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Welcome to the first edition of OncoFacts for 2010. As in past years, we will be reporting relevant and breaking issues on a monthly basis. In this issue, I will be highlighting abstracts that were released in December at the 2009 San Antonio Breast Cancer Symposium.

Bone Health

Since the reporting of ABCSG-12, which suggested that the addition of zoledronic acid to hormone therapy in the adjuvant setting could improve DFS, investigators have been looking at other trials or data sets that include the use of bisphosphonates in women. Not only do bisphosphonates have a role in the treatment of bone metastases, and for the bone loss associated with cancer therapies, they may also play a role in prevention of breast cancer.

Prevention:
Chlebowski et al reported on a study where they attempted to associate the use of oral bisphosphonates and the incidence of breast cancer in women on the Women’s Health Initiative (WHI) study. The population of the women in the study was 154,768 women who were excluded for prior breast cancer or SERM use. Because a low bone mineral density is associated with a reduced risk of breast cancer, a hip fracture risk score was used to compensate for the potential bone mineral density difference between patients on versus not on bisphosphonates.

Results:
The reporting was categorized as incidence of an event per 1000 person years. For invasive breast cancer, the incidence was 4.38 versus 3.29 per 1000 person years either being exposed to no bisphosphonates versus using bisphosphonates for a HR of 0.68 and P<.01. There was a higher preponderance of protection from ER-positive breast cancer than ER-negative with the HR being 0.70 for ER-positive and a P-value of .02. The data was adjusted for age, ethnicity, smoking, alcohol use, body mass index (BMI), physical activity, endocrine therapy, calcium and vitamin D levels, Gail model, the 5-year hip fracture risk, and stratified by the WHI trial randomization arm. For the women who developed breast cancer, Surveillance Epidemiology and Ed Results (SEER) stage and tumor grade were similar regardless of whether or not they received bisphosphonate therapy. In situ breast cancer incidence was not affected by bisphosphonate use.

Reference
Chlebowski RT, Chen Z, Cauley JA, et al. Oral bisphosphonate and breast cancer: prospective results from the Women's Health Initiative (WHI). Cancer Res. 2009;69(24 Suppl 3). Abstract 21 and oral presentation at: San Antonio Breast Cancer Symposium; December 9 – 13, 2009. San Antonio, TX.

Treatment of Bone Metastases

The use of either zoledronic acid or pamidronate has been the standard of care as a treatment for women with breast cancer metastatic to the bone in order to reduce skeletal related events. Denosumab is a fully human monoclonal antibody to RANK ligand and there is extensive clinical trial data using this compound in women who have developed a skeletal related event (SRE) on bisphosphonates. This led to the initiation of a large phase III trial comparing denosumab 120 mg subcutaneously every (q) 4 weeks versus zoledronic acid 4 mg intravenously (IV) q 4 weeks in women with advanced breast cancer and bone metastases. Stopeck et al reported on this phase III double-blinded study that randomized 2046 eligible women. The primary endpoint of the study was the time to first on-study SRE as a noninferiority endpoint. Secondary endpoints include time to first on-study SRE for superiority, and time to first and subsequent on-study SRE for superiority.

Results:
Denosumab results compared to zoledronic acid results were superior in most ways except disease progression. Denosumab had a 23% risk reduction for time to first and subsequent SRE (P = .001), a 22% relative reduction of skeletal related morbidity, a 26% risk reduction for time to first radiation to the bone, and a 13% risk reduction for time to moderate or severe pain. Overall adverse events were similar except for pyrexia, bone pain, and renal-related toxicities, all of which were more common in the zoledronic acid arm. Two percent of the patients on denosumab and 1% of the patients on zoledronic acid experienced osteonecrosis of the jaw. Although denosumab is not yet available on the market, the FDA will be reviewing the indications for this drug in both the bone metastases setting as well as therapy for osteoporosis.

Reference
Stopeck A, de Boer R, Fujiwara Y, et al. A comparison of denosumab versus zoledronic acid for the prevention of skeletal-related events in breast cancer patients with bone metastases. Cancer Res. 2009;69(24 Suppl 3). Abstract 22 and oral presentation at: San Antonio Breast Cancer Symposium; December 9 – 13, 2009. San Antonio, TX.

Genomic Profiling

The 21-Gene recurrence score assay has been shown to have both prognostic significance for 10-year distant disease-free status and is predictive for benefit from chemotherapy. Previously, Albain et al had presented the 5-year breast cancer survival estimates from women on the Southwest Oncology Group (SWOG) 8814 trial that randomized postmenopausal women with ER-positive, lymph node-positive breast cancer to tamoxifen alone versus cytoxan, adriamycin, and 5-FU (CAF) chemotherapy followed by tamoxifen. The 5-year presentation showed that the 21-gene recurrence score assay was prognostic for outcome even in the lymph node-positive population, but was also predictive for a lack of benefit of CAF chemotherapy in those women with a low recurrence score.

Albain et al presented an updated 10-year breast cancer survival estimate from this same group of women. For women with a low recurrence score (<18), the 10-year DFS was 60%, compared to 49% for those with an intermediate recurrence score, and 43% for those with a high recurrence score. The 10-year OS numbers were 77%, 68%, and 51%, respectively. Furthermore, a high recurrence score was predictive of strong benefit from CAF chemotherapy in addition to tamoxifen with a 10-year breast cancer-specific survival (BCSS) of 54% for those women on tamoxifen alone, versus 73% for those women receiving CAF followed by tamoxifen. The 10-year BCSS for women with a low recurrence score was 92% for women receiving tamoxifen alone versus 87% for those receiving CAF followed by tamoxifen. It was also noted that the nodal status (1 to 3 positive versus 4 positive) did not affect benefit from anthracyclines in the lower recurrence score groups.

Reference:
Albain KS, Barlow WE, Shak S, et al. Prediction of 10-year chemotherapy benefit and breast cancer-specific survival by the 21-gene recurrence score (RS) assay in node-positive, ER-positive breast cancer - An update of SWOG-8814 (INT0100). Cancer Res. 2009;69(24 Suppl 3). Abstract 112 and poster presentation at: San Antonio Breast Cancer Symposium; December 9 – 13, 2009. San Antonio, TX.