Histone deacetylases (HDACs) regulate the acetylation of a variety of histone and nonhistone proteins, controlling the transcription and regulation of genes involved in cell cycle control, proliferation, survival, DNA repair and differentiation. Unsurprisingly, HDAC expression is frequently altered in hematologic and solid tumor malignancies. Two HDAC inhibitors (vorinostat and romidepsin) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. As single agents, treatment with HDAC inhibitors has demonstrated limited clinical benefit for patients with solid tumors, prompting the investigation of novel treatment combinations with other cancer therapeutics. In this article, the rationales and clinical progress of several combinations with HDAC inhibitors are presented, including DNA-damaging chemotherapeutic agents, radiotherapy, hormonal therapies, DNA methyltransferase inhibitors and various small-molecule inhibitors. The future application of HDAC inhibitors as a treatment for cancer is discussed, examining current hurdles to overcome before realizing the potential of this new approach.

A B S T R A C T PurposeChemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer. Patients and MethodsPremenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (Ͻ 35, 35 to 39, Ͼ 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels. ResultsTargeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P ϭ .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P ϭ .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status. ConclusionWhen stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.

African American and Hispanic women develop more triple negative breast cancer at younger ages than Caucasian women. The frequently observed association between race and socioeconomic status (SES) has confounded our understanding of the outcomes disparities seen in these groups. Given the association between inflammatory cells and high-grade, triple negative tumors, we sought to investigate whether differences in the presence of these cells varies by race. We evaluated breast tumor specimens for the presence PCNA+ tumor-associated macrophages (TAMs) in consecutive cases from a county hospital serving primarily un- or under-insured patients. All patients in this cohort had elevated PCNA + TAM levels. Higher PCNA + TAM counts were associated with hormone receptor (HR) negative tumors and non-Caucasian ethnicity. Hispanic women specifically had significantly higher PCNA + TAM counts than Caucasian patients and shorter disease-free survival. These findings implicate immune function in the development of aggressive breast cancer and suggest a possible link between SES and the inflammatory response.

The presence of high numbers of PCNA(+) TAMs and Mac387-positive cells in breast cancers with poor outcomes may implicate a subset of TAMs in breast cancer pathogenesis, and may ultimately serve to develop potential cellular targets for therapeutic interventions.