N. Turner (London, United Kingdom)
The Royal Marsden Hospital - NHS Foundation TrustAuthor Of 2 Presentations
cfDNA testing for early detection of breast cancer and breast cancer relapse. Ready for prime time? (ID 276)
1O - Detection of homologous recombination repair deficiency (HRD) in treatment-naive early triple negative breast cancer (TNBC) by RAD51 foci and comparison with DNA-based tests (ID 243)
Abstract
Background
PARP inhibitors (PARPi) are approved for the treatment of metastatic breast cancers (BC) associated with germline BRCA1/BRCA2 (gBRCA) mutations. Tumours from these patients are defective in double strand break DNA repair, namely homologous recombination repair (HRR). HRR alterations also exist beyond gBRCA mutation in 60% of TNBC. HRR results in RAD51 foci formation. Here, we aimed to evaluate the functional status of HRR with an immunofluorescence (IF) tissue-based test, to identify tumours lacking RAD51 foci, and correlate this with genomic HRD tests or treatment activity.
Methods
The percentage of RAD51 foci in the S/G2-phase of the cell cycle was scored using an IF test (RAD51-IF) in baseline and end of treatment (EOT) FFPE tumour samples from 29 patients diagnosed with early TNBC, receiving the PARPi rucaparib in the RIO trial (EudraCT 2014-003319-12). The baseline RAD51 score, predefined as low if ≤10%, was correlated with trial endpoints including HRR alterations, HRDetect status, RAD51 by immunohistochemistry (RAD51-IHC) at EOT and change in ctDNA levels.
Results
The RAD51-IF test scored 17/17 baseline tumour samples (100%), and 27/28 EOT samples (96%), compared to 93% success rate for HRDetect or 73% of RAD51-IHC EOT. RAD51-IF scores increased from baseline to EOT (p=0.026), reflecting rucaparib induced RAD51-mediated repair. The prevalence of HRD according to the RAD51-IF test was 47% (8 out of 17). Six out of eight tumours with known HRR alterations had low RAD51-IF (75%). Two tumours without known HRR alterations had low RAD51-IF, suggesting the presence of underlying HRR alterations. Seven out of ten HRDetect-positive tumours had low RAD51-IF, and none of the HRDetect-negative tumours had low RAD51-IF (p=0.054). RAD51-IF low tumours had greater ctDNA suppression on rucaparib than RAD51 high tumours (n=12, p=0.052), with 4 out of 5 (80%) RAD51-low tumours undergoing a substantial decrease in ctDNA levels, similar to 78% for RAD51-IHC EOT.
Conclusions
The RAD51-IF test is feasible in treatment-naive FFPE tumour samples from early TNBC to assess the functional status of HRR and identifies PARPi-sensitive tumours.
Clinical trial identification
EudraCT 2014-003319-12.
Legal entity responsible for the study
RMH and ICR.
Funding
Instituto de Salud Carlos III, Asociación Española Contra el Cáncer. Clovis Oncology Inc., Cridlan Foundation, CRUK, Breast Cancer Now, NHS, Wellcome Trust.
Disclosure
V. Serra Elizalde: Licensing/Royalties, PCT/EP2018/086759 (WO2019122411A1): Patent; Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Tesaro; Advisory/Consultancy: AbbVie. A. Llop-Guevara: Licensing/Royalties, PCT/EP2018/086759 (WO2019122411A1): Patent. C. Cruz: Licensing/Royalties, PCT/EP2018/086759 (WO2019122411A1): Patent. M. Castroviejo-Bermejo: Licensing/Royalties, PCT/EP2018/086759 (WO2019122411A1): Patent. H. Tovey: Research grant/Funding (self): Clovis Oncology Inc. C. Toms: Research grant/Funding (self): Clovis. R. Roylance: Honoraria (self): Pfizer. A. Tutt: Honoraria (self): Pfizer; Honoraria (self): Vertex; Honoraria (self): prIME Oncology; Honoraria (self): Artios; Honoraria (self), Shareholder/Stockholder/Stock options: InBiomotion; Honoraria (self): AstraZeneca; Honoraria (self): Medivation; Honoraria (self): Myriad Genetics; Honoraria (self): Merck Serono; Licensing/Royalties, PARP inhibitor: Institute of Cancer Research. H.R. Davies: Licensing/Royalties, WO2017191074A1: Patent. S. Nik-Zainal: Licensing/Royalties, WO2017191074A1: Patent; Honoraria (self): GTx; Honoraria (self): Radius; Honoraria (self): Orion; Honoraria (self): G1therapeutics; Speaker Bureau/Expert testimony: Myriad and; Speaker Bureau/Expert testimony: NanoString; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Radius; Licensing/Royalties, Abiraterone: Institute of Cancer Research. J. Balmaña: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Licensing/Royalties, PCT/ EP2018/086759 (WO2019122411A1): Patent. N. Turner: Research grant/Funding (self): Clovis; Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Lilly; Honoraria (self): Merck Sharpe and Dohme; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Research grant/Funding (self): Roche/Genentech; Honoraria (self): Tesaro; Honoraria (self): Bicycle Therapeutics; Research grant/Funding (self): BioRad; Research grant/Funding (self): Guardant Health. All other authors have declared no conflicts of interest.
Presenter Of 1 Presentation
cfDNA testing for early detection of breast cancer and breast cancer relapse. Ready for prime time? (ID 276)
Author Of 1 Presentation
- B. Kingston (London, United Kingdom)
- R. Cutts (London, United Kingdom)
- M. Beaney (London, United Kingdom)
- G. Walsh-Crestani (London, United Kingdom)
- S. Hrebien (London, United Kingdom)
- L. Kilburn (London, United Kingdom)
- S. Kernaghan (London, United Kingdom)
- L. Moretti (London, United Kingdom)
- K. Wilkinson (London, United Kingdom)
- I. Macpherson (Glasgow, United Kingdom)
- R. Baird (Cambridge, Ca, United Kingdom)
- R. Roylance (London, United Kingdom)
- J. Reis-Filho (New York, NY, United States of America)
- M. Hubank (London, United Kingdom)
- I. Faull (Redwood City, CA, United States of America)
- K. Banks (Redwood City, CA, United States of America)
- I. Garcia-Murillas (London, United Kingdom)
- J. Bliss (London, United Kingdom)
- A. Ring (London, United Kingdom)
- N. Turner (London, United Kingdom)