title: DNA-methylation of the homeodomain transcription factor PITX2 reliably predicts risk of distant disease recurrence in tamoxifen-treated, node-negative breast cancer patients--Technical and clinical validation in a multi-centre setting in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC) PathoBiology group.
abstract: Our aim was to identify and validate DNA-methylation markers associated with very good outcome in node negative, hormone receptor positive breast cancer patients after adjuvant endocrine therapy which might allow identifying patients who could be spared the burden of adjuvant chemotherapy. Using a methylation microarray, we analysed 117 candidate genes in hormone receptor-positive tumours from 109 breast cancer patients treated by adjuvant tamoxifen. Results were validated in an independent cohort (n=236, 5 centres). Independent methodological validation was achieved by a real-time polymerase chain reaction (PCR)-based technique. DNA methylation of PITX2 showed the strongest correlation with distant recurrence. Its impact on patient outcome was validated in the independent cohort: 86% of patients with low PITX2 methylation were metastasis-free after 10 years, compared to 69% with elevated PITX2 methylation. Moreover, PITX2 methylation added significant independent information to established clinical factors. All clinical and technical findings were confirmed by quantitative DNA-methylation PCR. These results provide strong evidence that DNA-methylation analysis allows clinically relevant risk assessment in tamoxifen-treated primary breast cancer. Based on PITX2 methylation, about half of hormone receptor-positive, node-negative breast cancer patients receiving adjuvant tamoxifen monotherapy can be considered low-risk regarding development of distant recurrences and may thus be spared adjuvant chemotherapy. In addition, these low-risk postmenopausal patients seem to respond sufficiently well to tamoxifen so that they may not require up-front aromatase inhibitor therapy.
authors.affiliation: Department of Research, Epigenomics AG, Berlin, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Maier
authors.forename: Inko
authors.initials: I
authors.lastname: Nimmrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Koenig
authors.forename: Serenella
authors.initials: S
authors.lastname: Eppenberger-Castori
authors.forename: Inga
authors.initials: I
authors.lastname: Bohlmann
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.forename: Frédérique
authors.initials: F
authors.lastname: Spyratos
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomssen
authors.forename: Volkmar
authors.initials: V
authors.lastname: Mueller
authors.forename: Jörg
authors.initials: J
authors.lastname: Nährig
authors.forename: Francesco
authors.initials: F
authors.lastname: Schittulli
authors.forename: Ronald
authors.initials: R
authors.lastname: Kates
authors.forename: Ralf
authors.initials: R
authors.lastname: Lesche
authors.forename: Ina
authors.initials: I
authors.lastname: Schwope
authors.forename: Antje
authors.initials: A
authors.lastname: Kluth
authors.forename: Almuth
authors.initials: A
authors.lastname: Marx
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D046228:Microarray Analysis / Q000379:methods; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000175:diagnosis / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D012307:Risk Factors; D013629:Tamoxifen / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D013629:Tamoxifen; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2