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. 2018 Sep 4;20(1):103.
doi: 10.1186/s13058-018-1040-9.

Novel 18-gene signature for predicting relapse in ER-positive, HER2-negative breast cancer

Richard Buus  1   2 , Belinda Yeo  3   4 , Adam R Brentnall  5 , Marie Klintman  6 , Maggie Chon U Cheang  7 , Komel Khabra  8 , Ivana Sestak  5 , Qiong Gao  9 , Jack Cuzick  5 , Mitch Dowsett  9   10
Affiliations

Novel 18-gene signature for predicting relapse in ER-positive, HER2-negative breast cancer

Richard Buus et al. Breast Cancer Res. .

Abstract

Background: Several prognostic signatures for early oestrogen receptor-positive (ER+) breast cancer have been established with a 10-year follow-up. We tested the hypothesis that signatures optimised for 0-5-year and 5-10-year follow-up separately are more prognostic than a single signature optimised for 10 years.

Methods: Genes previously identified as prognostic or associated with endocrine resistance were tested in publicly available microarray data set using Cox regression of 747 ER+/HER2- samples from post-menopausal patients treated with 5 years of endocrine therapy. RNA expression of the selected genes was assayed in primary ER+/HER2- tumours from 948 post-menopausal patients treated with 5 years of anastrozole or tamoxifen in the TransATAC cohort. Prognostic signatures for 0-10, 0-5 and 5-10 years were derived using a penalised Cox regression (elastic net). Signature comparison was performed with likelihood ratio statistics. Validation was done by a case-control (POLAR) study in 422 samples derived from a cohort of 1449.

Results: Ninety-three genes were selected by the modelling of microarray data; 63 of these were significantly prognostic in TransATAC, most similarly across each time period. Contrary to our hypothesis, the derived early and late signatures were not significantly more prognostic than the 18-gene 10-year signature. The 18-gene 10-year signature was internally validated in the TransATAC validation set, showing prognostic information similar to that of Oncotype DX Recurrence Score, PAM50 risk of recurrence score, Breast Cancer Index and IHC4 (score based on four IHC markers), as well as in the external POLAR case-control set.

Conclusions: The derived 10-year signature predicts risk of metastasis in patients with ER+/HER2- breast cancer similar to commercial signatures. The hypothesis that early and late prognostic signatures are significantly more informative than a single signature was rejected.

Keywords: Biomarkers; Breast cancer; Late recurrence; Oestrogen receptor; Prognostic tests.

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Conflict of interest statement

Ethics approval and consent to participate

The TransATAC study was approved by the South-East London Research Ethics Committee, and all patients gave informed consent. The POLAR study was approved by the RMH Research Ethics Committee (CCR: 4122) and the ethics committee of Lund University Hospital (LU 240-01), and all patients gave informed consent.

Consent for publication

Not applicable.

Competing interests

MCUC reports patents, royalties, other intellectual property: PAM50 patent. The other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flowchart of gene signature derivation in the microarray and TransATAC cohorts. QC Quality control, ATAC Arimidex, Tamoxifen, Alone or in Combination
Fig. 2
Fig. 2
Consolidated Standards of Reporting Trials (CONSORT) diagram of the availability of samples for analysis from (a) the ATAC trial and (b) the POLAR collection of samples. POLAR Molecular Predictors Of early versus LAte Recurrence in ER-positive breast cancer, ATAC Arimidex, Tamoxifen, Alone or in Combination, ER Oestrogen receptor, PgR Progesterone receptor, RMH Royal Marsden Hospital, LUH Lund University Hospital, ET Endocrine therapy, HER2 Human epidermal growth factor receptor 2
Fig. 3
Fig. 3
HRs and ORs for the 10-year signature genes in TransATAC and POLAR, respectively. POLAR Molecular Predictors Of early versus LAte Recurrence in ER-positive breast cancer, ATAC Arimidex, Tamoxifen, Alone or in Combination
See this image and copyright information in PMC

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