IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-16142-7.html
   My bibliography  Save this article

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

Author

Listed:
  • Neha Chopra

    (The Institute of Cancer Research)

  • Holly Tovey

    (The Institute of Cancer Research)

  • Alex Pearson

    (The Institute of Cancer Research)

  • Ros Cutts

    (The Institute of Cancer Research)

  • Christy Toms

    (The Institute of Cancer Research)

  • Paula Proszek

    (The Royal Marsden Hospital)

  • Michael Hubank

    (The Royal Marsden Hospital)

  • Mitch Dowsett

    (The Institute of Cancer Research
    Royal Marsden Hospital)

  • Andrew Dodson

    (Royal Marsden Hospital)

  • Frances Daley

    (The Institute of Cancer Research)

  • Divya Kriplani

    (The Institute of Cancer Research)

  • Heidi Gevensleben

    (The Institute of Cancer Research)

  • Helen Ruth Davies

    (The Clinical School
    University of Cambridge)

  • Andrea Degasperi

    (The Clinical School
    University of Cambridge)

  • Rebecca Roylance

    (NIHR University College London Hospitals Biomedical Research Centre)

  • Stephen Chan

    (Nottingham University Hospital Trust (City Campus))

  • Andrew Tutt

    (The Institute of Cancer Research
    King’s College London)

  • Anthony Skene

    (Royal Bournemouth Hospital)

  • Abigail Evans

    (Poole Hospital NHS Foundation Trust)

  • Judith M. Bliss

    (The Institute of Cancer Research)

  • Serena Nik-Zainal

    (The Clinical School
    University of Cambridge)

  • Nicholas C. Turner

    (The Institute of Cancer Research
    The Royal Marsden Hospital)

Abstract

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.

Suggested Citation

  • Neha Chopra & Holly Tovey & Alex Pearson & Ros Cutts & Christy Toms & Paula Proszek & Michael Hubank & Mitch Dowsett & Andrew Dodson & Frances Daley & Divya Kriplani & Heidi Gevensleben & Helen Ruth D, 2020. "Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16142-7
    DOI: 10.1038/s41467-020-16142-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-16142-7
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-020-16142-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Lorena Espinar & Marta Garcia-Cao & Alisa Schmidt & Savvas Kourtis & Antoni Gañez Zapater & Carla Aranda-Vallejo & Ritobrata Ghose & Laura Garcia-Lopez & Ilir Sheraj & Natalia Pardo-Lorente & Marina B, 2024. "Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Naser Ansari-Pour & Yonglan Zheng & Toshio F. Yoshimatsu & Ayodele Sanni & Mustapha Ajani & Jean-Baptiste Reynier & Avraam Tapinos & Jason J. Pitt & Stefan Dentro & Anna Woodard & Padma Sheila Rajagop, 2021. "Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Yonina R. Murciano-Goroff & Alison M. Schram & Ezra Y. Rosen & Helen Won & Yixiao Gong & Anne Marie Noronha & Yelena Y. Janjigian & Zsofia K. Stadler & Jason C. Chang & Soo-Ryum Yang & Diana Mandelker, 2022. "Reversion mutations in germline BRCA1/2-mutant tumors reveal a BRCA-mediated phenotype in non-canonical histologies," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16142-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.