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
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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
Sjoerd Rodenhuis, MD
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)