BackgroundSocial isolation is associated with accelerated breast cancer progression and increased disease recurrence and mortality, but the underlying biological mechanisms remain poorly understood. In preclinical models, beta-adrenergic signaling from fight-or-flight stress responses can stimulate prometastatic processes in the tumor microenvironment including upregulation of M2 macrophages, epithelial–mesenchymal transition (EMT), and lymphovascular invasion. This study examines whether the same pathways are upregulated in breast tumors from socially isolated cancer patients.MethodsEMT and M1/M2 macrophage gene expression programs were analyzed by genome-wide transcriptional profiling, and lymphatic and vascular density were assessed by immunohistochemistry in primary tumors from 56 early-stage breast cancer patients who were part of the UCLA RISE study. Social isolation was quantified by the Social Provisions Scale, and disease characteristics were assessed by medical record review. General linear models were used to quantify differential gene expression across risk factor groups. Linear regression models were used to examine associations between social isolation and lymphovascular invasion.ResultsTumors from socially isolated patients showed upregulated expression of genes involved in EMT (average score difference = +0.080 log2 mRNA abundance ± 0.034 standard error) and M2 macrophage polarization (+0.033 ± 0.014) as well as increased density of lymphatic vessels (β= –.29) but no difference in blood vessel density. TELiS promoter–based bioinformatics analyses indicated activation of CREB family transcription factors that mediate the gene-regulatory effects of β-adrenergic signaling (log2 fold-difference in promoter binding site prevalence: mean ± standard error = +0.49 ± 0.19). ConclusionsPrimary breast tumors from socially isolated patients show multiple prometastatic molecular alterations, providing a plausible biological pathway through which poor social support may accelerate breast cancer progression and defining new targets for intervention.

Adult T-cell leukemia-lymphoma (ATL) is an uncommon highly aggressive T-cell lymphoma associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. It is rarely encountered during pregnancy and is particularly challenging to treat due to its aggressive nature and because of the lack of robust data on optimal chemotherapy. We report a case of a Jamaican immigrant diagnosed with ATL during pregnancy.

Background: Inhibitor of apoptosis proteins (IAPs) negatively regulate cell death through a variety of mechanisms. LCL161 is an oral small-molecule antagonist of IAPs that has demonstrated single-agent activity and synergy with paclitaxel in breast cancer tumor models. In preclinical studies, a gene expression signature has been shown to enrich for response to LCL161. The recommended dose of LCL161 1800 mg once weekly has demonstrated preliminary antitumor activity with paclitaxel in an ongoing Phase Ib study in patients with breast cancer. Trial design: This is a Phase II, randomized, open-label study of neoadjuvant paclitaxel with or without LCL161 in women with operable, newly diagnosed triple-negative breast cancer (NCT01617668). Key inclusion criteria include women with histologically confirmed diagnosis of triple-negative breast cancer; clinical stages T2, N0–N2, M0; candidates for mastectomy or breast-conserving surgery; ECOG performance status ≤1; known status of the LCL161-predictive gene expression signature (positive and negative gene signature is a stratification factor); and adequate bone marrow and organ function. Key exclusion criteria are: bilateral or inflammatory breast cancer; locally recurrent breast cancer; patients currently receiving systemic therapy for any other malignancy, or having received systemic therapy for a malignancy in the preceding 3 months; impaired gastrointestinal function that may affect the absorption of LCL161; or uncontrolled cardiac disease. Patients are randomized 1:1 to receive paclitaxel IV (80 mg/m2 weekly) with or without oral LCL161 (1800 mg once weekly) for 12 weeks (corresponding to 4 treatment cycles). Each treatment arm is stratified 1:1 based on gene expression signature status (positive or negative). Endpoints: The primary endpoint is pathologic complete response (pCR), defined as the absence of invasive disease in the breast after 12 weeks of therapy, analyzed separately in the gene expression signature positive and negative groups. The key secondary endpoint is the pCR rate following treatment with LCL161 and paclitaxel in gene expression signature-positive or -negative tumors. Other secondary endpoints include: pCR rate in breast after 12 weeks of therapy in the full study population, and in patients with gene expression signature-positive and -negative tumors treated with paclitaxel alone; pCR rate in breast, regional nodes and axilla; biomarker evaluation including caspase 3 activation in tumor; safety; and pharmacokinetics of LCL161. Statistical methods: pCR analysis will be performed according to treatment group and gene expression signature status. An absolute increase of at least 7.5% in pCR rate of the experimental arm over the control arm will be considered as evidence of clinically relevant efficacy. Target accrual: Approximately 200 patients will be randomized into this study. Recruitment is ongoing across America, Europe, and Asia. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-04.

Frozen section (FS) for evaluation of sentinel lymph nodes (SLNs) can be used to detect metastasis. However, there is no standard protocol concerning histopathologic analysis of SLNs on FS. Diverse methods have been proposed. Nonetheless, several issues such as cost, potential loss of micrometastasis, and sampling error, among other factors arose. This study highlights our institutional protocol in evaluating SLNs on FS. Statistical analyses of collected data are enumerated. Retrospective analysis of 519 SLNs (219 primary breast cancer patients), who underwent breast surgery with FS of SLNs were examined. The study was conducted at Saint Barnabas Medical Center, Livingston, New Jersey during a 1-year period. Per protocol, SLNs greater than 1 cm are serially sectioned perpendicular to long axis; alternate pieces, including tips, are submitted on FS; and the remainder submitted for permanent microscopic analysis. If nodes are 1 cm or less, they are bisected exposing the greatest surface; half is submitted for FS and the remaining half is for permanent section. Suspicious area noted on gross examination is submitted for FS. Two step sections of hematoxylin and eosin-stained tissue are analyzed on FS. The entire lymph node is not submitted for FS to avoid potential loss of micrometastasis. Residual lymph nodes after FS submitted entirely for definitive microscopic examination employing one step section of H&E-stained slide. Lymph nodes that are negative on FS are reflexively stained with pan-cytokeratin to detect false negatives. Tissues are processed according to defined standards, slide-mounted tissues are examined by experienced pathologists. Overall, intraoperative FS analysis of 519 SLNs revealed sensitivity of 72.73% and specificity of 100%. Separate statistical analysis revealed sensitivity of 23.53% for micrometastasis compared to 95% sensitivity for macrometastasis. The specificity for identifying macrometastasis is 100%. Our protocol revealed very good sensitivity and an excellent specificity.

No abstract