TPS monitoring in metastatic breast cancer.

The management of metastatic breast cancer patients reflects the heterogeneous nature of the disease. While patients may benefit from hormonal treatment, in most cases more toxic chemotherapy is applied in the advanced stages. The pretreatment levels of TPS in patients with metastatic breast cancer are correlated with prognosis. Decreasing TPS levels (> 50%) during treatment are indicative of response. The fastest decrease in TPS levels is obtained in patients with a favorable prognosis. Increasing TPS levels (> 25%) predict disease progression with a considerable lead time (median 8 months). The clinical impact of these observations is discussed in this paper.     

Cranial reconstruction for metastatic breast cancer

All women with advanced breast cancer who are medically stable despite their disease are candidates for tumor extirpation and reconstruction. Advanced breast cancer today is incurable, and many prognostic factors can be used to try to predict a clinical course and response to therapy; however, no guidelines are available. Our case report most likely represents a metastasis to the calvarium with intracranial extension, reported to occur in about 3 percent of primary breast cancer patients. As demonstrated here, tumor ablation with immediate, one-stage reconstruction of large scalp defects is possible without the need for free tissue transfer or a delay in adjuvant therapy. Local tissue rearrangement has been employed for coverage of defects up to 50 percent of the cranium. The resulting donor defects can be closed with split-thickness skin grafts over pericranium. Serial tissue expansion and rearrangement can be used secondarily to replace skin grafts with hair-bearing scalp. Bony defects can be managed with either autogenous or alloplastic materials. Split-calvarial bone grafts can be harvested from the same operative field and cover small to medium-sized defects. Other sources of autogenous grafts include split ribs and iliac bone. Metals, calcium ceramics, and polymers such as methylmethacrylate can be used to cover intracranial contents and restore calvarial contour when defects are large or when autogenous material is not available. Palliation from tumor burden, prevention of pathologic fracture and oncologic emergencies, controlling pain, and enhancing quality of life are the goals of the oncologic and reconstructive surgeons in cases of advanced breast cancer. These goals are becoming even more important as new forms and combinations of chemotherapy, radiation, and gene therapy are extending the life expectancy of women with breast carcinoma.     

Chronic diarrhea due to metastatic breast cancer

We report the case of a patient with chronic diarrhea due to infiltrative cancer to the colon from the breast. A 49-year-old woman with a history of metastatic breast cancer to the bones was admitted to hospital with 4 weeks of watery diarrhea. Computed tomography (CT) scan of the abdomen showed pancolitis. Colonoscopy showed patchy subepithelial hemorrhages, most prominently in the ascending colon and sigmoid colon, but no mass lesion. Random biopsies taken throughout the colon showed infiltrative adenocarcinoma of breast origin in multiple specimens. Infectious work-up was negative.     

Turning the tide in lung cancer

Researchers are testing a slew of targeted therapeutic strategies in lung cancer. Signs are emerging that these therapies are gaining increasing traction in what has long been one of oncology's minefields. Malorye Allison investigates.     

Evaluation of a proposed breast cancer screening regimen.

The Forrest working group on breast cancer screening recommended routine mammography for women in the United Kingdom at ages 50, 53, 56, 59, 62, and 65. Benefits were costed at about 3000 pounds for each life year recovered, but there was no estimate of the cost of each life saved, and the consequent reduction in mortality from breast cancer in the general population of the United Kingdom was not estimated. The present study addressed both of these issues using an interactive computer modelling process. Long term savings were calculated at 900 deaths a year in England and Wales--that is, about 8% of the total deaths from breast cancer--and 9% of life years currently lost. The cost of each death saved from breast cancer was estimated at 39,000 pounds.     

Prognostic significance of CA 15.3 in metastatic breast cancer

We have investigated the possible relation between serum levels of CA 15.3 and disease status in 110 patients after radical mastectomy for breast cancer, with metastatic diffusion. Its persistent elevation was usually related to a very poor prognosis. In patients who died within 18 months the marker was always elevated. In case of progression of the disease, the marker level appeared to be consistently correlated with the general clinical condition. In healthy patients with stable disease the marker remained near the normal range.     

Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer

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Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer

Cyclooxygenase-2 (COX-2) inhibitors are rapidly emerging as a new generation of therapeutic drug in combination with chemotherapy or radiation therapy for the treatment of cancer. The mechanisms underlying its antitumor effects are not fully understood and more thorough preclinical trials are needed to determine if COX-2 inhibition represents a useful approach for prevention and/or treatment of breast cancer. The purpose of this study was to evaluate the growth inhibitory mechanism of a highly selective COX-2 inhibitor, celecoxib, in an in vivo oncogenic mouse model of spontaneous breast cancer that resembles human disease. The oncogenic mice carry the polyoma middle T antigen driven by the mouse mammary tumor virus promoter and develop primary adenocarcinomas of the breast. Results show that oral administration of celecoxib caused significant reduction in mammary tumor burden associated with increased tumor cell apoptosis and decreased proliferation in vivo. In vivo apoptosis correlated with significant decrease in activation of protein kinase B/Akt, a cell survival signaling kinase, with increased expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-2. In addition, celecoxib treatment reduced levels of proangiogenic factor (vascular endothelial growth factor), suggesting a role of celecoxib in suppression of angiogenesis in this model. Results from these preclinical studies will form the basis for assessing the feasibility of celecoxib therapy alone or in combination with conventional therapies for treatment and/or prevention of breast cancer.     

Pattern of serum immunoreactivity against breast cancer cell lysates may predict severity of disease in breast cancer patients

Humoral tumor-specific immunity has been investigated as a potential tool to identify tumor-associated antigens and evaluate cancer diagnosis and prognosis. Using SDS-PAGE and western blotting techniques we investigated the humoral immune response against tumor cell antigens in 36 breast cancer patients, 17 node-positive (NP) and 19 node-negative (NN). As a source of antigens, we prepared protein lysates from four breast cancer cell lines (AU565, BT474, MCF-7 and MDA-MB-231) which in vitro exhibit different features of invasion, estrogen receptor/progesterone receptor status and HER2/neu expression thereby potentially representing mild to aggressive forms of clinical disease. A higher number of immunocomplexes Ag–Ab were formed when serum from NN patients was immunoreacted against lysates from AU565 and MCF-7 in comparison to serum from NP patients (P < 0.01). BT474 cells were not a good antigenic source. MDA-MB-231 cells could not significantly discriminate between NN and NP patients since both groups showed higher amounts of reactivity against the lysate. However, comparative analysis of protein preparations purified from MCF-7 and MDA-MB-231 cells and immunodetected concomitantly with the same serum samples showed that serum from patients with cancers with worse prognosis (stage, nodality, HER2/neu and hormonal status) reacted more intensely to proteins purified from the relatively more invasive cell line MDA-MB-231 compared to MCF-7. These findings suggest that the study of serum antibody reactivity to antigens purified from breast cancer cell lines with different invasive properties should be further investigated for its potential in providing beneficial prognostic information in breast cancer. Supported by the United States Military Cancer Institute and the Department of Clinical Investigation at Walter Reed Army Medical Center. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense.     

Low-dose recombinant interleukin-2 and low-dose cyclophosphamide in metastatic breast cancer

Summary We undertook a preliminary study to examine the response rate of recombinant interleukin-2 (rIL-2) in patients with advanced measurable breast cancer, in a phase II clinical trial. The regimen we utilized was designed to allow outpatient administration. A treatment cycle consisted of low-dose cyclophosphamide (350 mg/m²) given on day -3 followed by the bolus administration of rIL-2 (3.6 × 10⁶ Cetus units/m²) on days 1–5, and 8–12. Toxicity was significant but acceptable. One partial remission was seen in 13 evaluable patients. In 2 additional patients clear evidence of an antitumor response was observed. The study was terminated prematurely owing to a shortage of rIL-2. Additional evaluation of rIL-2 in breast cancer appears warranted.     

Vacuolar ATPase driven potassium transport in highly metastatic breast cancer cells

Breast cancer is the second leading cause of death in women and thus has received a great deal of attention by researchers. Recent studies suggested decreased occurrence of cancer in patients treated with cardiac glycosides (CGs) for heart conditions. Because CGs induce their cellular effects via the Na⁺, K⁺ ATPase (Na–K), we treated four breast cancer cell lines (MCF-7, T47D, MDA-MB453, and MDA-MB231) and a non-cancerous breast ductal epithelial cell line (MCF-10A) with ouabain, a well-characterized CG, and measured cell proliferation by measuring bromodeoxyuridine incorporation. Ouabain (1 μM) decreased cell proliferation in all cell lines studied except MDA-MB453 cells. Western blot of Na–K α and β subunits showed α1, α3, and β1 expression in all cell lines except MDA-MB453 cells where Na–K protein and mRNA were absent. Potassium uptake, measured as rubidium (⁸⁶Rb) flux, and intracellular potassium were both significantly higher in MDA-MB453 cells compared to MCF-10A cells. RT-qPCR suggested a 7 fold increase in voltage-gated potassium channel (KCNQ2) expression in MDA-MB453 cells compared to MCF-10A cells. Inhibition of KCNQ2 prevented cell growth and ⁸⁶Rb uptake in MDA-MB453 cells but not in MCF-10A cells. All cancer cells had significantly higher vacuolar H-ATPase (V-ATPase) activity than MCF-10A cells. Inhibition of V-ATPase decreased ⁸⁶Rb uptake and intracellular potassium in MDA-MB453 cells but not in MCF-10A cells. The findings point to the absence of Na–K, high hERG and KCNQ2 expression, elevated V-ATPase activity and sensitivity to V-ATPase inhibitors in MDA-MB453. We conclude that cancer cells exhibit fundamentally different metabolic pathways for maintenance of intracellular ion homeostasis.