Expression of the BAD pathway is a marker of triple-negative status and poor outcome.

Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.

Neoadjuvant and Adjuvant Therapies for Breast Cancer.

Breast cancer remains the most common cancer in women in the United States, the second most common cause of cancer death, and the main cause of death in women ages 45 to 55 years. Molecular analyses have shown that breast cancer is divided into several subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2] enriched, and basal-like), based on microarray techniques. Patients diagnosed as having breast cancer may undergo adjuvant or neoadjuvant chemotherapy, depending on the tumor size, hormone receptor, HER2/neu status, and desire for breast preservation. Patients with positive estrogen and/or progesterone receptor status benefit from treatment with selective estrogen receptor modulators such as tamoxifen or aromatase inhibitors, based on menopausal status and risk of recurrence. HER2-targeted agents such as trastuzumab and pertuzumab are used in combination with chemotherapy in patients with HER2/neu breast cancer. Triple-negative breast cancer is a unique subtype that lacks specific targets, and its treatment primarily includes chemotherapy. This article reviews the current clinical approaches to the management of patients diagnosed as having breast cancer treated with neoadjuvant and/or adjuvant chemotherapy.

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma.

BACKGROUND: The anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naïve. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy. PATIENTS AND METHODS: A multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed. RESULTS: In total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively. CONCLUSIONS: Ipilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naïve patients.

Evidence for Selective Benefit of Sequential Treatment With Hypomethylating Agents in Patients With Myelodysplastic Syndrome.

BACKGROUND: Hypomethylating agents (HMAs) remain the mainstay of treatment of patients with myelodysplastic syndrome (MDS). Azacitidine is the only agent shown to improve overall survival in higher risk MDS. The sequential use of HMAs is common practice, given the limited alternatives. The response rate to azacitidine after decitabine is unknown. To investigate the potential benefit of this approach, we reviewed all cases of sequential HMA treatment. PATIENTS AND METHODS: The Moffitt Cancer Center MDS database was reviewed, and 2 groups were identified. Group 1 had received decitabine after azacitidine failure and group 2 had received azacitidine after decitabine failure. The primary objective was to estimate the overall response rate according to the International Working Group 2006 criteria. The χ2 test and t test were used for the categorical and continuous variables, respectively. The Kaplan-Meier method was used to estimate the median overall survival. RESULTS: The overall response rate for hematologic improvement or better was 63% in group 1% and 50% in group 2. The response to second-line treatment in groups 1 and 2 was 19% and 40%, respectively. The median overall survival for group 1 from diagnosis was 48 months and for group 2 was 100 months (P = .7). CONCLUSION: Enrollment in clinical trials should be strongly encouraged in the case of HMA failure. Sequential use of HMAs could be considered as an alternative approach in the treatment of MDS after first-line HMA failure if clinical trials are not available. The outcomes of patients with progressive disease after treatment with HMAs remain poor and continue to be an unmet need.

Liver-Directed Embolization for the Long-Term Control of Hypercalcemia of Malignancy in Metastatic Breast Cancer.

Hypercalcemia of malignancy is a common complication of certain types of cancers. No standard therapies exist for the treatment of hypercalcemia secondary to paraneoplastic syndromes that result in the long-term control of serum calcium levels. We report a case of metastatic breast cancer with parathyroid hormone-related protein associated with hypercalcemia of malignancy that was treated with transarterial embolization of the hepatic metastatic lesions.

An overview of investigational Histone deacetylase inhibitors (HDACis) for the treatment of non-Hodgkin's lymphoma.

INTRODUCTION: Histone acetylation alters DNA transcription and protein expression. Aberrant acetylation is seen in tumor cells. Histone deacetylase inhibitors (HDACis) act by modifying gene expression and are the newest class of drugs shown to be promising in patients with several malignancies including relapsed and/or refractory lymphoma. Multiple HDACis are currently under various phases of clinical trials for the treatment of Non-Hodgkin's lymphoma (NHL). AREAS COVERED: This review discusses the mechanism of histone acetyl transferases (HAT's), histone deacetylases (HDAC's) and their role in B - and T-cell malignancies with a particular focus on the mechanism of action and clinical application of HDACis in NHL. Discussion includes: HDACi's like vorinostat, romidepsin, belinostat, panobinostat, entinostat and chidamide; pivotal clinical trials leading to the approval of HDACis in NHL; ongoing active clinical trials and combination therapies with novel agents. EXPERT OPINION: Relapsed and or refractory lymphoma poses a challenge to the clinician given the poor outcomes. HDACis show promising clinical activity in patients with relapsed/refractory NHL. Active pursuit of developing newer HDACis and clinical trials using combination therapies that help understand the molecular characteristics and synergistic actions of these agents is warranted. This would help improve efficacy, drug tolerability and expand the horizon of these novel agents.

Tacrolimus associated posterior reversible encephalopathy syndrome - a case series and review.

Tacrolimus is an immunosuppressive drug mainly used to lower the risk of transplant rejection in individuals who are post solid organ or hematopoietic transplantation. It is a macrolide which reduces peptidyl-propyl isomerase activity and inhibits calcineurin, thus inhibiting T-lymphocyte signal transduction and interleukin-2 (IL-2) transcription. It has been associated with Posterior Reversible Encephalopathy Syndrome (PRES), a disease of sudden onset that can present as a host of different symptoms, depending on the affected area of the brain. While infectious causes of encephalopathy must always be entertained, the differential diagnosis should also include PRES in the appropriate context. We report three cases of PRES in patients with acute myeloid leukemia (AML) placed on tacrolimus after receiving a bone marrow transplant (BMT). The focus of this review is to enhance clinical recognition of PRES as it is related to an adverse effect of Tacrolimus in the setting of hematopoietic transplantation.