Judith Balmaña (Barcelona, Spain)
Hospital Vall D'HebronAuthor Of 2 Presentations
12P - Prevalence of functional and genomic homologous recombination deficiency (HRD) in germline RAD51C/D patients (ID 30)
- Alba Llop-Guevara (Barcelona, Spain)
- Marcel Romey (Marburg, Germany)
- Sara Gutierrez-Enriquez (Barcelona, Spain)
- Paolo G. Nuciforo (Barcelona, Spain)
- Orland Diez (Barcelona, Spain)
- Gemma Llort Pursals (Sabadell, Spain)
- Alexandre Teule (Barcelona, Spain)
- Anna Vallmajó (Lleida, Spain)
- Isabela Diaz De Corcuera (Galdakao, Spain)
- Isabel Chirivella Gonzalez (Valencia, Spain)
- Santiago Gonzalez Santiago (Caceres, Spain)
- Pilar Sanchez Henarejos (El Palmar, Spain)
- Judit Sanz Buxo (Manresa, Spain)
- Carmen Guillen Ponce (Madrid, Spain)
- Ana Beatriz Sanchez (Elche, Spain)
- Joan Maria Brunet Vidal (Girona, Spain)
- Carsten Denkert (Marburg, Germany)
- Violeta Serra Elizalde (Barcelona, Spain)
- Judith Balmaña (Barcelona, Spain)
Abstract
Background
RAD51C and RAD51D are two paralogs of RAD51, essential for the repair of DNA breaks by homologous recombination (HRR). Germline pathogenic variants (PV) in these genes have been associated with HRR deficiency (HRD) and antitumor response to DNA damaging agents, including PARP inhibitors. The evaluation of RAD51 nuclear foci provides a functional measure of HRD, whereas genomic HRD captures accumulated tumor genomic instability. Biallelic inactivation of RAD51C has been associated with genomic HRD. We aimed to evaluate functional and genomic HRD in patients with primary breast and ovarian cancer (BC/OC) and germline PV in RAD51C/D (gRAD51C/D) to help understand the impact of these alterations in HRR status and provide evidence for therapeutic decision-making.
Methods
51 primary and untreated FFPE tumor samples were obtained from gRAD51C/D high-grade OC (n=26), ER- BC (n=14) and ER+ BC (n=11) patients, included in the Spanish Hereditary Cancer-SEOM registry. An immunofluorescence-based assay was used to evaluate RAD51 and functional HRD was defined as RAD51 score ≤10%. The genomic instability score (GIS), tumor HRR-gene mutation calling and gene-specific LOH (gsLOH) status was obtained with the Myriad myChoice CDx assay and analysis via the Myriad review algorithm.
Results
A successful RAD51 score was obtained in 40/51 (78%) and GIS in 27/29 (93%). The prevalence of HRD by the RAD51 test in gRAD51C was 12/30 (40%) and in gRAD51D was 8/10 (80%), compared to >90% in gBRCA1/2 and gPALB2 BC. Genomic HRD was 11/18 (61%) in gRAD51C samples and 8/9 (89%) in gRAD51D tumors. RAD51 scores and GIS were concordant in 19/21 (91%) cases. Of these, all HRD tumors by the RAD51 test (12/21) were also HRD by GIS and presented gsLOH. HRR proficiency by RAD51 (9/21) was consistent with low GIS, except for two OC cases with high GIS, gRAD51C mutation and gsLOH. Interestingly, all ER+ BC cases (n=5) were HRR proficient by RAD51 and GIS, and lacked gsLOH.
Conclusions
RAD51 scores and GIS are highly concordant in gRAD51C/D BC/OC and reveal a lower prevalence of HRD than expected, primarily in gRAD51C tumors. HRP was predominant in gRAD51C ER+ BC, which did not exhibit biallelic inactivation.
Legal entity responsible for the study
The authors.
Funding
Asociación Española Contra el Cáncer (AECC) LaCaixa Foundation (CaixaImpulse grant) Generalitat de Catalunya (AGAUR-Producte and PERIS) Instituto de Salud Carlos III (ISCIII) Fondo Europeo de Desarrollo Regional (FEDER).
Disclosure
A. Llop-Guevara: Other, Personal and Institutional, Proprietary Information, Patent WO2019122411A1: Methods based on the detection of RAD51 foci in tumor cells: None. M. Romey: Financial Interests, Institutional, Funding: Myriad Genetics. P.G. Nuciforo: Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Institutional, Advisory Board: MSD Oncology; Financial Interests, Institutional, Invited Speaker: Novartis; Other, Institutional, Other, Consultant: Targos Molecular Pathology GmbH. C. Denkert: Financial Interests, Personal, Advisory Board: MSD Oncology; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Molecular Health; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Ownership Interest, Cofounder and shareholder of Sividon Diagnostics until 2016: Sividon Diagnostic; Financial Interests, Personal, Invited Speaker: VmScope digital pathology software; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Research Grant: Myriad. V. Serra Elizalde: Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Other, WO2019122411A1: Methods based on the detection of rad51 foci in tumor cells: TBD; Financial Interests, Institutional, Research Grant, Testing various novel targeted agents in patient-derived tumour models: AstraZeneca. J. Balmaña: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Other, Steering Committee Member: AstraZeneca; Financial Interests, Institutional, Principal Investigator, Local PI in clinical trials: MedSir; Financial Interests, Institutional, Principal Investigator, Local PI in clinical trials: Pfizer; Other, Personal, Proprietary Information, Patent WO2019122411A1: Methods based on the detection of RAD51 foci in tumor cells: None. All other authors have declared no conflicts of interest.
161O - VIOLETTE: Randomised Phase 2 Study of Olaparib (ola) + Ceralasertib (cer) or Adavosertib (ada) vs Ola Alone in Patients (pts) With Metastatic Triple-Negative Breast Cancer (mTNBC) (ID 278)
- Andrew Tutt (London, United Kingdom)
- Zbigniew Nowecki (Warsaw, Poland)
- Renata Szoszkiewicz (Skorzewo, Poland)
- Seock-Ah Im (Seoul, Korea, Republic of)
- Hendrik-Tobias Arkenau (London, United Kingdom)
- Anne Armstrong (Manchester, United Kingdom)
- William Jacot (Montpellier, France)
- Jee Hyun Kim (Seongnam, Korea, Republic of)
- Marc Webster (Calgary, Canada)
- Judith Balmaña (Barcelona, Spain)
- Suzette Delaloge (Villejuif, France)
- Natasha Lukashchuk (Cambridge, United Kingdom)
- Ronny Odegbami (Cambridge, United Kingdom)
- Ed Casson (Cambridge, United Kingdom)
- Arsene B. Loembe (Oss, Netherlands)
- Moritz W. Drachsler (Cambridge, United Kingdom)
- Emma J. Dean (Cambridge, United Kingdom)
- Kevin Punie (Leuven, Belgium)
Abstract
Background
Combining DNA damage response (DDR) inhibitors to inhibit multiple DDR pathways may enhance tumour cell death. Preclinical models show synergistic antitumour effects of ola (PARP1 inhibitor) + cer (ATR inhibitor) or ada (WEE1 inhibitor). VIOLETTE (NCT03330847), a phase 2 open-label study, evaluated ola ± cer or ada as 2nd–3rd line in pts with mTNBC.
Methods
Randomisation was stratified within each arm by mutation status (BRCAm, non-BRCAm homologous recombination repair pathway mutations [HRRm], or no HRRm [non-HRRm]) based on a prospective central tumour test and prior platinum therapy. Pts received ola 300 mg BID, 28-d cycle; cer 160 mg d 1–7 + ola 300 mg BID (cer+ola), 28-d cycle; or ada 150 mg BID d 1–3, 8–10 + ola 200 mg BID (ada+ola), 21-d cycle. Primary study endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), safety, and tolerability. Ada+ola was discontinued early due to higher than expected grade ≥3 haematologic toxicity, which limited its interpretation. We focus on cer+ola vs ola. The sponsor stopped VIOLETTE after reviewing BRCAm stratum efficacy data.
Results
Of 273 pts (450 planned; median age: 53 y), 114 received ola, 112 cer+ola, and 47 ada+ola. Primary analyses showed no statistically significant difference in PFS for cer+ola vs ola (BRCAm: n=83; HR 1.02 [90% CI 0.63–1.66, P=0.94], HRRm: n=40; 0.54 [0.28–1.03, 0.13], non-HRRm: n=103; 0.76 [0.50–1.14, 0.30]). No statistically significant difference in ORR was seen for cer+ola vs ola in BRCAm (50% vs 44%) or HRRm (20% vs 15%). ORR was higher in non-HRRm for cer+ola (15%, n=8) vs ola (4%, n=2) (odds ratio 4.45; 90% CI 1.30–21.20, P=0.04). In all pts, nausea and anaemia were the most common adverse events (AEs). Grade ≥3 AEs: 36% ola, 47% cer+ola, 78% ada+ola. Details of exploratory and subgroup analyses will be presented.
Conclusions
Cer+ola did not improve PFS vs ola as 2nd–3rd line for mTNBC. Clinical significance of higher ORR with cer+ola in non-HRRm pts is unclear. Cer+ola had a manageable safety profile consistent with known profiles of each. Further analyses may identify pts likely to benefit from each treatment.
Clinical trial identification
NCT03330847.
Editorial acknowledgement
Medical writing assistance, funded by AstraZeneca, was provided by Anna Frangou, PhD, and Stephan Lindsey, PhD, of Peloton Advantage, LLC, an OPEN Health company, under the direction of the authors.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
A. Tutt: Financial Interests, Personal, Advisory Board, Personal fees /Advisory Board related to targeted therapies in DNA repair deficient: Pfizer; Financial Interests, Personal, Advisory Board, Personal fees from /Advisory Board related to targeted therapies in DNA repair deficient: Vertex; Financial Interests, Personal, Advisory Board, Personal fees/Advisory Board related to targeted therapies in DNA repair deficient: Artios; Financial Interests, Personal, Advisory Board, Personal fees/Advisory Board related to targeted therapies in DNA repair deficient: prIME Oncology; Financial Interests, Personal, Advisory Board, Personal Fees/Moon Shot Breast Cancer Scientific Advisory Board Honoraria: MD Anderson; Financial Interests, Personal, Advisory Board, Personal fees/Scientific Ad Board function and stock options: Inbiomotion; Financial Interests, Personal, Invited Speaker, Speaking role at mini symposium: SABCS 2020; Financial Interests, Personal, Advisory Board, Personal fees relating to advisory board: Gilead 21.05.21; Financial Interests, Institutional, Expert Testimony, CRUK expert panel monies going to my research account at the Institute of Cancer Research/Honoraria associated with Deputy Chair also going into research account: CRUK; Financial Interests, Institutional, Invited Speaker, Paid into research account at the Institute of Cancer Research: AZ Symposium ESMO 2021; Financial Interests, Personal, Advisory Board, Personal fees from Advisory Boards: MERCK Serano; Financial Interests, Institutional, Expert Testimony, Paid into research institute account: GE Healthcare 17.06.21; Financial Interests, Personal, Expert Testimony, Personal fees paid for expert testimony: EM Partners 16.06.21; Financial Interests, Institutional, Invited Speaker, Speaker at round table and monies went into research account: VJ Oncology 11.06.21; Financial Interests, Personal, Expert Testimony, Personal fees for an educational video: Medscape Education; Financial Interests, Personal, Advisory Board, Personal and institution fees for Ad Board: Gilead; Financial Interests, Personal, Full or part-time Employment, Head of Division for Breast Research, Director Breast Cancer Now Research Centre, Honorary Consultant Clinical Oncologist, Royal Marsden Hospital, joint leadership appointment with KCL that is processed through ICR payroll: Institute of Cancer Research; Financial Interests, Personal, Full or part-time Employment, Director of Breast Cancer Now Research Unit, King's College London, Honorary Consultant Clinical Oncologist, Breast Unit, Guy’s and St Thomas’ NHS Foundation Trust, joint leadership appointment with ICR that is processed through ICR payroll: King's College London; Financial Interests, Personal, Stocks/Shares: Inbiomotion; Financial Interests, Personal, Royalties, AstraZeneca with royalties paid to The Institute of Cancer Research (ICr) for the use of PARP inhibitors in DNA deficient cancers, licensee - AstraZeneca. ICR rewards to inventor's payments paid to Andrew Tutt's research accounts at The Institute of Cancer Research and to personal accounts: AstraZeneca; Financial Interests, Institutional, Research Grant, Received research support for TNT trial: Myriad genetics; Financial Interests, Personal and Institutional, Invited Speaker, Financial support to my academic and hospital institutions for costs associated with global academic study chair and local site costs for OlympiA trial/Travel expenses related to any trial related travel. Payments through Breast International Group for trial conduct in Olympic trial and through CRO's for commercial PARP inhibitor trial: AstraZeneca; Financial Interests, Institutional, Research Grant, Local site trial associated with clinical trial DNA: MERCK KGAA; Financial Interests, Institutional, Research Grant, Financial support for research at ICR: Medivation; Non-Financial Interests, Other, Member of Strategy Group: NCRI Strategy Group; Non-Financial Interests, Other, Member of the Committee: ESMO Guidelines Committee; Non-Financial Interests, Officer, Committee Member: ESMO 2023 Scientific Committee; Non-Financial Interests, Institutional, Product Samples, Responsible for care of patients receiving Olaparib on named patient programme in Breast Cancer @ Guy's London: Guy's Hospital; Other, Grant funded to study homologous recombination deficient breast and other cancers, BCN receive payments through AstraZeneca related to PARP inhibitor patents: Breast Cancer Now; Other, Grant funded to study homologous recombination deficient breast and other cancers, CRUK receive payments through AstraZeneca related to PARP inhibitor patents: CRUK. Z. Nowecki: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Sanofi Aventis; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Other, Traveler Grant: Roche. R. Szoszkiewicz: Financial Interests, Personal, Principal Investigator: Centrum Medyczne Pratia Poznan. S. Im: Non-Financial Interests, Personal, Advisory Role: AstraZeneca; Non-Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Non-Financial Interests, Personal, Advisory Role: Eisai; Non-Financial Interests, Personal, Advisory Role: GSK; Non-Financial Interests, Personal, Advisory Role: Hanmi; Non-Financial Interests, Personal, Advisory Role: Idience; Non-Financial Interests, Personal, Advisory Role: Lilly; Non-Financial Interests, Personal, Advisory Role: MSD; Non-Financial Interests, Personal, Advisory Role: Pfizer; Non-Financial Interests, Personal, Advisory Role: Novartis; Non-Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Daewoong Pharm; Financial Interests, Institutional, Research Grant: Boryung Pharm; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Roche. H. Arkenau: Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Invited Speaker: Guardant; Financial Interests, Personal, Advisory Board: iOnctura; Financial Interests, Personal, Advisory Board: Beigene; Financial Interests, Institutional, Invited Speaker: multiple small and large Pharma/Biotechs. A. Armstrong: Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Other, Conference Fees: Gilead; Financial Interests, Personal, Other, Conference Fees: MSD; Financial Interests, Institutional, Other, Research Funding: AstraZeneca; Financial Interests, Personal, Other, Spousal Shares: AstraZeneca. W. Jacot: Financial Interests, Institutional, Other, Research Funding: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Other, Personal, Other, Congress Travel Support: AstraZeneca; Other, Personal, Other, Congress Travel Support: Pfizer; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Lilly France; Other, Personal, Other, Congress Travel Support: Lilly France; Financial Interests, Personal, Advisory Board: Eisai; Other, Personal, Invited Speaker, Congress Travel Support: Eisai; Financial Interests, Personal, Advisory Board: BMS; Other, Personal, Other, Congress Travel Support: Chugai Pharma; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Other, Personal, Other, Congress Travel Support: Glaxo Smith Kline; Financial Interests, Personal, Advisory Board: Novartis; Other, Personal, Other, Congress Travel Support: Novartis; Financial Interests, Personal, Advisory Board: MSD; Other, Personal, Other, Congress Travel Support: Pierre Fabre; Financial Interests, Personal, Advisory Board: Roche; Other, Personal, Other, Congress Travel Support: Roche; Financial Interests, Personal, Advisory Board: Rain Pharmaceuticals; Other, Personal, Other, Congress Travel Support: Sanofi Aventis; Financial Interests, Personal, Advisory Board: Seagen. J.H. Kim: Financial Interests, Institutional, Other, Research Funding: Ono Pharma Korea Co., Ltd. M. Webster: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Seagen; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Knight; Financial Interests, Personal, Advisory Role: Gilead; Financial Interests, Personal, Advisory Role: Genomic Health. J. Balmana: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Pfizer. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Pierre fabre; Financial Interests, Institutional, Advisory Board: Orion; Financial Interests, Institutional, Advisory Board: Sanofi; Financial Interests, Institutional, Advisory Board: Rappta; Financial Interests, Institutional, Advisory Board: Cellectis; Financial Interests, Institutional, Advisory Board: Isis/servier; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare; Financial Interests, Institutional, Invited Speaker: Roche Genentech; Financial Interests, Institutional, Invited Speaker: BMS; Financial Interests, Institutional, Invited Speaker: Puma; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Orion; Financial Interests, Institutional, Invited Speaker: Sanofi; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker, clinical research funding to my institution: Taiho; Non-Financial Interests, Invited Speaker, Société Française de Sénologie et Pathologie Mammaire: SFSPM. N. Lukashchuk: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. R. Odegbami, A.B. Loembe, M.W. Drachsler: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. E. Casson: Financial Interests, Personal, Full or part-time Employment, Independent contractor: AstraZeneca. E.J. Dean: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. K. Punie: Financial Interests, Personal, Other, Travel Support: AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Advisory Board: Gilead Sciences; Financial Interests, Institutional, Invited Speaker: Medscape; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Institutional, Invited Speaker: MundiPharma; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Institutional, Advisory Role: Novartis; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Personal, Other, Travel Support: Pfizer; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Advisory Role: Pierre Fabre; Financial Interests, Personal, Other, Travel Support: Roche; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Institutional, Advisory Role: Roche; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Personal, Advisory Role: Seagen; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Advisory Role: Teva; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Advisory Role: Vifor Pharma; Financial Interests, Personal, Other, Travel Support: PharmaMar.