Sensitization of breast cancer patients to vinorelbine following p53 induction and microtubule associated protein-4 repression by doxorubicin

Molecular determinants of drug sensitivity promise to lead to more precise selection of patients (pts) for treatment. p53 transcriptionally represses MAP4, a microtubule-associated protein that promotes micrtotubule polymerization and determines sensitivity to microtubule drugs. In preclinical studies, the induction of wild-type p53 by DNA-damaging agents, such as doxorubicin (DOX), repressed MAP4, decreased microtubule polymerization and increased sensitivity to vinca alkaloids. We conducted a phase I/II study of sequential DOX and vinorelbine (V) in previously untreated pts with stage IIIB or IV breast cancer to test if DNA damage by DOX represses MAP4 in patients and if chemotherapy effectiveness can be improved by sequencing V 24 or 48 h later when we anticipated maximal repression of MAP4. The rationale for this regimen is based on the demonstrated activity of these agents when delivered in combination. Patients received DOX (40 vs 50 mg/m²) followed by V (20 vs. 25 mg/m²) D2 and D9 alternating with V D3 and D10. 16 pts (7 metastatic/9 locally advanced) received 82 treatment cycles. Gr 3 infection/febrile neutropenia was observed in 5/82 cycles. Grade 3 and 4 non-hematological toxicities included: congestive heart failure (2), fatigue (4), pulmonary embolism (1), deep venous thrombosis (3), and depression (1). 15 patients were evaluable for response. Best response observed was PR (7), SD (6) and progressive disease (2). Peripheral blood mononuclear cells (PBMCs) and tumor tissue were obtained prior to DOX administration and 24 and/or 48h later prior to V. Western blots showed that DOX increased p53 in PBMCs in 12/15 pts and breast cancer biopsies (5/10). Western blots of PBMNCs in 7/12 pts and tumor from 4/5 pts showed a reduction in MAP4 levels that correlated with increased p53. MAP4 assessed by immunohistochemistry was generally lower post-DOX. MAP4 was repressed in the tumors of 2/4 respondent. This phase I clinical trial demonstrates the feasibility of administering DOX followed by V 24 or 48 h later to patients with breast cancer. These data demonstrate that DOX treatment can increase p53 and repress MAP4. The phase II portion will determine response in pts with p53 wild-type tumors as we anticipate maximal repression of MAP4 in wtp53 tumors thereby increasing sensitivity to V.