Activity of trastuzumab based chemotherapy in metastatic breast cancer patients with HER2-negative primary tumor but HER2 positive circulating tumor cells

Today*s treatment of metastatic breast cancer is guided by characteristics of
the primary tumor, while 90% of deaths due to breast cancer occur as a
consequence of metastases. It is appreciated that tumor characteristics may
differ between the primary tumor and the metastases. In addition, evidence is
accumulating that there are patients with HER2-negative primary tumors who
respond to trastuzumab-based chemotherapy. One group of patients with
HER2-negative primary tumors who might benefit from trastuzumab-based
approaches is patients with HER2-positive circulating tumor cells (CTCs). CTCs
are cancer cells present in the peripheral blood of patients with metastatic
breast cancer and are thought to represent characteristics of the metastases.
We hypothesize that patients with a HER2-negative primary tumor but with at
least one HER2-positive CTC benefit from HER2 targeted treatment with
trastuzumab.

The primary objective is to determine if metastatic breast cancer patients with
HER2-negative primary tumors but with at least one HER2-positive CTC benefit
from trastuzumab-containing chemotherapy. Secondary objectives are to determine
the impact of ER, phosphorylated HER2 (pHER2) and PIK3CA mutations in CTCs on
the outcome of trastuzumab-based chemotherapy and to determine the PIK3CA
mutation status, pHER2 and ER expression status on primary tumor tissue to
compare with CTCs. Furthermore, two methods to enumerate and characterize CTCs
will be compared.

Multi-center prospective intervention study

1x20 mL of blood will be drawn to screen patients for the presence of
HER2-positive CTCs. In patients with at least one HER2-positive CTC, an
additional 60 mL of blood will be drawn for CTC characterization. These
patients will be treated with trastuzumab starting in combination with
docetaxel or paclitaxel at the following dose:
For the docetaxel-containing regimen: : Intravenous administration starts the
first cycle at a dose of 8 mg/kg, lowering the dose to 6 mg/kg for the
subsequent cycles, intravenously, every 3 weeks, continuing until disease
progression. Subcutaneous administration is always 600mg, regardless of the
body weight of the patient, given every 3 weeks, continuing until disease
progression. This is combined with docetaxel at 100mg/m2 intravenously every 3
weeks, for a maximum of 6 cycles.
Fro the paclitaxel containing regimen: Intravenous administration starts the
first week at a dose of 4mg/kg, lowering the dose to 2mg/kg for the subsequent
weeks. Subcutaneous administration of 600mg given every 3 or 4 weeks, depending
on a 3- or 4- weekly paclitaxel regimen, regardless of the body weight of the
patient, continuing until disease progression. This is combined with weekly
paclitaxel 80-90mg/m2 intravenously for a maximum of 12 administrations.

20 mL blood will be drawn for screening for CTC enumeration. The laboratory for
Translational Tumor Immunology will report back whether the patient has
HER2-positive CTCs or not within 4 days. These 4 days waiting time are not
considered as a relevant delay of treatment. In case a patient has at least one
HER2-positive CTC, an additional 60 mL blood for CTC characterization will be
collected and patients will be treated with trastuzumab and docetaxel or
paclitaxel, which is a well-known treatment with potential risks of toxicity.
All blood will be drawn during another blood draw that is already required for
standard care.