Abstract PD7-02: Identification of breast cancers with an indolent disease course: 70 gene indolent threshold validation in a Swedish randomized trial of tamoxifen vs. not, with 20 year outcomes
Authors: Esserman LJ , Yau C , Thompson CK , van't Veer LJ , Borowsky AD , Hoadley KA , Tobin NP , Nordenskjöld B , Fornander T , Stål O , Benz CC , Lindström LS 
Published: March 2017

Abstract
Importance: The frequency of cancers with indolent behavior has increased with screening. We asked whether an ultralow risk threshold on a multigene classifier would identify women whose cancers had an indolent course over 2 decades of follow-up, and which features were most predictive of outcome.
Methods: An ultralow risk threshold of the FDA-cleared MammaPrint 70-gene expression score was set to predict long-term absence of breast cancer-specific mortality in the absence of systemic therapy. The Stockholm Tamoxifen (STO) trial conducted between 1976 and 1990, where postmenopausal women with clinically detected node-negative breast cancers &lt;3cm were randomized to receive tamoxifen versus not, was used for validation. Immunohistochemistry markers (n=727) and Agilent microarrays for MammaPrint risk scoring (n=652) were performed from formalin-fixed paraffin-embedded primary tumor blocks. Recursive partitioning was performed using the rpart package in R to select variables and construct a regression tree that best predicts 20-year breast cancer specific survival. Input variables include: age, period of diagnosis, grade, hormone receptor status, HER2 and Ki69 status, 70-gene risk categories (high, low but not ultra, or ultralow), treatment arm and tumor size; and cross-validation was used to select the final regression tree model.
Results: In this trial conducted in the era before mammographic screening, 58% and 42% were MammaPrint low and high risk, respectively, while 15% were above the ultralow threshold. In the tamoxifen treated arm, women with tumors above the ultralow threshold had no deaths at 15 years and their 20-year disease-specific survival rates of 97%; whereas if untreated, their survival rates were 94%. Recursive partitioning identified the ultralow threshold classification as the first primary split in the model. Once the indolent tumors were partitioned out, among women with tumors below the ultralow threshold, the next most prognostic feature was size, where patients with tumors &gt;20mm have worse breast cancer specific survival. The last split in the model divides the patients with tumors ≤20mm into 70-gene high risk vs low but not ultralow risk groups.
Conclusions and Relevance: A threshold of the 70-gene MammaPrint assay can identify patients with indolent disease whose long-term risk of death from breast cancer after surgery alone is exceedingly low. This threshold emerged as the most prognostic variable, followed by tumor size, and mammaprint high vs. low but not ultralow in our recursive partitioning analysis. This suggests that finding indolent tumors early at a small size may not have much impact on patient outcome. Determining the presence of an ultralow risk breast cancer may prevent overtreatment. Conversely, once the indolent tumors are taken out of consideration, both biology and size impact outcome, and finding these tumors at a small size is likely still important and supports screening in this postmenopausal node negative population.
Citation Format: Esserman LJ, Yau C, Thompson CK, van't Veer LJ, Borowsky AD, Hoadley KA, Tobin NP, Nordenskjöld B, Fornander T, Stål O, Benz CC, Lindström LS. Identification of breast cancers with an indolent disease course: 70 gene indolent threshold validation in a Swedish randomized trial of tamoxifen vs. not, with 20 year outcomes [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 PD7-02.