Fernando Cabanillas

Epigenetic therapy of lymphoma using histone deacetylase inhibitors.

In this study, we reviewed epigenetic therapy of lymphomas using histone deacetylase inhibitors (HDACi), a promising new class of antineoplastic agents. Epigenetic therapy, a new therapeutic concept, consists of the use of HDACi and or DNA methyltransferase inhibitors (DNMTi). We conducted a comprehensive review of the literature for antitumour activity of HDACi and its mechanism of action. HDACi modify the expression of several genes related to cancer development, which can result in antineoplastic activity. To elucidate the benefits of HDACi in lymphoma treatment, we discuss the crucial interplay between BCL6, p53 and STAT3. Activated B-cell (ABC) diffuse large cell lymphoma (DLCL) is increasingly being recognised as an unfavourable and frequently therapy-refractory lymphoma. We discuss the fundamental causative role of the STAT3 oncogene in ABC type DLCL. STAT3 can be effectively suppressed by several HDACi, a promising treatment for this difficult subtype of DLCL. On the other hand, various HDACi can repress the germinal-centre B Cell (GCB) type DLCL by virtue of their inhibition of the BCL6 oncogene, usually expressed in this particular subtype. We summarise the results of recent clinical trials with HDACi such as romidepsin, panobinostat, MGCD-0103, entinostat, curcumin, JAK2 inhibitor TG101348, and valproic acid that have shown preliminary activity in recurrent and refractory lymphomas. The unique mechanism of action of HDACi makes them very attractive agents to pursue in combination. Several ongoing trials are already exploring HDACi combinations in various types of cancers. Their role in front-line management remains to be determined.

Therapeutic concepts in mantle cell lymphoma

Mantle cell lymphoma has been considered an incurable disease with current chemotherapy regimens. Recent intense chemoimmunotherapy induction regimens with or without consolidation with autologous stem cell transplantation procedures are showing a potential for cure in a sizable fraction of patients. Similarly, in the salvage setting, preliminary experience with non‐myeloablative allogeneic transplant may cure some patients even after multiple therapeutic failures. However, the recent knowledge of the three basic biologic derangements that are integrated in the disease may change the therapeutic approach of the disease in the near future. In fact, new drugs that target more specifically the major molecular alterations of the disease are being progressively incorporated into the therapeutic armamentarium of the disease. In the near future, more individualized approaches that will take into account not only risk factors present at diagnosis but also biomarkers representative of the molecular alterations present in the disease are foreseen. In this review, we are going to discuss the current therapeutic approaches and the main new drugs that target more specifically the major molecular pathways alterations of the disease.

Results of Upfront Therapy for Marginal Zone Lymphoma

Micro‐Abstract Marginal zone lymphomas are usually managed with either radiation therapy or watch and wait except for Helicobacter pylori positive gastric MALT lymphomas. We hereby describe the successful application of systemic upfront therapy for patients with advanced as as well as recurrent disease. Background: Marginal zone lymphomas (MZLs) are indolent disorders composed of 3 subtypes: extranodal marginal zone lymphoma (MALT), splenic marginal zone lymphoma (SMZL), and nodal marginal zone lymphoma (NMZL). Early‐stage MALT is treated with radiotherapy or antibiotics, and advanced MALT and NMZL are managed with either watch and wait or chemotherapy. SMZLs are treated with splenectomy or rituximab. However, because these approaches have failed to cure patients with SMZL and NMZL, we have systematically used upfront chemotherapy for them, as well as for advanced MALT. We report the outcomes of this approach. Patients and Methods: A total of 44 patients with MZL were identified from our database and divided into 2 groups. Group 1 (22 with early‐stage MALT) patients received either radiotherapy (n = 17) or antibiotics with or without surgery (n = 5). Group 2 included 9 patients with advanced MALT, 9 with SMZL, and 4 with NMZL. Group 2 was treated with FND‐R (fludarabine 25 mg/m2 on days 1 to 3, mitoxantrone 10 mg/m2 on day 1, dexamethasone 20 mg on days 1 to 5, and rituximab 375 mg/m2 on day 1; n = 14) or CHOP‐R (cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 2 mg intravenous push on day 1, prednisone 100 mg/m2 orally on days 1 to 5, rituximab 375 mg/m2 on day 1; n = 8), followed by maintenance rituximab for 70%. Results: All patients achieved complete remission, and only 2 patients in group 1 had developed a relapse at 70 and 75 months. Both relapses were stage I MALT that had initially been treated with radiotherapy. Both were salvaged with FND‐R and remained free of disease at 27 and 39 months after the relapse. At 10 years, the failure‐free survival for the 44 patients was 80% and the overall survival was 100%. None of the patients in group 2 developed a relapse. The long‐term toxicities have been acceptable. Conclusions: The excellent responses using upfront chemotherapy for MZL suggests that this disorder is curable. Our results should be confirmed in a prospective trial.

Abstract P3-14-17: Results of a novel neoadjuvant chemotherapy (NAC) for breast cancer

Background: Achieving a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) has been associated with improved disease free survival (DFS) and overall survival (OS). The Residual Cancer Burden Score (RCB) method is a useful tool that predicts DFS and OS after NAC. We present the results of pts with either triple negative or HER2 positive breast cancer treated with a novel NAC. Methods : 34 pts with localized breast cancer >1 cm with HER2+ (N = 19) or triple negative breast cancer (TNBC) (N = 15) were treated with this novel regimen consisting first of TEC (docetaxel 75 mg/m2, epirubicin 80 mg/m2, and cyclophosphamide 500 mg/m2) + PEG Filgrastim x 4 cycles. Following the 4th course, TNBC patients received 4 additional TEC cycles if they achieved CR by MRI, or were switched to a non cross-resistant regimen (vinorelbine, bevacizumab, capecitabine) if they had 5% after 1st TEC had 84% pCR while none with < 5% achieved pCR (p = 0.001). Comparison of our results with other NAC regimens reported in the literature is summarized in the table below: View this table: Conclusions: This novel chemotherapy approach results in a high pCR rate and RCB 0-1, which have been associated with improved clinical outcomes. Early PET can predict pCR. Although sample size is modest, results are encouraging and deserve further evaluation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-17.

Abstract 873: Prevalence and correlates of HER2/neu overexpression among invasive breast cancer cases in two hospitals in Puerto Rico

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction Breast cancer (BC) is the most common female malignancy in Puerto Rico. Cases with human epidermal growth factor receptor 2 (HER-2)/neu oncoprotein overamplification are consistently associated with poor prognosis, poor response to endocrine treatment, and an increased likelihood of recurrence. The objective is to evaluate the prevalence of HER2 /neu gene overexpression among a hospital-based female population of BC cases in Puerto Rico, and to determine its association with other clinical characteristics. Methods This cross-sectional study analyzed data from female patients with invasive BC diagnosed between 2000 and 2005, at the I. Gonzalez Martinez Hospital and the Auxilio Mutuo Hospital (n=1,082) in San Juan, Puerto Rico. Information on Her-2 status and other clinical characteristics was retrieved form the hospitals cancer registries and from medical record review. This study was approved by the Institutional Review Boards of the participating hospitals. Logistic regression models were used to evaluate the associations between relevant clinical characteristics and Her-2 status. Results: The prevalence of Her-2/neu overexpression in our study aas 20.9%, whereas 72.3% of the cases were ER positive and 59.3% were PR positive. In multivariate analysis, women with an age at diagnosis ≤ 50 years were 1.74 (95% CI=1.26-2.41) times more likely to be Her-2 positive as compared with those with an age at diagnosis ≥ 50 years. Regarding ER/PR status, women with ER+/PR- and those with ER+/PR+ were 1.97 (95% CI=1.30-2.98) and 2.15 (95% CI=1.49-3.10) times more likely to be Her-2 positive as compared to those with ER-/PR- status. Finally, women with invasive ductal histology were 1.79 (95% CI=1.08-2.95) more likely to be Her-2 positive as compared to those with invasive lobular histology. Women with tumor grade III/IV, tumor size ≥ 2 cm and lymph node metastasis were also more likely to be Her-2 positive (p<0.05). Conclusions: The prevalence of Her-2/neu overexpression in this population of Puerto Rican patients (20.9) and its association with earlier age at diagnosis, tumor size, lymph node metastasis and other clinical characteristics shows that BC patients with Her-2 positive tumors followed similar profiles as Her-2 positive BC patients in the US population. Results from this study will be useful for the development of future BC prevention and control strategies in Puerto Rico. Sponsors: This work was supported by an unrestricted grant from Glaxo SmithKline with additional support from the National Institutes of Health and National Center for Research Resources (NCRR) [grant number G12RR03051 and U54CA96297]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 873.