title: Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy.
abstract: OBJECTIVE
  Although most patients with estrogen receptor (ER)-positive breast cancer benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies.
  
  
  METHODS
  We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy patients, evaluating 486,478 single-nucleotide polymorphisms (SNP). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totaling 5,011 patients, with 3,485 receiving endocrine therapy.
  
  
  RESULTS
  A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine-treated patients [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.37-2.07; P = 6.34 × 10(-7)] and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment, indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI, 1.30-3.60; Pinteraction = 0.003) and HR = 7.77 (95% CI, 0.93-64.71) for the homozygous genotype carriers. A biologic rationale is suggested by in silico functional analyses.
  
  
  CONCLUSIONS
  Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment.
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, Hants, UK.
authors.forename: Sajjad
authors.initials: S
authors.lastname: Rafiq
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, Hants, UK.
authors.forename: William
authors.initials: W
authors.lastname: Tapper
authors.affiliation: Department of Clinical Genetics, Helsinki University Hospital and Genome Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.affiliation: Human Genetics, Genome Institute of Singapore, 60 Biopolis St, Singapore.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Oncology, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, Hants, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006720:Homozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D040641:Quantitative Trait Loci; D011960:Receptors, Estrogen / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D005819:Genetic Markers; D011960:Receptors, Estrogen