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Randomized Phase II/III Study of Individualized Neoadjuvant Chemotherapy in ' Triple Negative' Breast Tumors

Phase 2/Phase 3
18 Years
59 Years
Open (Enrolling)
Breast Cancer

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Trial Information

Randomized Phase II/III Study of Individualized Neoadjuvant Chemotherapy in ' Triple Negative' Breast Tumors

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.

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

- 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

- 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

- 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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)

Outcome Time Frame:

end of neo adjuvant chemotherapy

Safety Issue:


Principal Investigator

Sjoerd Rodenhuis, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:



Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

January 2010

Completion Date:

Related Keywords:

  • Breast Cancer
  • Neo adjuvant
  • Triple negative
  • primary tumor over 2 cm and/or positive lymphnodes
  • Breast Neoplasms