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Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold ( P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors. [ABSTRACT FROM AUTHOR]

Background: Proteomic analysis has become an effective tool in breast cancer research. In this study, we applied the new gel-free tandem mass tag (TMT) reference method for the first time in breast cancer. Materials and Methods: Proteomic analysis was used to compare 10 estrogen receptor (ER)-positive and 10 ER-negative samples. The results of the proteomic approach were validated by Western blot, immunohistochemistry and gene expression analysis. Results: 17 proteins with significant differences in expression were identified. 13 proteins were overexpressed in ER-negative tumors and 4 were overexpressed in ER-positive samples. All these proteins were characterized by relatively high cellular abundance. Conclusions: Our results demonstrate that the gel-free TMT approach allows the quantification of differences in protein expression levels. Further improvement of the sensitivity by subfractionation of the tissue should allow also the identification of low-abundance proteins and might lead to the use of this method in breast cancer research. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The new web tool Adjuvant Consensus gives the user access to the most recent information on how world leading experts suggest to treat a specific breast cancer with systemic therapy. By entering tumor characteristics, age, and menopausal status, the user can find out what experts and national guidelines suggest for this specific tumor. The basis for the suggested treatment options and guidelines are coming from 2 world leading resources: They reflect the reached expert consensus on the implications of evidence for patient treatment selection at the world leading consensus conference on adjuvant therapy held regularly in St. Gallen, and the ‘Clinical Practice Guidelines in Oncology’ for breast cancer published in the US by the National Cancer Center Network in January 2007. The calculated treatment options include the suggested systemic treatment – chemotherapy, hormonal therapy, and antibody therapy, alone or in combination – and the duration and sequence of therapy. Furthermore, the user can find information on the mode of action and important side effects of the different drugs. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: GABG-IV B-93 is a prospective, randomised study comparing goserelin (n =384) with no further treatment (n =392) in hormone receptor (HR)-negative breast cancer patients (n =465) after 3 cycles cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for patients with 0–3 positive lymph nodes (LN) or 4 cycles epirubicin, cyclophosphamide (EC) followed by 3 cycles CMF for patients with 4–9 positive LN. After completion of the ZEBRA trial the study was amended to enrol also HR-positive patients with 1–9+LN (n =311). After a median follow-up of 4.7 years neither HR-negative nor HR-positive patients showed a benefit for goserelin. The adjusted estimated hazard ratio for event-free survival in HR-negative patients was 1.01 (goserelin versus control, 95% confidence interval [CI] 0.72–1.42, P =0.97) and 0.77 in HR-positive patients (95% CI 0.47–1.24, P =0.27). These results do not support the general use of goserelin after adjuvant chemotherapy in this group of premenopausal patients. [Copyright &y& Elsevier]

The primary goal of most protocols of past and present mammary cancer clinical trials is the reduction of breast cancer incidence. The assumption that the selective estrogen receptor modulator (SERM) tamoxifen could prevent mammary cancer resulted from the experience obtained in palliative and adjuvant treatments. Several prevention clinical trials involve this SERM, e.g. P1, IBIS I, Royal Marsden Hospital Tamoxifen Prevention Trial, Italian Randomized Trial Among Hysterectomized Women. Second-generation trials tested other types of substances, such as aromatase inhibitors which were included in the IBIS II trial. Other trials investigate alternative SERMs, such as raloxifene, arzoxifene and lasofoxifene, as well as endocrine substances, such as gonadotropinreleasing hormone agonists and enzyme inhibitors (e.g. Cox-2 cyclooxigenases). [ABSTRACT FROM AUTHOR]

Abstract: Breast cancer remains a leading cause of cancer death in women worldwide, and the risk for disease recurrence continues despite improvements in screening and treatment and the use of prophylactic estrogen-inhibiting therapies such as tamoxifen. A number of long-term studies now indicate a significant risk for breast cancer recurrence among patients who have undergone the currently recommended five years of tamoxifen adjuvant therapy following successful treatment of their initial disease. This ongoing recurrence risk extends even to patients commonly considered at low risk for relapse, that is, those with low-grade, small tumors, and/or node-negative disease. Treatment with tamoxifen for more than five years appears detrimental rather than beneficial and, therefore, tamoxifen is not indicated for use beyond the initial five years. Endometrial cancer and thromboembolism are among the serious adverse events that have been observed with long-term tamoxifen treatment. The aromatase inhibitors are able to reduce overall estrogen levels and appear to be better tolerated over a long term. Letrozole is the most potent aromatase inhibitor and has been available in Europe since 1996 and in the United States since 1997. Letrozole has been approved for first-line treatment of postmenopausal women with hormone-receptor – positive or hormone-receptor – unknown, advanced or metastatic breast cancer in the United States and Europe, as well as for neoadjuvant treatment (primary systemic therapy) of early breast cancer prior to surgery in many countries. The results of the pivotal MA-17 trial demonstrate that letrozole is unique in its ability to improve disease-free survival in breast cancer patients who have undergone tamoxifen therapy for five years. The MA-17 results indicate that extended adjuvant therapy with letrozole reduces risk of recurrence in this setting by 42%, reduces risk of distant recurrence (metastasis), and may improve patient survival in the node-positive patient population. The results also show letrozole to be well tolerated and safe over the length of follow-up. The trial outcomes have led to the approval of letrozole for the extended adjuvant indication in more than 40 countries worldwide. Re-randomization of letrozole-treated patients from this pivotal trial is underway to investigate if ten years of extended adjuvant endocrine therapy leads to further improvement, and the results of this extension study should aid in resolving several open questions regarding extended adjuvant therapy, including who should be treated and for how long. [Copyright &y& Elsevier]

The increasing understanding of the pathophysiological background of breast cancer is associated with new molecular techniques, improved risk assessment, targeted therapy and individualized treatment. Gene expression profiling may provide predictive and prognostic gene signatures which could help characterize tumors and enable more tailored therapies. Beyond this, gene expression profiling allows us to better understand tumor development and can help identify new molecular markers which should be investigated in terms of specific clinical objectives. There is also an increasing trend towards translational research in large clinical trials which gives new insight into pathophysiology and the prediction of response according to specific therapeutic approaches. Even if the detection of new molecular markers gives rise to new hypotheses, most studies lack a prospective setting, and thus the use of identified markers or specific gene signatures in clinical routine is still limited. [ABSTRACT FROM AUTHOR]

Summary: Preoperative systemic treatment (PST) is a valid option not only for advanced breast cancer stages but also for operable breast cancer. We know that disease-free and overall survival after PST are equivalent to those after adjuvant therapy. Furthermore, PST is able to improve surgical treatment by increasing the rate of breast conservation surgery, which minimises psychological distress for patients fearing mastectomy. Response to PST is a predictor of long-term outcome and gives prognostic information after a short-term interval in contrast to adjuvant trials, which do not show their results until after a 5- to 10-year follow-up. More often, endocrine non-responsive tumours demonstrate a pathological complete response (pCR). Thus, PST can change the formerly bad prognostic marker into one that indicates a favourable prognosis if pCR is achieved by PST. If PST is performed outside clinical trials, anthracycline/taxane-based regimens should be used, especially in sequential prolonged schedules. The use of aromatase inhibitors in preoperative endocrine therapy in elderly postmenopausal patients with endocrine-responsive breast cancer yields a larger proportion of local response than tamoxifen. The duration of PST is not well established, but at least four cycles of chemotherapy should be administered and endocrine therapy needs a minimal time to show greatest benefit when given for at least 3–4 months . The concurrent use of chemotherapy and endocrine drugs did not show any benefit, even in endocrine-responsive tumours and should therefore be avoided. Sentinel node biopsy is a reasonable approach, but this technique should be reserved for experienced surgeons. PCR is the most important surrogate marker of PST, demonstrating an improved disease-free and overall survival. But even if pCR of the primary tumour is achieved, the detection of lymph node metastases is the most important prognostic factor, indicating a substantial risk of cancer recurrence. PST will lead to individualised (tailored) treatment in patients with primary breast cancer. [Copyright &y& Elsevier]

Purpose. In our recent studies, we demonstrated that breast cancer treatment by anti-EGF-R antibody resulted in a significant therapeutic effect in vivo. Furthermore, we were able to elucidate histopathologic parameters with an impact on therapy success. The aim of this study was the evaluation of EGF-R and Her2/neu protein expression on a large series of primary breast cancer, to elucidate if anti-EGF-R antibody therapy is a new therapeutic option for patients who are Her2/neu negative and where, therefore, anti-Her2/neu antibody treatment is not applicable. Methods. We analyzed EGF-R and Her2/neu protein expression of 149 consecutive primary breast cancer specimens by fully quantitative enzyme-linked immunosorbent assay. For evaluation of stochastic independence, we used χ2-test as goodness-of-fit test. Results. We found EGF-R and Her2/neu expression as stochastically independent in primary breast cancer. Conclusions. Anti-EGF-R antibody treatment is a potential therapeutic option for patients with Her2/neu negative breast cancer. [ABSTRACT FROM AUTHOR]

Several in vitro studies have correlated dysfunction of the sphingolipid-signaling pathway with promotion of tumor cell growth as well as progression and resistance of tumors to chemotherapeutic agents. As ceramides (Cer) constitute the structural backbones of all sphingolipids, we investigated the endogenous ceramide levels in 43 malignant breast tumors and 21 benign breast biopsies and compared them with those of normal tissues using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The total ceramide levels in malignant tumor tissue samples were statistically significantly elevated when compared with normal tissue samples. Upregulation of the total ceramide level averaged 12-fold and 4-fold higher than normal tissue samples, for malignant tumors and benign tissues, respectively. Specifically, the levels of C16:0-Cer, C24:1-Cer and C24:0-Cer were significantly raised in malignant tumors as compared with benign and normal tissue. The augmentation of the various ceramides could be assigned to an increase of the messenger RNA levels of ceramide synthases (CerS) LASS2 (longevity assurance), LASS4 and LASS6. Notably, elevated levels of C16:0-Cer were associated with a positive lymph node status, indicating a metastatic potential for this ceramide. Moreover, the levels of C18:0-Cer and C20:0-Cer were significantly higher in estrogen receptor (ER) positive tumor tissues as compared with ER negative tumor tissues. In conclusion, progression in breast cancer is associated with increased ceramide levels due to an upregulation of specific LASS genes. [ABSTRACT FROM AUTHOR]

The anthracyclines doxorubicin and epirubicin, and the taxanes paclitaxel and docetaxel, are effective chemotherapeutic agents for the first-line and second-line treatment of metastatic breast cancer, and their clinical use is widespread. However, for women whose disease has progressed despite receiving these drugs, treatment options are limited. These women often have a good performance status, and may survive for many months or even years, so they should be given the opportunity to benefit from further chemotherapy. The goals of chemotherapy in these patients are to obtain maximum control of symptoms, prevent serious complications, and increase survival without diminishing quality of life. Several agents are used for this purpose, including fluorouracil, docetaxel (in patients who have already received paclitaxel), vinorelbine, and mitomycin c, but because data from controlled trials are limited, a standard regimen has not yet been established. Moreover, these agents may be inconvenient to administer and can be associated with adverse events requiring hospitalisation. Therefore, there is a clear need for additional therapeutic options for patients with metastatic breast cancer. Ideally, agents should have a convenient method of administration, eg, oral, and should be suitable for home-based rather than hospital-based therapy. Treatment should control disease in at least 20–30% of patients with an acceptable side-effect profile. Novel oral therapies have now been developed and are being used increasingly in patients whose disease has progressed following taxane therapy. [Copyright &y& Elsevier]