High-dose alkylating chemotherapy in oligo-metastatic breast cancer harboring homologous recombination deficiency

Breast cancer patients with metastases beyond the regional lymph nodes are
unlikely to be cured of their disease. Long-term survivors tend to
have limited metastatic disease also referred to as oligometastatic. No uniform
definition exists for oligometastatic breast cancer, but the term
has become synonymous with small volume metastatic disease amenable to
effective local control. Patients undergoing combined modality
approaches including local and systemic therapy appear to have a better chance
for long-term progression-free survival and even cure in case
of oligometastatic disease. These findings, however, may be biased by selection
of a relatively healthy patient population.
High dose alkylating chemotherapy has previously been used in the treatment of
oligometastatic breast cancer. In the past few years, a great
deal of new data has become available pertaining to the mechanism of action of
alkylating agents. Tumor cells deficient in homologous
recombination, such as those in BRCA1/2 carriers, are especially vulnerable to
the action of alkylating agents. Recent findings suggest that an
aCGH profile, MLPA test and BRCA1 promotor methylation can be used to detect
patients with BRCA1/2-like characteristics that are extremely sensitive to
treatment with high-dose alkylating
agents.

This study will investigates the effect of high dose alkylating chemotherapy
compared to standard dose chemotherapy as part of a multimodality approach in
patients with oligometastatic HRD positive and/or BRCA1/2 related breast cancer.

This is a phase III trial investigates the effect of high dose alkylating
chemotherapy compared to standard dose chemotherapy as part of a multimodality
approach in patients with oligometastatic HRD positive or BRCA1/2 related
breast cancer.

After the screenings investigations and routinely taken tumor biopsies from the
metastatic lesion, patients are treated with three cycles of induction
chemotherapy.
The type of chemotherapy is selected based on the previous chemotherapy. This
is described in detail in the study protocol.
After three cycles of chemotherapy, tumor evaluation is done and the results of
the HRD test will be reported.

Patients with at least stable disease of all evaluable lesions or no evaluable
lesion availabe, whose tumor harbors HRD are randomized to receive three more
cycles of the same induction chemotherapy versus a fourth course chemotherapy
with cyclofosfamide, G-CSF and peripheral blood progenitor cell (PBPC) harvest
followed by two cycles of intensified alkylating chemotherapy with
PBPC-reinfusion.

Following diagnosis, informed consent, and baseline investigations, all
patients receive three cycles of induction chemotherapy depending on
previously received agents. Patients can be treated with one of the following
schedules;
- docetaxel-doxorubicine-cyclophosphamide
- adriamycine-cyclophosphamide
- carboplatin-paclitaxel
- capecitabine-docetaxel
- carboplatin-gemcitabine
- capecitabine- docetaxel
- carboplatin-gemcitabine
- capecitabine- vinorelbine
- capecitabine-carboplatin

Next, a re-evaluation is performed.

Patients with at least stable disease of all evaluable lesions or no evaluable
lesion availabe, whose tumor harbors HRD are randomized to receive either:
a similar series of three conventional chemotherapy courses four cycles of
carboplatin + paclitaxel for patients who received ddAC as induction courses.
or:
a fourth course chemotherapy with cyclofosfamide, G-CSF and peripheral blood
progenitor cell (PBPC) harvest followed by tandem intermediate-dose alkylating
therapy (miniCTC, carboplatin 800 mg/m2, thiotepa 240 mg/m2, and
cyclophosphamide 3000 mg/m2) with PBPC-reinfusion.

Patients with at least stable disease of all evaluable lesions or with no
evaluable lesion availabe, whose tumor does not harbor HRD will receive a
similar series of three conventional chemotherapy courses.
In case of disease progression, further treatment is left to the discretion of
the multidisciplinary breast team.

Patients who receive the intensified alkylating chemotherapy will receive 2
cycles of chemotherapy (CTC) that are clearly more toxic than the
chemotherapy in the other arm. There may be a small risk of toxic death,
although this is probably (and considerable) below 1%.
Patients in the intensified treament arm will also receive a catheter to
harvest the stemcells and a catheter to administer the high dose chemotherapy.
They will visit the hospital more frequent for this stemcell harvest and high
dose chemotherapy.
Patients in the conventional arm will not have these extra visits and burden.
Recent findings suggest that a subgroup of patients can be recognized that is
sensitive to treatment with high-dose alkylating agents.
It is therefore reasonable to expect that patients in the CTC arm will have
increased disease free cancer survival.