Prognostic DNA Methylation Markers for Hormone Receptor Breast Cancer: A Systematic Review

Tim C de Ruijter 1 2, Frank van der Heide 1, Kim M Smits 1 2 3, Maureen J Aarts 1 2, Manon van Engeland 2 3, Vivianne C G Heijnen 4 5

Affiliations

PMID: 32005275
PMCID: PMC6993426
DOI: 10.1186/s13058-020-1250-9

Abstract

Background: In patients with hormone receptor-positive breast cancer, differentiating between patients with a low and a high risk of recurrence is an ongoing challenge. In current practice, prognostic clinical parameters are used for risk prediction. DNA methylation markers have been proven to be of additional prognostic value in several cancer types. Numerous prognostic DNA methylation markers for breast cancer have been published in the literature. However, to date, none of these markers are used in clinical practice.

Methods: We conducted a systematic review of PubMed and EMBASE to assess the number and level of evidence of published DNA methylation markers for hormone receptor-positive breast cancer. To obtain an overview of the reporting quality of the included studies, all were scored according to the REMARK criteria that were established as reporting guidelines for prognostic biomarker studies.

Results: A total of 74 studies were identified reporting on 87 different DNA methylation markers. Assessment of the REMARK criteria showed variation in reporting quality of the studies. Eighteen single markers and one marker panel were studied in multiple independent populations. Hypermethylation of the markers RASSF1, BRCA, PITX2, CDH1, RARB, PCDH10 and PGR, and the marker panel GSTP1, RASSF1 and RARB showed a statistically significant correlation with poor disease outcome that was confirmed in at least one other, independent study.

Conclusion: This systematic review provides an overview on published prognostic DNA methylation markers for hormone receptor-positive breast cancer and identifies eight markers that have been independently validated. Analysis of the reporting quality of included studies suggests that future research on this topic would benefit from standardised reporting guidelines.

Keywords: Biomarkers; Breast cancer; DNA methylation; Hormone receptor positive; Luminal breast cancer; Oestrogen receptor positive; Prognosis; Promoter CpG island methylation; Survival.

Conflict of interest statement

Prof. dr. Tjan-Heijnen reports grants from AstraZeneca, during the conduct of the study; grants and non-financial support from Roche; grants and non-financial support from Pfizer; grants and non-financial support from Novartis; grants and non-financial support from E Lilly; and grants from Eisai, outside the submitted work. The other authors declare that they have no competing interests.