Tumoral pSMAD2 as a prognostic biomarker in early-stage breast cancer: insights from the randomized SweBCG91RT trial

TL;DR

This study shows that high levels of pSMAD2, a marker of TGF-β signaling, are linked to better outcomes in early-stage breast cancer, suggesting a tumor-suppressive role.

Contribution

The study identifies pSMAD2 as a potential prognostic biomarker in early-stage breast cancer, revealing its association with recurrence risk and tumor-infiltrating lymphocytes in Luminal tumors.

Findings

Medium pSMAD2 levels were associated with higher ipsilateral breast tumor recurrence risk compared to high pSMAD2 levels.

In Luminal tumors, higher pSMAD2 levels were inversely correlated with tumor-infiltrating lymphocytes.

Radiotherapy benefit was consistent across all pSMAD2 groups.

Abstract

The TGF-β pathway can influence breast cancer progression and therapy efficacy, exhibiting both pro- and anti-tumoral effects. This study examined the impact of active TGF-β signaling on recurrence and radiotherapy (RT) benefit in early-stage breast cancer, using nuclear phosphorylated Smad2 (pSMAD2) as a marker for pathway activation.

Tissue-microarrays from 1178 stage I-IIA breast cancer patients in the SweBCG91RT trial (randomized to breast-conserving surgery with or without RT) were analyzed. pSMAD2 immunohistochemistry was scored as the mean percentage of tumor cells with nuclear staining. Recurrence risk and RT benefit were evaluated.

pSMAD2 scores were heavily skewed, with 45% of tumors demonstrating high staining (≥ 80% tumor cells), 38% medium (21–79%), and 17% low (≤ 20%). Low pSMAD2 tumors were associated with higher grade and larger size but not with subtype. Medium pSMAD2 tumors had a significantly increased ipsilateral breast tumor recurrence risk than high pSMAD2 tumors (HRadjusted = 1.82, p = 0.002), while no differences were observed for low pSMAD2 tumors. A similar result was obtained with all recurrences as endpoint. RT benefit was consistent across all pSMAD2 groups. In Luminal tumors, higher tumoral pSMAD2 levels were inversely correlated with tumor-infiltrating lymphocytes (TILs).

Medium pSMAD2 levels were linked to an increased recurrence risk compared to high levels, suggesting a tumor-suppressive role of TGF-β in early breast tumorigenesis. However, no significant differences were noted for low pSMAD2 levels. In Luminal tumors, TGF-β signaling was negatively associated with TILs. These findings indicate that therapeutic targeting of TGF-β warrants careful consideration of tumor stage and subtype.

The online version contains supplementary material available at 10.1007/s10549-025-07744-0.

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