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.
18 Years
59 Years
Female
Breast Cancer
Trial Information
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.
This phase II/III trial will investigate the ability of chemotherapy with 'Intensified
Alkylating Agents' (IAA) to achieve a high pathological complete response (pCR) rate when
employed in the preoperative chemotherapy of breast cancer with evidence of a Homologous
Recombination Deficiency (HRD).
Homologous Recombination (HR) is a DNA repair mechanism that can repair double-strand DNA
breaks. It is the only reliable repair mechanism that can repair the consequences of DNA
adducts caused by bifunctional alkylating agensts (such as cyclophosphamide, thiotepa or
carboplatin). Alternative DNA repair mechanisms are available in case of HRD, but these
induce DNA mutations and chromosome aberrations and thus give rise to major genetic
instability. HRD is a consequence of inactivation of BRCA-1 or BRCA-2, but may also be
caused by defects in the Fanconi anemia pathway or by amplification of the EMSY gene. HRD is
present in breast cancer cells but not in healthy cells of BRCA-1 or BRCA-2 mutation
carriers, and also in up to 30% of sporadic breast cancers.
Patients under 60 years of age with intermediate or high risk breast cancer, whose tumors
show evidence of HRD and do not contain a HER2/neu amplification are eligible. All patients
will receive 3 courses of standard preoperative chemotherapy with dose-dense Doxorubicin and
Cyclophosphamide (ddAC). Patients with a favorable response according to repeat MRI, will be
randomized to undergo either a further 3 courses of ddAC prior to local therapy and
endocrine adjuvant therapy (standard arm) or 1 course of ddAC followed by peripheral blood
progenitor cell (PBPC) harvest and 2 courses of IAA with Cyclophosphamide (3 g/m2), thiotepa
(240 mg/m2) and carboplatin (800 mg/m2) (experimental arm). IAA is administered during a 1
or 2-night hospital stay, the bone marrow aplasia phase is managed on an out-patient basis
and the second course will be started on day 22 of the first one. Patients who do not
achieve a favorable response as determined by their MRI after 3 cycles of ddAC will be
offered treatment according to the experimental arm as salvage therapy.
The primary endpoint of the study is the pCR rate of the breast. The phase II part of the
study will serve to further develop the pathology tests for HRD and to estimate the pCR
rates of HRD-breast cancers to both the conventional and the experimental treatments. The
phase III part of the study will be initiated when the test for HRD is sufficiently
standardized to be employed in a multi-center setting and when the preliminary information
collected at that point continues to be consistent with the assumption that HRD renders
tumor cells highly sensitive to IAA. If breast cancer is indeed exquisitely sensitive to
IAA, the pCR rate in the experimental arm could rise from 10% to 30% in luminal tumor types
and from 50% to 80% in basal-like tumor types. For 80% power to detect such a
response-improvement, 186 patients with HRD must be included in the phase III part of the
study.
Inclusion Criteria
- Proven infiltrating breast cancer with either a primary tumor over 3 cm in size
(clinical examination) or cytologically proven spread to the axillary lymph nodes.
- Stage II or stage III disease (revised AJCC staging system 2001). Patients with
'locally advanced breast cancer' are consequently eligible, including those with
ipsilateral supraclavicular lymph node metastases. In stage II patients with T1N1
disease, N1 status must have been demonstrated by either fine needle aspiration from
an axillary lymph node or by a metastasis of over 2 mm in diameter in a sentinel node
biopsy. Stage IIA patients without lymph node metastases are only eligible if the
tumor is over 3 cms in diameter.
- High-risk disease, according to Adjuvant Online version 8.0: the expected 10-year
recurrence-free survival without systemic adjuvant therapy according to this program
must be 60% or lower.
- The tumor must be HER2/neu-negative (either score 0 or 1 at immunohistochemistry or
negative at in situ hybridization [CISH or FISH] in case of score 2 or 3 at
immunohistochemistry).
- The tumor must test positive for homologous recombination deficiency, as defined by
the test of the pathology department of the NKI-AVL (M.J. van de Vijver).
- Age 18 to 59 years; patients older than 59 years may be included when considered
'biologically 59 years or younger'.
- Performance status: WHO 0 or I.
- No previous radiation therapy or chemotherapy.
- No other malignancy except carcinoma in situ, unless the other malignancy was treated
5 or more years ago with curative intent without the use of chemotherapy or radiation
therapy.
- Adequate bone marrow function (W.B.C. count > 3.0 x 109/l, platelets > 100 x 109/l).
- Adequate hepatic function (ALAT, ASAT and bilirubin < 2 x upper limit of normal).
- Adequate renal function (creatinine clearance > 60 ml/min).
- Radionuclide ejection fraction > 0.50.
- Pregnancy or breast feeding must be excluded and patients must use adequate
contraceptive protection.
- No evidence of distant metastases. Staging examinations must have included a chest
roentgenogram, an ultrasound examination of the liver and an isotope bone scan.
Abnormal uptake on the isotope bone scan can only be accepted if bone metastases were
excluded by MRI.
- At randomization, hormone receptor status and HER2/neu receptor status must be known.
In case of 2+ HER2/neu expression by immunohistochemistry, FISH or CISH examination
is required.
- Informed consent.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Percentage of tumors with HRD (phase II part)
Principal Investigator
Sjoerd Rodenhuis
Investigator Role:
Principal Investigator
Investigator Affiliation:
The Netherlands Cancer Institute
Authority:
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Study ID:
N06IAA
NCT ID:
NCT00448266
Start Date:
May 2007
Completion Date:
Related Keywords:
- Breast Cancer
- Breast cancer
- high-dose chemotherapy
- Homologous Recombination Deficiency
- Alkylator therapy
- Peripheral Blood Progenitor Cell Support
- Breast Neoplasms
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