A proof-of-principle study of epigenetic therapy added to neoadjuvant doxorubicin cyclophosphamide for locally advanced breast cancer.
BACKGROUND
Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy.


METHODS
This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day -7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate.


RESULTS
16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1-2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5mC content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively.


CONCLUSIONS
Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy.
Arce
Claudia
C
Division de Investigación Clinica, Instituto Nacional de Cancerología (ICAN), Mexico City, Mexico.
Pérez-Plasencia
Carlos
C
González-Fierro
Aurora
A
de la Cruz-Hernández
Erick
E
Revilla-Vázquez
Alma
A
Chávez-Blanco
Alma
A
Trejo-Becerril
Catalina
C
Pérez-Cárdenas
Enrique
E
Taja-Chayeb
Lucia
L
Bargallo
Enrique
E
Villarreal
Patricia
P
Ramírez
Teresa
T
Vela
Teresa
T
Candelaria
Myrna
M
Camargo
Maria F
MF
Robles
Elizabeth
E
Dueñas-González
Alfonso
A
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage*; D019175:DNA Methylation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006830:Hydralazine / Q000008:administration & dosage; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D014635:Valproic Acid / Q000008:administration & dosage
D056572:Histone Deacetylase Inhibitors; D006830:Hydralazine; D014635:Valproic Acid; D004317:Doxorubicin; D003520:Cyclophosphamide