SABCS--San Antonio meeting summaries on bisphosphonates, obesity, Denosumab

[Lani]

Bisphosphonates and beyond: Managing bone density and reducing breast cancer

Bisphosphonates are routinely given to women with postmenopausal breast cancer, but new data suggests that these agents may play a role in reducing recurrent breast cancer as well.
4083. 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 5-Year Final Follow-Up
Zoledronic acid is both safe and effective in preventing bone loss in postmenopausal women with breast cancer who are treated with aromatase inhibitors, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium.
"Women who take aromatase inhibitors need some sort of bone protection, and this five-year data show that zoledronic acid is a viable option," said Adam Brufsky, M.D., Ph.D., associate professor of medicine, associate chief of hematolgy-oncology, and associate director for clinical investigation, University of Pittsburgh Cancer Institute.
Brufsky estimates that between 20,000 to 30,000 women a year will benefit from this therapy and that number is growing. Anastrozole, currently sold as Arimidex by AstraZeneca, is scheduled to go off patent within the next few years.
"Women who are on Medicare tend to go with tamoxifen because the cost of anastrozole puts them squarely in the donut hole of Medicare Part D, but once the cost barrier is removed there will likely be a mass switch to the aromatase inhibitor, which will necessitate the need for bone protection," said Brufsky.
Beyond the aging population, use of zoledronic acid could increase even further if the signs that it prevents breast cancer recurrence continue in larger studies.
Brufsky's study, Z-FAST (Zometa-Femara Adjuvant Synergy Trial), focused on 602 postmenopausal women with stage I to IIIa estrogen or progesterone receptor-positive breast cancer. The researchers randomized patients to immediate zoledronic acid or delayed zoledronic acid. The delayed group received it only if the T-score dropped below two or a clinical fracture occurred.
After five years, patients in the immediate treatment arm had a bone mineral density increase of 6.2 percent in their lumbar spine area, while those in the delayed arm had a decrease of 2.4 percent. In the hip area, the increase was 2.6 percent with immediate treatment compared with a 4.1 percent decrease with delayed treatment.
Fractures occurred in 10.7 percent of the patients treated immediately and 12.4 percent of the patients who received delayed treatment.
There were no serious renal events and no osteonecrosis of the jaw, which confirmed that the drug was safe and well tolerated.

Oral Bisphosphonate and Breast Cancer: Prospective Results: from the Women's Health Initiative (WHI)
Results: of a new analysis of data from the Women's Health Initiative (WHI) observational study showed that women who used bisphosphonates, which are commonly prescribed bone-strengthening pills, had significantly fewer invasive breast cancers than women who did not use bisphosphonates. These findings were presented at the CRTC-AACR San Antonio Breast Cancer Symposium.
In the 150,000-plus cohort of generally healthy postmenopausal women, the researchers found that women who used bisphosphonates, mostly alendronate, which is sold as Fosamax by Merck, had 32 percent fewer cases of invasive breast cancer compared to women who did not use such drugs.
"The idea that bisphosphonates could reduce breast cancer incidence is very exciting because there are about 30 million prescriptions for these agents written annually in the United States targeting bone health, and more could easily be used to counteract both osteoporosis and breast cancer," said the study's lead investigator, Rowan Chlebowski, M.D., Ph.D., medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center.
The concept arose from findings in a report on an adjuvant breast cancer trial where use of the bisphosphonate zoledronic acid given intravenously every six months resulted in fewer contralateral breast cancers.
"It appeared to make bone less hospitable to breast cancer," Chlebowski said.
However, since bisphosphonates are prescribed for women with low bone mineral density and low bone mineral density has been associated with lower breast cancer incidence, a means to control for potential differences between women prescribed bisphosphonate and those not prescribed bisphosphonate in the cohort was needed.
Given that, Chlebowski and colleagues devised a way to control for use of bisphosphonates in the WHI. About 10,000 of the participants had bone mineral density analysis as part of the study, and for the rest they used a 10-item hip fracture predictive score to measure bone density. The researchers were able to correlate the findings from the women who had bone mineral density tests to findings from the predictive score in order to correct for any potential difference in bone density in women using bisphosphonates compared to non-users. Studying 2,216 WHI participants who were using bisphosphonates when they entered the study, the researchers found that only 64 women developed breast cancer, and most of those cases (50) were estrogen receptor positive. Overall, there was a mean 32 percent fewer breast cancers in women using bisphosphonates compared to women who did not. There were 30 percent fewer estrogen receptor-positive cancers and 34 percent fewer entry receptor-negative cancers in bisphosphonate users. The latter finding was not statistically significant as there were very few receptor-negative cases.
"Bisphosphonates reduce angiogenesis and stimulate immune cells responsible for tumor cell surveillance as potential mediators," Chlebowski said. "This association needs to be studied further.Wwhile we currently have several options for reducing receptor-positive breast cancers, none are available for receptor-negative cancers."
Several ongoing adjuvant breast cancer trials evaluating oral and intravenous bisphosphonate will be available in the near future to provide randomized clinical trial evidence regarding their influence on new contralateral breast cancer risk, Chlebowski said

Use of Bisphosphonates and Risk of Postmenopausal Breast Cancer
The use of bisphosphonates for more than one year was associated with a 29 percent reduction in the risk of postmenopausal breast cancer, according to results presented at the CTRC-AACR San Antonio Breast Cancer Symposium.
Lead researcher Gad Rennert, M.D., Ph.D., chairman of the Department of Community Medicine and Epidemiology at the Carmel Medical Center of Clalit Health Services and a faculty member at the Technion-Israel Institute of Technology in Israel, said these data help shed light on a possible new pathway for breast cancer prevention.
"We have identified a new class of drugs that is associated with a reduced risk of breast cancer, and if proven in randomized trials, we may be able to recommend it to postmenopausal women for this purpose," said Rennert.
Rennert and colleagues extracted data from the Breast Cancer in Northern Israel Study, which is a population-based, case-control study. They evaluated the use of bisphosphonates for at least five years in 4,575 postmenopausal study participants using a structured interview.
The self-reported, long-term use of bisphosphonates prior to diagnosis was associated with a significant reduced relative risk for breast cancer by approximately 34 percent.
This reduction remained significant, at 29 percent, even after adjusting for a large variety of risk factors for breast cancer such as age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body mass index, calcium supplement and hormone replacement therapy use, number of pregnancies, months of breastfeeding and age at first pregnancy.
Moreover, the breast tumors identified among patients who used bisphosphonates were more often estrogen receptor positive and less often poorly differentiated.
"These tumors are the type that are associated with a better prognosis," said Rennert.

A Comparison of Denosumab Versus Zoledronic Acid on the Incidence of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases
Among patients with bone metastasis from breast cancer, denosumab was superior to zoledronic acid in reducing the incidence of complications from bone metastases.
"Denosumab prevented more events, was better tolerated and is more convenient for patients," said Alison Stopeck, M.D., associate professor of medicine at the University of Arizona Cancer Center.
Stopeck and colleagues enrolled 2,048 patients with bone metastasis who had never received treatment with intravenous bisphosphonates. They randomly assigned patients to treatment with subcutaneous denosumab or intravenous zoledronic acid every four weeks.
Denosumab works by inhibiting RANKL, which regulates osteoclast activity and function and has been linked with increased bone loss and complications from bone metastases.
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Randomised Placebo Controlled Trial Studying Short Term Biological Effects of the Combination of Letrozole and Zoledronic Acid on Invasive Breast Cancer
Preoperative combination therapy with letrozole and zoledronic acid is safe and effective, but more research is needed to verify the impact on overall survival or reduced morbidity.
Nigel J. Bundred, M.D., professor in surgical oncology at the University Hospital of South Manchester and the University of Manchester, United Kingdom, and colleagues conducted this study to determine whether the addition of the bisphosphonate zoledronic acid to treatment with letrozole increased cell death or lowered proliferation.
Letrozole is an oral, non-steroidal aromatase inhibitor used for treatment of local or metastatic breast cancer that is hormone receptor-positive. Zoledronic acid, also known as zoledronate, is used to prevent bone fractures in patients with cancers like prostate cancer and multiple myeloma, or for treatment of bone metastases.
Researchers conducted the study in 109 postmenopausal women with early, invasive hormone receptor-positive breast cancer. Patients were randomized and treated for 14 days with placebo, letrozole 2.5 mg per day, or to letrozole with adjuvant use of zoledronic acid 4 mg intravenously two to four days before surgery.
While the addition of zoledronic acid was safe, results showed no other benefits compared with letrozole use alone.
"Letrozole significantly lowered proliferation," said Bundred. "A combination of letrozole and a bisphosphonate, while lowering proliferation, did not do significantly greater than letrozole on its own."

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SABCS 2009: ABSTRACT #4083: 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 5-Year Final Follow-Up

Background: Aromatase inhibitor (AI) therapy effectively increases disease-free survival in postmenopausal women (PMW) with ER+ and/or PR+ breast cancer (BCa). However, the use of AIs results in nearly complete ablation of estrogen production which can lead to accelerated bone loss and increased fracture risk. The Z-FAST study evaluated the efficacy and safety of zoledronic acid (ZOL) in preventing AI associated bone loss in PMW with early breast cancer (EBC) who received adjuvant letrozole (LET).
Material and Methods: 602 PMW with stage I-IIIa ER+ and/or PR+ BCa starting LET (2.5 mg qd x 5 yrs) were randomized (1:1) to upfront ZOL (4 mg IV q 6 mos) vs delayed ZOL. The delayed arm (D) received ZOL when either the post-baseline T-score decreased to <-2 or a clinical fracture occurred. All patients (pts) were treated with calcium and vitamin D. The primary endpoint, the percent change in lumbar spine (LS) bone mineral density (BMD) at 12 mos, was previously reported (JCO; 25:829, 2007). The 5 year (5y) final study results are reported here.
Discussion: Baseline characteristics were similar between groups. 180 pts in upfront ZOL arm (U) and 175 pts in D completed full 5y study. Of pts with BMD data available, U (n=140) showed a mean increase of 6.2% in LS BMD while D (n=132) showed a mean decrease of 2.4%, resulting in an absolute difference of 8.6% (p<0.001). U (n=141) showed a mean increase of 2.6% in total hip (TH) BMD while D (n=132) showed a mean decrease of 4.1%, resulting in an absolute difference of 6.7% (p<0.001). When BMD data in D was excluded after pts started ZOL (censored analysis), the absolute difference in LS and TH BMD between the two arms was 11.3% and 8.7%, respectively. Among pts with baseline LS T-score between -1 and -2, 27.9% (19) U pts [8.6% (7) D pts] returned to normal T-score (T-score >-1), and no U pts as compared to 4.9%(4) D pts became severely osteopenic (T <-2). 17.7% (53) D pts met criteria that required initiation of ZOL. Although the study was not designed to detect a significant difference in the fracture rate between treatment arms, fractures occurred in 10.7% (29) U pts and 12.4% (33) D pts. Administration of ZOL q 6 mos for up to 5y was safe and well tolerated. No serious renal adverse events suspected related to ZOL and no confirmed osteonecrosis of the jaw cases (ONJ) were reported. Disease recurrence including death due to disease progression was reported in 7.0%, 95% C.I. (3.7%-10.3%) from K-M (16) pts in U, and 8.8%, 95% C.I. (5.2%-12.5%) (21) pts in D.
Conclusion: The 5y follow-up of the Z-FAST trial show that the overall difference in the percentage change in BMD between U and D, at both LS and TH, progressively increased from baseline through 5y. These data demonstrate that ZOL 4mg IV q 6 mos is effective in preventing bone loss associated with adjuvant AI therapy in PMW with EBC.

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SABCS 2009: ABSTRACT #21: Oral Bisphosphonate and Breast Cancer: Prospective Results from the Women's Health Initiative (WHI)

Background: Emerging clinical evidence suggest intravenous bisphosphonates may directly inhibit breast cancer (Gnant SABCS 2008) while oral bisphosphonates in US clinical practice have received limited evaluation regarding breast cancer influence.
Methods: To investigate associations between oral bisphosphonates and invasive breast cancer we examined data for 151,592 postmenopausal women enrolled in the WHI. Information was collected on breast cancer risk factors and oral bisphosphonate use. To control for bone mineral density (BMD) we employed a published hip fracture prediction model which did not incorporate BMD (Robbins 2007) against the 10,296 WHI participants who had baseline total hip BMD determination. Breast cancers were centrally adjudicated by pathology report review. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).
Results: Of the 151,592 participants, 2,216 were oral bisphosphonate users at entry (90% alendronate, 10% etidronate). An analysis comparing hip fracture risk score to BMD in those with both found a significant correlation (regression line = .79-.0478 log predicted hip fracture, r=0.43). As a result, the hip fracture risk score was used to control for potential BMD group differences. HRs for invasive breast cancer by bisphosphonate use are outlined below after 7.8 (1.7) mean years (SD).
Conclusion: There was a statistically significant association between oral bisphosphonate use and lower invasive breast cancer incidence with fewer ER positive breast cancers and a non-significant trend for ER negative breast cancers in bisphosphonate users. This result suggests oral bisphosphonates may have direct inhibiting effects on breast cancer.
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SABCS 2009: ABSTRACT #27: Use of Bisphosphonates and Risk of Postmenopausal Breast Cancer

Background: Bisphosphonates are commonly used for the treatment of osteoporosis and for prevention and treatment of skeletal lesions due to malignancy. However the association between the use of bisphosphonates and the risk of developing breast cancer has not been reported.
Methods: The Breast Cancer in Northern Israel Study (BCINIS) is a population-based case-control study in northern Israel of breast cancer cases and age/clinic/ethnic-group matched controls. Use of bisphosphonates for at least 5 years was assessed in 4,575 postmenopausal cases and controls using a structured interview. It was further validated by data from prescription records among participants for whom they were available.
Results: The self-reported long-term use of bisphosphonates prior to diagnosis was associated with a significantly reduced relative risk of breast cancer (Odds Ratio=0.66, 95% CI: 0.47-0.93). This association remained significant in a pharmacy records based analysis after adjustment for age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, BMI, use of calcium supplements, HRT use, number of pregnancies, months of breast feeding and age at first pregnancy (OR=0.71, 0.57-0.90). A significant dose response association between length of use of bisphosphonates and breast cancer risk was found. Breast tumors identified in bisphosphonates users were more often ER positive and less often poorly differentiated.
Conclusions: The use of bisphosphonates for more than 1 year was associated with a 29% relative reduction in the risk of postmenopausal breast cancer. Tumors developing under bisphosphonates treatment tended to have a favorable prognostic factors profile.

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SABCS 2009: ABSTRACT #22: A Comparison of Denosumab Versus Zoledronic Acid for the Prevention of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases

Background: Up to 75% of advanced breast cancer patients develop bone metastases (BM) that induce increased osteoclast activity resulting in local bone destruction. The ensuing skeletal complications, including fractures, may have serious consequences. Denosumab, a fully human monoclonal antibody, inhibits RANKL, a key mediator of osteoclast activity. Denosumab has been shown to increase bone mineral density and reduce fractures in postmenopausal women with low bone mass. Primary results from a recently completed randomized pivotal study demonstrated that denosumab was superior to zoledronic acid (ZA) in delaying and preventing skeletal-related events (SREs) in breast cancer patients with bone metastases. Here, we describe results of other endpoints from the study.
Methods: Patients with breast cancer and BM (N=2046) who had not been treated with intravenous (IV) bisphosphonates were randomized 1:1 to receive either subcutaneous (SC) denosumab 120 mg and IV placebo, or SC placebo and IV ZA 4 mg every 4 weeks. All patients were encouraged to take daily supplemental calcium (≥500 mg) and vitamin D (≥400 IU). The primary endpoint was time to first on-study SRE (predefined as pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). Other endpoints included time to first radiation of bone; time to first on-study SRE or hypercalcemia of malignancy (HCM); skeletal morbidity rate (SMR; the number of SREs per year); and the proportion of patients with at least 1 on-study SRE. SMR was defined as the ratio of the number of SREs, allowing for one event every 21 days, divided by the patient's time at risk.
Results: As previously reported, denosumab was superior to ZA in significantly delaying the time to first on-study SRE (hazard ratio [HR] 0.82; 95% CI: 0.71, 0.95; P<0.0001 noninferiority; P=0.01 superiority) and the time to first and subsequent on-study SRE (rate ratio 0.77; 95%CI: 0.66, 0.89; P=0.001). Denosumab also significantly delayed the time to first radiation to bone (HR 0.74; 95% CI: 0.59, 0.94; P=0.01) and the time to first on-study SRE or HCM (HR 0.82; 95% CI: 0.70, 0.95; P=0.007) compared with ZA. Denosumab reduced the mean SMR compared with ZA (0.45 vs 0.58, respectively; P=0.004). The total number of SREs was 491 events for denosumab and 623 events for ZA. At the primary data analysis cut-off date (study duration: 34 months), the proportion of patients (95% CI) experiencing at least 1 on-study SRE was lower in the denosumab arm (30.7% [27.9%, 33.5%]) than the ZA arm (36.5% [33.5%, 39.4%]). Overall, the incidence of adverse events (AEs) and serious AEs was consistent with what has been previously reported for these two agents. AEs potentially associated with acute phase reactions during the first 3 days of study were reported in 10% of the denosumab arm and 27% of the ZA arm.
Conclusion: Denosumab was more efficacious than ZA in delaying time to first radiation to bone and first on-study SRE or HCM and in reducing skeletal morbidity (SMR) and the proportion of patients with an SRE.

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SABCS 2009: ABSTRACT #2009: Randomised Placebo Controlled Trial Studying Short Term Biological Effects of the Combination of Letrozole and Zoledronic Acid on Invasive Breast Cancer

Background: To determine whether the addition of Zoledronic Acid to endocrine therapy increases apoptosis or decreases proliferation in early invasive breast cancer, a placebo controlled randomised trial comparing 14 days treatment with Letrozole or Letrozole and Zoledronic Acid pre-operatively was performed.
Patients: In total 109 postmenopausal women with early invasive hormone receptor positive breast cancer were randomised (1:1:1) to either placebo, Letrozole 2.5mg/day or Letrozole with Zoledronic Acid 4mg single dose intravenously 2-4 days before definitive surgical excision. Epithelial proliferation and apoptosis were measured on paired baseline and surgical biopsy specimens (after 14 days of treatment) using Ki67 and Activated Caspase 3 immunohistochemistry. Alterations in angiogenic markers (VCAM/VEGF and CD31) were also studied. The primary endpoint was fall in Ki67 between diagnosis and surgical excision.
Results: Overall 109 women were enrolled but paired biopsies were only available for 101 patients. Statistically significant reductions in Ki67 and Cell Turnover Index were seen with Letrozole and Let & Zol (p ≤ 0.001) but there was no significant different between Letrozole and Letrozole plus Zoledronic Acid groups (p = 0.26). Apoptosis did not change between the three groups.
Conclusion: Letrozole reduces proliferation by 70% when used for 14 days prior to surgery. Zoledronic Acid administration prior to surgery is safe but when administered as a single dose at a median of 3 days before surgery did not significantly increase apoptosis or decrease proliferation compared to Letrozole alone.
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Obesity linked with poorer breast cancer outcomes

Breast cancer patients with a high body mass index (BMI) have a poorer cancer prognosis later in life. Specifically, their treatment effect does not last as long and their risk of death increases.
"Overall, women should make an effort to keep their BMI less than 25," said Marianne Ewertz, M.D., professor in the Department of Oncology at Odense University Hospital, Denmark. "Those who have a high BMI should be encouraged to participate in mammography screening programs for prevention efforts."
Ewertz and colleagues examined the influence of obesity on the risk of breast cancer recurrence and mortality in relation to adjuvant treatment. She presented study results at the CTRC-AACR Annual San Antonio Breast Cancer Symposium, held Dec. 9-13.
Using the Danish Breast Cancer Cooperative Group database, they evaluated health information — such as status at diagnosis, tumor size, malignancy grade, number of lymph nodes removed, estrogen receptor status, treatment regimen, etc. — from almost 54,000 women. Ewertz and colleagues were able to calculate BMI for 35 percent of the women, whose information about height and weight was available. A healthy, normal BMI score is between 20 and 25; a score below the normal range indicates underweight and a score above indicates overweight.
After 30 years of follow-up (from 1977 through 2006), the researchers found that women with higher BMIs were older and had more advanced disease at diagnosis compared with those who had a BMI within the normal range. The risk of distant metastases increased the higher the BMI. However, BMI played no role in loco-regional recurrence.
Women with a high BMI had an increased risk of dying from breast cancer, a finding that remained constant over the study period. Further, adjuvant treatment seemed to lose its effect more rapidly in obese patients, according to Ewertz.
"More research is needed into the mechanisms behind the poorer response to adjuvant treatment among obese women with breast cancer," she said.
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SABCS 2009: ABSTRACT #18: Effect of Obesity on Prognosis after Early Breast Cancer

Background: Obesity is associated with an increased risk of dying from breast cancer. There may be several explanations for this such as obese women being diagnosed at a more advanced stage of disease or that treatment is less effective in obese patients. The aim of this study was to examine the influence of obesity on the risk of recurrence and death from breast cancer or other causes in relation to adjuvant treatment.
Material and methods: From the database of the Danish Breast Cancer Co-operative Group (DBCG) we identified 53816 women who received treatment for early breast cancer according to the DBCG protocols between 1977 and 2006 with complete data on follow up. Information was available on age and menopausal status at diagnosis, tumor size, number of lymph nodes removed, number of positive lymph nodes, deep fascia invasion, histological type, grade of malignancy, estrogen receptor status, treatment regimen, and protocol version (year), while data on height and weight to derive the body mass index (BMI, weight in kilograms divided by the square of height in meters) were available for 18967 patients or 35 % of the patients. The chemotherapy regimens included cyclophosfamide, metotrexate, and fluorouracil (CMF) up to 1999 and cyclophosfamide, epirubicin, and fluorouracil (CEF) from 1999 onwards. Endocrine therapy included mainly tamoxifen of durations from one to five years depending on time period. Associations between BMI (<25 vs ≥25,<30 vs ≥30) and other prognostic factors were analyzed by using the chi square test. Cause specific survival and invasive disease-free survival (type of first failure) were analysed by univariate and multivariate methods using Cox proportional hazards regression models.
Results: Compared with patients with a BMI less than 25, those with a higher BMI were older, more often postmenopausal, had larger tumors, more lymph nodes removed and more positive lymph nodes, more often invasion into deep fascia (all p<0.0001), and more often grade III tumors (p=0.04). Univariate analyses showed that the risk of a loco-regional recurrence was not related to BMI while the risk of distant metastases increased with increasing BMI after 3 years of follow up. The risk of dying from breast cancer remained elevated for patients with high BMI throughout 30 years of observation. Adjusting for the effect of other prognostic factors, multivariate analyses confirmed an independent prognostic effect of obesity. Within the first 10 years of follow-up chemotherapy and endocrine treatment were equally effective in lean and obese patients. However, after 10 or more years of follow-up, the treatment effect did not last in obese patients who had a poorer survival despite treatment.
Conclusion: Results: from this population-based cohort of almost 19000 patients followed for up to 30 years confirmed that obesity is associated with a poorer prognosis after breast cancer. This is likely to be due to obese patients having a higher risk of developing distant metastases than lean patients and that adjuvant treatment seems to loose its effect more rapidly in obese patients.