Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel.

Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus. The panel recommended that bisphosphonates should be considered as part of routine clinical practice for the prevention of CTIBL in all patients with a T score of <-2.0 or ≥2 clinical risk factors for fracture. Compelling evidence from a meta-analysis of trial data of >18,000 patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breast cancer mortality in post-menopausal women or those receiving ovarian suppression therapy. Therefore, the panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients.

Primary Therapy of Patients with Early Breast Cancer: Evidence, Controversies, Consensus: Opinions of German Specialists to the 14th St. Gallen International Breast Cancer Conference 2015 (Vienna 2015).

For the first time, this year's St. Gallen International Consensus Conference on the treatment of patients with primary breast cancer, which takes place every two years, was held not in St. Gallen (Switzerland) but - for logistical reasons - in Vienna (Austria) under its usual name. The 2015 St. Gallen International Consensus Conference was the 14th of its kind. As the international panel of the St. Gallen conference consists of experts from different countries, the consensus mirrors an international cross-section of opinions. From a German perspective, it was considered useful to translate the results of the votes of the St. Gallen conference into practical suggestions, particularly in light of the recently updated treatment guideline of the Gynecologic Oncology Group (AGO-Mamma 2015) in Germany. A German group consisting of 14 breast cancer experts, three of whom are members of the international St. Gallen panel, has therefore provided comments on the results of this year's votes at the 2015 St. Gallen Consensus Conference and their impact on clinical care in Germany. The 14th St. Gallen conference once again focused on surgery of the breast and the axilla, radio-oncologic and systemic treatment options for primary breast cancer depending on tumor biology, and the clinical use of multigene assays. The conference also considered targeted therapies for older and for younger patients, including the diagnosis/treatment of breast cancer during and after pregnancy and the preservation of fertility.

Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.

BACKGROUND: Osteonecrosis of the jaw (ONJ) has been reported in patients receiving bisphosphonates for metastatic bone disease. ONJ incidence, risk factors, and outcomes were evaluated in a combined analysis of three phase III trials in patients with metastatic bone disease receiving antiresorptive therapies. PATIENTS AND METHODS: Patients with bone metastases secondary to solid tumors or myeloma were randomly assigned to receive either s.c. denosumab (120 mg) or i.v. zoledronic acid (4 mg) every 4 weeks. On-study oral examinations were conducted by investigators at baseline and every 6 months. Oral adverse events were adjudicated by an independent blinded committee of dental experts. RESULTS: Of 5723 patients enrolled, 89 (1.6%) patients were determined to have ONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab (P = 0.13). Tooth extraction was reported for 61.8% of patients with ONJ. ONJ treatment was conservative in >95% of patients. As of October 2010, ONJ resolved in 36.0% of patients (29.7% for zoledronic acid and 40.4% for denosumab). CONCLUSIONS: In this combined analysis of three prospective trials, ONJ was infrequent, management was mostly conservative, and healing occurred in over one-third of the patients. Educating physicians about oral health before and during bone-targeted therapy may help reduce ONJ incidence and improve outcomes.

Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up.

BACKGROUND: Adding oral clodronate to postoperative adjuvant breast cancer therapy significantly improves disease-free survival (DFS) and overall survival (OS). Long-term follow-up data from the prospective, randomized, controlled study are reported. PATIENTS AND METHODS: Patients with primary breast cancer received clodronate 1600 mg/day for 2 years or no treatment along with standard adjuvant breast cancer treatment. RESULTS: Analysis of 290 of 302 patients demonstrated that a significant improvement in OS was maintained in the clodronate group at a median follow-up of 103 +/- 12 months; 20.4% of patients in the clodronate group versus 40.7% of control group patients (P = 0.04) died during the 8.5 years following primary surgical therapy. Significant reductions in the incidence of bony and visceral metastases and improvement in duration of DFS at 36- and 55-month follow-up periods were no longer seen with clodronate. CONCLUSION: These long-term survival data extend the survival advantage reported in previous studies with oral clodronate in breast cancer.

[Bisphosphonates in oncology]. / Einsatz der Bisphosphonate in der Onkologie.

Since bone metastases occur as a result of hematogenous spreading of tumor cells, therapy with curative intent is no longer feasible and palliative options for treating and preventing skeletal events are essential. Today, bisphosphonates are established in the systemic treatment of bone metastases. This report provides an overview of molecular mechanisms of action and clinical data of bisphosphonates in patients with skeletal metastases of breast and prostate cancer as the most common solid tumors which spread to the bone.

Intravenous ibandronate does not affect time to renal function deterioration in patients with skeletal metastases from breast cancer: phase III trial results.

As patients with metastatic bone disease typically receive long-term treatment with bisphosphonates, and often antineoplastic compounds, drug-related safety is of considerable importance. Clinical trial data for intravenous (i.v.) ibandronate suggest that its nephrotoxic potential is comparable with placebo. We conducted a post hoc Kaplan-Meier analysis of time to serum creatinine increase with i.v. ibandronate throughout 2 years of treatment. After 96 weeks, 12% of patients in the placebo group and 6% in the ibandronate 6 mg group (ns, P = 0.22) had defined serum creatinine increases. After 12 treatment months (48 weeks), 4% of patients receiving placebo and 2% of patients receiving ibandronate 6 mg showed increased serum creatinine. These results suggest that there is no clinically relevant change in serum creatinine levels with i.v. ibandronate 6 mg infused every 3-4 weeks for 2 years. Comparative trials to examine the renal safety of ibandronate and other i.v. bisphosphonates are warranted.

Micrometastatic bone marrow cells at diagnosis have no impact on survival of primary breast cancer patients with extensive axillary lymph node involvement treated with stem cell-supported high-dose chemotherapy.

BACKGROUND: To determine the impact of micrometastatic bone marrow cells (MMC) on survival in high-risk primary breast cancer (HRPBC) patients treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Ninety-one HRPBC patients (73 patients with > or =10 involved axillary lymph nodes (ALN), 18 premenopausal women with > or =4 involved ALN) received one cycle (eight patients) or two cycles of HDCT and ASCT. Bone marrow aspiration was performed before systemic treatment to search for MMC using a cocktail of four monoclonal epithelial-specific antibodies (5D3, HEA125, BM7 and BM8). The influence of MMC and other prognostic factors on disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) was analysed. RESULTS: In 23 of 91 patients (25%) we detected a median of three MMC (range, 1-43) among 10(6) mononuclear cells. With a median follow-up of 62 months (range, 10-117), the detection of MMC was not associated with DFS (P=0.929), DDFS (P=0.664) or OS (P=0.642). In multivariate analysis the strongest predictor was nodal ratio for DFS (P=0.012) and expression of p53 for OS (P <0.001). CONCLUSION: The detection of MMC at diagnosis has no impact on survival in HRPBC patients treated with HDCT and ASCT.

Rapid administration of ibandronate does not affect renal functioning: evidence from clinical studies in metastatic bone disease and hypercalcaemia of malignancy.

Ibandronate is a third-generation aminobisphosphonate that has an excellent safety record in hypercalcaemia of malignancy, and has recently been approved for the prevention of skeletal events from metastatic breast cancer. This paper reviews the safety data from clinical studies of intravenous ibandronate by infusion or injection, focusing on renal adverse events (AEs). In clinical trials of patients with hypercalcaemia of malignancy, 2-h infusions of ibandronate at doses of up to 6 mg had a low potential for renal events. In a phase III trial of patients with metastatic bone disease from breast cancer, 6 mg ibandronate infused over 1-2 h had a renal safety profile comparable to that of placebo. In pilot studies, repeated daily infusions of ibandronate (4 mg infused over 2 h for four consecutive days, or 6 mg infused over 1 h for three consecutive days) for severe metastatic bone pain were not associated with any renal AEs. The safety of single 15-min infusions of 6 mg ibandronate has been demonstrated in healthy volunteers and patients with metastatic bone disease from breast cancer or multiple myeloma. Furthermore, single and rapid bolus injections of 2 or 3 mg ibandronate did not increase the risk of renal dysfunction in patients with skeletal metastases. Implications for the renal safety of ibandronate in the management of patients with metastatic bone disease are discussed.

Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer.

Bone metastases occur in most women with advanced breast cancer and can lead to considerable morbidity and a rapid deterioration in the patient's quality of life. It was the aim of the present study to assess changes in quality of life and bone pain due to intravenous (i.v.) ibandronate, a potent third-generation bisphosphonate. In a phase III randomised, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomised to receive placebo, 2 mg ibandronate or 6 mg ibandronate for up to 96 weeks. Treatment was administered i.v. at 3- or 4-weekly intervals. Clinical endpoints included the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale - Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0=none to 4=intolerable). Ibandronate was generally well tolerated. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (-0.28+/-1.11, P < 0.001). A significant improvement in quality of life was demonstrated for patients treated with ibandronate (P < 0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (P = 0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (P < 0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. I.v. ibandronate treatment leads to significant improvements in quality of life, and is an effective and well-tolerated palliative treatment in patients with bone metastases due to breast cancer.

Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies.

Although intravenous (i.v.) bisphosphonates are the standard of care for metastatic bone disease, they are less than ideal for many patients due to infusion-related adverse events (AEs), an increased risk of renal toxicity and the inconvenience of regular hospital visits. The use of oral bisphosphonate therapy is limited by concerns over efficacy and gastrointestinal (GI) side effects. There remains a clinical need for an oral bisphosphonate that offers equivalent efficacy to i.v. bisphosphonates, good tolerability and dosing convenience. Oral ibandronate, a highly potent, third-generation aminobisphosphonate, has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer. In two pooled phase III studies, patients with breast cancer and bone metastases were randomised to receive oral ibandronate 50 mg (n=287) or placebo (n=277) once daily for up to 96 weeks. The primary end point was the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new skeletal complications. Multivariate Poisson's regression analysis was used to assess the relative risk of skeletal-related events in each treatment group during the study period. Oral ibandronate 50 mg significantly reduced the mean SMPR compared with placebo (0.95 vs 1.18, P=0.004). There was a significant reduction in the mean number of events requiring radiotherapy (0.73 vs 0.98, P<0.001) and events requiring surgery (0.47 vs 0.53, P=0.037). Poisson's regression analysis confirmed that oral ibandronate significantly reduced the risk of a skeletal event compared with placebo (hazard ratio 0.62, 95% CI=0.48, 0.79; P=0.0001). The incidence of mild treatment-related upper GI AEs was slightly higher in the oral ibandronate 50 mg group compared with placebo, but very few serious drug-related AEs were reported. Oral ibandronate 50 mg is an effective, well-tolerated and convenient treatment for the prevention of skeletal complications of metastatic bone disease.

Concentration of insulin-like growth factor (IGF)-I in iliac crest bone matrix in premenopausal women with idiopathic osteoporosis.

Previous studies have shown a link between low serum insulin-like growth factor-I (IGF-I) and decreased bone mass of patients with osteoporosis. However, whether serum levels are representative for the growth factor concentration or activity available in human bone tissue is controversial. In the present study, IGF-I was assessed in serum and bone matrix extracts from the iliac crest in 19 eugonadal women with idiopathic osteoporosis and in 38 age-matched controls. In addition, the relationship between the skeletal levels of IGF-I and bone mineral density (BMD) or the susceptibility to osteoporotic fractures in women with osteoporosis was examined. Bone matrix extraction was performed based on a guanidine-HCL/ethylendiamine-tetraacetic acid (EDTA) method. No significant difference in both serum and bone matrix IGF-I levels between groups was observed. Serum IGF-I concentrations failed to be associated with bone matrix IGF-I levels in osteoporotic patients. However, in premenopausal women with idiopathic osteoporosis, skeletal IGF-I positively correlated with BMD at the lumbar spine (r = + 0.58, p = 0.01). In contrast, neither femoral neck BMD nor Ward's triangle BMD was associated with bone matrix IGF-I concentrations. A tendency towards lower levels of bone matrix IGF-I in subjects with vertebral fractures as compared to those without fractures was observed in age-adjusted analyses, however the difference failed to remain statistically significant after adjustment for bone mineral density. These data provide no clear evidence for low bone matrix IGF-I as a determinant factor of age-unrelated osteoporosis. However, low skeletal IGF-I concentrations may aggravate osteoporosis in these women.

Influence of fluor salts, hormone replacement therapy and calcitonin on the concentration of insulin-like growth factor (IGF)-I, IGF-II and transforming growth factor-beta 1 in human iliac crest bone matrix from patients with primary osteoporosis.

OBJECTIVE: Data from cell culture experiments suggest that local growth factors (GFs) may mediate the effects of estrogens, calcitonin or fluor ions on the skeleton. To assess the in vivo relevance of the in vitro reports, the effect of fluor salts, hormone replacement therapy (HRT) and calcitonin on the concentrations of IGF-I, IGF-II and transforming growth factor (TGF)-beta 1 in bone matrix extracts from osteoporotic patients was evaluated. DESIGN: Iliac crest bone biopsies were obtained from 170 patients (76 men and 94 women) with primary osteoporosis aged 55.5+/-0.8 Years. METHODS: Bone matrix extraction was performed based on a guanidine-HCl/ethylendiamine-tetra-acetic acid method. RESULTS: In comparison with age- and body mass index (BMI)-matched controls, no influence of long-term therapy with fluor ions (n=41) or calcitonin (n=16) on the bone matrix concentration of GFs was noticed. Postmenopausal women with osteoporosis on HRT (n=39) had lower skeletal IGF-I but not IGF-II levels as compared with age- and BMI-matched non-users. However, the lower rate of bone turnover in women with HRT may account for this difference, since the significance was lost after adjustment for alkaline phosphatase. Likewise, a tendency for lower TGF-beta 1 levels was observed in HRT users as compared with non-users but was lost after adjustment for bone turnover. None of the therapies influenced the serum levels of GFs when patients receiving continuous therapy for at least 1 Year before bone biopsy were considered. CONCLUSIONS: Our data suggest no direct effect of fluor therapy on skeletal GFs levels. At the concentrations used, neither HRT nor calcitonin appeared to exert any significant influence on serum or bone matrix GF levels.

Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.

BACKGROUND: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer. PATIENTS AND METHODS: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated. CONCLUSIONS: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.

Long-term variability of bone turnover markers in patients with non-metastatic breast cancer.

Variability of bone marker measurements is a major problem in their clinical application. Most studies on marker variability have been performed in healthy subjects and over relatively short intervals of time. We prospectively evaluated the long-term variability of bone markers in 102 postmenopausal women diagnosed with primary breast cancer. During follow up (8-48, median 30 mo.), no patient developed bone metastases or other skeletal disease. Patients were seen every 3 months and exactly timed blood/urine specimens were obtained. All analyses were performed after study end by the same technician, using a single batch of reagents per analyte. The coefficient of variation was calculated as CV (%) = square root(sigma(CVi2)/n) (CVi = SD/mean x 100; n = n of CVi). The least significant change (LSC) was then LSC (%) = Z x CV x square root(2). Z = 1.96 for a 95% confidence interval (LSC-95). In a subset of n = 10 patients with no potential interference during follow-up, lowest CVs were recorded for serum (s) calcium (5%), sTAP (12%) and sBAP (14%). The LSC-95 for these markers were 14%, 33% and 39%, respectively. Highest CVs were seen with urine (56%) and serum (42%) CTX (LSC-95: 155%, 117% resp.). We conclude that in breast cancer patients without bone metastases, long-term variability varied greatly between markers. For certain markers, the LSC seems considerably higher than previously reported.

Markers of bone turnover do not predict bone metastases in breast cancer.

Markers of bone turnover are often elevated in patients with prevalent bone metastases (BM). To test whether bone markers may be used as early indicators of developing BM, we prospectively studied 113 women with primary breast cancer. At the time of study inclusion, none of the women had BM, skeletal disease or was on bone active drugs. During follow-up (8-52, median 30 mo.), pt. were seen every 3 mo. and blood/urine specimens were obtained. Eleven patients developed BM (BM+) and each of them was matched to 4 women remaining free of BM (BM-). Markers were serum (s) calcium, sTAP, sBAP, sOC, sPICP, sNTX, sCTX and urinary (u) PYD, uDPD, uNTX, uCTX. All analyses were done in single batches after study end. At any given point in time, marker levels in the BM+ group did not differ from those in the BM- group. Levels at baseline did not predict later BM (OR 0.14-1.01, all ns). 93% of all changes in bone markers were below the least significant change, as defined in an independent group of similar patients. The remaining 7% of values could not be associated in a consistent pattern with the occurrence of BM. We conclude that in patients with primary breast cancer, biochemical markers of bone turnover can not be used to predict or diagnose incident BM. This lack in diagnostic validity is mainly attributable to the high overall and long-term variability of the currently used bone markers.

Expression of Interleukin-6 (IL-6) and IL-6 receptor mRNA in human bone samples from pre- and postmenopausal women.

Interleukin-6 (IL-6) has been attributed to induction of osteoclastogenic-precursor cell proliferation and maturation. Estrogens suppress IL-6 production in stromal/osteoblastic cells in vitro. Conversely, estrogen withdrawal is associated with increased IL-6 production. IL-6 is therefore thought to be an important mediator of the increased bone resorption after menopause. However, evidence supporting a rise in the expression of IL-6 or the IL-6 receptor in human bone tissue with menopause is still lacking. To address this question, we established a 5'-nuclease assay to quantitate the expression of human IL-6 and the gp80 subunit of the IL-6 receptor in human bone samples. The number of mRNA copies was normalized to the number of copies of beta actin mRNA. Osteocalcin expression served as an independent control. The study population consisted of 169 women (mean age 52.4 +/- 11.6 years) who underwent surgery for early breast cancer. Serum IL-6 was measured by enzyme-linked immunosorbent assay, serum crosslaps as a marker of bone resorption were measured by electrochemiluminescent assay, and serum osteocalcin was measured by chemoluminescence assays. RNA expression of osteocalcin in bone tissue from early postmenopausal women was higher compared with premenopausal women. Local expression was positively associated with circulating osteocalcin and crosslaps concentrations. Postmenopausal women also had higher circulating IL-6 concentrations. In contrast, bone samples from postmenopausal women lacked an increased expression of either IL-6 or gp80 compared with bone samples from premenopausal women. In conclusion, we failed to detect local increases in IL-6 or IL-6 receptor expression in human bone tissue with menopause. If direct changes in the IL-6 system in bone tissue are involved in postmenopausal bone loss, these changes appear to be below the detection limit of our assay system.