Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methyla...

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Vydáno v:	Nature communications Ročník 12; číslo 1; s. 2487 - 13
Hlavní autoři:	Swisher, Elizabeth M., Kwan, Tanya T., Oza, Amit M., Tinker, Anna V., Ray-Coquard, Isabelle, Oaknin, Ana, Coleman, Robert L., Aghajanian, Carol, Konecny, Gottfried E., O’Malley, David M., Leary, Alexandra, Provencher, Diane, Welch, Stephen, Chen, Lee-may, Wahner Hendrickson, Andrea E., Ma, Ling, Ghatage, Prafull, Kristeleit, Rebecca S., Dorigo, Oliver, Musafer, Ashan, Kaufmann, Scott H., Elvin, Julia A., Lin, Douglas I., Chambers, Setsuko K., Dominy, Erin, Vo, Lan-Thanh, Goble, Sandra, Maloney, Lara, Giordano, Heidi, Harding, Thomas, Dobrovic, Alexander, Scott, Clare L., Lin, Kevin K., McNeish, Iain A.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 03.05.2021 Nature Publishing Group Nature Portfolio
Témata:	631/67/1517/1709 631/67/1857 Adult Aged Aged, 80 and over AKT protein Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Biomarkers BRCA1 protein BRCA1 Protein - genetics BRCA2 protein BRCA2 Protein - genetics Breast cancer Cancer Cancer therapies Carcinoma, Ovarian Epithelial - drug therapy Cell cycle Cross-resistance DNA methylation DNA Methylation - genetics DNA-Binding Proteins - genetics Female Health services Homologous recombination Homology Humanities and Social Sciences Humans Indoles - adverse effects Indoles - therapeutic use Inhibitors Methylation Middle Aged Modulators multidisciplinary Mutation Neoplasm Recurrence, Local - drug therapy Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - drug therapy Patients Platinum Platinum - therapeutic use Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - adverse effects Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Promoter Regions, Genetic - genetics Scars Science Science (multidisciplinary)
ISSN:	2041-1723, 2041-1723
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Abstract	ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1 / BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers
AbstractList	ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1 / BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1 / BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers
ArticleNumber	2487
Author	Provencher, Diane Elvin, Julia A. Dominy, Erin Kristeleit, Rebecca S. Coleman, Robert L. Ma, Ling Konecny, Gottfried E. Chambers, Setsuko K. Aghajanian, Carol Goble, Sandra Ghatage, Prafull Dobrovic, Alexander Tinker, Anna V. Maloney, Lara Oza, Amit M. Dorigo, Oliver Lin, Kevin K. Chen, Lee-may O’Malley, David M. Welch, Stephen Wahner Hendrickson, Andrea E. Swisher, Elizabeth M. Oaknin, Ana Kaufmann, Scott H. Harding, Thomas Kwan, Tanya T. Vo, Lan-Thanh Ray-Coquard, Isabelle McNeish, Iain A. Scott, Clare L. Leary, Alexandra Musafer, Ashan Lin, Douglas I. Giordano, Heidi
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/33941784$$D View this record in MEDLINE/PubMed
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Snippet	ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post... The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the...
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SubjectTerms	631/67/1517/1709 631/67/1857 Adult Aged Aged, 80 and over AKT protein Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Biomarkers BRCA1 protein BRCA1 Protein - genetics BRCA2 protein BRCA2 Protein - genetics Breast cancer Cancer Cancer therapies Carcinoma, Ovarian Epithelial - drug therapy Cell cycle Cross-resistance DNA methylation DNA Methylation - genetics DNA-Binding Proteins - genetics Female Health services Homologous recombination Homology Humanities and Social Sciences Humans Indoles - adverse effects Indoles - therapeutic use Inhibitors Methylation Middle Aged Modulators multidisciplinary Mutation Neoplasm Recurrence, Local - drug therapy Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - drug therapy Patients Platinum Platinum - therapeutic use Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - adverse effects Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Promoter Regions, Genetic - genetics Scars Science Science (multidisciplinary)
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Title	Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)
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