Department of Developmental and Molecular Biology, Center of Reproductive Biology and Women’s Health, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA.

In many human cancers, the abundance of macrophages in the tumor microenvironment is correlated with poor prognosis. Experimental evidence for the causal relationship between macrophages and poor prognosis came from mouse models of breast cancer in which genetic ablation of macrophages resulted in attenuation of tumor progression and metastasis, and premature recruitment to hyperplastic lesions accelerated these processes. Malignancy is defined by the invasion of tumor cells into the stroma, a process that allows escape of these cells into the circulation and dissemination to distant sites. In this review, I argue that macrophages are recruited to the invasive front by expression of tumor-derived chemotactic factors and in response to the disruption of the basement membrane. At this invasive site, macrophages enhance tumor cell migration and invasion through their secretion of chemotactic and chemokinetic factors including epidermal growth factor (EGF). They promote angiogenesis by the synthesis of angiogenic factors including vascular EGF, and they remodel the extracellular matrix and in particular, regulate collagen fibrillogenesis. A combination of these factors provides a triple-whammy, as the more mobile and invasive tumor cells track along collagen fibers that are also anchored to blood vessels, which are fabricated at sites of invasion and through which macrophages potentiate tumor cell intravasation. All of these activities suggest that macrophage functions are significant targets for the generation of novel therapeutics that should improve the current cytotoxic armamentarium.

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Objective: To determine physical activity (PA) self-efficacy correlates in breast cancer survivors. Methods: Mail survey of 192 breast cancer survivors. Results: Structural equation analyses demonstrated significant and direct associations for perceived PA barriers (beta=-.29), fatigue (beta=-.24), social support (beta=.12), enjoyment (beta=.12), and prediagnosis PA (beta=.11) with barriers self-efficacy. Prediagnosis PA (beta=.51), social support (beta=.26), and barriers self-efficacy (beta=.13) demonstrated direct associations with current leisure PA. Task self-efficacy analysis results were similar except perceived barriers and prediagnosis PA were not associated with task self-efficacy. Conclusions: Multiple potential efficacy correlates exist and may vary based on the aspect of self-efficacy examined.

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Bone Research Program, ANZAC Research Institute, University of Sydney, Hospital Road, Concord NSW 2139, Sydney, Australia.

Osteosclerotic metastases account for 20% of breast cancer metastases with the remainder osteolytic or mixed. In mouse models, osteolytic metastases are dependent on bone resorption for their growth. However, whether the growth of osteosclerotic bone metastases depends on osteoclast or osteoblast actions is uncertain. In this study, we investigate the effects of high and low bone resorption on tumour growth in a mouse model of osteosclerotic metastasis. We implanted human breast cancer, MCF-7, cells into the tibiae of mice. Low and high levels of bone resorption were induced by osteoprotegerin (OPG) treatment or calcium deficient diet respectively. We demonstrate that OPG treatment significantly reduces tumour area compared to vehicle (0.42 +/- 0.06 vs. 1.27 +/- 0.16 mm(2), P < 0.01) in association with complete inhibition of osteoclast differentiation. In contrast, low calcium diet increases tumour area compared to normal diet (0.90 +/- 0.30 vs. 0.58 +/- 0.20 mm(2), P < 0.05) in association with increased osteoclast numbers (84.44 +/- 5.18 vs. 71.11 +/- 3.56 per mm(2) bone lesion area, P < 0.05). Osteoblast surfaces and new woven bone formation were similarly increased within the tumour boundaries in all treatment groups. Tumour growth in this model of osteosclerotic metastasis is dependent on ongoing bone resorption, as has been observed in osteolytic models. Bone resorption, rather than bone formation, apparently mediates this effect as osteoblast surfaces in the tumour mass were unchanged by treatments. Treatment of breast cancer patients through correction of calcium deficiency and/or with anti-resorptive agents such as OPG, may improve patient outcomes in the adjuvant as well as palliative settings.

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Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo, 135-8550, Japan, tomo.osako@jfcr.or.jp.

PURPOSE: We retrospectively evaluated the efficacy and safety of combination therapy of trastuzumab plus capecitabine in heavily pretreated patients with HER2-positive metastatic breast cancer (MBC). METHODS: Patients with HER2-positive MBC who had been administered the combination therapy between July 2003 and July 2006 at the Cancer Institute Hospital, Tokyo, were retrospectively reviewed. Capecitabine (828 mg/m(2)) was given twice daily for 3 weeks followed by a 1-week rest period; this was repeated every 4 weeks. Trastuzumab was given at 4 mg/kg as an initial loading dose intravenously, followed by 2 mg/kg weekly. We investigated objective response rate (ORR), clinical benefit rate (CBR), and time-to-treatment failure (TTF) according to the Response Evaluation Criteria in Solid Tumors guidelines. Adverse events were graded according to the National Cancer Institute, Common Toxicity Criteria, version 3.0. RESULTS: A total of 49 patients were assessed and median follow-up time of patients was 16.2 months (1.4-43.5 months). ORR was 16% (95% confidence interval: 7-30%) and CBR was 47% (95% confidence interval: 32-62%). Median TTF was 5.4 months. Common adverse effects were hand-foot syndrome, liver dysfunction, and bone marrow suppression. Grade 3 adverse events were observed in nine patients (18%). One patient (2%) suffered from symptomatic chronic heart failure, which improved after discontinuation of trastuzumab. CONCLUSIONS: The combination therapy of trastuzumab plus capecitabine is effective and tolerable for heavily pretreated patients with HER2-positive MBC.

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University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue K4/6 CSC, Madison, WI, 53792, USA, hhbailey@facstaff.wisc.edu.

PURPOSE: Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer. METHODS: Eligible women were treated with POH four times daily at 1,200-1,500 mg m(-2) dose(-1) on a 28-day cycle. Patients tolerating 1,200 mg m(-2) day(-1) four times daily after one cycle were dose-escalated to 1,500 mg/m(2). The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations. RESULTS: Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m(2). Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29-123 days). Median overall survival was 389 days (95% CI, 202-776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-beta1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability. CONCLUSIONS: Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.

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