Geburtshilfe Frauenheilkd 2014; 74 - FV_04_09
DOI: 10.1055/s-0034-1388571

Genetic breast cancer susceptibility variants and prognosis in the prospectively randomized SUCCESS A trial

A Hein 1, L Häberle 1, AB Ekici 2, MP Lux 1, B Rack 3, T Weissenbacher 3, U Andergassen 3, C Scholz 4, L Schwentner 4, A Schneeweiss 5, R Lorenz 6, H Forstbauer 7, H Tesch 8, I Schrader 9, 10, M Rezai 11, W Janni 12, MW Beckmann 1, RM Weinshilboum 13, L Wang 13, PA Fasching 1, 14
  • 1Universitätsklinikum Erlangen, Frauenklinik, Erlangen, Germany
  • 2Universitätsklinikum Erlangen, Humangenetisches Institut, Erlangen, Germany
  • 3Klinikum der Universität München, Campus Innenstadt, Frauenheilkunde und Geburtshilfe, München, Germany
  • 4Universitätsklinikum Ulm, Klinik für Gynäkologie und Geburtshilfe, Ulm, Germany
  • 5Klinikum der Ruprecht-Karl-Univ. Heidelberg, Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany
  • 6Frauenärztliche Gemeinschaftspraxis Schwerpunktpraxis Onkologie, Braunschweig, Germany
  • 7Hämatologisch-Onkologische Schwerpunktpraxis, Troisdorf, Germany
  • 8Hämatologisch-Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus, Frankfurt, Germany
  • 9Henriettenstiftung Diakoniekrankenhaus, Hannover, Germany
  • 10Gynäkologisch-Onkologische Schwerpunktpraxis am Pelikanplatz, Hannover, Germany
  • 11Luisenkrankenhaus GmbH & Co. KG, Düsseldorf, Germany
  • 12Universitätsklinikum Ulm, Frauenklinik, Ulm, Germany
  • 13Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Rochester, United States
  • 14University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division of Hematology/Oncology, Los Angeles, United States

Large scale genotyping studies have identified more than 70 single nucleotide polymorphisms (SNPs) that are associated with breast cancer (BC) risk. The knowledge about risk factors that are associated with prognosis is however growing much slower. Aim of this study was therefore to investigate nine known breast cancer risk SNPs for their prognostic relevance.

Breast cancer risk SNPs rs17468277(CASP8), rs2981582(FGFR2), rs13281615(8q24), rs3817198(LSP1), rs889312(MAP3K1), rs3803662(TOX3), rs13387042(2q35), rs4973768(SLC4A7) rs6504950(COX11) of 1,687 BC patients from a random sample from the SUCCESS A study were genotyped. Cox proportional hazards models were used to test the association of these SNPs with overall survival (OS) and disease free survival (DFS). Additional analyses were carried out for molecular subgroups.

The median follow-up time was 59 months for OS and 58 months for DFS. When comparing the genetic survival model with the clinical survival model rs3817198 was the only SNP that significantly influenced DFS and OS (likelihood ratio test, corrected p < 0.001 and p = 0.01). In particular this effect was limited to patients with triple negative tumors, where patients with two minor alleles had significantly improved OS [HR 0.03; 95% CI (0.00, 0.28)] and DFS [HR 0.09; 95% CI (0.02, 0.36)] compared to patients with two common alleles.

We showed that the intron variant rs3817198 in LSP1 (encoding lymphocyte-specific protein 1) has a prognostic relevance, especially in this subgroup of triple negative patients treated with anthracycline and taxane based chemotherapy. Further studies are needed to confirm this most likely pharmacogenetic effect and to identify the underlining mechanism.