The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.

The role of RANKL-RANK pathway in progesterone-driven mammary carcinogenesis and triple negative breast cancer tumorigenesis has been well characterized. However, and despite evidences of the existence of RANK-positive hormone receptor (HR)positive breast tumors, the implication of RANK expression in HR-positive breast cancers has not been addressed before. Here, we report that RANK pathway affects the expression of cell cycle regulators and decreases sensitivity to fulvestrant of estrogen receptor (ER)-positive (ER+)/HER2-breast cancer cells, MCF-7 and T47D. Moreover, RANK overexpressing cells had a staminal and mesenchymal phenotype, with decreased proliferation rate and decreased susceptibility to chemotherapy, but were more invasive in vivo. In silico analysis of the transcriptome of human breast tumors, confirmed the association between RANK expression and stem cell and mesenchymal markers in ER+HER2-tumors. Importantly, exposure of ER+HER2cells to continuous RANK pathway activation by exogenous RANKL, in vitro and in vivo, induced a negative feedback effect, independent of RANK levels, leading to the downregulation of HR and increased resistance to hormone therapy. These results suggest that ER+HER2-RANK-positive cells may constitute an important reservoir of slow cycling, therapy-resistance cancer cells; and that RANK pathway activation is deleterious in all ER+HER2-breast cancer cells, independently of RANK levels.

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The most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease.

hormone receptor status, HER2 and proliferation via Ki-67. This study compares the mRNA expression analysis of ER, PR, HER2, and Ki-67 in a large clinical trial cohort by an automated in-vitro diagnostic platform and central IHC. Methods: Breast cancer patients from the prospective GBG multicenter trial GeparX (NCT02682693) (still recruiting) were included in this biomarker project. We used formalin-fixed paraffin embedded (FFPE) pretherapeutical core biopsies with a tumor content >10%. A 4mm FFPE tissue section was first processed with the XpertV R FFPE Lysis Kit, the sample lysate was placed in the GeneXpert V R cartridge system in which the purification, amplification and real-time detection of the gene expression of ER, PR, HER2 and Ki-67 took place automatically. Results: Of 503 samples with valid mRNA measurements, 258 samples (51,3%) were ER-positive, 196 (39%) PR-positive, 78 (15,5%) HER-positive and 421 (83.7%) were Ki-67-high (>20%). The simple kappa coefficient was for ER ¼ 0.7938, PR ¼ 0.6540, HER2¼0.8172 and Ki-67¼0.3655. This implies that the ER, PR and HER2 measurements show a high correlation between both methods, whereas the Ki-67 measurement does not. The accuracy between the STRAT4 and IHC was 89.7% for ER, 83.3% for PR, 94.6% for HER2 and 86.7% for Ki-67. Conclusions: Our results show a high concordance between standardized central IHC and automated mRNA expression analysis for the most important BC biomarkers ER, PR and HER2. For the continuous proliferation marker Ki-67, the concordance is slightly lower. The STRAT4 assay might offer an additional option to conventional methods for BC biomarker assessment, in particular in situations where ICH is not feasible. To determine the clinical validity, additional outcome analyses are necessary. Clinical trial identification: GeparX NCT02682693.

Advances in medical and surgical treatment have played a major role in increasing the survival rates of cancer patients with metastatic bone disease. The clinical course of patients with bone metastases is often impaired by bone complications, such as bone fractures, which have a substantial negative impact on clinical outcomes. To optimize clinical results and prevent a detrimental impact on patients’ health, a tailored approach should be defined for any given patient. The optimal management of impending or pathologic fractures is unknown and relies on a multidisciplinary approach to tailor clinical decisions to each individual patient. The ability to control systemic disease, the extent, location and nature of bone metastases, and the biology of the underlying tumor, are the main factors that will define the strategy to follow. The present review covers the most recent data regarding impending and pathologic fractures in patients with bone metastases, and discusses the medical and surgical management of patients presenting with metastatic bone disease in different clinical settings.

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