title: CYP1A2--a novel genetic marker for early aromatase inhibitor response in the treatment of breast cancer patients.
abstract: BACKGROUND
  Endocrine resistance is a major obstacle to optimal treatment effect in breast cancer. Some genetic markers have been proposed to predict response to aromatase inhibitors (AIs) but the data is insufficient. The aim of the study was to find new genetic treatment predictive markers of AIs.
  
  
  METHODS
  The ongoing population-based BC-blood study in Lund, Sweden includes women with primary breast cancer. This paper is based on AI-treated patients with estrogen receptor positive tumors who underwent breast cancer surgery in 2002-2008. First, an exploratory analysis of 1931 SNPs in 227 genes involved in absorption, distribution, metabolism, and elimination of multiple medications, using DMET™ chips, was conducted in a subset of the cohort with last follow-up in December 31st 2011 (13 cases, 11 controls). Second, selected SNPs from the first analysis were re-analyzed concerning risk for early breast cancer events in the extended cohort of 201 AI-treated with last follow-up in June 30th 2014. Clinical data were obtained from medical records and population registries.
  
  
  RESULTS
  Only CYP1A2 rs762551 C-allele was significantly associated with increased risk for early events in the 24 patients (P = 0.0007) and in the extended cohort, adjusted Hazard ratio (HR) 2.22 (95% CI 1.03-4.80). However, the main prognostic impact was found within five years, adjusted HR 7.88 (95% CI 2.13-29.19). The impact of the CYP1A2 rs762551 C-allele was modified by a functional polymorphism in the regulator gene AhR Arg554Lys (G > A). Compared to patients who were homozygous for the major allele in both genes (CYP1A2 A/A and AhR G/G), a 9-fold risk for early events was found in patients who had at least one minor allele in both genes, adjusted HR 8.95 (95% CI 2.55-31.35), whereas patients with at least one minor allele in either but not both genes had a 3-fold risk for early events, adjusted HR 2.81 (95% CI 1.07-7.33). The impact of CYP1A2 rs762551 C-allele was also modified by the CYP19A1 rs4646 C/C, adjusted HR 3.39 (95% CI 1.60-7.16) for this combination. This association was strongest within the first five years, adjusted HR 10.42 (95% CI 3.45-31.51).
  
  
  CONCLUSIONS
  CYP1A2 rs762551 was identified as a new potential predictive marker for early breast cancer events in AI-treated breast cancer patients. Moreover, combined genotypes of CYP1A2 rs762551 and CYP19A1 rs4646 or AhR Arg554Lys could further improve prediction of early AI-treatment response. If confirmed, these results may provide a way to more personalized medicine.
authors.affiliation: Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Simonsson
authors.affiliation: Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Veerla
authors.affiliation: Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Markkula
authors.affiliation: CREATE Health and Department of Immunotechnology, Lund University, Medicon Village, Lund, Sweden.
authors.forename: Carsten
authors.initials: C
authors.lastname: Rose
authors.affiliation: Department of Clinical Sciences, Lund, Division of Surgery, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.affiliation: Department of Clinical Sciences, Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden. helena.jernstrom@med.lu.se.
authors.forename: Helena
authors.initials: H
authors.lastname: Jernström
mesh_terms: D000368:Aged; D001141:Aromatase / Q000235:genetics*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
chemical_list: D047072:Aromatase Inhibitors; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D001141:Aromatase; C561410:CYP19A1 protein, human; D019388:Cytochrome P-450 CYP1A2
keywords: AhR; Aromatase inhibitor; Breast cancer; CYP19A1; CYP1A2; Polymorphisms; Treatment response