Trial Information

Pilot Study to Evaluate the Impact of Denosumab on Disseminated Tumor Cells (DTC) in Patients With Early Stage Breast Cancer

The presence of disseminated tumor cells (DTC) in the bone marrow in women with early stage
breast cancer is an important prognostic factor associated with an increase in both
recurrence and disease-associated death. In a pooled analysis of 4703 invasive breast cancer
patients, detection of DTC in the bone marrow was associated with an increase in disease
recurrence, distant metastases, and death from breast cancer over a median follow-up period
of 5.2 years. Subsequent studies have demonstrated that the presence of DTC in the bone
marrow of women with early breast cancer following completion of adjuvant therapy have an
even greater impact on the risk of recurrence and death from breast cancer. Multivariate
analysis demonstrated that the presence of marrow cells was an independent prognostic factor
for reduced breast cancer specific survival with a relative risk of 6.3 (2.3-17.6,
p<0.0001). Clearly, the detection of DTC in women with early stage breast cancer is a marker
for increased risk of relapse and death, and this could serve as a unique indicator to
select higher risk patients for intervention with targeted therapeutics.

It has long been recognized that there is close relationship between bone and immune system,
recent studies also suggests that in addition to monocytes/macrophage, T cells (especially
Th17, a subset of T helper cells that produces IL-17), B cells and dendritic cells all play
an important role in osteoclast formation. RANKL, in addition to its effect on osteoclasts,
also induces local inflammation. Several recent studies have demonstrated that the presence
of tumor associate macrophages (TAM) is associated with more aggressive disease, and a worse
outcome. Preclinical data suggests that TAM plays an important role in promoting metastases
and resistance to therapy. In addition to RANKL, there are other genes secreted by breast
cancer cells, including TGF-β, TNF associated factor 6 (TRAF6), Hypoxia Induced Factor -1
(HIF-1) and Bone morphogenetic protein 2 (BMP2), also involve in bone-cancer "vicious cycle"
and induce RANKL expression. Cytokines, such as IL-4, IL-6, IL-17, TNF-α and CSF-1, also
play an important role in osteolysis and immune response in bone microenvironment by
regulating TAM function (CSF-1, IL-4 and IL-17) and RANKL expression. Recently, CD47 and
Signal Regulatory Protein α (SIRPA) were also shown to impair macrophage function, and
associated with increased risk for recurrence in patients with breast cancer. The
investigators hypothesize that patients with higher DTC may have higher expression of RANKL
and chronic inflammatory cytokines. The investigators plan to evaluate the expression of
RANK, RANKL, TRAF6, BMP2, CSF-1, CD47, IL-17 and SIRPA on isolated DTC and bone marrow
hematopoietic cells, and correlate these results to the outcome of patients enrolled in the
trial.

The investigators hypothesize that treatment with denosumab will decrease the number of DTC
in women with early stage breast cancer who have completed adjuvant or neoadjuvant cytotoxic
therapy possibly by preventing cancer cell migration, and by promoting cancer cell death by
changing the bone into a "hostile" environment .

The investigators propose to conduct a non-randomized phase II trial testing this hypothesis
in women with early stage breast cancer and persistent DTC following adjuvant systemic
therapy. Patients with DTC will receive denosumab monthly for 6 months, then every 3 months
for a total of one-year treatment, to mirror the schedule utilized in the ongoing randomized
phase III denosumab versus placebo D-CARE trial. DTC will be monitored following 6 months
and 12 months of therapy. The investigators anticipate that this treatment will reverse the
"vicious cycle" between bone and cancer cells.