Genetic Breast Cancer Susceptibility Variants and Prognosis in the Prospectively Randomized SUCCESS A Study

A. Hein; B. Rack; L. Li; A. B. Ekici; A. Reis; M. P. Lux; J. M. Cunningham; M. Rübner; B. L. Fridley; A. Schneeweiss; H. Tesch; W. Lichtenegger; T. Fehm; G. Heinrich; M. Rezai; M W. Beckmann; W. Janni; R. M. Weinshilboum; L. Wang; P. A. Fasching; L. Häberle

doi:10.1055/s-0042-113189

Geburtshilfe und Frauenheilkunde, Table of Contents

Geburtshilfe Frauenheilkd 2017; 77(06): 651-659
DOI: 10.1055/s-0042-113189

GebFra Science

Original Article

Georg Thieme Verlag KG Stuttgart · New York

Genetic Breast Cancer Susceptibility Variants and Prognosis in the Prospectively Randomized SUCCESS A Study

Veranlagung für Brustkrebs: genetische Varianten und Prognose in der prospektiv randomisierten SUCCESS A-Studie

Authors

A. Hein

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
B. Rack

²Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany
L. Li

³Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, MN, USA

⁴Department of Oncology; Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences & Peking Union Medical College; Tiantan Xili, Beijing, 100050, China
A. B. Ekici

⁵Institute of Human Genetics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
A. Reis

⁵Institute of Human Genetics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
M. P. Lux

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
J. M. Cunningham

⁶Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN, USA
M. Rübner

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
B. L. Fridley

⁷Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

⁸Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
A. Schneeweiss

⁹Department of Gynecology and Obstetrics, University Hospital Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany
H. Tesch

¹⁰Department of Oncology, Onkologie Bethanien, Frankfurt am Main, Germany
W. Lichtenegger

¹¹Department of Gynecology and Obstetrics, Charité University Hospital Campus Virchow, Berlin, Germany
T. Fehm

¹²Department of Gynecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University, Düsseldorf, Germany
G. Heinrich

¹³Department of Gynecologic Oncology, Schwerpunktpraxis für Gynäkologische Onkologie, Fürstenwalde, Germany
M. Rezai

¹⁴Department of Breast Diseases, Breast Center of Düsseldorf, Luisenkrankenhaus, Düsseldorf, Germany
M W. Beckmann

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
W. Janni

¹⁵Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
R. M. Weinshilboum

³Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, MN, USA
L. Wang

³Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, MN, USA
P. A. Fasching

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany

¹⁶Department of Medicine, Division of Hematology/Oncology, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA
L. Häberle

¹Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany

¹⁷Biostatistics Unit, Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

Abstract

Large-scale genotyping studies have identified over 70 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. However, knowledge regarding genetic risk factors associated with the prognosis is limited. The aim of this study was therefore to investigate the prognostic effect of nine known breast cancer risk SNPs. BC patients (n = 1687) randomly sampled in an adjuvant, randomized phase III trial (SUCCESS A study) were genotyped for nine BC risk SNPs: rs17468277(CASP8), rs2981582(FGFR2), rs13281615(8q24), rs3817198(LSP1), rs889312(MAP3K1), rs3803662(TOX3), rs13387042(2q35), rs4973768(SLC4A7), rs6504950(COX11). Cox proportional hazards models were used to test the SNPsʼ association with overall survival (OS) and progression-free survival (PFS). Additional analyses were carried out for molecular subgroups. rs3817198 in LSP1 (lymphocyte-specific protein 1) was the only SNP that significantly influenced OS (p = 0.01) and PFS (p < 0.01) in the likelihood ratio test comparing the genetic survival model with the clinical survival model. In the molecular subgroups, triple-negative patients with two minor alleles in rs3817198 had a much better prognosis relative to OS (adjusted HR 0.03; 95% CI 0.002 – 0.279) and PFS (HR 0.09; 95% CI 0.02 – 0.36) than patients with the common alleles. The same effect on PFS was shown for patients with luminal A tumors (HR 0.19; 95% CI 0.05 – 0.84), whereas patients with luminal B tumors had a poorer PFS with two minor alleles (HR 2.13; 95% CI 1.02 – 4.40). The variant in rs3817198 has a prognostic effect particularly in the subgroup of patients with triple-negative BC, suggesting a possible link with immunomodulation and BC.

Zusammenfassung

In verschiedenen großangelegten Studien, in denen umfangreiche Genotypisierungsstudien vorgenommen wurden, wurden bislang über 70 Einzelnukleotid-Polymorphismen (SNPs) identifiziert, die mit einem erhöhten Brustkrebsrisiko einhergehen. Aber das Wissen über die mit der Prognose assoziierten Risikofaktoren wächst weniger schnell. Ziel dieser Studie war es daher, die Auswirkungen von 9 bekannten Brustkrebsrisiko-SNPs auf die Prognose zu untersuchen. In einer adjuvanten randomisierten Phase-III-Studie (SUCCESS A-Studie) wurden Brustkrebspatientinnen (n = 1687) einer Genotypisierung unterzogen. Die Patientinnen waren zuvor nach dem Zufallsprinzip ausgewählt worden. Bei der Genotypisierung standen 9 Brustkrebsrisiko-SNPs im Mittelpunkt: rs17468277(CASP8), rs2981582(FGFR2), rs13281615(8q24), rs3817198(LSP1), rs889312(MAP3K1), rs3803662(TOX3), rs13387042(2q35), rs4973768(SLC4A7), rs6504950(COX11). Zur Überprüfung des Zusammenhangs zwischen SNP und Gesamtüberleben (OS) bzw. progressionsfreiem Überleben (PFS) wurde eine Cox-Regressionsanalyse durchgeführt. Molekulare Untergruppen wurden einer weiteren Analyse unterzogen. rs3817198 in LSP1 (Lymphozyten-spezifisches Protein 1) war der einzige SNP, für den im Likelihood-Ratio-Test, der das genetische Überlebensmodell mit dem klinischen Überlebensmodell verglich, eine signifikante Auswirkung auf das Gesamtüberleben (p = 0,01) und das progressionsfreie Überleben (p < 0,01) festgestellt wurde. In den molekularen Untergruppen hatten triple-negative Patientinnen mit 2 seltenen Allelen in rs3817198 eine viel bessere Prognose im Hinblick auf ihr Gesamtüberleben (adjustierte HR 0,03; 95%-KI 0,002 – 0,279) und ihr progressionsfreies Überleben (HR 0,09; 95%-KI 0,02 – 0,36), verglichen mit Patientinnen, welche die häufig vorkommenden Allele aufwiesen. Dieselbe Auswirkung auf das progressionsfreie Überleben fand sich auch bei Patientinnen mit Brustkrebs vom Luminal-A-Typ (HR 0,19; 95%-KI 0,05 – 0,84), während Patientinnen mit Brustkrebs vom Typ Luminal-B und 2 seltenen Allelen ein geringeres progressionsfreies Überleben aufwiesen (HR 2,13; 95%-KI 1,02 – 4,40). Die Variante in rs3817198 hatte besonders auf die Untergruppe von Patientinnen mit triple-negativem Brustkrebs eine prognostische Auswirkung, was auf eine mögliche Assoziation zwischen Immunmodulation und Brustkrebs hindeutet.

Key words

breast cancer - SNP - LSP1 - prognosis - TNBC

Schlüsselwörter

Brustkrebs - SNP - LSP1 - Prognose - TNBC

Full Text

References

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