Paolo G. Nuciforo (Barcelona, Spain)
Vall d'Hebron Institute of Oncology (VHIO)-Cellex CenterAuthor Of 3 Presentations
2MO - Development of a prognostic gene-expression signature for early stage HER2-positive breast cancer patients (ID 297)
- Serena Di Cosimo (Milan, Italy)
- Chiara Maura Ciniselli (Milan, Italy)
- Christos Sotiriou (Brussels, Belgium)
- Katherine Pogue-Geile (Pittsburgh, United States of America)
- Debora Fumagalli (Brussels, Belgium)
- Evandro De Azambuja (Brussels, Belgium)
- David Venet (Brussels, Belgium)
- Loris De Cecco (Milan, Italy)
- Nan Pong (Pittsburgh, United States of America)
- Vera Cappelletti (Milan, Italy)
- Elda Tagliabue (Milan, Italy)
- Yongyu Wang (Florham Park, United States of America)
- Cristina Saura Manich (Barcelona, Spain)
- Paolo G. Nuciforo (Barcelona, Spain)
- Sherko Kuemmel (Essen, Germany)
- Lajos Pusztai (New Heaven, United States of America)
- Maria Grazia Daidone (Milan, Italy)
- Sara Pizzamiglio (Milan, Italy)
- Giancarlo Pruneri (Milan, Italy)
- Paolo Verderio (Milan, Italy)
Abstract
Background
With increasing evidence showing the complexity of HER2-positive breast cancer, this study aimed to identify a gene-expression signature with potential prognostic value to assist therapeutic decision in the early disease setting.
Methods
Gene-expression profiles of NeoALTTO tumor biopsies before and after 2 weeks of neoadjuvant treatment were generated by microarrays (Clariom S, ThermoFisher). Genes associated with event free survival (EFS) were selected at the two time points with Cox univariate analysis and combined by multivariate approaches. Independent technical and clinical validation were sought.
Results
Overall, 180 patients were analyzed (NeoALTTO cohort, median follow-up 6.7 yrs [IQR 6.1-6.8]; 53 events). The expression of 18 genes combined by principal component analysis (S18) was significantly associated with EFS in the trastuzumab (T)-arm (Hazard Ratio for each unit increment [HR] 2.4, 95%Confidence Interval [CI] 1.6-3.5) and in the entire NeoALTTO cohort (HR 1.7, CI 1.4-2.2). Notably, S18 showed no overlap with HER2 and/or ESR1 genes and/or their signaling. A more parsimonious signature of five genes (S5) was next developed. Both S18 and S5 retained their prognostic value independently of pathological complete response, age, tumor size, estrogen receptor and node status both in the T-arm and in the entire NeoALTTO cohort. The prognostic value of S18 was technically confirmed by RNAseq in the T-arm (HR 2.1, CI 1.4-3.1) and entire cohort (HR1.3, CI 1.03-1.7) whereas the S5 was confirmed within the T-arm alone (HR 1.5, CI 1.1-1.9). An additional technical validation is currently ongoing by customized open arrays. The prognostic capability of S18 was clinically confirmed by in silico analysis of the Italian GHEA expanded access study of adjuvant trastuzumab (HR 1.9,CI 1.2-2.9). Currently, we are seeking to validate the prognostic value of S5 in the NSABP B-31 study and results are expected to be presented at the congress.
Conclusions
These findings hold the potential to accurately identify patients with early HER2-positive breast cancer at low risk of relapse when treated with trastuzumab-based therapy and may be useful to select patients for single or dual anti-HER2 therapies.
Legal entity responsible for the study
Serena Di Cosimo.
Funding
Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC) IG 20774 to Serena Di Cosimo.
Disclosure
Y. Wang: Financial Interests, Personal, Funding: Wang. All other authors have declared no conflicts of interest.
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.
87P - EPClin vs OncotypeDx in invasive lobular cancer (ILC) (ID 101)
- Ines Leao (Vila Nova de Gaia, Portugal)
- Esther Zamora (Barcelona, Spain)
- Patricia Gomez Pardo (Barcelona, Spain)
- Miriam A. Arumi de Dios (Barcelona, Spain)
- Isabel Pimentel (Barcelona, Spain)
- Santiago Escriva de Romani (Barcelona, Spain)
- Carolina Ortiz Velez (Barcelona, Spain)
- Mara Cruellas Lapena (Barcelona, Spain)
- Lucia Sanz (Barcelona, Spain)
- Maria Borrell (Barcelona, Spain)
- KREINA S. VEGA CANO (Barcelona, Spain)
- Diego Gómez-Puerto (Barcelona, Spain)
- Javier De La Torre (Barcelona, Spain)
- Martin Espinosa-Bravo (Barcelona, Spain)
- Ana Mafalda Antunes De Melo e Oliveira (Barcelona, Spain)
- ROBERTA Fasani (Barcelona, Spain)
- Paolo G. Nuciforo (Barcelona, Spain)
- Cristina Saura Manich (Barcelona, Spain)
- Vicente Peg (Barcelona, Spain)
- Meritxell Bellet (Barcelona, Spain)
Abstract
Background
ILC represents ≈10% of all breast cancers (BC). Genomic signatures (GS) used to define prognosis and chemo (CT) benefit in early BC may capture mainly the biology of the most frequent invasive carcinoma non otherwise specified. Utility of OncotypeDx (ODx) for adjuvant CT decisions has been questioned in ILC. By contrast, EPclin performance seems to be similar for both histologies. We studied the role of ODx and EPclin to guide CT in our series of ILC patients (pts).
Methods
Pts with pT1-2N0-1 ER+/PgR±/HER2- ILC diagnosis from 2017 to 2021 and with EPclin or ODx data were reviewed (cohort 1 and 2, respectively). In each cohort, pts were classified in high vs low risk groups and clinicopathological features, percent of high risk pts and prescribed CT were analyzed. High risk defined as: EPClin score ≥3.3; ODx recurrence score ≥26 if >50y and ≥21 if ≤50y. In cohort 1, the likelihood of ODx high risk was calculated (https://utgsm.shinyapps.io/OncotypeDXCalculator/). Risk groups by ODx and by Endopredict (molecular part of EPclin assay, High risk ≥5) were correlated with Ki67, as both are based only in genomic results, while EPclin score also takes pT and pN into account.
Results
46 pts eligible. Median age: 61y; pre-menopausal: 33; EPClin 25, ODx 21; with no differences in pathological features between cohorts. Proportion of high risk pts and CT indication were both 48% with EPClin and 9.5% and 19% with ODx, respectively. In cohort 1, the calculated probability of an ODx high risk result was 4% for EPclin low risk and 5% for EPclin high risk pts. Risk groups defined by Endopredict correlated with median Ki67 (low risk 3% vs high risk 11%. P=.05), while no association with ODx was seen (low risk 8% vs high risk 13%).
Conclusions
In our ILC pts the EPclin use correlated with a greater proportion of high risk pts compared to ODx, consistently with prior non-comparative studies. Albeit findings are limited for the type of analysis (2 separate small size cohorts), the similarity in clinic-pathologic features among cohorts and the disparity between the EPClin risk groups and those predicted by the ODx calculator support a distinct performance of both GS in ILC. Interestingly, Ki67 values were associated with Endopredict score but not with ODx categories, suggesting that EPclin captures better the ILC underlying biology.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.