Potential Factors in Prognostic Discrepancies Among Tests for Recurrence Risk in Patients With Breast Cancer Receiving Endocrine Therapy

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The TransATAC study reported by Buus et al in the Journal of Clinical Oncology sought to identify causes of discrepancies among tests for determining the risk of breast cancer recurrence in patients with estrogen receptor–positive, HER2-negative disease receiving endocrine therapy. The investigators found that the Oncotype DX recurrence score (RS) is dominated by information on estrogen signaling, whereas the Prosigna Prediction Analysis of Microarray 50 (PAM50) Risk of Recurrence (ROR) in particular, as well as the EndoPredict (EP) and Breast Cancer Index (BCI) scores, are dominated by information on proliferation.

TransATAC is a translational study of samples from patients with hormone receptor–positive, early-stage breast cancer who received 5 years of tamoxifen or anastrozole in the randomized ATAC trial.

Study Details

Analyses of RS, ROR, EP, and BCI were conducted by the manufacturers using the TransATAC sample collection from the tamoxifen and anastrozole arms of the ATAC trial. The study included 785 patients with estrogen receptor–positive, HER2-negative disease who did not receive treatment with chemotherapy.

Clinicopathologic features included in some of the tests were excluded from comparisons. Estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the molecular features accounting for discrepancies among tests. Correlations are expressed as Spearman’s rank correlation (ρ).

Key Findings

With regard to correlations of overall molecular risk scores for the four tests, RS exhibited a strong correlation with EP (ρ = 0.63) and a moderate correlation with ROR (ρ = 0.32) and BCI (ρ = 0.35); however, nearly all patents with RS scores ≥ 31 had ROR and BCI scores above their median values. Strong correlations were observed for ROR vs EP (ρ = 0.68), ROR vs BCI (ρ = 0.74), and EP vs BCI (ρ = 0.67).

RS exhibited a strong negative correlation with its estrogen module (ρ = −0.79), a moderate positive correlation with its proliferation module (ρ = 0.36), a weak positive correlation with its invasion module (ρ = 0.26), and no correlation with its HER2 module in the HER2-negative study cohort.

The RS estrogen module accounted for 59.1% of RS variance (59.1%), and the proliferation module accounted for 19.4% (1.3% and 2.2% for invasion and HER2 modules).

Overall, 72.5% of the ROR score variance could be explained by the RS proliferation module score, with only 0.6% explained by the RS estrogen module score. Both EP score variance (50.0%) and BCI score variance (54.3%) were also largely accounted for by the RS proliferation module score, with the RS estrogen module having a lesser contribution to EP score variance (20.2%) and almost no contribution to BCI score variance (2.7%).

Scores for each of ROR, EP, and BCI had minimal associations with the RS HER2 module score (explained variance of 0.6%–2.4%). Although the correlation of each of the three other tests with the RS invasion module score was > 0.3, the explained variance was minimal (0.3%–0.7%).

The investigators concluded, “In contrast to common understanding, RSs are determined more strongly by estrogen-related features and only weakly by proliferation markers. However, the EP, BCI, and particularly ROR scores are determined largely by proliferative features. These relationships help to explain the differences in the prognostic performance of the tests.”

Richard Buus, PhD, of The Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Breast Cancer Now in partnership with Walk the Walk, National Institute for Health Research Royal Marsden/The Institute of Cancer Research Biomedical Research Centre, and Cancer Research UK. For full disclosures of the study authors, visit

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