Abstract P3-07-05: Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study
Authors: Buus Richard , Sestak Ivana , Dowsett Mitch , Kronenwett Ralf , Ferree Sean , Schnabel Catherine , Baehner Frederick L , Cuzick Jack 
Published: March 2020

Background: Oncotype DX Recurrence Score (RS), Prosigna PAM50 ROR score, the EndoPredict score (EP, EPclin) and the Breast Cancer Index (BCI) all provide substantial molecular prognostic information and are used in clinical practice for guiding the treatment for large numbers of patients with primary ER+/HER2- breast cancer. Despite this, there is incomplete information on the concordance between these scores and very little understanding of the molecular features that drive the individual scores. Here we report from a unique database (i) the correlation between all 4 scores when measured by the respective manufacturers in the TransATAC set of samples and (ii) the degree to which each of the scores is driven by proliferation, oestrogen signalling, HER2 signalling and invasive properties insomuch as these are reflected by each component module of the RS test (PM, EM, HM and IM, respectively).

Methods: The TransATAC tumour sample set was collected from patients in the tamoxifen or anastrozole arms from the ATAC clinical trial of 5 years of endocrine therapy in postmenopausal patients with primary hormone receptor positive breast cancer. Cases were included if HER2- and all 4 scores were available. None of the patients received adjuvant chemotherapy. EP and ROR both include some clinical features in their final score but components were excluded for the purposes of this study. The RS module scores were provided by the manufacturer. The genes that contribute to the module scores are as follows: PM: Ki67, STK15, Survivin, CCNB1, MYBL2; EM: ER, PGR, BCL2, SCUBE2; HM: GRB7, HER2; IM: MMP11, CTSL2). Spearman rank correlation was used to study the association between molecular components.

Results: Data was available for all four molecular scores for 785 TransATAC patients. Correlations were moderate to strong for RS vs EP (r=0.63), ROR vs EP (r=0.68), ROR vs BCI (r=0.74) and EP vs BCI (r=0.67) but were weak for RS vs ROR (r=0.32) and RS vs BCI (r=0.35).

The correlation between each score with the RS module scores are shown in the Table.

Molecular scoreRS moduleRSROREPBCIPM0.360.860.710.74EM-0.790.00-0.38-0.10HM-0.04-0.14-0.15-0.18IM0.260.380.340.32

The RS had a strong negative correlation with its EM (r= -0.79) and a weak positive correlation with its PM (r= 0.36) although the latter was stronger when the PM was thresholded; 78% of the cases had a PM score below the threshold of 6.5 and were assigned a value of 6.5 in the RS with no correlation between RS and PM in these samples (r=-0.03). ROR showed a very strong correlation with the PM (r=0.86), but none with the EM (r: 0.00). EP and BCI both showed strong correlation with the PM (r= 0.71 and 0.74, respectively) and with low or near absent correlation with

EM (r= -0.38 and -0.10, respectively). There was little correlation between the HM with each of the scores while the IM correlation was similar for each score varying from 0.26 to 0.38. Of the two module components of BCI, MGI was strongly associated with the PM (r= 0.84) and not at all with the EM while H/I moderately correlated with PM (r=0.51) and weakly correlated with EM (r= -0.31).

Conclusion: EP scores are moderately correlated with each of the other 3 scores while RS scores are dissimilar to those from the ROR and BCI. In contrast to common thinking the RS is driven only weakly by proliferative features and more by those related to ER/PR pathways. The EP, BCI and particularly ROR are dominated by proliferative features. These relationships provide and explanation for the differences that we and others have reported in the prognostic performance of the tests for both early and late recurrence.

Citation Format: Richard Buus, Ivana Sestak, Mitch Dowsett, Ralf Kronenwett, Sean Ferree, Catherine Schnabel, Frederick L Baehner, Jack Cuzick. Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-05.