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. METHODOLOGY: 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/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 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 5(m)C 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

Granulocytic sarcoma of the breast without development of bone marrow involvement: a case report

© 2009 Vela-Chávez et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Granulocytic sarcoma of the breast without development of bone marrow involvement: a case report

Abstract A 29-year-old woman presented with a breast tumor with a primary diagnosis of MALT lymphoma. A repeat biopsy revealed a hematological neoplasm with diffuse, Indian file, and targetoid patterns. The cells were intermediate size with eosinophilic granules; the immunophenotyping showed monocytic differentiation, and no lymphoepithelial lesion was observed. The diagnosis was granulocytic sarcoma. Three different bone marrow biopsies were negative for neoplastic infiltration. After treatment, she developed secondary pancytopenia which contributed to her death 16 months after primary diagnosis. Granulocytic sarcoma of the breast is uncommon. A complete panel of immunohistochemistry is necessary to perform this diagnosis.</p

Argon plasma coagulation and hyperbaric oxygen therapy in chronic radiation proctopathy, effectiveness and impact on tissue toxicity Argón plasma y oxígeno hiperbárico para el control de la rectorragia crónica secundaria a la proctopatía por radiación

Background: chronic radiation proctopathy (CRP) is associated with recurrent rectal bleeding and transfusional requirements. Argon plasma coagulation (APC) and hyperbaric oxygen therapy (HOT) have been shown to be effective in the control of CRP. No prospective comparisons have been reported between these treatments. Aim: the aim was to evaluate the effectiveness, safety and impact on tissue toxicity of APC compared to HOT in patients with CRP. Material and methods: a prospective study for evaluating treatment response was conducted. Patients with cervical cancer and CRP with rectal bleeding were recruited. They had not received previous treatment. Collected data included: demographics, previous radiation dosage, duration and severity of rectal bleeding. Hemoglobin, transfusional requirements, and tissue toxicity (SOMA LENT questionnaire) at baseline and at 1, 2, and 3 months follow up were recorded. Results: thirty-one patients were included, 14 in the APC group and 17 in the HOT group. No response was noted in 13 and 18% of patients in the APC and HOT group respectively (p = NS). At the 1 and 2 months follow-up, the APC group showed a significantly better response in terms of transfusional requirements (0.6 vs. 3.4 and 0.7 vs. 2.5) and tissue toxicity score (5.3 vs. 8.6 and 3.8 vs. 7.248). After 3 months, both groups showed further improvement in all parameters without significant differences between them. Conclusions: APC and HOT were effective, safe and decreased the tissue toxicity scores in patients with CRP. However, response rate was higher and faster in the APC group.<br>Introducción: la proctopatía por radiación (PPR) se asocia con rectorragía recurrente y requerimientos de trasfusiones. La coagulación con argón plasma (APC) y la terapia con oxígeno hiperbárico (HOT) han sido efectivas en el control de la PPR. No hay estudios prospectivos comparativos entre ambas técnicas. Objetivo: el objetivo del estudio es evaluar la efectividad, seguridad y el impacto en la toxicidad tisular de la APC comparado con el HOT en los pacientes con PR. Material y métodos: se realizó un estudio prospectivo para evaluar la respuesta al tratamiento. Se incluyeron a pacientes con cáncer cervicouterino y PPR con rectorragia recurrente, sin haber recibido tratamientos previos. Se tomaron datos demográficos, dosis de radiación, duración y severidad de la rectorragia, niveles de hemoglobina, requerimientos de trasfusiones y la toxicidad tisular (Cuestionario de SOMA-LENT) al inicio, y a los 1, 2 y 3 meses del tratamiento. Resultados: se incluyeron a 31 pacientes con PPR, 14 en el grupo de APC y 17 en el grupo de HOT. No hubo respuesta en el 13 y 18% de los pacientes en el grupo de APC y OHT respectivamente (p = NS). Al primer y segundo mes de seguimiento, el grupo APC mostró una mejoría significativa en los parámetros de requerimientos trasfusionales (0,6 vs. 3,4 y 0,7 vs. 2,5) y en la toxicidad tisular (5,3 vs. 8,6 y 3,8 vs. 7,2). Después de 3 meses de seguimiento, ambos grupos mostraron mejoría en todos los parámetros sin haber diferencias estadísticamente significativas. Conclusiones: APC y HOT fueron efectivos, seguros y disminuyeron la toxicidad tisular en los pacientes con PPR. Sin embargo la respuesta fue más efectiva y rápida en el grupo del APC

Gene expression by RT-PCR.

<p>RT-PCR of NDUFA13 and DAPPER genes in biopsies from the primary tumor showing that these genes were reactivated after treatment. This corresponds to one of the three patients whose biopsy (only post-treatment) was analyzed by microarray and showed over-expression of these genes.</p

Histone deacetylase activity.

<p>The five patients assayed showed a reduction in enzymatic activity. In Y axis are the absolute values in optical density (OD) units. Higher and lower decreases were 0.3845 and 0.0175, for a mean decrease of 0.1624. This difference was statistically significant (p = 0.042).</p

Hierarchical Cluster Analysis.

<p>The cluster shown represents 3,117 genes. Each row represents a gene, whereas each column corresponds to a tissue sample. The relative abundance of the gene in the tissue correlates with color intensity (red, induced; green, repressed; black, no change). On the dendogram, post-treated clinical samples clustered together.</p

Flow diagram of the trial.

<p>Flow diagram of the trial.</p