Title: Prognostic and treatment predictive markers for radioresistance and a low-risk profile in breast cancer

Main supervisor: Emma Niméus

Reviewers: Niklas Loman, Oliver Mortusewicz

Abstract

Background

Breast cancer treatment often consists of surgery, radiotherapy, and neo-/adjuvant treatment. To escalate treatment when necessary and minimize when possible, markers predictive of treatment efficacy and prognosis are needed.

Surgical axillary staging is performed even when the risk for lymph node metastasis is low. It has been and still is associated with post-operative morbidity.

DNA repair is important for cancer cells to survive radiotherapy. The proteins WRAP53 and PFKFB3 are both involved in DNA repair and increased in cancer cells. PFKFB3 inhibition is a potential target for radiosensitization.

Research questions

We have two overarching aims, to search for a low-risk profile in very early-stage breast cancer to find patients in which surgical axillary staging and adjuvant treatment safely can be omitted and to study markers of radiotherapy resistance and prognosis in early-stage breast cancer.

Preliminary results

In a study where women with very early-stage breast cancer were omitted surgical axillary staging the isolated axillary recurrences were very few. The breast cancer-specific survival was high, even for patients not receiving adjuvant treatment.

In the randomized clinical trial SweBCG91RT, low levels of WRAP53 RNA were predictive of radioresistance and low levels of WRAP53 protein were prognostic for ipsilateral breast tumor recurrences and breast cancer death.

In the same cohort, we observed that tumors with high levels of PFKFB3 protein and RNA had the largest effect of radiotherapy and that PFKFB3 expression was associated with tumor subtype.

Significance

Our results indicate that axillary surgery can safely be omitted in patients with very early-stage breast cancer. We aim to further evaluate the need of axillary staging and adjuvant therapy in this subgroup of patients by performing modern subtyping of the tumors.

WRAP53 could potentially be used as a marker of radioresistance and worse prognosis in early-stage breast cancer, indicating the need of escalated adjuvant treatment. We aim to evaluate the prognostic significance of WRAP53 in a separate cohort with triple negative breast cancer.

PFKFB3 is not useful as a radioresistance marker in early-stage breast cancer. It can still be a treatment target for radiosensitization, potentially more effective in HER2 positive tumors.

Published studies and manuscripts

Ingvar C, Ahlgren J, Emdin S, Lofgren L, Nordander M, Niméus E, Arnesson LG. Long-term outcome of pT1a-b, cN0 breast cancer without axillary dissection or staging: a prospective observational study of 1543 women. Br J Surg. 2020 Sep;107(10):1299-1306. doi: 10.1002/bjs.11610. Epub 2020 Apr 26. PMID: 32335901.

Egelberg M, De Marchi T, Pekar G, Tran L, Bendahl PO, Tullberg AS, Holmberg E, Karlsson P, Farnebo M, Killander F, Nimeús E. Low levels of WRAP53 predict decreased efficacy of radiotherapy and are prognostic for local recurrence and death from breast cancer: a long-term follow-up of the SweBCG91RT randomized trial. Mol Oncol. 2023 Oct;17(10):2029-2040. doi: 10.1002/1878-0261.13426. Epub 2023 Apr 19. PMID: 36975842; PMCID: PMC10552889.

Egelberg M, De Marchi T, Schultz N, Tran L, Karlsson P, Holmberg E, Pekar G, Killander F, Nimeús E. Characterization of the potential radiosensitization target PFKFB3 in SweBCG91RT: a randomized clinical trial with long-term follow-up. To be submitted / Submitted?