Breast cancer bone metastasis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-In-Chief: Jack Khouri, B.S.

Overview

Bone is the most common site of breast cancer distant spread. Bone metastases due to breast cancer cause major morbidity, decrease survival and reduce quality of life of many patients. Cancer influence on the skeleton results in two main negative consequences: pain and Skeletal-Related events (SREs), defined as any of the following:

• pathologic fracture,
• a requirement for surgical intervention and palliative radiotherapy to bone lesions,
• spinal cord compression,
• hypercalcemia of malignancy .

In fact, SREs constitute readily measured clinical parameters that are employed in clinical trials.

Many disciplines should be involved in the management of breast cancer bone metastases, including medical oncology, pain and palliative care, radiation oncology and orthopedic surgery. Systemic therapy is implemented in order to delay the progression of bone metastases and may include endocrine therapy, biologic agents, chemotherapy, bisphosphonate therapy and the new osteoclast inhibitors.

Pathogenesis

The normal balance between bone resorption and deposition is significantly affected by cancer. Bone metastases due to breast cancer are mostly osteolytic lesions, though a considerable number of patients have predominant osteoblastic disease . The breast cancer cells and the bone microenvironment interact extensively through many chemical mediators (pimarily Osteopontin, and Interleukin-11) resulting in bone destruction and tumor growth. These molecular mediators encompass exert their effect on the osteoclasts which in turn cause bone resorption. This osteoclast-mediated bone resorption is thought to be triggered by many molecules including: PTHrP (Parathyroid Hormone–related Peptide), Tumor Necrosis Factor α (TNF-α), and cytokines such as Interleukin-1, Interleukin-6, Interleukin-8, and interleukin-11. These facors signal osteoblasts (the bone-building cells) to induce osteoclast differentiation through the RANKL (the ligand for the receptor activator of nuclearfactor-κB [RANK])- RANK interaction. When Osteoclasts lyse bone, they cause the release of growth factors such as bone morphogenetic proteins (BMPs), IGF-I and TGF-β from the bone matrix which stimulate and maintain tumor cell proliferation and induce further release of PTHrP . A thorough knowledge of the molecular basis of bone metastasis caused by breast cancer is essential for the understanding of the therapeutic approach.

Systemic Therapy

Bisphosphonates

Bisphosphonates are a mainstay standard of care for patients with bone metastases. They are potent inhibitors of osteoclast-mediated bone resorption through multiple mechanisms, including downregulation of osteoclast activity, promotion of osteoclast apoptosis and inhibition of osteoclast maturation and differentiation . Furthermore, they may trigger the apoptosis of cancer cells, inhibit matrix metalloproteinase 1 ( an enzyme that degrades extracellular matrix proteins), reduce angiogenesis ( and decreasing vascular endothelial growth factor (VEGF) levels)and break the adhesion of tumour cells to bone .