V. Serra (Barcelona, Spain)
Vall d’Hebron Institute of OncologyAuthor Of 2 Presentations
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.
2O - Association of RAD51 with Homologous Recombination Deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial (ID 244)
Abstract
Background
Current genetic and genomic tests that measure HRD show limited predictive value. We compare the performance of a functional HRD test based on scoring RAD51 nuclear foci with genetic/genomic HRD tests, and assess its capacity to select patients (pts) with primary TNBC sensitive to platinum-based neoadjuvant chemotherapy (NACT).
Methods
A retrospective, blinded analysis from the GeparSixto randomized trial was conducted on TNBC pts who received neoadjuvant paclitaxel plus non-pegylated liposomal doxorubicin (Myocet®) and bevacizumab (PM) or PM plus carboplatin (PMCb). Functional HRD biomarkers (RAD51, BRCA1 and yH2AX nuclear foci) were quantified in formalin-fixed paraffin-embedded (FFPE) tumor samples on a tissue microarray format (TMA). Concordance analyses were performed between the RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (myChoice® CDx). Associations with clinical outcomes were studied by logistic (pathological complete response, pCR) and Cox (disease-free survival, DFS) regression models. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low).
Results
RAD51, BRCA1 and yH2AX were successfully scored in 133/200 TMA cores (67%). Functional HRD by RAD51-low was evidenced in 81/133 tumors (62%). The RAD51 test identified 93% of tBRCA-mutated tumors and 45% of the non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% (95%CI 79-93%). In pts with RAD51-high tumors, the pCR rate was similar between treatment arms (PMCb 31% vs PM 39%, odds ratio (OR) 0.71, 0.23-2.24, p=0.561). Pts with RAD51-low tumors benefited from PMCb (66% vs 33%, OR 3.96, 1.56-10.05, p=0.004; interaction test p=0.023). The addition of Cb showed a trend towards better DFS in both RAD51-high (hazard ratio (HR) 0.40, 0.12-1.29, p=0.125) and RAD51-low (HR 0.45, 0.16-1.25, p=0.124) groups.
Conclusions
The RAD51 test is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51-testing in the clinical decision making.
Clinical trial identification
NCT01426880.
Legal entity responsible for the study
Violeta Serra, ERAPERMED.
Funding
Has not received any funding.
Disclosure
A. Llop-Guevara: Research grant/Funding (self): AECC (INVES20095LLOP); Research grant/Funding (self): La Caixa Foundation and European Institute of Innovation and Technology/Horizon 2020 (LCF/TR/CC19/52470003). A. Schneeweiss: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, Medical writing grant: Roche; Research grant/Funding (institution): AbbVie; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. G. Villacampa: Honoraria (self): MSD; Honoraria (self): AstraZeneca. P. Jank: Research grant/Funding (institution): EU funding EraPerMed JTC2019 \"RAD51predict\"; Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Myriad Genetics, Inc. M. van Mackelenbergh: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self): Mylan; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. P.A. Fasching: Honoraria (self): Novartis; Research grant/Funding (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Research grant/Funding (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. F. Marmé: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Clovis; Honoraria (self): GSK/Tesaro; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Seagen; Honoraria (self): Myriad Gen; Honoraria (self): PharmaMar; Honoraria (self): Eisai; Honoraria (self): Janssen-Cilag. R. Dienstmann: Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Amgen; Honoraria (self): Sanofi; Honoraria (self): Servier; Honoraria (self): Ipsen. J. Balmaña: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer. C. Denkert: Research grant/Funding (institution): European Commission H2020; Research grant/Funding (institution): German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Research grant/Funding (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options: Sividon diagnostics; Licensing/Royalties, patent royalties: MScope digital pathology software; Licensing/Royalties, patent pending: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties, patent issued: WO2015114146A1 and WO2010076322A1- therapy response. S. Loibl: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution): Seagen; Research grant/Funding (institution): Immunomedics/Gilead Sciences Inc; Honoraria (institution): prIME/Medscape; Honoraria (institution): Eirgenix; Research grant/Funding (self), Research grant/Funding (institution): DSI; Honoraria (institution): BMS; Honoraria (institution): Merck; Honoraria (institution): Puma; Speaker Bureau/Expert testimony: Chugai; Licensing/Royalties, patent pending: EP14153692.0-Immunsignature in TNBC. V. Serra: Research grant/Funding (institution): ISCIII (CPII19/00033); Research grant/Funding (institution): TRANSCAN-2 (AC15/00063; Research grant/Funding (institution): AECC (LABAE16020PORTT); Research grant/Funding (institution): ERAPERMED2019-215. All other authors have declared no conflicts of interest.
Presenter Of 1 Presentation
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.
Author Of 1 Presentation
- F. Brasó-Maristany (Barcelona, Spain)
- M. Palafox (Barcelona, Spain)
- L. Monserrat (Barcelona, Spain)
- M. Bellet Ezquerra (Barcelona, Spain)
- M. Oliveira (Barcelona, Spain)
- M. Capelán (Barcelona, Spain)
- P. Galván (Barcelona, Spain)
- D. Martínez (Barcelona, Spain)
- N. Chic (Barcelona, Spain)
- C. Viaplana (Barcelona, Spain)
- R. Dienstmann (Barcelona, Spain)
- P. Nuciforo (Barcelona, Spain)
- C. Saura Manich (Barcelona, Spain)
- A. Prat (Barcelona, Spain)
- V. Serra (Barcelona, Spain)
16P - Understanding the biologic determinants of ribociclib efficacy in breast cancer
Abstract
Background
Ribociclib improves survival in hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (BC). Deeper understanding of the biology associated with ribociclib efficacy is needed, especially within the HER2-enriched (HER2-E) subtype given recent analysis of MONALEESA program. Here, we performed gene expression (GE) analysis with/without ribociclib monotherapy in BC patient-derived xenografts (PDX).
Methods
Eighteen PDXs representative of HR+/HER2- (n=11, 61%), HER2+ (n=6, 33%) and triple-negative (n=1, 6%) BC were treated with ribociclib monotherapy (75 mg/kg/day). The % change in tumor volume from baseline was calculated at day 35. RNA was obtained from flash-frozen tumors at baseline and day 12. PAM50 GE was analyzed by nCounter and associated with tumor response (as a continuous variable) using quantitative Statistical Analysis Microarrays (SAM). Differential GE during ribociclib treatment was identified using two-class paired SAM. All SAM used a false-discovery rate<5%.
Results
Baseline PAM50 subtype distribution was Luminal B (44%), HER2-E (33%) and Basal-like (B-L) (22%). HER2-E and Luminal B PDXs showed a statistically significant higher response to ribociclib (mean change in volume >40% and >140%), than B-L (>660%). Baseline GE analysis identified 6 genes highly expressed in responders (FOXA1, ERBB2, GRB7, MLPH, GPR160 and CXXC5), and 7 lower expressed genes (SFRP1, KRT17, MYC, CDH3, KRT5, MIA and KRT14). Paired GE analyses across PDXs identified 12 upregulated genes during treatment, including estrogen activation-related genes (ESR1, PGR, FOXA1, MAPT or BLVRA); and 12 downregulated genes, including proliferation-related genes (MKI67 or KIF2C) and HER2-E-related genes (ERBB2 or TMEM45B). Similar results were obtained with HR+/HER2- PDXs when analyzed separately.
Conclusions
In BC PDXs, B-L biology associates with lower response to ribociclib monotherapy than Luminal or HER2-E. Ribociclib induces a luminal phenotype with high GE of estrogen-regulated genes and low GE of proliferation genes, a biological switch that could explain the better efficacy of ribociclib in the endocrine therapy (ET)-resistant HER2-E subtype observed in clinical trials when combined with ET.
Legal entity responsible for the study
Institut d'Investigacions Biomèdiques August Pi i Sunyer.
Funding
Has not received any funding.
Disclosure
M. Oliveira: Honoraria (self): Roche, Novartis, Seattle Genetics; Advisory/Consultancy: Roche/Genentech, GlaxoSmithKline, Puma Biotechnology, AstraZeneca, Seattle Genetics; Research grant/Funding (institution): Philips Healthcare (Inst), Roche/Genentech (Inst), Novartis (Inst), AstraZeneca (Inst), Immunomedics (Inst), Seattle Genetics (Inst), Boehringer Ingelheim (Inst), GlaxoSmithKline (Inst), Cascadian Therapeutics (Inst), Sanofi (Inst), Celldex Therapeutics; Travel/Accommodation/Expenses: Roche, Novartis, Grünenthal Group, Pierre Fabre, GP Pharm, Eisai. N. Chic: Travel/Accommodation/Expenses: Novartis, Eisai, Pierre Fabre. R. Dienstmann: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Servier; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Research grant/Funding (self): Merck; Research grant/Funding (self): Pierre Fabre. C. Saura Manich: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca, Daiichi Sankyo, Merck, Sharp and Dohme España SA, Novartis, Pfizer, Puma, Synthon; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene, Clovis Oncology, Eisai, F. Hoffmann-La Roche Ltd., Genomic Health, Odonate Therapeutics, Philips Healthwork, Pierre Fabre, prIME Oncology, Sanofi Aventis, Zymeworks; Research grant/Funding (institution): Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Piqur Therapeutics, Roche, Synthon. A. Prat: Advisory/Consultancy, Research grant/Funding (self): Novartis Farma, SA; Advisory/Consultancy: Lilly Spain; Advisory/Consultancy: Pfizer, SLU; Advisory/Consultancy, Research grant/Funding (self): Roche Farma, SA; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Amgen, SA; Advisory/Consultancy: Daiichi; Advisory/Consultancy: Oncolytics Bioteck; Research grant/Funding (self): Sysmex Europe GmbH; Research grant/Funding (self): Medica Scientia Inno, Research, SL; Research grant/Funding (self): Celgene, SLU; Research grant/Funding (self): Astellas Pharma, SA; Research grant/Funding (self): NanoString Technologies; Officer/Board of Directors, Member executive Board: Breast International Group (BIG).; Officer/Board of Directors, Member executive Board and Foundation: SOLTI; Research grant/Funding (self): Puma; Research grant/Funding (self): Incyte. V. Serra: Research grant/Funding (self): Novartis, Genentech. All other authors have declared no conflicts of interest.