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The potential radiosensitization target PFKFB3 is related to response to radiotherapy in SweBCG91RT : a randomized clinical trial with long-term follow-up

Egelberg, Moa LU orcid ; De Marchi, Tommaso LU ; Schultz, Niklas ; Tran, Lena LU ; Karlsson, Per ; Holmberg, Erik ; Pekar, Gyula LU ; Killander, Fredrika LU and Niméus, Emma LU (2025) In BMC Cancer 25(1).
Abstract

Background: Several cancer types have increased PFKFB3, a glycolytic enzyme for which potent inhibitors have been found. Inhibition of PFKFB3 impairs DNA repair after irradiation of cancer cells, making it a possible radiosensitization target. The SweBCG91RT trial, in which breast cancer patients were randomized to postoperative radiotherapy or not, was used to investigate PFKFB3 as a clinical marker of sensitivity to adjuvant radiotherapy. Methods: Nuclear protein levels of PFKFB3 were assessed with immunohistochemistry in primary breast tumors (n = 970) and whole-cell RNA levels with microarray gene expression (n = 765). Multivariable competing risks regression analysis was employed for the effect of radiotherapy on incidence of... (More)

Background: Several cancer types have increased PFKFB3, a glycolytic enzyme for which potent inhibitors have been found. Inhibition of PFKFB3 impairs DNA repair after irradiation of cancer cells, making it a possible radiosensitization target. The SweBCG91RT trial, in which breast cancer patients were randomized to postoperative radiotherapy or not, was used to investigate PFKFB3 as a clinical marker of sensitivity to adjuvant radiotherapy. Methods: Nuclear protein levels of PFKFB3 were assessed with immunohistochemistry in primary breast tumors (n = 970) and whole-cell RNA levels with microarray gene expression (n = 765). Multivariable competing risks regression analysis was employed for the effect of radiotherapy on incidence of ipsilateral breast tumor recurrence (IBTR), depending on PFKFB3 levels. Results: Tumors with high levels of nuclear protein and RNA had the largest effect on incidence of IBTR of adjuvant radiotherapy, however without evidence of an interaction. PFKFB3 RNA correlated with subtype, as high levels were more common among the human epidermal growth factor receptor 2 (HER2) positive and Luminal A subtypes than Luminal B and triple negative tumors. Conclusion: High PFKFB3 is associated with a larger reduction of IBTR after radiotherapy but PFKFB3 cannot reliably be used as a predictive marker of sensitivity to adjuvant radiotherapy in breast cancer. PFKFB3 expression differed with subtype, indicating that it may be a better marker among Luminal A and HER2 positive tumors, but this is yet to be investigated. Trial registration: The trial has been retrospectively registered at clinicaltrials.gov 2024-10-03 (NCT06637202).

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, DNA repair, PFKFB3, Radiosensitization, Radiotherapy
in
BMC Cancer
volume
25
issue
1
article number
374
publisher
BioMed Central (BMC)
external identifiers
  • pmid:40022029
  • scopus:85219592135
ISSN
1471-2407
DOI
10.1186/s12885-025-13703-1
language
English
LU publication?
yes
id
8a5ba5e6-79b6-4638-8cab-dc912ba93998
date added to LUP
2025-06-09 08:40:48
date last changed
2025-07-21 12:28:56
@article{8a5ba5e6-79b6-4638-8cab-dc912ba93998,
  abstract     = {{<p>Background: Several cancer types have increased PFKFB3, a glycolytic enzyme for which potent inhibitors have been found. Inhibition of PFKFB3 impairs DNA repair after irradiation of cancer cells, making it a possible radiosensitization target. The SweBCG91RT trial, in which breast cancer patients were randomized to postoperative radiotherapy or not, was used to investigate PFKFB3 as a clinical marker of sensitivity to adjuvant radiotherapy. Methods: Nuclear protein levels of PFKFB3 were assessed with immunohistochemistry in primary breast tumors (n = 970) and whole-cell RNA levels with microarray gene expression (n = 765). Multivariable competing risks regression analysis was employed for the effect of radiotherapy on incidence of ipsilateral breast tumor recurrence (IBTR), depending on PFKFB3 levels. Results: Tumors with high levels of nuclear protein and RNA had the largest effect on incidence of IBTR of adjuvant radiotherapy, however without evidence of an interaction. PFKFB3 RNA correlated with subtype, as high levels were more common among the human epidermal growth factor receptor 2 (HER2) positive and Luminal A subtypes than Luminal B and triple negative tumors. Conclusion: High PFKFB3 is associated with a larger reduction of IBTR after radiotherapy but PFKFB3 cannot reliably be used as a predictive marker of sensitivity to adjuvant radiotherapy in breast cancer. PFKFB3 expression differed with subtype, indicating that it may be a better marker among Luminal A and HER2 positive tumors, but this is yet to be investigated. Trial registration: The trial has been retrospectively registered at clinicaltrials.gov 2024-10-03 (NCT06637202).</p>}},
  author       = {{Egelberg, Moa and De Marchi, Tommaso and Schultz, Niklas and Tran, Lena and Karlsson, Per and Holmberg, Erik and Pekar, Gyula and Killander, Fredrika and Niméus, Emma}},
  issn         = {{1471-2407}},
  keywords     = {{Breast cancer; DNA repair; PFKFB3; Radiosensitization; Radiotherapy}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{BMC Cancer}},
  title        = {{The potential radiosensitization target PFKFB3 is related to response to radiotherapy in SweBCG91RT : a randomized clinical trial with long-term follow-up}},
  url          = {{http://dx.doi.org/10.1186/s12885-025-13703-1}},
  doi          = {{10.1186/s12885-025-13703-1}},
  volume       = {{25}},
  year         = {{2025}},
}