RANDOMIZED PHASE II/III STUDY OF INTENSIFIED ALKYLATING AGENT CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL SUPPORT IN THE PREOPERATIVE CHEMOTHERAPY OF BREAST TUMORS THAT ARE DEFICIENT FOR HOMOLOGOUS RECOMBINATION.

Nearly all patients who die from breast cancer die from the consequences of
distant metastases. Adjuvant chemotherapy, either administered before or after
surgery, has been shown to reduce the risk of metastases and death. Four main
groups of chemotherapeutic agents are employed in breast cancer: alkylating
agents, anthracyclines, antimetabolites and taxanes. It is currently not
possible for an individual tumor to predict which of these agents or which
combination will be optimal.
Recent studies have strongly suggested that many hereditary breast cancers and
up to 30% of sporadic tumors may lack a DNA-repair mechanism called homologous
recombination. This DNA-repair mechanism is required to reliably repair
DNA-adducts resulting from exposure to bifunctional alkylating agents. Thus,
homologous recombination deficient (HRD) tumor cells are hypersensitive to
these drugs and this phenomenon could well explain the activity of these agents
in some but not all breast cancers. If HRD is found in a tumor, this could
disclose the Achilles* heel of this individual cancer.

Nearly all patients who die from breast cancer die from the consequences of
distant metastases. Adjuvant chemotherapy, either administered before or after
surgery, has been shown to reduce the risk of metastases and death. Four main
groups of chemotherapeutic agents are employed in breast cancer: alkylating
agents, anthracyclines, antimetabolites and taxanes. It is currently not
possible for an individual tumor to predict which of these agents or which
combination will be optimal.
Recent studies have strongly suggested that many hereditary breast cancers and
up to 30% of sporadic tumors may lack a DNA-repair mechanism called homologous
recombination. This DNA-repair mechanism is required to reliably repair
DNA-adducts resulting from exposure to bifunctional alkylating agents. Thus,
homologous recombination deficient (HRD) tumor cells are hypersensitive to
these drugs and this phenomenon could well explain the activity of these agents
in some but not all breast cancers. If HRD is found in a tumor, this could
disclose the Achilles* heel of this individual cancer.

This is a randomized phase II/III study. Eligible patients are registered and
staged. A MRI of the breast is part of the staging examination. All patients
receive 3 courses of doxorubicin and cyclophosphamide, every 2 weeks with
Filgrastim support (ddAC). Following this induction chemotherapy, the MRI is
repeated to determine the presence of a *favorable response*. This is defined
as a shrinkage of at least 25% of the longest diameter of the tumor, as
determined by the gadolinium wash out area. Patients who have achieved such a
favorable response will be randomized to receive either a further 3 courses of
dose-dense AC (conventional arm), or to receive a single course of ddAC
followed by peripheral blood progenitor cell mobilization and harvest. They
will subsequently receive 2 courses of intensified alkylating agent
chemotherapy, each of which will be followed by a peripheral blood progenitor
cell reinfusion to hasten bone marrow recovery.
Following chemotherapy, all patients will undergo local treatment (surgery, in
most cases followed by radiation therapy) and endocrine adjuvant therapy if
appropriate.
In the phase II part of the study, preliminary information will be collected
such as the actual proportion of patients that presents with a tumor with
evidence of HRD. The phase III part of the study will be started when the phase
II has confirmed feasibility when it has shown that a reasonable proportion of
patients has a tumor with HRD. If the latter is lower than 30%, additional
centers may be asked to participate in the study (which will require an
amendment of the protocol).

All patients receive 3 courses of doxorubicin and cyclophosphamide, every 2
weeks with Filgrastim support (ddAC). Following this induction chemotherapy,
the MRI is repeated to determine the presence of a *favorable response*.
Patients who have achieved such a favorable response will be randomized to
receive either a further 3 courses of dose-dense AC (conventional arm), or to
receive a single course of ddAC followed by peripheral blood progenitor cell
mobilization and harvest. They will subsequently receive 2 courses of
intensified alkylating agent chemotherapy, each of which will be followed by a
peripheral blood progenitor cell reinfusion to hasten bone marrow recovery.

Patients who receive the experimental treatment (intensified alkylating agent
chemotherapy) will receive 2 non-standard courses of chemotherapy which are
clearly more toxic than the corresponding 2 chemotherapy courses in the
conventional treatment arm. Each of the IAA courses will take 3 weeks of
recovery rather than 2, and 2 nights of hospital stay per course versus nil in
the conventional arm. Side effects such as nausea and vomiting, fatigue, bone
marrow suppression and neutropenic fever are more frequent in the experimental
arm. There may be a small risk of toxic death, although this is probably (and
considerably) below 1%.
Previous experience with an earlier IAA regimen (high-dose chemotherapy with
CTC) has shown a significant survival benefit for patients with HER2-negative
breast cancer when employed in the adjuvant setting. A recent meta-analysis of
the Early Breast Cancer Trialists* Collaborative Group has shown that high-dose
chemotherapy in the adjuvant treatment of breast cancer is associated with a
significant reduction in recurrence and in breast cancer death rate. It is
therefore reasonable to expect that, even if the central hypothesis of the
study proves to be incorrect, patients in the experimental arm will have
increased breast cancer survival.