Bone metastases in breast carcinoma are common. So-called bone-modifying agents (bisphosphonates, denosumab) are combined with system therapy. They significantly reduce “skeletal-related events.”
Why the bone in particular? During progression of breast carcinoma, tumor cells disseminate from the primary tumor and usually become dormant in different regions (so-called “dormant cells”). Genetic and epigenetic phenomena are held responsible for their growth into macrometastases. There is a special tropism for the so-called “microenvironment” of the bone. Cancer cells then destroy the physiological balance between bone resorption and formation. This results in mixed osseous lesions, mainly lytic in breast carcinoma [1].
Bone metastases in breast carcinoma are common: autopsy studies show that in the case of metastasis, the bones are affected in almost 80%. A study in adjuvant patients with breast carcinoma (stage I-III) showed that a mean of 12% developed bone metastases over an observation period of 60 months. Of the patients with already metastatic disease at study entry, 58% (median) suffered from bone metastases [2]. These figures highlight the frequency and associated suffering caused by bone metastases in breast cancer. Breast cancer is the most common cancer in women worldwide. Due to demographic trends, a significant increase in breast cancer patients is expected in the coming years. Already today, one in three breast cancer patients is over the age of 70.
Forecast
Patients with osseous-only metastasis live an average of 24-55 months [3]. Not infrequently, then, years of survival are possible, during which careful management contributes to a good quality of life for a long time. In the clinic, we often accompany patients for many years. Favorable courses are seen primarily in women with oligo-metastatic extension versus multiple osseous lesions. The time after primary treatment until the appearance of a solitary metastasis is longer than in multitoper metastasis. In solitary bone lesions, even complete remissions are occasionally observed [4].
The spine, ribs, pelvis and long tubular bones are most commonly affected. The majority of patients who develop bone metastases as the first site of metastasis experience bone-associated complications such as pain or hypercalcemia and so-called “skeletal-related events” (SRE) [5]. The latter include pathologic fractures, spinal compression, need for radiotherapy and/or surgery. SREs are associated with significantly increased morbidity and have a critical impact on overall survival-about seven more months in the presence of SREs [6]. Quality of life is sensitively affected by pain, reduced mobility, and limited social life (overview 1).
Diagnostics
Localized, new-onset skeletal symptoms in women with known breast carcinoma should be rapidly evaluated by imaging (usually computed tomography, or MRI if there is evidence of spinal pathology) (Figs. 1 and 2).
Therapy
Patients with symptomatic osseous metastasis benefit on the one hand from effective systemic therapy, which can often control extensive metastases. Especially in Her2-positive tumors, very effective and well-tolerated drug combinations (chemo-/immunotherapies) exist in the metastatic situation, which act rapidly and effectively. On the other hand, targeted local radiotherapies can provide excellent pain management.
If a bone is already fractured or at risk of fracture, orthopedic intervention for stabilization should be evaluated. As a rule, the region is still irradiated postoperatively. This should be assessed on an interdisciplinary basis in each case, as radiotherapy can occasionally delay the onset of effective chemotherapy.
Neurological deficits due to spinal constriction are considered emergencies, and rapid action is required for decompression. Imaging with MRI “long spine” should be performed with a view to immediate neurosurgical decompression. If surgical intervention is not feasible, emergency radiotherapy is the treatment of choice.
Use of bone-modifying agents (BMA)
Bisphosphonates are structurally analogues of endogenous pyrophosphates, and several are approved for this indication (zoledronate, ibandronate, clodronate). They have been at our disposal for almost 20 years. They effectively reduce complications from bone metastases (pain, hypercalcemia) with good tolerability.
Denosumab (Xgeva® 120 mg s/c monthly) is a monoclonal antibody that binds to RANKL (“receptor activator of nuclear factor κB ligand”), thereby inhibiting osteoclast activity and reducing further cancer-mediated destruction. A large phase III trial demonstrated an improvement in skeletal-related events compared with zoledronate [7]. The side effect profile is also favorable (very low nephrotoxicity, hardly any acute phase reaction after application, rare occurrence of osteonecrosis of the jaw, subcutaneous administration). Because of the frequent occurrence of hypocalcemia, supplementation of calcium and vitamin D3 is recommended with denosumab.
How long should BMA be used?
Pressing for all clinicians is the question of the duration of treatment, as well as the interval of application. It is known that the risk of osteonecrosis of the jaw increases with longer duration of use. At least of zoledronate (4 mg over 15 minutes i.v.), there are data that the three-monthly interval shows no worse efficacy compared with the monthly interval in terms of reduction of SRE, this with a clear difference in cost. In an analysis that was not pharma-supported, drug costs, application, and SRE were examined. Costs by denosumab vs. three-monthly zoledronate were increased ninefold, and the so-called “quality-adjusted life-years” were virtually identical [8,9]. Currently, the extended interval is also being investigated for denosumab as part of a study by SAKK (Swiss Working Group for Clinical Cancer Research) together with other countries. What is remarkable about this study protocol is that it was not sponsored by the pharmaceutical industry, but co-financed by the health insurance funds.
A summary of the treatment of bone metastases is shown at 2.
Take-Home Messages
- Patients with breast cancer and bone metastases often have a life expectancy of several years, with a good quality of life.
- Effective tumor therapy is critical and is considered to prevent complications (pain, fractures, etc.). Surgery and radiotherapy are other pillars of therapy.
- So-called bone-modifying agents (bisphosphonates, denosumab) are combined with system therapy and reduce skeletal-related events.
- significant.
- De-escalation (zoledronate three-monthly instead of monthly) should be considered; data on prolonged interval with denosumab follow (SAKK study 96/12).
Literature:
- Kang Y: New tricks against an old foe: molecular dissection of metastasis tissue tropism in breast cancer. Breast Dis 2006-2007; 26: 129-138.
- Body JJ, et al: Systematic review and meta-analysis on the proportion of patients with breast cancer who develop bone metastases. Reviews in Oncology/Hematology 2017; 115: 67-80.
- Ahn SG, et al: Prognostic factors for patients with bone-only metastasis in breast cancer. Yonsei Med J 2013; 54: 1168-1177.
- Koizumi M, et al: Comparison between solitary and multiple skeletal metastatic lesions of breast cancer patients. Ann Oncol 2003; 14: 1234-1240.
- Coleman RE: Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006; 12: 6243s-6249s.
- Yong M, et al: Survival in breast cancer patients with bone metastases and skeletal-related events: a population-based cohort study in Denmark (1999-2007). Breast Cancer Res Treat 2011; 129: 495-503.
- Stopeck AT, et al: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. JCO 2010; 28: 5132-5139.
- Himelstein AL, et al: A randomized phase III study of standard dosing vs. longer interval dosing of zoledronic acid in metastatic cancer CALGB 70604 (Alliance). JCO 2015; 33(15 suppl): 9501.
- Shapiro CL, et al: Cost-effectiveness analysis of monthly zoledronic acid, zoledronic acid every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases: CALGB 70604 (Alliance). JCO 2017; 35: 3949-3955.
InFo ONCOLOGY & HEMATOLOGY 2018; 6(5): 5-7.
