Cargando…
A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer
In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response t...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458434/ https://www.ncbi.nlm.nih.gov/pubmed/34552099 http://dx.doi.org/10.1038/s41467-021-25904-w |
_version_ | 1784571301338284032 |
---|---|
author | Konstantinopoulos, Panagiotis A. da Costa, Alexandre André B. A. Gulhan, Doga Lee, Elizabeth K. Cheng, Su-Chun Hendrickson, Andrea E. Wahner Kochupurakkal, Bose Kolin, David L. Kohn, Elise C. Liu, Joyce F. Stover, Elizabeth H. Curtis, Jennifer Tayob, Nabihah Polak, Madeline Chowdhury, Dipanjan Matulonis, Ursula A. Färkkilä, Anniina D’Andrea, Alan D. Shapiro, Geoffrey I. |
author_facet | Konstantinopoulos, Panagiotis A. da Costa, Alexandre André B. A. Gulhan, Doga Lee, Elizabeth K. Cheng, Su-Chun Hendrickson, Andrea E. Wahner Kochupurakkal, Bose Kolin, David L. Kohn, Elise C. Liu, Joyce F. Stover, Elizabeth H. Curtis, Jennifer Tayob, Nabihah Polak, Madeline Chowdhury, Dipanjan Matulonis, Ursula A. Färkkilä, Anniina D’Andrea, Alan D. Shapiro, Geoffrey I. |
author_sort | Konstantinopoulos, Panagiotis A. |
collection | PubMed |
description | In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17–0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13–0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47–2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required. |
format | Online Article Text |
id | pubmed-8458434 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84584342021-10-07 A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer Konstantinopoulos, Panagiotis A. da Costa, Alexandre André B. A. Gulhan, Doga Lee, Elizabeth K. Cheng, Su-Chun Hendrickson, Andrea E. Wahner Kochupurakkal, Bose Kolin, David L. Kohn, Elise C. Liu, Joyce F. Stover, Elizabeth H. Curtis, Jennifer Tayob, Nabihah Polak, Madeline Chowdhury, Dipanjan Matulonis, Ursula A. Färkkilä, Anniina D’Andrea, Alan D. Shapiro, Geoffrey I. Nat Commun Article In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17–0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13–0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47–2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required. Nature Publishing Group UK 2021-09-22 /pmc/articles/PMC8458434/ /pubmed/34552099 http://dx.doi.org/10.1038/s41467-021-25904-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Konstantinopoulos, Panagiotis A. da Costa, Alexandre André B. A. Gulhan, Doga Lee, Elizabeth K. Cheng, Su-Chun Hendrickson, Andrea E. Wahner Kochupurakkal, Bose Kolin, David L. Kohn, Elise C. Liu, Joyce F. Stover, Elizabeth H. Curtis, Jennifer Tayob, Nabihah Polak, Madeline Chowdhury, Dipanjan Matulonis, Ursula A. Färkkilä, Anniina D’Andrea, Alan D. Shapiro, Geoffrey I. A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer |
title | A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer |
title_full | A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer |
title_fullStr | A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer |
title_full_unstemmed | A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer |
title_short | A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer |
title_sort | replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and atr inhibitor therapy in ovarian cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458434/ https://www.ncbi.nlm.nih.gov/pubmed/34552099 http://dx.doi.org/10.1038/s41467-021-25904-w |
work_keys_str_mv | AT konstantinopoulospanagiotisa areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT dacostaalexandreandreba areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT gulhandoga areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT leeelizabethk areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT chengsuchun areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT hendricksonandreaewahner areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT kochupurakkalbose areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT kolindavidl areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT kohnelisec areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT liujoycef areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT stoverelizabethh areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT curtisjennifer areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT tayobnabihah areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT polakmadeline areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT chowdhurydipanjan areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT matulonisursulaa areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT farkkilaanniina areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT dandreaaland areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT shapirogeoffreyi areplicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT konstantinopoulospanagiotisa replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT dacostaalexandreandreba replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT gulhandoga replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT leeelizabethk replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT chengsuchun replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT hendricksonandreaewahner replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT kochupurakkalbose replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT kolindavidl replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT kohnelisec replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT liujoycef replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT stoverelizabethh replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT curtisjennifer replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT tayobnabihah replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT polakmadeline replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT chowdhurydipanjan replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT matulonisursulaa replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT farkkilaanniina replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT dandreaaland replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer AT shapirogeoffreyi replicationstressbiomarkerisassociatedwithresponsetogemcitabineversuscombinedgemcitabineandatrinhibitortherapyinovariancancer |