Background: A number of prognostic signatures have been developed for the prediction of breast cancer recurrence in the past decade. We have developed two signatures (Clinical Treatment Score (CTS), four immunohistochemical markers (IHC4)) and validated four prognostic signatures (Oncotype Dx Recurrence Score (RS), PAM50-based Prosigna (ROR), Breast Cancer Index (BCI), and EndoPredict (EPclin)) in the TransATAC cohort. Here, we compare the prognostic performance of these six signatures for distant recurrence (DR) in years 0-10, and specifically in years 5-10 after treatment cessation.

Methods: 1231 postmenopausal women with hormone receptor positive and HER2-negative breast cancer had at least one test performed. Of these, 818 women had data on all six signatures available. IHC4, RS and BCI (linear) are molecular only signatures whereas CTS, ROR and EPclin include clinicopathological factors. The primary endpoint was DR and the primary objective was to compare the prognostic value of the six signatures in terms of DR for years 0-10, 0-5, and 5-10. Secondary objectives included the comparison of the prognostic performance for node-negative and node-positive patients separately and the additional prognostic performance of each signature to the others. Likelihood ratio statistics (LR-χ2) were used to assess the prognostic information of each signature alone or in combination with other signatures.

Results: Median follow-up for this analysis was 9.94 years (IQR 8.01-10.09) and a total of 126 DR were recorded. 818 women with HER2-negative disease for whom data of all six signatures were available were included in this analysis. For all patients, CTS and EPclin were the most prognostic signatures in years 0-10 (CTS: LR-χ2=124.9; EPclin: LR-χ2=116.2) and years 5-10 (CTS: LR-χ2=59.6; EPclin: LR-χ2=56.8) in the univariate analysis. The other four signatures performed similarly well in years 0-5, but of those only BCI and ROR provided substantial prognostic information in years 5-10 (BCI: LR-χ2=25.3; ROR: LR-χ2=43.8). In multivariate analyses comparing the added information of the molecular signatures over CTS, IHC4 and BCI provided the most information (IHC4: ΔLR-χ2=19.0; BCI: ΔLR-χ2=19.8). In node-negative patients (72.3%), the ROR showed the most prognostic value in years 0-10 (LR-χ2=48.6) and years 5-10 (LR-χ2=31.3) whereas the RS was least prognostic in this patient group. For patients with node-positive disease (27.7%), the CTS and EPclin were the most prognostic and the other four signatures provided much less prognostic information for this patient population (data not shown).

Conclusion: Overall, the CTS and EPclin were the most prognostic signatures for DR and also added significant prognostic value to the other scores in women with HER2-negative disease, primarily due to the incorporation of nodal status in these signatures. For women with node-negative disease, the ROR, BCI, and EPclin signatures provided most prognostic value whereas for those with positive nodes CTS and EPclin were most prognostic. Our analyses showed that the inclusion of clinic-pathological factors into gene signatures is highly important for deriving an accurate prognostic assessment, particularly in node-positive patients.

Citation Format: Sestak I, Buus R, Cuzick J, Dubsky P, Kronenwett R, Ferree S, Sgroi D, Schnabel C, Baehner R, Mallon E, Dowsett M. Comprehensive comparison of prognostic signatures for breast cancer in TransATAC [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S6-05.