15P - Germline predictors of recurrence in patients with ER-positive and HER2-negative breast cancer: A GWAS analysis of multiple cohorts totaling 10,640 patients

Background

Animal, epidemiological, and candidate gene studies have suggested an influence of germline polymorphisms on the risk of breast cancer recurrence. Genome-wide association studies (GWAS) have become a valuable tool for investigating complex polygenic interactions.

Methods

This analysis included ER+/HER2- BC patients from the SIGNAL cohort and three metastatic cohorts: SAFIR01, SAFIR02-BREAST IMMUNO and SToRM. Germline variants were assessed from blood samples, genotyped using Illumina SNP arrays and imputed against 1kG dataset for a final dataset, after quality controls, of 932,683 single nucleotide polymorphisms (SNPs) with a Minor allele frequency > 5% and 5436 patients ER+/HER2-. We performed a discovery GWAS analysis between these SNPs and relapse, using multivariable logistic regression. The outcome of interest is the occurrence of relapse, stratified by time to occurrence < 5 years (1005 patients) or any time (1457 patients). The control cohort for these analyses consisted of patients with >= 5 years of follow-up and no reported recurrence of any type (2259 patients). Relevant associations were reported with SNPs at an alpha threshold of 5x10-5. A polygenic risk score (PRS) was defined for each component. The predictive value of this score for metastatic recurrence was then assessed on the 6,924 patients with early ER+/HER2- breast cancer from the CANTO cohort.

Results

61 SNPs in 11 loci were associated with a higher risk of breast cancer recurrence in our discovery cohort. Among them, polymorphisms in DNAH6, CLASP2, PACSIN1, WDR66, QRSL1, and HUNK were identified. Dysregulation of these genes has been described as potentially involved in cancer progression and cell motility. In the validation cohort, the PRS showed a non-statistically significant trend toward a higher recurrence rate in patients with a score in the fourth quartile of high risk. No recurrences occurred in patients with the lowest risk score.

Conclusions

We identified germline SNPs associated with breast cancer recurrence. This association was partially confirmed in our validation cohort. As follow-up of the CANTO cohort is still ongoing, the statistical power of this validation step will increase.

Editorial acknowledgement

During the preparation of this work the authors used DeepL in order to correct grammatical and spelling mistakes and to find more natural ways of formulating sentences in English. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Clinical trial identification

SIGNAL: RECF1098, SAFIR01: NCT01414933, SAFIR02-BREAST IMMUNO: NCT02299999, STORM: NCT01460186, CANTO: NCT01993498.

Legal entity responsible for the study

Unicancer.

Funding

French Government under the “Investment for the Future” program managed by the National Research Agency (ANR).

Disclosure

E. Turcotte: Financial Interests, Personal, Invited Speaker: Novartis. I. Vaz-Luis: Financial Interests, Institutional, Other, Honoraria: AstraZeneca, Amgen, Pfizer, Novartis, Sandoz, ResilienceCare; Financial Interests, Institutional, Research Grant: ResilienceCare; Non-Financial Interests, Personal, Other, Travelling expenses: Novartis. F. André: Financial Interests, Personal, Advisory Board: Lilly France; Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health, N-Power Medicine, Servier, Gilead, Boston Pharmaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi Sankyo, Guardant Health, Owkin. T. Bachelot: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Lilly; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: Roche, AstraZeneca. All other authors have declared no conflicts of interest.