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Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a “Molecular Second Look”

OBJECTIVES: The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sens...

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Autores principales: Schwartz, Melissa, Camacho-Vanegas, Olga, Wood, Ashley M., Dashkoff, Matthew, Whitelock, Courtney, Harkins, Timothy T., Cohen, Carmel J., Beddoe, Ann Marie, Dottino, Peter, Martignetti, John A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839702/
https://www.ncbi.nlm.nih.gov/pubmed/29324546
http://dx.doi.org/10.1097/IGC.0000000000001190
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author Schwartz, Melissa
Camacho-Vanegas, Olga
Wood, Ashley M.
Dashkoff, Matthew
Whitelock, Courtney
Harkins, Timothy T.
Cohen, Carmel J.
Beddoe, Ann Marie
Dottino, Peter
Martignetti, John A.
author_facet Schwartz, Melissa
Camacho-Vanegas, Olga
Wood, Ashley M.
Dashkoff, Matthew
Whitelock, Courtney
Harkins, Timothy T.
Cohen, Carmel J.
Beddoe, Ann Marie
Dottino, Peter
Martignetti, John A.
author_sort Schwartz, Melissa
collection PubMed
description OBJECTIVES: The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sensitive and specific method to assess actual treatment response and tailor future therapy and to compare this “molecular second look” with conventional cytology and histopathology-based findings. METHODS/MATERIALS: We identified 10 patients with advanced-stage, high-grade serous ovarian cancer who had undergone second-look laparoscopy and for whom DNA could be isolated from biobanked paired blood, primary and recurrent tumor, and second-look peritoneal washes. A targeted 56 gene cancer-relevant panel was used for next-generation sequencing (average coverage, >6500×). Mutations were validated using either digital droplet polymerase chain reaction (ddPCR) or Sanger sequencing. RESULTS: A total of 25 tumor-specific mutations were identified (median, 2/patient; range, 1–8). TP53 mutations were identified in at least 1 sample from all patients. All 5 pathology-based second-look positive patients were confirmed positive by molecular second look. Genetic analysis revealed that 3 of the 5 pathology-based negative second looks were actually positive. In the 2 patients, the second-look mutations were present in either the original primary or recurrent tumors. In the third, 2 high-frequency, novel frameshift mutations in MSH6 and HNF1A were identified. CONCLUSIONS: The molecular second look detects tumor-specific evidence of residual disease and provides genetic insight into tumor evolution and future recurrences beyond standard pathology. In the precision medicine era, detecting and genetically characterizing residual disease after standard treatment will be invaluable for improving patient outcomes.
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spelling pubmed-58397022018-03-20 Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a “Molecular Second Look” Schwartz, Melissa Camacho-Vanegas, Olga Wood, Ashley M. Dashkoff, Matthew Whitelock, Courtney Harkins, Timothy T. Cohen, Carmel J. Beddoe, Ann Marie Dottino, Peter Martignetti, John A. Int J Gynecol Cancer Ovarian Cancer OBJECTIVES: The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sensitive and specific method to assess actual treatment response and tailor future therapy and to compare this “molecular second look” with conventional cytology and histopathology-based findings. METHODS/MATERIALS: We identified 10 patients with advanced-stage, high-grade serous ovarian cancer who had undergone second-look laparoscopy and for whom DNA could be isolated from biobanked paired blood, primary and recurrent tumor, and second-look peritoneal washes. A targeted 56 gene cancer-relevant panel was used for next-generation sequencing (average coverage, >6500×). Mutations were validated using either digital droplet polymerase chain reaction (ddPCR) or Sanger sequencing. RESULTS: A total of 25 tumor-specific mutations were identified (median, 2/patient; range, 1–8). TP53 mutations were identified in at least 1 sample from all patients. All 5 pathology-based second-look positive patients were confirmed positive by molecular second look. Genetic analysis revealed that 3 of the 5 pathology-based negative second looks were actually positive. In the 2 patients, the second-look mutations were present in either the original primary or recurrent tumors. In the third, 2 high-frequency, novel frameshift mutations in MSH6 and HNF1A were identified. CONCLUSIONS: The molecular second look detects tumor-specific evidence of residual disease and provides genetic insight into tumor evolution and future recurrences beyond standard pathology. In the precision medicine era, detecting and genetically characterizing residual disease after standard treatment will be invaluable for improving patient outcomes. Lippincott Williams & Wilkins 2018-03 2018-01-10 /pmc/articles/PMC5839702/ /pubmed/29324546 http://dx.doi.org/10.1097/IGC.0000000000001190 Text en Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of IGCS and ESGO. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Ovarian Cancer
Schwartz, Melissa
Camacho-Vanegas, Olga
Wood, Ashley M.
Dashkoff, Matthew
Whitelock, Courtney
Harkins, Timothy T.
Cohen, Carmel J.
Beddoe, Ann Marie
Dottino, Peter
Martignetti, John A.
Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a “Molecular Second Look”
title Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a “Molecular Second Look”
title_full Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a “Molecular Second Look”
title_fullStr Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a “Molecular Second Look”
title_full_unstemmed Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a “Molecular Second Look”
title_short Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a “Molecular Second Look”
title_sort applying precision medicine to ovarian cancer: proof-of-principle for a “molecular second look”
topic Ovarian Cancer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839702/
https://www.ncbi.nlm.nih.gov/pubmed/29324546
http://dx.doi.org/10.1097/IGC.0000000000001190
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