Abstract P4-11-18: FOXA1 and PR predict ipsilateral event risk and identify a group with strong radiation response in ductal carcinoma in situ (DCIS)
Authors: Linke Steven P , Bremer Troy M , Whitworth Pat , Lui Aflred , Savala Jess , Noskina Yelina , Barry Todd , Lyle Stephen , Walters Stephanie C , Taglienti Cherie , Simin Karl , Zhou Wenjing , Jirström Karin , Amini Rose-Marie , Wärnberg Fredrik 
Published: May 2015

Background: Identification of biomarkers in DCIS is critical to help guide treatment decisions, particularly for patients receiving breast-conserving surgery (BCS). The goal of this study was to assess FOXA1 levels in the context of PR status in primary DCIS to predict ipsilateral invasive and DCIS events, given the established roles of these endocrine signaling factors in breast cancer.

Material and Methods: Patients included in this study (n=518) were women diagnosed with DCIS without evidence of invasive cancer treated with BCS, and for whom tumor tissue was evaluable for both PR and FOXA1. An Uppsala University Hospital (UUH) set was diagnosed in 1986-2004 (117 treated and 122 not treated with adjuvant radiation therapy [RT]); and a University of Massachusetts Memorial Hospital (UMass) set was diagnosed in 1999-2008 (195 treated and 84 not treated with RT).

Tumors were immunohistochemically stained for PR and FOXA1 and scored by pathologists for percentage (0-100) and intensity (0-3), with the product being calculated for FOXA1 immunoscore (0-300). Patients were considered PR+ when ≥10% of cells stained positively, and immunoscore thresholds of 100 and 270 were used to separate patients into FOXA1 low, intermediate, and high groups. Event rates were assessed for 10-year outcome using Kaplan-Meier survival analysis. Hazard ratios (HR) were determined using Cox proportional hazards analysis.

Results: Neither FOXA1 nor PR were prognostic as independent factors for either invasive or DCIS event risk. However, in PR- patients, the invasive event rate decreased with increasing FOXA1 (24%, 4%, and 0%, respectively, in the FOXA1 low, intermediate, and high groups, HR=6.7/bin, p=0.0034), and, in PR+ patients, the invasive event rate increased with increasing FOXA1 (0%, 10%, and 13%, respectively, HR=2.95/bin, p=0.041). In contrast, the DCIS event rate increased in PR- patients with increasing FOXA1 (3%, 12%, and 26%, respectively, HR=2.7/bin, p=0.020), and the DCIS event rate was lower in PR+ patients with elevated FOXA1 levels (28% in FOXA1 low vs. 8% in FOXA1 intermediate plus high, HR=4.0, p=0.011).

In the full population, RT-treated patients (n=312) fared better than the unirradiated (n=206) with invasive event rates of 6% and 10%, respectively (HR=0.41, p=0.021). By comparison, the patients with high marker-based invasive event risk (PR-/FOXA1 low and PR+/FOXA1 high, n=191) had a remarkable response to RT–event rate reduced from 19% to 4% (HR=0.13, p&lt;0.001). In contrast, the remainder of patients (n=327) showed no evident RT response--event rate increased from 5% to 6%. In an interactional Cox analysis, the high-risk group (HR=5.0, p=0.0045) and RT response within that group (HR=0.10, p=0.020) were significant, but baseline RT response was not (p=0.72).

Discussion: These results indicate a complex interaction between PR and FOXA1, in which the prognosis for invasive and DCIS events flips both within and between the event types. Thus, the biology that drives these events differs and, in order to predict both event types, risk models must include biomarkers in context. In addition, PR/FOXA1 identify a risk group with remarkably strong RT response with the remaining patients exhibiting no measurable response.

Citation Format: Steven P Linke, Troy M Bremer, Pat Whitworth, Aflred Lui, Jess Savala, Yelina Noskina, Todd Barry, Stephen Lyle, Stephanie C Walters, Cherie Taglienti, Karl Simin, Wenjing Zhou, Karin Jirström, Rose-Marie Amini, Fredrik Wärnberg. FOXA1 and PR predict ipsilateral event risk and identify a group with strong radiation response in ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-18.