TrkC: a new predictive marker in breast cancer?

Available data involve neurotrophins and their receptors in carcinomas. Quantitative evaluation of these molecules in these tumors might be useful as prognostic marker and eventual treatments. Our study on 40 mammary tumors tries to correlate expression of these molecules and prognosis. Immunohistochemistry for NGF, BDNF, NT3, TrkA, TrkB, TrkC, and p75 was used. Patient's age, histopathology, Bloom-Richardson grading, estrogen and progesterone receptors, Ki-67 index, HER-2, p53 were evaluated. Statistics found inverse relationship between grading and TrkC expression. We found significantly higher TrkC expression in Grade I than in Grade III tumors. Rise in TrkC expression could indicate good prognosis.     

Obesity hormone leptin: a new target in breast cancer?

Leptin is a multifunctional hormone produced mainly by the adipose tissue and involved in the regulation of food intake and energy balance. In addition, leptin can stimulate mitogenic and angiogenic processes in peripheral organs. Because leptin levels are elevated in obese individuals and excess body weight has been shown to increase breast cancer risk in postmenopausal women, attempts have been made to evaluate whether leptin can promote breast cancer. Data obtained in cell and animal models and analyses of human breast cancer biopsies indeed suggest such an involvement. Furthermore, a recent report clearly shows that targeting leptin signaling may reduce mammary carcinogenesis. Thus, leptin should become a new attractive target in breast cancer.     

Gemcitabine plus docetaxel: a new treatment option for anthracycline pretreated metastatic breast cancer patients?

Antimetabolite-taxane combinations have been shown to be effective chemotherapy in patients with metastatic breast cancer (MBC). A multicentre phase III trial comparing gemcitabine-docetaxel with capecitabine-docetaxel in women with anthracycline pretreated MBC was carried out in several European countries. Its results were presented recently [1]. One-hundred and fifty-three patients were randomly assigned to receive docetaxel (75 mg/m2, day 1) plus gemcitabine (1000 mg/m2, days 1, 8) and 152 received docteaxel plus capecitabine (1250 mg/m2, bid days 1-14) every 3 weeks until disease progression. No difference in efficacy of the two treatment regimens was observed in terms of progression-free survival (35 weeks in both treatment arms), overall response rate (32% vs. 32%), time to treatment failure (19 vs. 18 weeks, respectively), or response duration (36 vs. 42 weeks). Drug-related toxicity, particularly hand-foot syndrome, mucositis and diarrhoea, was more frequent with capecitabine-docetaxel and there was a higher incidence of drug-related treatment withdrawals with this combination. Gemcitabine-docetaxel appeared to have a more favourable risk-benefit profile than capecitabine-docetaxel, and is an important new treatment option for women with anthracycline-pretreated MBC.     

ADAM10: a new player in breast cancer progression?

Background:

The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. As cleavage of several of these proteins has been implicated in cancer formation and progression, we hypothesised that ADAM10 is also involved in these processes.

Methods:

ADAM10 expression was decreased by RNA interference and the effects of this on cell numbers, invasion and migration were determined. We also examined the effect of ADAM10 inhibition on breast cancer cell line invasion and migration.

Results:

Using the triple-negative (TN) breast cancer cell lines, BT20, MDA-MB-231 and the non-TN cell line MDA-MB-453, knockdown of ADAM10 expression significantly decreased in vitro migration (P<0.01; for each cell line). Similarly, treatment with the ADAM10-selective inhibitor GI254023X reduced migration in the three cell lines (for BT20, P<0.001; for MDA-MB-231, P=0.005; for MDA-MB-453, P=0.023). In contrast, neither knockdown of ADAM10 nor treatment with the ADAM10-selective inhibitor GI254023X significantly affected cell numbers. Using extracts of primary breast cancers, higher levels of ADAM10 were found more frequently in high-grade vs low-grade tumours (P<0.001) and in oestrogen receptor (ER)-negative compared with ER-positive tumours (P=0.005). Analysis of pooled publicly available data sets found that high levels of ADAM10 mRNA were associated with adverse outcome in patients with the basal subtype of breast cancer.

Conclusions:

Based on our combined cell line and breast cancer extract data, we conclude that ADAM10 is likely to be involved in breast cancer progression, especially in the basal subtype.     

Epigenetics in breast cancer: what's new?

Epigenetic changes are critical for development and progression of cancers, including breast cancer. Significant progress has been made in the basic understanding of how various epigenetic changes such as DNA methylation, histone modification, miRNA expression, and higher order chromatin structure affect gene expression. The present review will focus on methylation and demethylation of histones. While the acetylation of histones has been at the forefront of well-characterized post-translational modifications of histones, including the development of inhibitors targeting de-acetylating enzymes, the past few years have witnessed a dramatic increase in knowledge regarding the role of histone methylation/demethylation. This is an exciting and rapidly evolving area of research, with much promise for potential clinical intervention in several cancers including breast cancer. We also summarize efforts to identity DNA methylation signatures that could be prognostic and/or predictive markers in breast cancer, focusing on recent studies using genome-wide approaches. Finally, we briefly review the efforts made by both the National Institutes of Health Epigenome Project and The Cancer Genome Atlas, especially highlighting the study of breast cancer epigenetics, exciting technological advances, potential roadblocks, and future directions.     

Stereotactic body radiotherapy for oligometastatic breast cancer: a new standard of care,or a medical reversal in waiting?

Metastases-directed therapy via surgery or stereotactic body radiotherapy (SBRT) has become the de facto standard of care in the United States and abroad despite a lack of high quality prospective, randomized trials. Oligometastatic tumors may behave in an inherently more indolent manner secondary to underlying biologic characteristics, including discrepant microRNA expression patterns. This biologic discrepancy suggests that historic improvements in survival observed in retrospective series may stem from the inherent biology of oligometastases and selection biases as opposed to advances in novel localized treatments. In this review, we discuss the theoretical basis for metastases-directed therapies, retrospective data supporting these approaches, recent advances in oligometastasis biology, and ongoing prospective randomized trials designed to compare SBRT and standard of care systemic therapies. We focus on metastases-directed therapy, primarily SBRT, for oligometastatic breast cancer with references to other tumor types when these other tumor types inform oligometastatic breast cancer treatment.     

XMRV: a new virus in prostate cancer?

Several recent articles have reported the presence of a gammaretrovirus, termed "XMRV" (xenotropic murine leukemia virus-related virus) in prostate cancers (PCa). If confirmed, this could have enormous implications for the detection, prevention, and treatment of PCa. However, other articles report failure to detect XMRV in PCa. We tested nearly 800 PCa samples, using a combination of real-time PCR and immunohistochemistry (IHC). The PCR reactions were simultaneously monitored for amplification of a single-copy human gene, to confirm the quality of the sample DNA and its suitability for PCR. Controls showed that the PCR assay could detect the XMRV in a single infected cell, even in the presence of a 10,000-fold excess of uninfected human cells. The IHC used 2 rabbit polyclonal antisera, each prepared against a purified murine leukemia virus (MLV) protein. Both antisera always stained XMRV-infected or -transfected cells, but never stained control cells. No evidence for XMRV in PCa was obtained in these experiments. We discuss possible explanations for the discrepancies in the results from different laboratories. It is possible that XMRV is not actually circulating in the human population; even if it is, the data do not seem to support a causal role for this virus in PCa.     

Nipple-sparing mastectomy in breast cancer: a viable option?

BACKGROUND: In women with breast cancer for whom breast-conserving therapy (BCT) is not the best option, a nipple and areola complex-(NAC) sparing mastectomy with immediate reconstruction has been proposed as a good and safe alternative to conventional, more radical mastectomy. Surgeons hesitate to perform this operation for fear of recurrence of tumour in the NAC due to undetected nipple involvement (NI) of the tumour. In order to determine whether a NAC-sparing mastectomy is a viable option, the frequency and predictive factors of NI by the tumour were studied in the literature. METHODS: A literature survey was performed by searching the Medline database. Other references were derived from the material perused. RESULTS AND CONCLUSIONS: NI is found in up to 58% of mastectomy specimens and correlates with tumour size, tumour-areola or tumour-nipple distance, positive lymph nodes and clinical suspicion. Best candidates for NAC-sparing mastectomy are patients with a small tumour (T1) at a large distance (>4-5 cm) from the nipple. However, in these patients BCT has excellent results with low complications and recurrence rates. Considering the incidence of NI in larger tumours (T2 average 33%, T3 average >50%) a NAC-sparing mastectomy may carry an unacceptable high risk for local relapse and should therefore not be advocated.