Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

Taru Muranen ,Jeffrey N Weitzel,Hebon Investigators ,Caroline Maria Rossing,Susan L Slager ,Joe Dennis,Jacques Simard,Eric Hahnen,Melissa C Southey,Inge Søkilde Pedersen ,Rita K Schmutzler,Michael T Parsons,Goska Leslie,Gabriel Wagner,Lesley Mcguffog,Julie M Cunningham,Sofia Khan,Kristiina Aittomäki,Anna Jakubowska,Rainer Fagerholm,Esther M John,Marjanka K Schmidt,Carl Blomqvist,Judy E Garber ,Penny Soucy,Douglas F Easton,Paul James,Christian F Singer,Barbara Wappenschmidt,Georgia Chenevix-Trench,Kconfab Investigators ,Manuel R Teixeira,Susan M Domchek,Katherine L Nathanson,Antonis C Antoniou,Amanda B Spurdle,Swe-Brca Investigators ,Irene L Andrulis,Marc Tischkowitz,Maartje J Hooning,Drakoulis Yannoukakos,Conxi Lázaro ,Mads Thomassen,Heli Nevanlinna

doi:10.1038/s41523-020-00185-6

Abstract

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03–6.30, P = 3.1 × 10−9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

Highlights

Breast cancer is globally the leading cause of cancer-related mortality for women[1]
We studied germline genetic variants associated with the survival of breast cancer patients carrying pathogenic variants in the highrisk BRCA1 and BRCA2 genes
Rs57025206, which was highly significantly associated with poor survival of BRCA1 carriers with ER-negative breast cancer, with HR = 4.37, 95% CI 3.03–6.30, P = 3.1 × 10−9

Summary

Introduction

Breast cancer is globally the leading cause of cancer-related mortality for women[1]. The average 5-year survival rate is 83–90% in the Western countries, substantially better than for many other cancers, but due to its high incidence, breast cancer still leads the statistics for cancer mortality in Europe and comes second in North America[1,2]. Women with early-stage, localized disease have a very good 5-year prognosis of ~97–99%, but for 10–15% of women, diagnosed with locally advanced disease, the expected 5- and 10-year survival rates range between 40–80% and 30–40%, respectively. The mortality associated with metastatic breast cancer is even higher, with median survival of

Methods

Results

Conclusion