

KW - DNA damage

KW - HR-deficiency

KW - Ovarian cancer

KW - PARP inhibitors

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