Orland Diez (Barcelona, Spain)

Vall d'Hebron University Hospital

Author Of 2 Presentations

Poster Display session (ID 9)

12P - Prevalence of functional and genomic homologous recombination deficiency (HRD) in germline RAD51C/D patients (ID 30)

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.

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Poster Display session (ID 9)

139P - Breast cancer risk estimation (CanRisk tool) and perception in unaffected women with family history of breast cancer (ID 152)

Abstract

Background

Improvement of the accuracy of risk estimation is one of the most challenging goals of cancer risk assessment for women at risk of familial breast cancer (BC) without germline pathogenic variants in known susceptibility genes. Comprehensive risk prediction models such as CanRisk achieve the highest risk stratification by considering a full set of established risk factors. Our aims were: (i) to assess the difference between women´s risk perception and CanRisk-based risk prediction; and (ii) to compare CanRisk-based BC risk estimation with and without the incorporation of breast density (BD).

Methods

Registries from five Spanish cancer genetic clinics were screened for unaffected women aged 30-65y with BC family history, who were not carriers of a germline pathogenic variant in BRCA1/2, PALB2, CHEK2 and ATM genes (N=595). Data on personal factors, family history, BD and BC risk perception were collected by questionnaires through the REDCap platform and medical records. The cumulative 10-year BC risk and lifetime risk (LTR) were calculated with the CanRisk(v5) tool. BC risk was classified as population, moderate and high risk. We used descriptive statistics.

Results

In 341 women (57%) there was a discordance between their BC risk perception and LTR calculation: 301 (50%) overestimated and 40 (7%) underestimated their risk (Table). Overall, 33/301 (11%) with a CanRisk-based population-risk perceived a high BC risk. After the incorporation of BD into the model (n=585), 144 (24%) women were re-assigned to a different 10y-risk group (p<0.01): 60 (10%) increased their group and 84 (14%) decreased. Among those who increased risk-group after BD, 16 reached high-risk, and among those who decreased, 80 fell at population-risk.

BC risk perception CanRisk-based LTR estimation
Population 176 Population 139
Moderate 36
High 1
Moderate 343 Population 232
Moderate 108
High 3
High 76 Population 33
Moderate 36
High 7

Conclusions

There is a misperception of BC risk, mainly with overestimation. The addition of BD to CanRisk allows reassignment of calculated risk in 1/4 of women, which may help to individualize informed decision-making on screening.

Legal entity responsible for the study

The authors.

Funding

Instituto Salud Carlos III (PI19/01195).

Disclosure

All authors have declared no conflicts of interest.

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