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 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 investigate whether oligometastatic triple negative or BRCA1/2
related breast cancer can be treated effectively with a multimodality approach
including induction chemotherapy, and whether high dose alkylating chemotherapy
can improve the outcome of patients with tumors that harbor HRD compared with
conventional dose alkylating chemotherapy.

This will be a phase II trial assessing the effect of a multimodality treatment
including chemotherapy in patients with oligometastatic triple negative or
BRCA1/2 related breast cancer.
After the screenings investigations and the tumor biopsies 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.
Depending on these results the treatment after evaluation will be local
treatment (PD) , three more cycles of the same induction chemotherapy (non-PD
and HRD negative tumor) or a randomisation between three more cycles of the
same induction chemotherapy versus 2 cycles of intensified alkylating
chemotherapy (HRD positive tumors).

Following diagnosis, informed consent, and baseline investigations, all
patients receive three cycles of induction chemotherapy depending on previously
received agents. Patients who:
* are chemotherapy naïve receive three cycles of docetaxel, doxorubicin, and
cyclofosfamide
* previously received anthracyclines without taxanes receive three cycles of
carboplatinum and paclitaxel
* previously received anthracyclines and taxanes receive three cycles of
carboplatinum and gemcitabine
The principal investigator may adapt the optimal chemotherapy regimen for
individual patients.
Next, a re-evaluation is performed.
* In case of disease progression local treatment will be initiated unless the
patient no longer meets the criteria for oligometastatic disease.
* In case of at least stable disease of all evaluable lesions or if no
evaluable lesion is availabe, patients are treated with a similar series of
three conventional chemotherapy courses.
* Patients without evaluable lesions or with at least stable disease of all
evaluable lesions, whose tumor harbors HRD are invited to an optional
randomized treatment allocation using a separate informed consent between
either:
a similar series of three conventional chemotherapy 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 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 visit the hospital for this stemcell harvest.
Patients in the conventional arm will not have these extra visits and burden.
All patients in the study will have tumor biopsies for HRD assessment. With
these biopsies there is a small risk on complications.
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.