Violeta Serra Elizalde (Barcelona, Spain)
Vall d'Hebron Institute of Oncology (VHIO)-Cellex CenterAuthor 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.
57TiP - SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL (ID 75)
- Judith Balmana (Barcelona, Spain)
- Tomas Pascual (Barcelona, Spain)
- Alba Llop-Guevara (Barcelona, Spain)
- Pablo Tolosa (Madrid, Spain)
- Isabel Blancas López-Barajas (Granada, Spain)
- Maria Eva Perez Lopez (A Coruña, Spain)
- Barbara Adamo (Barcelona, Spain)
- Iris Teruel-Garcia (Badalona, Spain)
- Jose Ponce (Alicante, Spain)
- Marta González-Cordero (Badajoz, Spain)
- Gemma Viñas Villaro (Girona, Spain)
- Laura Lema Roso (Madrid, Spain)
- Francisco Javier Salvador Bofill (Seville, Spain)
- Maria Teresa M. Martinez (Valencia, Spain)
- Alejandra Nallely E. Guerrero (Barcelona, Spain)
- Aleix Prat (Barcelona, Spain)
- Violeta Serra Elizalde (Barcelona, Spain)
Abstract
Background
The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is »60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis. We have previoulsy shown that the functional HRD biomarker RAD51, tested in FFPE tumor samples using an optimized immunofluorescence-based assay, is associated with platinum response in early TNBC and PARPi response in preclinical BC models. We hypothesize that the RAD51 test would help to expand the clinical benefit of PARPi by predicting response to olaparib in MBC with germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation and beyond.
Trial design
RADIOLA is an open-label, single-arm, multicentre phase II study evaluating treatment with olaparib in male or female ≥18 years patients with HER2-negative MBC with ≤ two prior chemotherapy lines in two cohorts: cohort 1 (N=41) with known germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation; cohort 2 (N=25) with functional HRD, namely RAD51-low score (≤10%), in wild-type/unknown mutation status at study entry. All patients will receive olaparib 300mg po BID until progression or unacceptable toxicity. Primary objective will assess, in terms of overall response rate (ORR), the capacity of the RAD51 score to predict olaparib efficacy in cohort 1. Secondary objectives include PFS, clinical benefit rate, duration of response, safety in both cohorts and ORR in cohort 2. Recruitment Recruitment (11 sites) started in March 2022.
Legal entity responsible for the study
SOLTI Cancer Research Group.
Funding
AstraZeneca.
Disclosure
J. Balmana: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MedSir. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly. I. Blancas López-Barajas: Non-Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Institutional, Research Grant: Lilly; Non-Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Kiowa-Kirin; Financial Interests, Personal, Advisory Board: Veracyte; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: Pierre Fabre; Financial Interests, Personal, Speaker’s Bureau: Celgene; Financial Interests, Personal, Sponsor/Funding: Roche; Financial Interests, Personal, Sponsor/Funding: Pierre Fabre; Financial Interests, Personal, Sponsor/Funding: Novartis; Financial Interests, Personal, Sponsor/Funding: Pfizer; Financial Interests, Personal, Sponsor/Funding: Lilly; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Pierre Fabre. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research:: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: Amgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. 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. All other authors have declared no conflicts of interest.