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...

INTRODUCTION: Although having high clinical efficacy in the treatment of human epidermal growth factor receptor-2 (HER2+) metastatic breast cancer, trastuzumab has been associated with cardiotoxicity, and the etiology and pathogenesis of this condition is currently under investigation. METHODS: This paper reviews the cardiotoxicity, associated with trastuzumab use and discusses the risk assessment and management of cardiac dysfunction. RESULTS: The increased risk of cardiotoxicity is lower when trastuzumab is given as monotherapy (3%-7%) compared with anthracyclines + trastuzumab therapy (27%). Type II cardiac changes occur in trastuzumab-treated patients, which do not appear to be dose-related, are not associated with histological changes, and are generally reversible. Several risk factors for cardiac events have been identified and assessing levels of troponin I and N-terminal pro-brain B-type natriuretic peptide before and after treatment with trastuzumab may allow early detection of cardiotoxicity. A symptomatic and functional evaluation scheme for patients indicated for treatment with trastuzumab has also been proposed to work alongside therapeutic options for the treatment of heart failure. CONCLUSION: The risk of cardiac dysfunction associated with trastuzumab can be justified given the increase in overall survival. This risk is lower when trastuzumab is given as monotherapy. The paradigm for cardiologists remains the same: treat the cancer effectively whilst preventing cardiotoxicity. 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...

Humanized antibodies vary and have certain effects, but they are expensive and require repeated administration. We developed cells which constantly express a humanized antibody, and we performed anticancer humanized antibody therapy involving cell transplantation. Genes with the same amino acid sequence as that of the variable region of trastuzumab (Herceptin) as the humanized anti-HER2 monoclonal antibody were produced by overlap-PCR and were connected to the anti-human CD16 antibody [anti-HER2+anti-CD16 single-chain antibody (anti-HER2+CD16 scAb)]. For transplantation, stem cell-like cells that are immunologically tolerant and do not transform into cancer [mouse embryo fibroblast cell line C3H10T1/2 (10T1/2)] were used. The antibody was incorporated into 10T1/2 (antibody-expressing cells) using the pMX-IRES-EGFP retroviral vector. Cell supernatants and human monocytes were exposed to the human breast cancer strain HTB131 expressing HER2, and the in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) effects were evaluated. After the transplantation of antibody-expressing and HTB131 cells into SCID mice, human monocytes were intermittently administered, and the in vivo ADCC effects were evaluated We found that the ex vivo dead cell rate was 15.4% for Herceptin, 5.6% for anti-HER2+CD16 scAb, 1.5% for anti-CD16 scAb, and 2.1% for the control, demonstrating the antitumor effects of anti-HER2+CD16 scAb. In an antibody-expressing cell transplantation model, the inhibitory effects of this antibody on HTB131 cell establishment were observed. In conclusion, the establishment of breast cancer cells in the peritoneum was inhibited by the transplantation of antibody-expressing cells. Since this method requires cell transplantation only once, the drug cost may be reduced. less...

Since late 1990s, many molecular target agents have been introduced to clinical trials for various kinds of tumors, and some of them showing significant benefits have been approved. However, these global trials were mainly conducted outside Japan, and the 'drag lag' has been a serious problem in Japan recently. Nowadays, Japanese institutions have been participating in some global trials, and the drug lags are getting shorter. For colorectal cancer, molecular target agents such as bevacizumab and cetuximab have been approved in Japan, resulting in improved clinical outcomes. For gastric cancer, Japanese institutions not only contribute to the global Phase III trials of trastuzumab and bevacizumab but also show leadership in the early development of other new agents. For pancreatic cancer, only erlotinib has shown a survival benefit in these 10 years. Worldwide approach including Japan is warranted to achieve better clinical outcomes. For liver cancer, although Japanese institutions did not participate even in the Asian trial of sorafenib, it has been approved in Japan. For esophageal cancer, because there has been no new molecular target agents developed by pharmaceutical companies, investigator-initiated registration trial will play an important role. For all gastrointestinal malignancies, molecular target agents have made a progress in their treatments. In the near future, Japanese institutions will participate in more and more global trials and should play a specific role in worldwide drug development. Furthermore, the optimal use of these new drugs, molecular target agents, based on the daily practice should also be explored in Japan. less...

BACKGROUND:: Extramammary Paget disease (EMPD) is categorized into 2 groups: primary EMPD or EMPD secondary to underlying malignancy. Primary EMPD has a better prognosis, and the ability to distinguish between the 2 subsets has clinical relevance. Recent studies have suggested that immunostains, including cytokeratin (CK) 7, CK20, and BRST-2, distinguish between the 2 groups. We analyzed a large series of EMPD with an expanded immunohistochemical panel to assess its value in distinguishing primary from secondary disease. DESIGN:: Formalin-fixed, paraffin-embedded sections of 98 EMPD specimens from 61 patients (45 primary and 16 secondary) were immunostained with CK7, CK20, HER-2/neu, BRST-2, CDX2, androgen receptor (AR), and cyclin D1. The study included 44 women and 17 men (median age: 73 years). Median follow-up time was 47 months. RESULTS:: All EMPD specimens were vibrantly positive for CK7. The frequency of positivity for all EMPD samples was CK20 (28%), BRST-2 (40%), HER-2/neu (64%), CDX2 (10%), AR (16%), and cyclin D1 (76%). For primary EMPD, the frequency of positivity was CK20 (22%), BRST-2 (48%), HER-2/neu (65%), CDX2 (2%), AR (21%), and cyclin D1 (84%). For secondary EMPD, the frequency of positivity was CK20 (50%), BRST-2 (25%), HER-2/neu (60%), CDX2 (33%), AR (0%), and cyclin D1 (53%). Notably, all 6 of 7 cases of EMPD secondary to an anorectal adenocarcinoma tested were HER-2/neu negative and 5 of those 6 cases (80%) were CDX2 positive. CONCLUSIONS:: The role of CK7, CK20, and BRST-2 in distinguishing primary and secondary EMPD is limited because CK20 and BRST-2 were positive in large subsets of both groups. An expanded immunohistochemical panel, including HER-2/neu and CDX2, may be useful in discriminating primary EMPD from EMPD secondary to anorectal adenocarcinoma but fails to distinguish primary EMPD from EMPD secondary to urothelial or prostatic malignancy. The consistent overexpression of HER-2/neu in primary EMPD suggests a role for trastuzumab therapy in patients with recurrent disease. less...

Background:Overexpression of ErbB2 receptor in breast cancer is associated with disease progression and poor prognosis. Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer, has proven to be effective; however, a relevant problem for clinical practice is that a high fraction of breast cancer patients shows primary or acquired resistance to trastuzumab treatment.Methods:We tested on trastuzumab-resistant cells two novel human anti-tumour immunoconjugates engineered in our laboratory by fusion of a human anti-ErbB2 scFv, termed Erbicin, with either a human RNase or the Fc region of a human IgG1. Both Erbicin-derived immunoagents (EDIAs) are selectively cytotoxic for ErbB2-positive cancer cells in vitro and vivo, target an ErbB2 epitope different from that recognised by trastuzumab and do not show cardiotoxic effects.Results:We report that EDIAs are active also on trastuzumab-resistant tumour cells both in vitro and in vivo, most likely because of the different epitope recognised, as EDIAs, unlike trastuzumab, were found to be able to inhibit the signalling pathway downstream of ErbB2.Conclusion:These results suggest that EDIAs are immunoagents that could not only fulfil the therapeutic need of patients ineligible to trastuzumab treatment due to cardiac dysfunction but also prove to be useful for breast cancer patients unresponsive to trastuzumab treatment.British Journal of Cancer advance online publication, 5 January 2010; doi:10.1038/sj.bjc.6605499 www.bjcancer.com. less...

BACKGROUND:: Little information is available regarding the effects of new adjuvant treatment regimens on menstrual functioning in premenopausal women with early breast cancer. METHODS:: The authors conducted a retrospective review of data from premenopausal women who received treatment for early breast cancer to evaluate the rates of amenorrhea in follow-up. The women who were included received treatment with either doxorubicin and cyclophosphamide (AC) or combined AC and paclitaxel (T) (AC-T) given either every 3 weeks, or as a dose-dense (DD) regimen, or as AC followed by weekly T with trastuzumab or followed by trastuzumab (AC-T+trastuzumab). A multivariate logistic regression analysis was conducted to evaluate amenorrhea during follow-up. RESULTS:: Of 431 patients who were eligible for analysis, the average age at diagnosis was 13 years (range, 25-55 years), 61% of women received AC only, and 39% received AC-T. Of the 39% who received AC-T, 49% of women received DD therapy, 14% received AC-T+trastuzumab, and 71% of all patients received tamoxifen (TAM). The median follow-up was 33 months (range, 6-114 months). After adjusting for age, weight, gravidity, parity, age at menarche, smoking, alcohol use, TAM use, type and regimen of chemotherapy, and use of trastuzumab, the likelihood of remaining amenorrheic was not statistically different in patients who received AC-T versus AC (odds ratio [OR], 1.59; 95% confidence interval [CI], 0.8-3.2), DD treatment versus treatment every 3 weeks (OR, 0.56; 95% CI, 0.25-1.3), or AC-T + trastuzumab (OR, 0.6; 95% CI, 0.22-1.61). Amenorrhea was associated significantly with TAM use and age at diagnosis. CONCLUSIONS:: Recent advances in the adjuvant treatment of early breast cancer do not appear to have increased the risk of amenorrhea in premenopausal women. Cancer 2010. (c) 2010 American Cancer Society. less...

Using a hormone-dependent xenograft model, we established that loss of response to letrozole was accompanied by upregulation of the Her-2/mitogen-activated protein kinase (MAPK) pathway and downregulation of estrogen receptor alpha (ERalpha) and aromatase activity. In our previous study, we showed that stopping letrozole treatment or adding trastuzumab could reverse acquired resistance. In this study, we compared the effects of intermittent letrozole treatment and switching treatment between letrozole and trastuzumab on tumor growth in an attempt to optimize discontinuous letrozole treatment. The mice were treated with letrozole until the tumors developed resistance and then were divided into three groups: (a) letrozole, (b) trastuzumab, and (c) "off" (Delta(4)A supplement only); tumors were collected every week to examine changes in tumor protein expression and activity. In off group tumors, Her-2/p-MAPK activation gradually decreased and ERalpha and aromatase protein (and activity) increased. Within the first week of trastuzumab treatment, Her-2 and MAPK were downregulated and ERalpha was upregulated. When letrozole-resistant MCF-7Ca tumors were taken off treatment for 4 weeks, the second course of letrozole treatment provided a much longer duration of response (P = 0.02). However, switching treatment to trastuzumab for 4 weeks did not provide any inhibition of tumor growth. Our studies revealed that the adaptation of cells to a low-estrogen environment by upregulation of Her-2/MAPK and downregulation of ERalpha/aromatase was reversed on letrozole withdrawal. The tumors once again became responsive to letrozole for a significant period. These results suggest that response to letrozole can be prolonged by a short "break" in the treatment. Mol Cancer Ther; 9(1); 46-56. less...

Overexpression of urokinase plasminogen activator receptor (uPAR) or HER2 (erbB-2) in breast cancer is associated with a poor prognosis. We previously reported that gene amplification and overexpression of HER2 and uPAR occur in 70% of HER2 -amplified tumor cells from blood or tissue of breast cancer patients. In this study we first examined if depletion of HER2 and uPAR synergized in suppression of the growth of breast cancer cells that overexpress both HER2 and uPAR (SKBR3 and ZR 751). The results showed that depletion of either HER2 or uPAR by RNA interference suppressed cell growth and induced cell apoptosis, but that these effects were significantly enhanced in cells depleted of both HER2 and uPAR. Mechanistic analysis demonstrated silencing of HER2 and uPAR caused suppression of MAPK signal pathways, resulting in decrease of ERK activity and prompting a high p38/ERK activity ratio. The level of the phosphorylated form of ERK was decreased in cells depleted of HER2, uPAR or both, and the effect in cells depleted of both is the most evident. Moreover, down-regulation of uPAR synergized with trastuzumab to suppress the growth and induce apoptosis of SKBR3 and ZR 751 cells. uPAR RNAi significantly enhanced the effect of trastuzumab on inhibition of MAPK signal pathways. In conclusion, targeting HER2 and uPAR has a synergistic inhibitory effect on breast cancer cells. Our results provide evidence that simultaneous downregulation of HER2 and uPAR may offer an effective tool for breast cancer therapy. (c) 2010 UICC. less...