Bone Loss and Bone Metastases in Breast Cancer
The 30th annual San Antonio Breast Cancer Symposium saw a number of bone-related studies presented. Important studies addressed the management of bone complications among women receiving adjuvant endocrine therapy, with a particular focus on women receiving an aromatase inhibitor. Studies also addressed bone loss among women receiving adjuvant chemotherapy, and the management of metastatic bone disease.
A study conducted by the Austrian Breast Cancer Study Group mirrors the ATAC trial, but was conducted in premenopausal women receiving endocrine therapy with the LHRH agonist, goserelin (3.6 mg every 28 days subcutaneously).1 In addition to goserelin, study participants were randomized to receive either tamoxifen (20 mg/d orally) or anastrozole (1 mg/d orally), and further randomized to receive or not receive zoledronic acid (4 mg intravenously every 6 months). The study involved a 3-year treatment period.
None of the patients accrued to this trial received adjuvant chemotherapy. The median age was 44.6 years; 75% had tumors measuring <2 cm and 60% had lymph node-negative disease. Results have previously been published in the Journal of Clinical Oncology.2
Of 1,801 patients in the trial, 404 were prospectively included in a bone mineral density (BMD) substudy and underwent serial BMD measurements at 0, 6, 12, 24, 36, and 60 months using standardized quality-controlled DEXA scans. 201 patients received adjuvant zoledronic acid together with their endocrine treatment, whereas 203 patients did not.
The results presented at SABCS represent the 5-year update. Reported BMD changes are all for the lumbar spine. After 3 years of treatment, patients who did not receive zoledronic acid showed a BMD loss of 11.3% as compared to baseline (p<0.0001). Treatment-induced bone loss was more pronounced if anastrozole was used in combination with goserelin as compared to tamoxifen (-13.6% vs. -9%). At 60 months of follow-up (i.e. two years after the completion of treatment) patients not receiving zoledronic acid still showed decreased BMD as compared to baseline (-6.8%, p=0.0005). In contrast, patients who received zoledronic acid showed unchanged BMD at 36 months (+.3%, p=0.85) and increased BMD at 60 months (+3.9%, p=0.02). Adjuvant endocrine therapy using goserelin plus either tamoxifen or anastrozole for three years in premenopausal women with endocrine-responsive breast cancer caused significant treatment-induced bone loss. Although there is some recovery after completion of treatment, patients still showed compromised BMD after 5 years, particularly those who received goserelin plus anastrozole. Zoledronic acid 4 mg every 6 months for three years completely inhibited treatment-induced bone loss, and led to improved BMD at 5 years. The investigators stated there was no difference between the group that received zoledronic acid versus the group that did not in terms of the period of recovery from amenorrhea after stopping goserelin. There was a trend toward improvement in bone mineral density following recovery of ovarian function. Less than 10% of participants received bisphosphonates during the recovery period (last 2 years of study). They estimate that one needs to treat 3 women to prevent osteopenia from occurring in 1.
This was followed by Adam Brufsky reporting on the Z-FAST trial.3 Twelve-month interim results were reported at last year’s SABCS and were also published in the JCO this year (Brufsky A et al., Journal of Clinical Oncology. 2007;25:829-836). The rationale for this trial was the decreased bone mineral density and increased fracture risk observed in patients treated with aromatase inhibitors, as well as the contention that oral bisphosphonates can be poorly tolerated.
The study involved 602 postmenopausal women with Stage I-IIIA, hormone receptor-positive breast cancer. All study participants were receiving adjuvant letrozole. Patients were randomized to receive either “early” or “delayed” zoledronic acid at a dose of 4 mg IV every 6 months. Both letrozole and zoledronic acid are products of Novartis. The “delayed” group crossed over to receiving zoledronic acid if they developed a significant decrease in bone mineral density (defined as a T-score of <-2 at either lumbar spine or total hip, or a fracture).
At 36 months, the upfront zoledronic acid group (n=189) showed a mean increase of 3.72% in lumbar spine BMD while the delayed group (n=188) showed a mean decrease of 2.95%, resulting in an absolute difference of 6.7% (p<0.001). The upfront group showed a mean increase of 1.66% in total hip BMD, while the delayed group showed a mean decrease of 3.51%, resulting in an absolute difference of 5.2% (p<0.001). The overall difference in lumbar spine and total hip BMD between the two groups was 8.2% and 6.7%, respectively, when BMD data in the delayed group was excluded after patients started zoledronic acid. Among patients with baseline T-scores between -1 and -2, 40.4% of upfront patients and 7.6% of the delayed group patients returned to normal T-scores (T score >-1); 13.4% of delayed patients, and 2.1% of those in the upfront group, became severely osteopenic (T <-2). Fifteen percent of patients in the delayed group had a decrease in BMD that required initiation of zoledronic acid therapy by study criteria.
Fractures occurred in 5.6% of patients in the upfront group and in 6.3% of patients in the delayed group. 199 upfront patients and 191 delayed patients had baseline and 36-month spinal X-rays. 0.5% upfront patients and 0.52% delayed pts had a radiological fracture detected at 36 months. The study was not designed to detect a significant difference in the fracture rate between treatment arms, although they were reported nonetheless. For patients developing fractures, mean age was 60, with average duration of post-menopausal period being 10 years.
There was a 6% increase in bone pain seen on the upfront arm. Increases in myalgia and pyrexia were also seen. No osteonecrosis of the jaw was reported, although 2 patients developed renal insufficiency.
By T-score, 5% of patients receiving upfront zoledronic acid developed a T-score of less than -2, compared to 23-24% of those receiving delayed zoledronic acid. For T-scores between -1 and -2, these percentages were 3-4% for ‘upfront,’ versus 15-20% for ‘delayed’ at 36 months.
The authors conclude that administration of zoledronic acid every 6 months for up to 36 months was safe and well tolerated. No serious renal adverse events and no confirmed cases of osteonecrosis of the jaw were reported. Disease recurrence was reported in 9 (3.0%) patients in the upfront group and 14 (4.7%) patients in the delayed group (p=0.24,). This represents 36 month follow-up of the Z-FAST trial and shows that zoledronic acid 4 mg IV every 6 months is effective in preventing bone loss associated with adjuvant letrozole therapy in post-menopausal women with endocrine-responsive early breast cancer.
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It was my privilege to present the first Phase III trial of denosumab in Amgen’s oncology development program for this compound.4 Denosumab is, I believe, the first fully human monoclonal antibody to be approaching market. Mice had their histocompatibility loci swapped out for ones of the human variety prior to being immunized to RANK-ligand. RANK-ligand is where osteoprotegerin (OPG) acts to modulate bone turnover. Denosumab functions similarly to OPG, binding RANK-ligand with high affinity, making it unavailable to bind to RANK. If RANK-ligand does not bind to RANK, pre-fusion osteoclasts do not fuse into multinucleated activated cells, and bone resorption is inhibited.
This study randomized 252 postmenopausal women with osteopenia (not osteoporosis) receiving adjuvant aromatase inhibitor therapy to denosumab versus placebo every six months for 4 treatments. Both study arms received daily calcium and vitamin D. The primary endpoint was bone mineral density at the lumbar spine at 12 months, where there was a 5.5% increase for the denosumab group compared to placebo. This increased to 7.6% at 24 months. Statistically significant increases were seen at the first measurement point, at one month following study drug initiation, as well as all subsequent points, and similar results were seen at the hip, femoral neck, and total skeleton, and also at the distal 1/3 of the radius, a predominantly cortical (as opposed to trabecular) bone site not generally affected by bisphosphonate therapy. Rates of adverse events were similar to what was seen for placebo, with no differences in grades 3, 4 and 5 toxicities. These results support the ongoing clinical trial program of denosumab for the prevention and treatment of bone loss. Additional trials are underway in osteoporosis and in cancer patients with established bone metastases.
Other Studies in Women Treated with Aromatase Inhibitors
A poster discussion session was held on bisphosphonates for bone loss and bone metastases, with discussion led by Alexander (Sandy) Paterson from the Tom Baker Cancer Centre in Calgary. Dr. Paterson chairs NSABP study B-34, their adjuvant clodronate trial. Whereas the Z-FAST trial was conducted in the United States, a companion trial was conducted in the rest of the world, known as ZO-FAST.5 DeBoer, et al., presented a poster on the 24-month results from this trial, with the same design as for Z-FAST. This trial accrued 1065 patients, 730 of which are evaluable for 24-month results. The group receiving upfront zoledronic acid shows a mean increase in lumbar spine BMD of 3.7%, with a decrease of 4.5% in the delayed group at 24 months, or an 8.2% difference (p<0.0001). Slightly fewer patients, 718, had data evaluable for the total hip. For this determination, the upfront zoledronic acid group showed a mean increase of 1.7%, compared to a decrease of 3% for the delayed group, or a difference of 4.7% (p<0.0001). Median duration of letrozole was 31.7 vs. 31.5 months, respectively. The upfront group received a median of 5 doses of zoledronic acid. One hundred of the patients on the delayed arm (16%) had started zoledronic acid by protocol criteria by 24 months. In the upfront group, 21 patients had experienced a breast cancer recurrence, compared to 32 in the delayed arm. Arthralgias were reported in 40.2 vs. 37.2% of patients. Thirty patients experienced non-traumatic fractures, 13 in the upfront group vs. 17 in the delayed group. Two patients in the delayed arm had episodes of renal failure; neither had received zoledronic acid. There were 2 cases of osteonecrosis of the jaw. Among patients with baseline T-scores of between -1 and -2, 34% of patients in the upfront group returned to normal (T-score greater than -1), whereas 15% of those in the delayed group developed T-scores of <-2.
Twelve-month data from the SABRE study (Study of Anastrozole with the Bisphosphonate Risedronate [Actonel]), using an oral bisphosphonate, were reported.6 Primary endpoint was again BMD at the lumbar spine. They also reported on laboratory indicators of bone turnover. All patients received adjuvant anastrozole and took daily calcium and vitamin D. Previous adjuvant chemotherapy was allowed. Patients were stratified by baseline bone density (>-1, between -1 and -2; and <-2). Only patients in the “intermediate” density group were randomized to receive or not receive risedronate at a dose of 35 mg PO weekly. There were 154 patients in this moderate risk group, half of which (n = 77) received risedronate. In this group, there was a small decrement in BMD at both lumbar and total hip sites at 12 months without risedronate compared with a small increase in BMD at both sites with risedronate. Numeric values were not given, but appear (extrapolating from the graph) to be on the order of a difference of 2.3% at the lumbar spine (p<0.0001), and of about 1.3% at the total hip (p=0.002).
With the many studies and concerns regarding this issue, investigators in Germany proposed “Practical Guidance for the Prevention of Aromatase Inhibitor-Associated Bone Loss in Women with Breast Cancer.”7These recommendations gave rise to a considerable number of comments. They performed a systematic literature review and employed an evidence-based medicine approach to identify risk factors and identify appropriate treatments. Their algorithm is based upon T-score and is as follows:
> T score < -2.0:
> Treat: zoledronic acid 4 mg every 6 months, calcium & vitamin D;
> Monitor DEXA scan annuallyT-score > -2.0, no risk factors
> Treat: calcium & vitamin D
> Monitor DEXA scan annuallyAny two of the following: T-score < -1.5, age > 65, BMI < 20, FHx hip fx, PMH frag fx > 50, smoking, oral steroids > 6 months
> Treat: zoledronic acid 4 mg every 6 months, calcium & vitamin D
> Monitor DEXA scan annually
Preservation of Bone Density in Women Receiving Adjuvant Chemotherapy
Results regarding interventions aimed at bone loss in breast cancer patients receiving chemotherapy were somewhat mixed. Dr. Chavez-MacGregor from Washington University reported on a randomized Phase II trial of 120 women with Stage II/III breast cancer to receive or not receive zoledronic acid at a dose of 4 mg IV given every 3 weeks for a year, starting with the first cycle of adjuvant chemotherapy.8 All patients received 6 cycles (4 neoadjuvant, 2 adjuvant) of chemotherapy with epirubicin and docetaxel, including prophylactic dexamethasone and filgrastim. Patients with endocrine-responsive cancers received either an aromatase inhibitor or tamoxifen after chemotherapy. Groups were said to be well-balanced in regards to stage, grade, menopausal status, ER positivity, and baseline BMD. Results, in terms of whether or not BMD increased or decreased at the measured sites, are as shown. Surprisingly, in spite of zoledronic acid being given at a dose higher than what is generally given for metastatic bone disease, 10% of patients experienced a decrement of BMD at the lumbar spine over a 12-month period.
Hershman et al reported on a multi-center trial using 4 mg of zoledronic acid administered every 3 months versus no bisphosphonate.9 One hundred twenty-two premenopausal patients were randomized; 104 completed the 6 month evaluation, 94 the 12-month. In the group who did not receive zoledronic acid, lumbar spine BMD declined by 2.4% at 6 months and by 4.1% at 12 months. Total hip BMD declined by 0.8% at 6 months and 2.6% at 12 months. In the group who did receive zoledronic acid, BMD remained stable over this period.
Metastatic Bone Disease
Allan Lipton, et al., reported on outcome measures for patients with metastatic bone disease treated with zoledronic acid, stratified by changes in urinary N-telopeptide (NTX) levels over a 25-month observation period.10 Patients with elevated levels at baseline, which remained elevated 3 months after beginning zoledronic acid (E-E) had the highest rate of skeletal-related events and death, compared to those who normalized their NTX levels in 3 months (E-N). The lowest cumulative incidence of SREs/death was in patients with normal baseline NTX. Median time to death was 446 days (1.2 years) for the E-E group, compared to >2 years for the other two groups, with patients having normal NTX values at baseline again doing the best.
Results presented at the 2007 SABCS demonstrate that bone complications can be effectively managed among women receiving adjuvant endocrine therapy. Several studies demonstrated the ability of zoledronic acid to preserve bone density in selected groups of women, and a phase III trial of denosumab also produced very promising results. This research is likely to have important implications for postmenopausal women receiving adjuvant treatment with an aromatase inhibitor, and may also benefit other women at risk of treatment-related bone loss.
1 Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al. Bone mineral density (BMD) at 5 years after diagnosis in premenopausal patients with endocrine-responsive breast cancer, after 3 years of adjuvant endocrine treatment with goserelin and tamoxifen or anastrozole or both treatments in combination with zoledronic acid new results from ABCSG-12. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 26.
2 Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2007;25:820-828.
3 Brufsky A, Bosserman L, Caradonna R, et al. The effect of zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: the Z-FAST study 36 month follow-up. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 27
4 Ellis G, Bone HG, Chlebowski R, et al. A phase 3 study of the effect of denosumab therapy on bone mineral density in women receiving aromatase inhibitors for non metastatic breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 47.
5 De Boer R, Eidtmann H, Lluch A, et al. The ZO-FAST trial: zoledronic acid effectively inhibits aromatase inhibitor associated bone loss in postmenopausal women with early stage breast cancer receiving adjuvant letrozole: 24 month BMD results. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 501.
6 Van Poznak D, Hannon RA, Clack G, et al. The SABRE (Study of Anastrozole with the Bisphosphonate RisedronatE) study: 12-month anlaysis. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 502.
7 Hadji P, Appro M, Brufsky A, et al. Practical guidance for the prevention of aromatase inhibitor-associated bone loss in women with breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 504.
8 Aft R, Chavez-MacGregor M, Trinkaus K, Naughton M, Weilbaecher K. Effect of zoledronic acid on bone loss in women undergoing chemotherapy for breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 505.
9 Hershman DL, McMahon D, Crew K, et al. Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early stage breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 506.
10 Lipton A, Cook R, Major P, Smith M, Coleman R, Milton S. Survival in breast cancer patients with bone metastases and reductions in markers of bone resorption during zoledronic acid treatment. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 508.
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