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

Buus, Richard ; Yeo, Belinda ; Brentnall, Adam R. ; Klintman, Marie LU ; Cheang, Maggie Chon U. ; Khabra, Komel ; Sestak, Ivana ; Gao, Qiong ; Cuzick, Jack and Dowsett, Mitch (2018) In Breast Cancer Research 20(1).
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Biomarkers, Breast cancer, Late recurrence, Oestrogen receptor, Prognostic tests
in
Breast Cancer Research
volume
20
issue
1
article number
103
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85052945512
  • pmid:30180877
ISSN
1465-5411
DOI
10.1186/s13058-018-1040-9
language
English
LU publication?
yes
id
1508ae8f-d83d-4ce1-9282-045b3c37faf0
date added to LUP
2018-10-12 08:32:50
date last changed
2024-05-13 17:07:17
@article{1508ae8f-d83d-4ce1-9282-045b3c37faf0,
  abstract     = {{<p>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.</p>}},
  author       = {{Buus, Richard and Yeo, Belinda and Brentnall, Adam R. and Klintman, Marie and Cheang, Maggie Chon U. and Khabra, Komel and Sestak, Ivana and Gao, Qiong and Cuzick, Jack and Dowsett, Mitch}},
  issn         = {{1465-5411}},
  keywords     = {{Biomarkers; Breast cancer; Late recurrence; Oestrogen receptor; Prognostic tests}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Breast Cancer Research}},
  title        = {{Novel 18-gene signature for predicting relapse in ER-positive, HER2-negative breast cancer}},
  url          = {{http://dx.doi.org/10.1186/s13058-018-1040-9}},
  doi          = {{10.1186/s13058-018-1040-9}},
  volume       = {{20}},
  year         = {{2018}},
}