Abstract PO4-22-02: pSmad2 as a marker of radiotherapy benefit in breast cancer- results from the randomized SweBCG91RT trial
Authors: Karlsson Per , Thurfjell Viktoria , Kovács Anikó , Killander Fredrika , Niméus Emma , Holmberg Erik , Strell Carina , Tullberg Axel Stenmark 
Published: May 2024

Abstract
Background: The TGF-beta pathway can have both pro- and antitumoral effects in breast cancer. Experimental studies further suggest that TGF-beta can mediate radioresistance, either through direct effects on tumor cells or indirectly by its immunomodulatory properties. However, the effect of TGF-beta signaling is highly depending on tumor stage, mutational status and microenvironmental cell composition. In order to explore TGF-beta signaling as a potential biomarker or therapeutical target it is therefore important to perform analyses in well-defined study populations. The purpose of this study was to study the effect of active TGF beta signaling in tumor cells, on the risk of ipsilateral breast tumor recurrence (IBTR) and benefit from radiotherapy (RT) in specifically early-stage breast cancer using nuclear, phosphorylated Smad2 (pSmad2) as a marker.
Methods: The SweBCG91RT cohort included 1179 patients with stage I-IIA tumors randomized to breast-conserving surgery (BCS) with or without postoperative RT. Nuclear pSmad2 expression was assessed as for 987 available tumors on TMAs as the mean proportion of tumor cells with positive nuclear staining. Based on the distributions, tumors were categorized as having high (≥80%, n=344), medium (21-79%, n=428) or low (≤20%, n=161) pSmad2 staining. The primary endpoint was time to ipsilateral breast tumor recurrence as the first event within 10 years.
Results: pSmad2Low tumors were more likely to be of grade III (p&lt; 0.001) and tended to be larger than pSmad2Medium (p=0.002, median 15 vs 12 mm) and pSmad2High (p&lt; 0.001, median 15 vs 12 mm) tumors. No associations between pSmad2 and subtype or age were found. Numerically, tumors with pSmad2low (HR 1.55, CI 95% 0.80-3.02, p=0.19) or pSmad2Medium (HR 2.53, CI 95% 1.52-4.22, p&lt; 0.001) had a higher risk of IBTR than pSmad2high tumors (reference). These findings remained significant after adjustment for age, histological grade, and RT. The benefit from RT was similar for pSmad2High (HR0.41, CI 95% 0.15-1.07, p=0.068), pSmad2Medium (HR 0.36, CI 95% 0.21-0.63, p&lt; 0.001), and pSmad2Low (HR 0.51, CI 95% 0.18-1.46, p=0.21) tumors (pinteraction=0.86).
Conclusions: Early-stage breast tumors with high nuclear pSmad2 staining may be at a reduced risk of an IBTR. However, the relative benefit from RT does not seem to differ from tumors with medium or low pSmad2 staining. These results need to be confirmed in additional studies, but they provide initial evidence that tumoral TGF-beta signaling has rather tumor restraining functions in early-stage breast cancer. Next analytical steps should include the tumor mutation status (particularly for TGF-beta signaling components TGFBR2, SMAD4 and TP53), as well as the TGF-beta signaling status within the tumor microenvironment.
Citation Format: Per Karlsson, Viktoria Thurfjell, Anikó Kovács, Fredrika Killander, Emma Niméus, Erik Holmberg, Carina Strell, Axel Stenmark Tullberg. pSmad2 as a marker of radiotherapy benefit in breast cancer- results from the randomized SweBCG91RT trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-22-02.