Breast Cancer
Conditions
Keywords
Neo adjuvant, Triple negative, primary tumor over 2 cm and/or positive lymphnodes
Brief summary
This study aims to compare the response of triple-negative breast cancer with deficient homologous recombination to intensified alkylating chemotherapy versus standard chemotherapy with dose dense AC and/or Docetaxel-Capecitabine.
Detailed description
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 agents (such as cyclophosphamide, thiotepa or carboplatin). Alternative DNA repair mechanisms exist, but these unavoidably induce DNA mutations, deletions and chromosome aberrations, giving give rise to genetic instability. HRD may be a consequence of inactivation of the BRCA-1 or BRCA-2 genes (as in hereditary breast cancer), but it 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 about half of the sporadic triple-negative breast cancers. This phase II/III controlled multicenter trial will investigate the ability of individualized chemotherapy to improve the objective response rate of 'triple-negative' breast cancer (estrogen receptor and progesterone receptor-negative, no HER2 amplification) to preoperative (neoadjuvant) chemotherapy. It will answer the question whether intensified alkylating chemotherapy improves the response rate of tumors with a Homologous Recombination Defect (HRD) and it will gather data required for the design of a phase III study documenting the efficacy of response monitoring by contrast-enhanced MRI in TN breast cancer without HRD.
Interventions
Carboplatin AUC = 6, Q 3 weeks, 3 courses Paclitaxel 80 mg/m2, weekly, 9 administrations
Two-weekly administrations of 600 mg/m2 cyclophosphamide and 60 mg/m2 doxorubicin PEG-filgrastim (Neulasta(r)) will be administered on the day following chemotherapy.
DRUGDoxorubicin, cyclophosphamide, carboplatin, thiotepa, cyclophosphamide
One course of of 600 mg/m2 cyclophosphamide and 60 mg/m2 doxorubicin. PEG-filgrastim (Neulasta(r)) will be administered on the day following chemotherapy. This course is followed by Peripheral Blood Progenitor Cell (PBPC) harvest and tandem intermediate-dose alkylating therapy (miniCTC, carboplatin 800 mg/m2, thiotepa 250 mg/m2, and cyclophosphamide 3000 mg/m2) with PBPC-reinfusion.
Sponsors
The Netherlands Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
* Proven infiltrating breast cancer with either a primary tumor over 2 cm in size (MRI or ultrasound examination) and/or cytologically proven spread to the axillary lymph nodes. * Patients with 'locally advanced breast cancer' are consequently eligible, including those with ipsilateral supraclavicular lymph node metastases. * 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 be Estrogen receptor (ER) -negative (\< 10% nuclear staining at IHC) and Progesterone receptor (PR) -negative (\< 10% nuclear staining at IHC). However, the rare tumors that are ER-negative and PR-positive will be eligible, if this pattern of hormone receptor expression can be verified in the NKI-AVL reference pathology lab. * Age 18 to 59 years; patients older than 59 years may be included when considered 'biologically 59 years or younger' (as judged by the investigator). * Performance status: WHO 0 or I. * 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, or minor abnormalities of these tests judged to be of no consequence by the study coordinator). * Adequate renal function (creatinine clearance \> 60 ml/min). * Informed consent
Exclusion criteria
* Previous radiation therapy or chemotherapy. * 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. * Pregnancy or breast feeding. * 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary endpoint (HRD tumors): Average Neoadjuvant Response Index (NRI) after intensified alkylating therapy in comparison to that after 'standard' neoadjuvant chemotherapy. Primary endpoint (non-HRD tumors): Average Neoadjuvant Response Index (NRI) | end of neo adjuvant chemotherapy |
Secondary
| Measure | Time frame |
|---|---|
| Recurrence-free survival and overall survival. | every year |
Countries
Netherlands
Outcome results
None listed