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 Ansel; 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. Shepherd; Elizabeth M. Swisher; Scott H. Kaufmann

doi:10.1016/j.ygyno.2019.01.015

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 Ansel, 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^*

^*Corresponding author voor dit werk

Onderzoeksoutput › Academic › peer review

58 Citaten (Scopus)

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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).

Originele taal-2	English
Pagina's (van-tot)	127-134
Aantal pagina's	8
Tijdschrift	Gynecologic Oncology
Volume	153
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1016/j.ygyno.2019.01.015
Status	Published - apr.-2019

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Hurley, R. M., Hendrickson, A. E. W., Visscher, D. W., Ansel, P., Harrell, M. I., Wagner, J. M., Negron, V., Goergen, K. M., Maurer, M. J., Oberg, A. L., Meng, X. W., Flatten, K. S., De Jonge, M. J. A., Van Herpen, C. D., Gietema, J. A., Koornstra, R. H. T., Jager, A., den Hollander, M. W., Dudley, M., ... Kaufmann, S. H. (2019). 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer. Gynecologic Oncology, 153(1), 127-134. https://doi.org/10.1016/j.ygyno.2019.01.015

@article{f1dff007bda94280811ab0dd2b097b69,

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

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. (C) 2019 Elsevier Inc. All rights reserved.",

keywords = "53BP1, PARP inhibitors, Ovarian cancer, DNA damage, HR-deficiency, POLYMERASE INHIBITORS, OPEN-LABEL, RESISTANCE, MUTATIONS, CARCINOMA, REPAIR, NIRAPARIB, CELLS, MULTICENTER, PROFICIENT",

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

year = "2019",

month = apr,

doi = "10.1016/j.ygyno.2019.01.015",

language = "English",

volume = "153",

pages = "127--134",

journal = "Gynecologic Oncology",

issn = "0090-8258",

publisher = "ACADEMIC PRESS INC ELSEVIER SCIENCE",

number = "1",

}

Hurley, RM, Hendrickson, AEW, Visscher, DW, Ansel, 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, vol. 153, nr. 1, blz. 127-134. https://doi.org/10.1016/j.ygyno.2019.01.015

TY - JOUR

T1 - 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer

AU - Hurley, Rachel M.

AU - Hendrickson, Andrea E. Wahner

AU - Visscher, Daniel W.

AU - Ansel, 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 - 2019/4

Y1 - 2019/4

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. (C) 2019 Elsevier Inc. All rights reserved.

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. (C) 2019 Elsevier Inc. All rights reserved.

KW - 53BP1

KW - PARP inhibitors

KW - Ovarian cancer

KW - DNA damage

KW - HR-deficiency

KW - POLYMERASE INHIBITORS

KW - OPEN-LABEL

KW - RESISTANCE

KW - MUTATIONS

KW - CARCINOMA

KW - REPAIR

KW - NIRAPARIB

KW - CELLS

KW - MULTICENTER

KW - PROFICIENT

U2 - 10.1016/j.ygyno.2019.01.015

DO - 10.1016/j.ygyno.2019.01.015

M3 - Article

SN - 0090-8258

VL - 153

SP - 127

EP - 134

JO - Gynecologic Oncology

JF - Gynecologic Oncology

IS - 1

ER -

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

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