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.
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.
Maier
Sabine
S
Department of Research, Epigenomics AG, Berlin, Germany.
Nimmrich
Inko
I
Koenig
Thomas
T
Eppenberger-Castori
Serenella
S
Bohlmann
Inga
I
Paradiso
Angelo
A
Spyratos
Frédérique
F
Thomssen
Christoph
C
Mueller
Volkmar
V
Nährig
Jörg
J
Schittulli
Francesco
F
Kates
Ronald
R
Lesche
Ralf
R
Schwope
Ina
I
Kluth
Antje
A
Marx
Almuth
A
Martens
John W M
JW
Foekens
John A
JA
Schmitt
Manfred
M
Harbeck
Nadia
N
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
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D013629:Tamoxifen; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2