Tumoral pSMAD2 as a prognostic biomarker in early-stage breast cancer : insights from the randomized SweBCG91RT trial
(2025) In Breast Cancer Research and Treatment 212(3). p.499-509- Abstract
Background/Aim: 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. Methods: 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. Results: pSMAD2 scores were heavily skewed, with 45% of tumors... (More)
Background/Aim: 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. Methods: 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. Results: 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). Conclusion: 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.
(Less)
- author
- Stenmark Tullberg, Axel ; Thurfjell, Viktoria ; Kovács, Anikó ; Micke, Patrick ; Moustakas, Aristidis ; Killander, Fredrika LU ; Niméus, Emma LU ; Holmberg, Erik ; Karlsson, Per and Strell, Carina
- organization
- publishing date
- 2025-08
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Breast cancer, Immune cells, Prognosis, Radiotherapy, SMAD2, TGF-β signaling
- in
- Breast Cancer Research and Treatment
- volume
- 212
- issue
- 3
- pages
- 11 pages
- publisher
- Springer
- external identifiers
-
- pmid:40488800
- scopus:105007542957
- ISSN
- 0167-6806
- DOI
- 10.1007/s10549-025-07744-0
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © The Author(s) 2025.
- id
- 9de93976-caf4-4a4e-a487-0675b4a91168
- date added to LUP
- 2025-11-20 16:12:37
- date last changed
- 2025-12-04 17:28:39
@article{9de93976-caf4-4a4e-a487-0675b4a91168,
abstract = {{<p>Background/Aim: 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. Methods: 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. Results: 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 (HR<sub>adjusted</sub> = 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). Conclusion: 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.</p>}},
author = {{Stenmark Tullberg, Axel and Thurfjell, Viktoria and Kovács, Anikó and Micke, Patrick and Moustakas, Aristidis and Killander, Fredrika and Niméus, Emma and Holmberg, Erik and Karlsson, Per and Strell, Carina}},
issn = {{0167-6806}},
keywords = {{Breast cancer; Immune cells; Prognosis; Radiotherapy; SMAD2; TGF-β signaling}},
language = {{eng}},
number = {{3}},
pages = {{499--509}},
publisher = {{Springer}},
series = {{Breast Cancer Research and Treatment}},
title = {{Tumoral pSMAD2 as a prognostic biomarker in early-stage breast cancer : insights from the randomized SweBCG91RT trial}},
url = {{http://dx.doi.org/10.1007/s10549-025-07744-0}},
doi = {{10.1007/s10549-025-07744-0}},
volume = {{212}},
year = {{2025}},
}