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Published on: April 22, 2019
The potential radiosensitization target PFKFB3 is related to response to radiotherapy in SweBCG91RT: a randomized
Moa Egelberg1,2,3, Tommaso De Marchi4, Niklas Schultz5
1Division of Surgery, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC D13, Lund, 221 83, Sweden. moa.egelberg@med.lu.se.
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).
Insights
High PFKFB3 levels in breast cancer tumors correlate with reduced recurrence after radiotherapy. However, PFKFB3 is not a reliable predictive marker for radiotherapy sensitivity in breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- PFKFB3, a glycolytic enzyme, is elevated in several cancers and shows potential as a radiosensitization target.
- Inhibition of PFKFB3 impairs DNA repair in cancer cells post-irradiation.
- The SweBCG91RT trial investigated PFKFB3 as a marker for adjuvant radiotherapy sensitivity in breast cancer.
Purpose of the Study:
- To evaluate 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) as a clinical marker for breast cancer sensitivity to adjuvant radiotherapy.
- To assess the association between PFKFB3 levels and ipsilateral breast tumor recurrence (IBTR) after radiotherapy.
Main Methods:
- Nuclear protein levels of PFKFB3 were measured using immunohistochemistry in 970 primary breast tumors.
- Whole-cell RNA levels were analyzed via microarray gene expression in 765 tumors.
- Multivariable competing risks regression was used to analyze the effect of radiotherapy on IBTR based on PFKFB3 levels.
Main Results:
- High nuclear protein and RNA levels of PFKFB3 were associated with a greater reduction in IBTR following adjuvant radiotherapy, though without statistical interaction.
- PFKFB3 RNA expression levels varied by breast cancer subtype.
- Elevated PFKFB3 RNA was more prevalent in HER2-positive and Luminal A subtypes compared to Luminal B and triple-negative tumors.
Conclusions:
- While high PFKFB3 expression correlates with improved outcomes after radiotherapy, it is not a reliable predictive marker for treatment sensitivity in breast cancer.
- PFKFB3 expression patterns differ across subtypes, suggesting potential utility in Luminal A and HER2-positive tumors, warranting further investigation.
