Introduction
During the past 15 years, several multiparameter genomic tests have entered mainstream care for patients with early breast cancer, with some being endorsed for use by authoritative guidelines groups (ASCO, National Institute for Health and Care Excellence).1,2 The predominant use of the tests is in the management of estrogen receptor (ER)-positive primary disease. All approved tests show prognostic ability that is beyond that provided by standard clinicopathologic factors such that patients in whom the tests indicate excellent prognosis may safely be excluded from the administration of chemotherapy. The Oncotype DX Recurrence Score (RS; Genomic Health, Redwood City, CA) has 16 genes that characterize tumor biology along with five reference genes and has been the most widely used test. Other tests include the Prediction Analysis of Microarray 50 (PAM50) Risk of Recurrence (ROR) score (Prosigna; NanoString Technologies, Seattle, WA),3 EndoPredict (EP; Myriad Genetics, Cologne, Germany),4 Breast Cancer Index (BCI; Biotheranostics, San Diego, CA),5 and MammaPrint (Agendia, Amsterdam, the Netherlands) that measure 46, 8, 7, and 70 genes, respectively, to characterize tumor biology in addition to reference genes. All but the last of these provide an estimate of residual risk of distant recurrence on the basis that patients will receive 5 years of adjuvant endocrine therapy. MammaPrint provides a prognostic estimate if no adjuvant treatment is to be administered. Understanding the molecular drivers of each of these tests and how they differ among the tests is key to interpreting discrepant estimates of risk that are made in many cases.7,8
Study Aim
The Oncotype DX Recurrence Score (RS), Prosigna Prediction Analysis of Microarray 50 (PAM50) Risk of Recurrence (ROR), EndoPredict (EP), and Breast Cancer Index (BCI) are used clinically for estimating risk of distant recurrence for patients receiving endocrine therapy. Discordances in estimates occur between them. We aimed to identify the molecular features that drive the tests and lead to these differences.
Methods
Analyses for RS, ROR, EP, and BCI were conducted by the manufacturers in the TransATAC sample collection that consisted of the tamoxifen or anastrozole arms of the ATAC trial. Estrogen receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative cases without chemotherapy treatment were included in which all four tests were available (n = 785). Clinicopathologic features included in some tests were excluded from the comparisons. Estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the respective molecular features. Spearman correlation and analysis of variance tests were applied.
Results
There were moderate to strong correlations among the four molecular scores (p = 0.63-0.74) except for RS versus ROR (p = 0.32) and RS versus BCI (p = 0.35). RS had strong negative correlation with its estrogen module (p = -0.79) and moderate positive correlation with its proliferation module (p = 0.36). RS’s proliferation module explained 72.5% of ROR’s variance, while the estrogen module explained only 0.6%. Most of EP’s and BCI’s variation was accounted for by the proliferation module (50.0% and 54.3%, respectively) and much less by the estrogen module (20.2% and 2.7%, respectively).
Conclusion
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.