Approximately 15%-30% of breast cancers have overexpression or amplification of human epidermal growth factor receptor 2 (HER2), which is associated with a worse prognosis in the absence of therapy. While HER2 testing is common there are issues associated with its sensitivity and specificity, which may impact the perceived usefulness of treatments. The objectives of this review are to understand the characteristics and peculiarities of HER2+ breast cancer, and to discuss the issues associated with the correlation of HER2 immunogenicity with therapeutic response, especially of trastuzumab. There are two issues associated with the correlation between HER2 immunogenicity and therapeutic response: possible resistance to trastuzumab through lack of phosphatase and tensin analog or receptor expression, and nonspecific or insensitive measurement of HER2 expression. These issues can be addressed through the evaluation of other factors in addition to HER2 status at diagnosis, and improvements in the performance and validation of HER2 testing. It is important that HER2 tests are of the highest quality and that laboratories performing the tests are assessed and validated correctly. Pathologists must proactively monitor the quality of their tests and oncologists should ensure that all breast cancer cases are assessed for HER2, as only then can the patients benefit from specific and appropriate therapy. less...

Brain metastases are a frequent complication of cancer. However, effective treatments are available. This article aims to review clinical aspects of patients with brain metastases discussing the various treatment options for such patients. It will address the importance and significance of brain metastases in patients with breast cancer and, finally, review the problem of brain metastasis associated with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. With ever-improving survival rates of patients with cancer, there is a greater likelihood that many will develop brain metastases. Treatments such as whole brain or stereotactic radiotherapy and surgery have been shown to be effective against brain metastases. In HER2+ breast cancer, trastuzumab has been shown to be very effective, although it cannot cross the blood-brain barrier. If patients with breast cancer who are being treated with trastuzumab and are responding systemically, develop brain metastases, then patient prognosis does need to be taken into account; however, maintaining treatment with trastuzumab while using available therapies to treat intracranial lesions should be considered as an option. less...

Targeted therapies with monoclonal antibodies have been shown to improve the outcome of non-small cell lung cancer (NSCLC). Current strategies focus on the blockade of growth factor receptors and the inhibition of angiogenesis. Epidermal growth factor receptor (EGFR)-directed monoclonal antibodies in combination with platinum-based first-line chemotherapy have shown promising efficacy in phase II trials. In a phase III trial, cetuximab combined with cisplatin/ vinorelbine resulted in superior survival compared to chemotherapy alone in patients with advanced EGFR-positive NSCLC. Inhibition of angiogenesis has also been successfully applied as a new treatment strategy. Bevacizumab added to palliative chemotherapy has improved progression-free survival in two phase III trials and overall survival in one of these trials in selected patients with advanced non-squamous cell lung cancer. Bevacizumab is now approved for selected patients with advanced NSCLC in combination with platinum-based chemotherapy. Figitumumab is a monoclonal antibody against the insulin-like growth factor-1 receptor (IGF-1R) which demonstrated activity in preclinical models of NSCLC and in a phase II trial. Because of these promising results, three randomized, open-label, international phase III trials of figitumumab in patients with locally advanced or metastatic NSCLC are in progress. less...

Current and old problems. Principally there are two different types of bladder cancer. Non-invasive papillary low grade tumors (pTa G1-G2) are genetically stable, recur frequently but show a low risk of progression. On the other hand there are high grade tumors (pT1-4, carcinoma in situ), which are genetically unstable, show biologically aggressive behaviour and progress. The distinction between non-invasive (pTa) and minimal-invasive (pT1) is one of the most challenging areas in bladder pathology. Due to the lack of appropriate auxiliary analysis the diagnosis is based entirely on histopathology. P53 immunohistochemistry can be helpful in the assessment of recurring high grade neoplasia. Targeted therapy in bladder cancer is particularly interesting, since a high number of oncogenes are activated and overexpressed (e.g. HER2 and EGFR). less...

Kidney donors, similar to the general population, are at risk for development of type 2 diabetes mellitus (T2DM). The course of donors who develop T2DM has not been studied. We surveyed 3777 kidney donors regarding the development of T2DM. Of the 2954 who responded, 154 developed T2DM 17.7 +/- 9.0 years after donation. The multivariable risk of development of T2DM was associated with type 1 DM in the recipient, male gender and body mass index >30 kg/m(2) at time of donation. Compared to age, gender, duration after donation and body mass index (BMI)-matched non-diabetic donor controls; diabetic donors were more likely to have hypertension (70.8% vs. 36.2%, p = 0.005), proteinuria (18.8% vs. 3.9%, p < 0.0001) but had a similar serum creatinine. eGFR change after T2DM development was -0.80 +/- 0.94 mL/min/year, -0.70 +/- 0.86 in nondiabetic donors with similar duration after donation and -0.61 +/- 0.76 mL/min/year in age, gender, BMI and duration after donation matched nondiabetic donor controls. These preliminary and shor-term data demonstrate that factors associated with T2DM in kidney donors are similar to those in the general population and donors screened carefully at the time of donation do not appear to have an acceleration of diabetic kidney disease. less...

A phase II clinical and molecular study of the Spanish group for digestive tumor therapy (TTD). PURPOSE: To evaluate the efficacy and safety of first-line single-agent cetuximab in fit elderly patients with metastatic colorectal cancer, as well as potential molecular predictive factors for efficacy. PATIENTS AND METHODS: Patients aged 70 or older with metastatic CRC without criteria for frailty and no prior treatment for advanced disease were treated with single-agent cetuximab 400mg/m(2) followed by weekly 250mg/m(2) until disease progression or unacceptable toxicity. RESULTS: Forty-one patients were included. Two patients achieved a complete response and 4 patients had a partial response for an overall response rate of 14.6%. Fifteen patients (36.6%) remained stable. Median time to progression was 2.9 months and median overall survival 11.1 months despite two-third of patients received chemotherapy at progression. Forty-five percent of EGFR gene copy number positive patients by FISH were progression-free at 12 weeks, in contrast with 12% of FISH negative patients (p=0.04). Grade 3 skin toxicity was reported in 5 patients (12.2%). Hypersensitivity infusion reactions were not reported and there were no toxic deaths CONCLUSION: Cetuximab is a safe monoclonal antibody with moderate activity in first-line metastatic colorectal cancer, but the present study does not support the use of cetuximab as single-agent in first-line fit elderly patients with metastatic CRC. less...

Transforming growth factor-alpha (TGFalpha) is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. EGFR signaling activates several intracellular signaling pathways including phosphatidylinositol 3'-kinase (PI3K). We previously showed that induction of lung-specific TGFalpha expression in transgenic mice caused progressive pulmonary fibrosis over a 4-week period. The increase in levels of phosphorylated Akt, detected after 1 day of doxycycline-induced TGFalpha expression, was blocked by treatment with the PI3K inhibitor, PX-866. Daily administration of PX-866 during TGFalpha induction prevented increases in lung collagen and airway resistance as well as decreases in lung compliance. Treatment of mice with oral PX-866 4 weeks after the induction of TGFalpha prevented additional weight loss and further increases in total collagen, and attenuated changes in pulmonary mechanics. These data show that PI3K is activated in TGFalpha/EGFR-mediated pulmonary fibrosis and support further studies to determine the role of PI3K activation in human lung fibrotic disease, which could be amenable to targeted therapy. less...

OBJECTIVES:: Lapatinib (GW572016) is a selective and potent dual tyrosine kinase inhibitor of the epidermal growth factor 1 (EGFR) and 2 (HER2), approved in the treatment of HER2 positive breast cancer. Since EGFR and HER2 overexpression has also been seen in prostate cancer and appears to correlate with a worse clinical outcome, Lapatinib may represent a novel therapeutic strategy in prostate cancer. This Phase II multicenter clinical trial is the first to evaluate Lapatinib in early stage, hormonally untreated recurrent or metastatic prostate cancer. METHODS:: Eligible patients received lapatinib 1500 mg PO daily until progression. The primary end point was prostate specific antigen (PSA) response Archival tumor tissue was collected for EGFR and HER2 analysis. RESULTS:: A total of 23 patients, median age 67, ECOG PS 0-2, mean baseline PSA 7.5, were evaluable for response. In total, 125 cycles were administered. The most frequent adverse events were lymphopenia, fatigue, rash, dyspepsia, and diarrhea. Grade 3+ increased alanine aminotransferase (ALT) was reported in 2 patients, and grade 4 blurry vision in 1 patient. No PSA responses were seen Median time to progression (TTP) was 4.6 months and 6 months progression-free estimate was 44.5%. CONCLUSIONS:: Lapatinib was well tolerated but like other EGFR- and HER2-targeted agents in advanced HRPC failed to show significant antitumor activity even in this very early stage hormonally untreated population. less...

Endocrine therapies targeting estrogen action are pivotal for the prevention and treatment of ER-positive breast cancers. Previous studies sought to recreate hormone responsiveness by the stable expression of ERalpha in the ER-negative MDA-MB-231 breast cancer cells. Paradoxically, estrogen inhibits breast cancer cell growth when an exogenous ERalpha is expressed. In this study, we have built on previous studies by developing a Tet-off adenoviral system to express ERalpha in the ER-negative SKBr3 breast cancer cells that over-express both EGFR and HER2. This system efficiently delivers ERalpha and the expression level of ERalpha is controlled by doxycycline in a concentration-dependent manner. The growth of SKBr3 was inhibited by ERalpha expression and further inhibited in the presence of 1 nM 17beta-estradiol. SKBr3 cells were arrested at G0/G1 cell cycle upon ERalpha expression, which corresponded to an increase of p21Cip1/Waf1, hypo-phosphorylation of pRb and decrease of E2F1. Estrogen also reduced EGFR and HER2 expression in SKBr3 cells after ERalpha was expressed. Given that estrogen-induced increase of p21Cip1/Waf1 and decrease of E2F1 was also observed in MDA-MB-231 cells stably transfected with ERalpha, our results suggest that a common pathway might be shared by different breast cancer cell lines whose growth is suppressed by ectopic ERalpha and estrogen. less...

Arsenic is well documented as a chemotherapeutic agent capable of inducing cell death; however, it is also considered as a human carcinogen. Although it has recently been shown that arsenite exposure can potentiate genotoxicity, little is known about its global effects exerted in cells at the proteome level. Immortalized human small airway epithelial cells exposed to arsenite were used to identify phosphoproteins of two major signaling cascades, such as the human phospho-receptor tyrosine kinase (Phospho-RTK) and the mitogen-activated protein kinases (MAPKs). These two arrays included several phosphoproteins, such as EGFR, ErbB2, ErbB4, InsulinR, Flt-3, extracellular signal-regulated kinases (ERK1/2), intracellular kinases such as AKT, GSK-3, c-Jun N-terminal kinases (JNK1-3) and different p38 isoforms (alpha/beta/delta/gamma). In arsenite-treated cells, phosphorylation of EGFR, InsulinR and Flt3R showed an increase when compared to their non-arsenite treated counterparts. Inhibitors of these proteins further confirmed the involvement of such proteins in the neoplasm transformation of arsenite-treated human small airway epithelial cells as seen in changes in plating efficiency, anchorage-independent growth and proliferation rate. It can be concluded that analysis of phosphoprotein by using phosphoproteomic profiling can be very useful to understand the mechanism of arsenite-induced carcinogenesis. less...