1506MO - Incorporating genetic and non-genetic risk factors in breast cancer risk prediction for healthy women with non-informative genetic test result

Background

Calculating breast cancer (BC) risks is becoming increasingly accurate and important in the care of healthy women with a cancer family history. Clinical recommendations are commonly based on cancer family history and germline mutation status. More recently, risk-modifying single- nucleotide polymorphisms (SNPs) which can be used to calculate polygenic risk score (PRS) as well as non-genetic risk factors (NGRF) have been incorporated into established risk prediction tools. We evaluated the impact of personalized BC risk calculation incorporating PRS and NGRF on clinical recommendations for intensified breast surveillance (IBS), based on the 10-year BC risk with a threshold of ≥5% for IBS indication (German Guideline) and a lifetime risk of ≥20 % (French/Dutch), respectively.

Methods

Cancer-unaffected women with a family history of BC and/or ovarian cancer were enrolled in a prospective observational study at their first counselling at the Familial Breast and Ovarian Cancer Centre Cologne from 11/2019 - 9/2020. BC-risks were calculated for women aged 30-50 years with non-informative genetic test results, variants of uncertain significance and pathogenic variants not associated with BC. Two risk versions were calculated using the CanRisk©-Tool (Boadicea-algorithm): A basic risk version (BR) and a comprehensive risk version (CR), that includes a >300 SNP PRS and NGRF.

Results

BC risks were calculated for 123 women aged 30 - 50 years (mean 40.37, SD: 5.63). With BR, 28 women (22.8%) were recommended IBS. With CR, 44 (35.8%) women were offered IBS. Clinical recommendations changed for 21.2% of all women when comparing BR/CR. With ≥20% lifetime BC-risk as cut-off for IBS indication, recommendations change for 24.4% (CR) of women compared with the German guideline: 7 women are not eligible anymore, 23 additional women are.

Conclusions

Integrating PRS and NGRF for risk calculation led to (1) an increase in patients eligible for IBS and (2) a recommendation change for every fifth woman. When switching country guideline, clinical recommendations changed for a quarter of women (CR). Prospective validation studies, as well as evaluating and harmonizing guidelines are necessary.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

European Commission: Horizon2020 funded BRIDGES (Breast Cancer Risk after Diagnostic Gene Sequencing) study.

Disclosure

K.E. Rhiem: Financial Interests, Personal and institutional, Advisory Board: MSD; Financial Interests, Personal and institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Honorars: AstraZeneca; Financial Interests, Personal, Other, Honorars: Roche; Financial Interests, Personal, Other, Honorars: MSD; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: MSD, Pfizer, Amgen; Non-Financial Interests, Personal and Institutional, Member: German Cancer Society (DKG), German Society for Gynaecology and Obstetrics, Lower Rhine-Westphalian Society for Gynaecology and Obstetrics e.V. (NWGGG), Arbeitsgemeinschaft Gynäkologische Onkologie (AGO); Non-Financial Interests, Personal and Institutional, Member, Patient organization/Self help: BRCA Netzwerk e.V., Brustkrebs Deutschland e.V.; Non-Financial Interests, Personal and Institutional, Member: German Consortium for Familial Breast and Ovarian Cancer (GC-HBOC), German Breast Group (GBG). D. Stoppa-Lyonnet: Financial Interests, Personal and Institutional, Invited Speaker: AstraZenec; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Other, Institutional, Other, PRS genotyping for MammaRisk test: Predilife. R.K. Schmutzler: Financial Interests, Personal, Advisory Role: AstraZeneca, GlaxoSmithKline, Pfizer, MSD, Clovis Oncology; Financial Interests, Personal, Writing Engagements: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Pfizer, Janssen-Cilag; Non-Financial Interests, Personal and Institutional, Member: Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Mamma, German Cancer Society (DKG); Non-Financial Interests, Personal and Institutional, Expert Testimony: S3 Guideline Commissions for Early Breast Cancer Detection and Diagnosis as well as Endometrial carcinoma, National Cancer Plan, Gene Diagnostics Commission at the Robert Koch Institute in Berlin; Non-Financial Interests, Personal and Institutional, Other, Steering Committee: National Cancer Plan; Non-Financial Interests, Personal and Institutional, Other, Patient organization/Self help: BRCA Network e.V; Non-Financial Interests, Personal and Institutional, Advisory Board, Member of the Ethics Advisory Board: National Cohort (NaKo); Non-Financial Interests, Personal and Institutional, Advisory Board: Scientific Advisory Board of the Cancer Information Service (KID) of the German Cancer Research Centre (DKFZ); Non-Financial Interests, Personal and Institutional, Other, Congress President: Congress PerMediCon; Non-Financial Interests, Personal and Institutional, Other, Coordinator: German Consortium for Familial Breast and Ovarian Cancer (GC-HBOC); Non-Financial Interests, Personal and Institutional, Advisory Board: Scientific Advisory Board of the Institute for Quality and Efficiency in Health Care (IQWIG); Non-Financial Interests, Personal and Institutional, Advisory Board: Scientific Advisory Board of the Federal Institute for Drugs and Medical Devices (BfArM); Non-Financial Interests, Personal and Institutional, Advisory Board: Scientific advisory board of the German Federal Ministry of Health; Non-Financial Interests, Personal and Institutional, Advisory Board: Technologie- und Methodenplattform für die vernetzte medizinische Forschung e.V. (TMF). All other authors have declared no conflicts of interest.