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Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes

PURPOSE: Deficiency in homologous recombination (HR) repair of DNA damage is characteristic of many high-grade serous ovarian cancers (HGSC). It is imperative to identify patients with homologous recombination–deficient (HRD) tumors as they are most likely to benefit from platinum-based chemotherapy...

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Autores principales: Pikkusaari, Sanna, Tumiati, Manuela, Virtanen, Anni, Oikkonen, Jaana, Li, Yilin, Perez-Villatoro, Fernando, Muranen, Taru, Salko, Matilda, Huhtinen, Kaisa, Kanerva, Anna, Koskela, Heidi, Tapper, Johanna, Koivisto-Korander, Riitta, Joutsiniemi, Titta, Haltia, Ulla-Maija, Lassus, Heini, Hautaniemi, Sampsa, Färkkilä, Anniina, Hynninen, Johanna, Hietanen, Sakari, Carpén, Olli, Kauppi, Liisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425726/
https://www.ncbi.nlm.nih.gov/pubmed/36805632
http://dx.doi.org/10.1158/1078-0432.CCR-22-3156
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author Pikkusaari, Sanna
Tumiati, Manuela
Virtanen, Anni
Oikkonen, Jaana
Li, Yilin
Perez-Villatoro, Fernando
Muranen, Taru
Salko, Matilda
Huhtinen, Kaisa
Kanerva, Anna
Koskela, Heidi
Tapper, Johanna
Koivisto-Korander, Riitta
Joutsiniemi, Titta
Haltia, Ulla-Maija
Lassus, Heini
Hautaniemi, Sampsa
Färkkilä, Anniina
Hynninen, Johanna
Hietanen, Sakari
Carpén, Olli
Kauppi, Liisa
author_facet Pikkusaari, Sanna
Tumiati, Manuela
Virtanen, Anni
Oikkonen, Jaana
Li, Yilin
Perez-Villatoro, Fernando
Muranen, Taru
Salko, Matilda
Huhtinen, Kaisa
Kanerva, Anna
Koskela, Heidi
Tapper, Johanna
Koivisto-Korander, Riitta
Joutsiniemi, Titta
Haltia, Ulla-Maija
Lassus, Heini
Hautaniemi, Sampsa
Färkkilä, Anniina
Hynninen, Johanna
Hietanen, Sakari
Carpén, Olli
Kauppi, Liisa
author_sort Pikkusaari, Sanna
collection PubMed
description PURPOSE: Deficiency in homologous recombination (HR) repair of DNA damage is characteristic of many high-grade serous ovarian cancers (HGSC). It is imperative to identify patients with homologous recombination–deficient (HRD) tumors as they are most likely to benefit from platinum-based chemotherapy and PARP inhibitors (PARPi). Existing methods measure historical, not necessarily current HRD and/or require high tumor cell content, which is not achievable for many patients. We set out to develop a clinically feasible assay for identifying functionally HRD tumors that can predict clinical outcomes. EXPERIMENTAL DESIGN: We quantified RAD51, a key HR protein, in immunostained formalin-fixed, paraffin-embedded (FFPE) tumor samples obtained from chemotherapy-naïve and neoadjuvant chemotherapy (NACT)-treated HGSC patients. We defined cutoffs for functional HRD separately for these sample types, classified the patients accordingly as HRD or HR-proficient, and analyzed correlations with clinical outcomes. From the same specimens, genomics-based HRD estimates (HR gene mutations, genomic signatures, and genomic scars) were also determined, and compared with functional HR (fHR) status. RESULTS: fHR status significantly predicted several clinical outcomes, including progression-free survival (PFS) and overall survival (OS), when determined from chemo-naïve (PFS, P < 0.0001; OS, P < 0.0001) as well as NACT-treated (PFS, P < 0.0001; OS, P = 0.0033) tumor specimens. The fHR test also identified as HRD those PARPi-at-recurrence–treated patients with longer OS (P = 0.0188). CONCLUSIONS: We developed an fHR assay performed on routine FFPE specimens, obtained from either chemo-naïve or NACT-treated HGSC patients, that can significantly predict real-world platinum-based chemotherapy and PARPi response. See related commentary by Garg and Oza, p. 2957
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spelling pubmed-104257262023-08-16 Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes Pikkusaari, Sanna Tumiati, Manuela Virtanen, Anni Oikkonen, Jaana Li, Yilin Perez-Villatoro, Fernando Muranen, Taru Salko, Matilda Huhtinen, Kaisa Kanerva, Anna Koskela, Heidi Tapper, Johanna Koivisto-Korander, Riitta Joutsiniemi, Titta Haltia, Ulla-Maija Lassus, Heini Hautaniemi, Sampsa Färkkilä, Anniina Hynninen, Johanna Hietanen, Sakari Carpén, Olli Kauppi, Liisa Clin Cancer Res Precision Medicine and Imaging PURPOSE: Deficiency in homologous recombination (HR) repair of DNA damage is characteristic of many high-grade serous ovarian cancers (HGSC). It is imperative to identify patients with homologous recombination–deficient (HRD) tumors as they are most likely to benefit from platinum-based chemotherapy and PARP inhibitors (PARPi). Existing methods measure historical, not necessarily current HRD and/or require high tumor cell content, which is not achievable for many patients. We set out to develop a clinically feasible assay for identifying functionally HRD tumors that can predict clinical outcomes. EXPERIMENTAL DESIGN: We quantified RAD51, a key HR protein, in immunostained formalin-fixed, paraffin-embedded (FFPE) tumor samples obtained from chemotherapy-naïve and neoadjuvant chemotherapy (NACT)-treated HGSC patients. We defined cutoffs for functional HRD separately for these sample types, classified the patients accordingly as HRD or HR-proficient, and analyzed correlations with clinical outcomes. From the same specimens, genomics-based HRD estimates (HR gene mutations, genomic signatures, and genomic scars) were also determined, and compared with functional HR (fHR) status. RESULTS: fHR status significantly predicted several clinical outcomes, including progression-free survival (PFS) and overall survival (OS), when determined from chemo-naïve (PFS, P < 0.0001; OS, P < 0.0001) as well as NACT-treated (PFS, P < 0.0001; OS, P = 0.0033) tumor specimens. The fHR test also identified as HRD those PARPi-at-recurrence–treated patients with longer OS (P = 0.0188). CONCLUSIONS: We developed an fHR assay performed on routine FFPE specimens, obtained from either chemo-naïve or NACT-treated HGSC patients, that can significantly predict real-world platinum-based chemotherapy and PARPi response. See related commentary by Garg and Oza, p. 2957 American Association for Cancer Research 2023-08-15 2023-02-20 /pmc/articles/PMC10425726/ /pubmed/36805632 http://dx.doi.org/10.1158/1078-0432.CCR-22-3156 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Precision Medicine and Imaging
Pikkusaari, Sanna
Tumiati, Manuela
Virtanen, Anni
Oikkonen, Jaana
Li, Yilin
Perez-Villatoro, Fernando
Muranen, Taru
Salko, Matilda
Huhtinen, Kaisa
Kanerva, Anna
Koskela, Heidi
Tapper, Johanna
Koivisto-Korander, Riitta
Joutsiniemi, Titta
Haltia, Ulla-Maija
Lassus, Heini
Hautaniemi, Sampsa
Färkkilä, Anniina
Hynninen, Johanna
Hietanen, Sakari
Carpén, Olli
Kauppi, Liisa
Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
title Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
title_full Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
title_fullStr Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
title_full_unstemmed Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
title_short Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
title_sort functional homologous recombination assay on ffpe specimens of advanced high-grade serous ovarian cancer predicts clinical outcomes
topic Precision Medicine and Imaging
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425726/
https://www.ncbi.nlm.nih.gov/pubmed/36805632
http://dx.doi.org/10.1158/1078-0432.CCR-22-3156
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