Estrogen Receptor Expression in 21-Gene Recurrence Score Predicts Increased Late Recurrence for Estrogen-Positive/HER2-Negative Breast Cancer

Abstract

Purpose: To identify the individual genes or gene modules that lead to the OncoptypeDx 21-gene recurrence score's reduced performance after 5 years and thereby identify indices of residual risk that may guide selection of patients for extended adjuvant therapy.Experimental Design: We conducted a retrospective assessment of the relationship between (i) the individual genes and gene modules of the Recurrence Score and (ii) early (0-5 years) and late (5-10 years) recurrence rates in 1,125 postmenopausal patients with primary estrogen receptor-positive breast cancer treated with anastrozole or tamoxifen in the Arimidex, Tamoxifen, Alone or Combined (ATAC) randomized clinical trial.Results: In the HER2-negative population (n ¼ 1,009), estimates of recurrence risk were similar between years 0-5 and 5-10 for proliferation and invasion modules but markedly different for the estrogen module and genes within it (all split at the median): for low estrogen module, annual recurrence rates were similar across the two time windows (2.06% vs. 2.46%, respectively); for high estrogen module, annual rates were 1.14% versus 2.72%, respectively (P interaction ¼ 0.004). Estrogen receptor transcript levels showed inverse prediction across the time windows: HR, 0.88 (0.73-1.07) and 1.19 (0.99-1.43), respectively (P interaction ¼ 0.03). Similar time-, module-, and estrogen-dependent relationships were seen for distant recurrence.Conclusions: Patients with tumors with high estrogen receptor transcript levels benefit most from 5 years' endocrine therapy but show increased recurrence rates after 5 years and may benefit from extended therapy. Improved prognostic profiles may be created by considering period of treatment and follow-up time.

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

“…Other studies have found that DUSP4 mRNA expression inversely correlated with a gene-expressionbased Ras-ERK pathway score in 230 primary breast cancers (11), and in 633 breast tumors from The Cancer Genome Atlas we observed an inverse correlation with BRAF and DUSP4 mRNA expression (Supplementary Table S3 À patients. Notably, HER2 expression was significantly associated with risk of relapse even in the HER2 À cohort, with low rather than high expression associated with greater risk, consistent with our previous reports on the ABC and ATAC adjutant trials (54,55). This may be partly due to a direct relationship between ER and HER2 expression in the HER2 À group (with higher ER expression being linked to better prognosis) or to loss of that locus on chromosome 17 in genetically unstable, poorer prognosis tumors.…”

Identifying Biomarkers to Select Patients with Early Breast Cancer Suitable for Extended Adjuvant Endocrine Therapy

“…The study found that Oncotype RS is strongly prognostic for late distant recurrence in women with a high ESR1 level (cut-off 9.1) and that extended tamoxifen therapy is warranted in those with high expression of ESR1 and intermediate/high risk patients. In contrast to this study, an exploratory analysis of the individual Oncotype RS genes in the transATAC cohort revealed that for oestrogen-related genes the prediction of distant recurrence was substantially different between early versus late follow-up period [17]. These differential findings need to be confirmed and a clearer understanding gained of whether a certain ESR1 level is needed for the use of Oncotype RS in the context of predicting late distant recurrence.…”

“…Other results [10] also demonstrated that proliferation-related factors, such as Ki67 or clinical tumour grade, are not prognostic for late distant recurrence. This is in contrast to the proliferation-related genes in the Oncotype RS, where similar recurrence risk and prognostic abilities were found for early and late time periods [17]. The BCI identifies women with node-negative disease at increased risk of late distant recurrence and might be used in the clinical setting to identify women who might benefit from further endocrine therapy.…”

Clinicopathological factors predicting early and late distant recurrence in estrogen receptor-positive, HER2-negative breast cancer

“…Moreover, host factors may influence tumor biology. To date, most studies analyzing prognostic factors for early and late relapse have been performed in postmenopausal women, mainly using patients and samples in adjuvant aromatase inhibitor trials [10][11][12][13], in which patients received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy. Kennecke and colleagues retrospectively analyzed risk of early [14] and late recurrence [15] among postmenopausal women with ER-positive early breast cancer treated with adjuvant tamoxifen.…”