Prospective evaluation of the predictive value of a circulating tumor cell (CTC) sensitivity profile to Cisplatin chemotherapy in metastatic breast cancer patients

Despite significant progress, there is a high need for new effective systemic
treatments for advanced/metastatic breast cancer (BC) patients. Cisplatin
(cDDP) is used in many tumor types but not in unselected BC patients. In old
studies (± 1980s), cDDP monotherapy, given to highly pretreated patients,
yielded response rates (RR) of maximum 21% and PFS of 3*4 months. Also,
cDDP-containing combination regimens given to pretreated metastatic BC patients
have not greatly improved outcomes. In addition, cDDP is associated with
relevant toxicity, consisting of nausea and vomiting, nephrotoxicity and
neurotoxicity. Fortunately, due to decades of acquired experience with cDDP and
improved anti-emetics, cDDP associated toxicity is nowadays more manageable.
However, due to the availability of effective and less toxic newer
chemotherapeutical and targeted agents, cDDP is not considered standard therapy
in unselected BC patients.

Recently, the use of cDDP in BC has regained interest. Several attempts have
been made to identify patients who are likely to benefit from cDDP-based
treatment based on primary tumor characteristics such as mutations,
overexpression and promotor hypermethylation of BRCA1, p53 mutations, so-called
triple-negative disease and expression of specific microRNAs. Since data from
prospective clinical trials exploring the use of the previously mentioned
factors is lacking, there is still an unmet need for factors identifying BC
patients likely to benefit from cDDP. If available, cDDP could add an extra
available anti-tumor agent for a particular subgroup of BC patients.
One potential pitfall that may cause the previously mentioned factors to be
less reliable is the fact that they all have been determined on primary tumor
tissue. It is becoming increasingly clear that the characteristics of the
primary tumor and metastases may differ, while systemic treatment and genomic
instability further augments these differences over time. As a result, primary
tumor material obtained at diagnosis is unlikely to reliably represent
characteristics of metastases. Unfortunately, tumor tissues of metastatic
lesions are hard to obtain, as taking biopsies is often a painful and
cumbersome procedure.

Circulating tumor cells (CTCs) are tumor cells that circulate in the peripheral
blood of cancer patients and are thought to represent features of metastases
better than the primary tumor does. In addition, CTC counts have been
correlated with clinical outcome in metastatic BC. Besides that, molecular
characterization of CTCs holds great promise as a tool to personalize medicine.
We have recently developed a panel of 96 genes, of which 55 mRNAs and 10 miRNAs
are CTC-specific, which can be reliably measured in CTCs enabling detailed CTC
characterization. From these 96 genes, we identified 23 genes that predict cDDP
sensitivity and resistance in our panel of 42 BC cell lines. Potentially,
determination of this gene expression profile in CTCs of BC patients will
enable the identification of BC patients responding to cDDP.

The aim of this study is to prospectively explore the predictive value of a
cDDP-sensitivity profile determined in CTCs of metastatic BC patients
previously treated with at least antracycline- and taxane-based chemotherapy.

Patients with metastatic breast cancer, pretreated with anthracycline and
taxanes, will be included in this phase II study. Of all patients, 20 mL blood
will be drawn at baseline for CTC enumeration and molecular characterization.
Based on the patients* CTC count and the cDDP-sensitivity gene expression
profile 3 groups will be identified: a group consisting of patients with *5
CTCs with a favorable cDDP-sensitivity profile, a group consisting of patients
with *5 CTCs but with an unfavorable cDDP-sensitivity profile and a group
comprising patients with <5 CTCs. Inclusion will continue until 10 patients
with * 5 CTCs and a favorable cDDP-sensitivity profile have been included. In
an ongoing study, 11% of metastatic breast cancer patients have *5 CTCs and a
favorable cDDP-sensitivity profile, rendering that in total approximately 100
patients will be accrued for CTC enumeration and for the determination of the
cDDP-sensitivity profile. All patients will receive 3-weekly cDDP at 70 mg/m2
for a maximum of 6 cycles.

Three interventions are considered as study-specific:
1) the blood collection for CTC enumeration and characterization
2) the administration of cDDP (though cDDP is also frequently given to this
patient category in daily clinical practice)
3) in patients consenting to this part of the study: a metastatic tissue biopsy

A potential risk of cDDP administration is toxicity. We do not expect the risk
of cDDP-toxicity to be significantly worse than the risk of toxicity with
alternative/comparable chemotherapeutic agents that are also used in daily
clinical practice for this indication.

In the optional part of the study, patients are asked if they are willing to
undergo a biopsy of a metastatic lesion. The risks associated with the
performance of a biopsy are usually mild. In some cases, patients will have to
be observed in the hospital for some hours after the biopsy has taken place.
All patients have been informed about these procedures by their treating
physician, furthermore, the patient information file states these procedures as
well.