With the aim of selecting patients who could benefit from denosumab therapy, scientists from the Spanish National Cancer Research Centre (CNIO) and the Bellvitge Biomedical Research Institute (IDIBELL) analyzed the expression of the RANK protein and its RANKL ligand in more than 2,000 breast tumors, including 777 without hormone receptor expression, from four independent cohorts.

Denosumab is currently used to treat osteoporosis and bone metastases. For more than a decade, its potential therapeutic benefit in the treatment of breast cancer has also been studied. However, due to conflicting clinical data, the survival benefit in breast cancer patients is unclear.

The research team’s results, which are described in a study “RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer” in EMBO Molecular Medicine, show that RANK protein expression is more frequent in tumors without hormone receptors, where it was associated with poor prognosis and poor response to chemotherapy.

Eva González-Suárez, PhD

“Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER) from four independent cohorts,” write the investigators.

“RANK protein expression was more frequent in ER tumors, where it associated with poor outcome and poor response to chemotherapy. In ER breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy.

“Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause.

“Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER tumors after menopause.”

Limited treatment options

Tumors without hormone receptors, where the cancer cells lack estrogen and progesterone receptors, have a worse prognosis and limited treatment options.

“Given the heterogeneity of the group of hormone receptor -negative breast tumors, it is essential to have biomarkers that better distinguish the prognosis of these patients, especially if these markers allow us to choose the most appropriate treatment,” says Eva González-Suárez, PhD, head of the Transformation and Metastasis Group at the CNIO.

“The reliability of the results is high. They suggest that there is a group of patients who could benefit from treatment with denosumab and reactivate the option of starting breast cancer trials by selecting patients.”

The next step would therefore be to “design a clinical trial in patients with hormone-receptor negative tumors expressing the RANK receptor and in pre- and post-menopausal patients,” adds González-Suárez.

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