Factors predicting trastuzumab-related cardiotoxicity in a real-world population of women with HER2+ breast cancer.

BACKGROUND: Trastuzumab may improve disease-free survival after chemotherapy for HER2-positive breast cancer. However, it carries a risk of cardiotoxicity and counseling patients about such risks is part of informed consent. The National Institute for Health and Clinical Excellence has published guidelines for cardiac assessment before and during treatment with trastuzumab in order to minimize the risk of cardiotoxicity. The aim of the present study was to identify risk factors for cardiotoxicity attributed to trastuzumab in a cohort population treated for primary and metastatic breast cancer. PATIENTS AND METHODS: This study included all women who started a course of trastuzumab from February 2006 - February 2011 at three NHS Trusts in the UK. Their cardiac function during treatment was recorded and cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% and a reduction to <50%, or a clinical reduction in cardiac function as defined by the New York Heart Association. An independent samples t-test was used to assess whether patient age predicted cardiotoxicity. Pearson's chi-squared tests of independence were used to investigate the association between cardiotoxicity, the indication for trastuzumab, exposure to anthracycline chemotherapy, and Adult Comorbidity Evaluation-27 index (ACE-27) scores. RESULTS: There were 388 female patients included in this study, with a mean age of 54 (range = 25-100 years). Cardiotoxicity was recorded during 61 (15.72%) courses of trastuzumab treatment. There were no associations between cardiotoxicity and the three factors (indication, exposure to anthracyclines, or ACE-27 score), and no significant difference in age between patients with and those without cardiotoxicity. However, subgroup analysis of patients who experienced cardiotoxicity (n = 61) showed that there was a negative correlation (-0.455; p = 0.001) between time-to-first cardiotoxicity event and age in the group who had received concurrent anthracycline therapy (n=49). CONCLUSION: In a real-world 5-year population of patients who received trastuzumab, the incidence of drug-related cardiotoxicity was higher than expected, and the age of the patients appeared to predict the first cardiotoxic event amongst those who experienced cardiotoxicity and had received prior anthracyclines. However, incidence of cardiotoxicity in the whole cohort did not appear to be predicted by age, comorbidity, indication, or exposure to anthracylines. Vigilance, therefore, seems justified when conducting cardiac surveillance for all patients during treatment with trastuzumab, but especially for those who are elderly and receiving concurrent anthracycline therapy.

Antiangiogenic drugs for chemotherapy of bladder tumours.

BACKGROUND: Bladder cancers have different angiogenic pathways distinguishing not only papillary from solid tumours, but even papillary superficial from papillary invasive ones, thus representing selective targets for antiangiogenic drugs. METHODS: The bacterial wall component tecogalan, inhibiting basic fibroblast growth factor (bFGF), the fumagillin derivative TNP-470, inhibiting vascular endothelial growth factor (VEGF), the distamycin A derivative PNU153429, and the tetracycline minocycline were administered to nude mice injected with the human bladder cancer cell lines 639V, causing bFGF-expressing papillary superficial tumours, or T24, causing VEGF-expressing papillary invasive tumours. RESULTS: Tecogalan had no effect even on 639V tumour growth, where bFGF was unaffected. TNP-470 only had an effect on T24 tumours, delaying tumour appearance and growth and lowering VEGF; these effects were augmented by adding minocycline. PNU153429 had no effect on 639V tumours, and a slight effect on T24 tumours. CONCLUSION: TNP-470 may represent a selective drug for the treatment of VEGF-expressing invasive papillary bladder tumours.

Tumor and metastasis suppression by the human RNASET2 gene.

The region 6q27 from human chromosome 6 has been reported to contain one or more tumor suppressor genes on the basis of cytogenetic, molecular and functional studies. We have recently carried out a detailed analysis of a candidate gene from 6q27 to evaluate its putative role as a tumor suppressor gene involved in ovarian cancer pathogenesis. The RNASET2 gene was shown to behave as a class II tumor suppressor and abolish the tumorigenic potential of an ovarian cancer-derived cell line. In this study, we have started the cellular and biochemical characterization of RNASET2 and showed that it is a secreted glycoprotein. Moreover, we have extended our previous studies by evaluating the effect of RNASET2 on the metastatic behavior of the highly-invasive ovarian cancer cell line HEY3MET2. From such analysis, RNASET2 was found to significantly decrease the metastatic potential of this cell line in vivo. Moreover, RNASET2-mediated suppression of tumorigenesis and metastasis was not affected by a double point mutation targeted to the putative ribonuclease catalytic sites, suggesting that tumor suppression by RNASET2 is not mediated by its ribonuclease activity. The potential biological implications of this unexpected finding are discussed in relation to the current evolutionary models.

An overview of the effect of linoleic and conjugated-linoleic acids on the growth of several human tumor cell lines.

Both n-6 and n-3 polyunsaturated fatty acids are dietary fats important for cell function, being involved in several physiologic and pathologic processes, such as tumorigenesis. Linoleic acid and conjugated linoleic acid, its geometrical and positional stereoisomer, were tested on several human tumor cell lines originating from different tissues and with different degrees of malignancy. This was to provide the widest possible view of the impact of dietary lipids on tumor development. While linoleic acid exerted different effects, ranging from inhibitory to neutral, even promoting growth, conjugated linoleic acid inhibited growth in all lines tested and was particularly effective against the more malignant cells, with the exception of mammary tumor cells, in which behavior was the opposite, the more malignant cell line being less affected. The inhibitory effect of conjugated linoleic acid on growth may be accompanied by different contributions from apoptosis and necrosis. The effects of conjugated linoleic acid on growth or death involved positive or negative variations in PPARs. The important observation is that a big increase of PPARalpha protein occurred in cells undergoing strong induction of apoptosis, whereas PPARbeta/delta protein decreased. Although PPARalpha and PPARbeta/delta seem to be correlated to execution of the apoptotic program, the modulation of PPARgamma appears to depend on the type of tumor cell, increasing as protein content, when inhibition of cell proliferation occurred. In conclusion, CLA may be regarded as a component of the diet that exerts antineoplastic activity and its effect may be antiproliferative or pro-apoptotic.