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Background: Adjuvant trastuzumab has been routinely used in HER2-positive operable breast cancer patients. Prognostic factors remain to be well characterized in these patients and might correlate with primary and/or acquired resistance to trastuzumab., Patients and Methods: The study subjects were 78 HER2-positive operable breast cancer patients treated with adjuvant chemotherapy followed by 1-year trastuzumab between 2005 and 2010 in our institute. All breast tumors showed a HercepTest score of 3+ or that of 2+ and positive fluorescence in situ hybridization. Expression levels of HER1, phosphorylated HER2 (pY1248), HER3, HER4, and p53 were assessed by immunohistochemistry. Prognostic factors were investigated with univariate and multivariate analyses using the Kaplan-Meier/log-rank test and Cox proportional hazards model, respectively., Results: The median age and follow-up period of the patients were 54 years and 39 months, respectively. The mean tumor size was 2.1 cm and the node-positive rate was 42 %. Eight patients had recurrent diseases but no patient died of cancer. Univariate analysis revealed that pHER2 positivity was only a significantly worse prognostic factor for relapse-free survival (RFS) (P = 0.049). A HercepTest score of 2+ and high expression level of p53 showed a trend. Multivariate analysis revealed three biological markers: pHER2 positivity [hazard ratio (HR) = 11.6, 95 % confidence interval (CI) 1.3-111.1, P = 0.031], p53 positivity (HR = 6.4, 95 % CI 1.0-40.0, P = 0.047) and a HercepTest score of 2+ (HR = 8.6, 95 % CI 1.6-45.2, P = 0.011) to be worse prognostic factors for RFS. Notably, three out of five patients with breast tumors expressing HER2 at a score of 2+ and pHER2 had recurrent diseases. Interestingly, the expression level of pHER2 significantly correlated with the expression levels of HER2 and HER3 in HER2-positive breast tumors., Conclusions: This retrospective cohort study suggests that a lower expression level of HER2 and high expression levels of pHER2 and p53 may indicate a worse prognosis in HER2-positive breast cancer patients treated with trastuzumab and chemotherapy. Further studies are needed to evaluate pHER2 expression in HER2-positive breast cancer as a prognostic and/or predictive marker.

Purposes: We conducted a study to analyze the clinicopathological characteristics of breast cancer in Japan registered to the Japanese Breast Cancer Registry of the Japanese Breast Cancer Society (JBCS). Trends in the management of breast cancer patients in Japan were also analyzed., Patients and Methods: More than 250,000 breast cancer patients were registered to the JBCS registry between 2004 and 2011. Demographic and clinicopathological factors in newly diagnosed primary breast cancer patients were registered to the JBCS through the Web-based system from affiliated institutes nationwide., Results: Two distinct peaks were observed, in patients in their late 40s and early 60s, in the population-adjusted age distribution of breast cancer patients. An increased rate of screen-detected breast cancer may contribute to an earlier detection of breast cancer and increased rate of non-invasive ductal carcinoma. The positive rate of either ER or PgR appears to have increased in recent years. The annual rates of patients treated with breast-conserving surgery increased until 2006, but these increases stopped in 2007 and thereafter plateaued at approximately 60 %. The annual rates of patients treated with sentinel lymph node dissection alone have steadily increased. The annual rates of patients treated with preoperative trastuzumab plus chemotherapy have also increased, as well as those treated with postoperative aromatase inhibitors. The annual rates of patients treated with postoperative anthracycline-containing regimens have decreased, whereas those treated with postoperative taxane-containing regimens have increased. The postoperative use of trastuzumab has markedly increased since 2007., Conclusion: Although this study was based on the registry database, several unique clinicopathological characteristics of breast cancer in Japan have been unveiled. Our results suggest that recent trends in the management of breast cancer patients in Japan were strongly followed by clinical evidence that originated from a number of clinical trials worldwide.

Aims: To elucidate the clinicopathological significance of Y416Src and Y527Src expression in breast cancer, and to evaluate their usefulness as potential predictive markers for Src inhibitors., Background: c-Src is a non-receptor tyrosine kinase; the active form of c-Src can catalyse tyrosine phosphorylation. The expression and activity of c-Src correlates with cell adhesion, survival, angiogenesis, migration, invasion and osteoclast function. There are limited clinicopathological data on Src expression and breast cancer characteristics., Methods: An immunohistochemical study was performed to determine the expression of c-Src, Y416Src, and Y527Src in 215 consecutive breast cancer cases. The correlation of their expression with various clinicopathological factors was analysed statistically., Results: c-Src was expressed in all 215 cases (100%). Y416Src was expressed in 174 cases (80.9%) and was highly expressed in 30 cases (14.0%). Y527Src was expressed in 138 cases (64.2%) and was highly expressed in 11 cases (5.1%). High expression of Y416Src was significantly associated with metastatic disease (p=0.0327), whereas high expression of Y527Src was significantly associated with metastatic disease (p=0.0004), clinical stage (p=0.0062), as well as HER2 status (p=0.0149). High expression of either Y416Src or Y527Src was significantly correlated with poor overall survival (p=0.0049 and p<0.0001, respectively). In the 192 curatively operated cases, Y416Src expression was significantly associated with poor disease-free survival (p=0.0088)., Conclusion: Although further studies to assess Src activity are necessary, investigation of Src inhibitors for breast cancer including in-vivo models should be encouraged more.

A 53-year-old woman with left breast tumor was diagnosed as bilateral breast cancer(left; T3N3M0, Stage III C/right; T2N0M0, Stage II )in our hospital, both of which were revealed as invasive ductal carcinoma shown to be ER-negative, PgR negative and HER2-positive by core needle biopsy. In December 2004, paclitaxel and trastuzumab combination therapy was tried, but she went into shock just during administration of paclitaxel, and this therapy was discontinued. After that the triweekly CTF therapy was tried as an anthracycline containing regimen, and the lymph node metastases obtained a complete response after a month and a 38. 5% reduction of left primary breast tumor, which was the best response observed after three months. Time to progression was prolonged to 7 months(9 cycles). Although febrile neutropenia occurred in the first cycle, the therapy could be continued safely thereafter as an outpatient. Anthracycline-containing regimens are likely to be avoided because of the difficulty of combining with trastuzumab in the treatment of HER2 overexpressing advanced/metastatic breast cancer. But the CTF therapy of less cardiotoxicity and less alopecia, can expect longer use and better QOL as an alternative for HER2 overexpressing advanced/metastatic breast cancer patients.

Epirubicin exerts its anti-tumor effect through binding to topoisomerase IIalpha (TOP2A) and inducing DNA double-strand breaks. BRCA1 is involved in the repair of these breaks. We investigated the relationship between TOP2A or BRCA1 immunohistochemical expression and pathological response in 108 primary breast cancers treated with epirubicin-based regimens. The pCR (pathological complete response) rate for TOP2A-positive (17%) was significantly (P < 0.005) higher than for TOP2A-negative (2%), while the pCR rate for BRCA1-negative (11%) was non-significantly higher than for BRCA1-positive (5%). The pCR rate of TOP2A-positive and BRCA1-negative (30%) was significantly higher than for TOP2A-negative and BRCA1-positive (3%; P < 0.05), or TOP2A-negative and BRCA1-negative (0%; P < 0.005). The TOP2A-positive and BRCA1-negative phenotype associates with a favorable response to epirubicin-based regimens.

Biomarkers are measured in the management of breast cancer patients for the following purposes: (1) early detection, (2) monitoring of advanced breast cancer patients, (3) prediction of prognosis, and (4) prediction of therapeutic response. Summarized results investigated by the Study Group of the Japanese Breast Cancer Society in 2001 concerning the present status of tumor marker measurement in Japan and usefulness of tumor markers for the evaluation for therapeutic response are presented. Significance of two prognostic markers, vessel invasion and HER2 status were discussed at the 9th St Gallen International Consensus Meeting in 2005. Current status, clinical significance, problems and future directions on predictive markers for response to endocrine therapy and cytotoxic chemotherapy are also discussed.

Background: Serum CA15-3 has been one of the most reliable tumor markers used in monitoring breast cancer patients; however, its sensitivity in detecting metastases is limited. To increase its sensitivity, the combined measurement of other tumor markers with CA15-3 was investigated., Methods: Serum CA15-3, carcinoembryonic antigen (CEA) and sialyl Lewis X (CSLEX) were simultaneously measured in a prospective series of 455 postoperative breast cancer patients with or without metastasis. The diagnostic parameters sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for detecting metastases were compared. The correlation of values between pairs of tumor markers was analyzed. The efficacy of combined measurement of two different tumor markers was also evaluated., Results: The sensitivity for detecting metastases was 61.5, 56.9 and 52.3%; specificity was 97.2, 93.6 and 96.2%; PPV was 78.4, 59.7 and 69.4%; NPV was 93.8, 92.9 and 92.4%; and accuracy was 92.1, 88.8 and 89.9% for CA15-3, CEA and CSLEX, respectively. The values for CA15-3 were significantly correlated with those for CEA (P < 0.001) but not those for CSLEX. The combined measurement of CSLEX and CA15-3 increased the sensitivity by 17.0% but that of CEA and CA15-3 increased the sensitivity by only 10.8%. All diagnostic parameters for the combined measurement of CSLEX and CA15-3 were higher than those for the combined measurement of CEA and CA15-3., Conclusions: These findings suggest that CSLEX may be more useful than CEA in combination with CA15-3 in monitoring breast cancer patients. The results of this study suggest that CSLEX may be more useful than CEA in combination with CA15-3 in monitoring breast cancer patients.

A number of breast cancer-orientated tumor markers have been utilized for various purposes in clinical practice in Japan. Their purposes are as follows: early detection of primary tumors, prediction of disease extent and prognosis, early detection of recurrent diseases, evaluation of therapeutic responses, monitoring patient outcome, and differential diagnosis of metastatic tumors of unknown origin. The clinical significance of the measurement of tumor markers for these purposes is overviewed in this article. In addition, the results are summarized for two clinical studies conducted by the Tumor Marker Study Group of Japanese Breast Cancer Society (Chairperson: Dr. Kurebayashi), a questionnaire survey on the current status of tumor markers in breast cancer in Japan and a multi-institutional study on the utility of tumor markers for evaluation of therapeutic responses. Future directions of clinical and experimental research for breast cancer-orientated tumor markers are also discussed.

Biomarkers are measured in the management of breast cancer patients for the following purposes. (1) Early detection of breast cancer: blood tumor markers such as CA 15-3 are useless for this detection because of a low sensitivity. Proteomics profiling has recently been investigated using blood or nipple aspirate fluid for the detection. Measurement of CEA and HER 2 in abnormal nipple discharge has been approved for diagnosis of breast cancer in Japan. (2) Monitoring of breast cancer patients: serum tumor markers are routinely measured for early detection of recurrent diseases, evaluation of therapeutic response and monitoring outcome of patients by a majority of breast cancer experts in Japan. Study results investigated by the Study Group of the Japanese Breast Cancer Society in 2001 are presented with regard to the questionnaire survey on the present status of tumor marker measurement and the clinical study on usefulness of tumor markers for the evaluation for therapeutic response. (3) Prognostic factors: new biomarkers have been investigated to select patients at high risk for distant metastases, which could not be selected by classic prognostic factors. Three prognostic factors (UPA/PAI-1, cyclin E, gene profiling), which were discussed at the 8th St. Gallen International Consensus Meeting last year, are mainly discussed. (4) Predictive factors for therapeutic response: hormone receptors (HR) have been used as reliable predictive factors for response to endocrine therapy. Other biomarkers have been investigated to select patients with tumors HR-positive but unresponsive to endocrine therapy. Current status, clinical significance, problems and future directions on predictive factors for response to cytotoxic chemotherapy are also discussed.

Objective: The significance of serum tumor markers in monitoring advanced breast cancer patients is still controversial. To clarify this issue, the Tumor Marker Study Group of the Japanese Breast Cancer Society conducted a prospective study., Methods: Patients with advanced breast cancer who were treated with systemic therapy between January and December 2002 were recruited from five collaborative institutes in Japan. The patients were monitored every four weeks using three serum tumor markers, CEA, CA 15-3 and NCC-ST-439 during the therapy., Results: Findings from 108 eligible patients were analyzed. The pretreatment positivity rates were 51.9% for CEA, 50% for CA 15-3, and 34.3% for NCC-ST-439. The changes in each marker level at 8 and 12 weeks but not at 4 weeks after the start of therapy seemed to correlate with the response to therapy in pretreatment marker-positive patients but not in negative patients. The Cox proportional hazard model revealed a greater than 20% reduction in CEA, CA 15-3 or NCC-ST-439 levels at 4, 8 and/or 12 weeks after the start of therapy to be an independent predictive factor for longer time-to-progression (TTP) in pretreatment marker-positive patients., Conclusion: This prospective study supported the findings obtained from our previous retrospective study that in pretreatment marker-positive patients 1) the changes in serum tumor marker levels after the start of therapy correlate with the response to therapy; and 2) a greater than 20% reduction in the tumor marker levels was a favorable predictive factor for TTP during systemic therapy. When the pretreatment serum level of these markers is over the respective cut-off value, sequential measurement of them may be useful for evaluating the efficacy of treatment as well as monitoring the outcome of patients with advanced breast cancer.

Objective: The significance of serum carcinoembryonic antigen (CEA) and CA 15-3 in monitoring advanced breast cancer is still controversial. To clarify this issue, the Tumor Marker Study Group of the Japanese Breast Cancer Society conducted a large-scaled retrospective study., Methods: The findings from four clinical trials and seven institutes of 528 patients with advanced breast cancer were collected. Three-hundred forty-eight patients, in whom both serum CEA and CA 15-3 were measured during therapy, were selected for analysis., Results: The pretreatment positivity rate of CA 15-3 was significantly higher than that of CEA (p<0.0001). Time-to-progression (TTP) in CEA- and CA 15-3-positive patients was significantly shorter than TTP in negative patients. The changes in either marker level correlated well with response to therapy in marker-positive patients but not in negative patients. TTP in the marker-positive patients with a greater than 20%-reduction in either marker level during therapy was significantly longer than that in positive patients without such a reduction (p<0.01 for CEA and CA 15-3)., Conclusion: CA 15-3 is more useful for monitoring advanced breast cancer than CEA and a greater than 20%-reduction in marker levels suggests longer TTP in pretreatment marker-positive patients.

The product of the HER-2/neu proto-oncogene, HER2, is the second member of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors and has been suggested to be a ligand orphan receptor. Ligand-dependent heterodimerization between HER2 and another HER family member, HER1, HER3 or HER4, activates the HER2 signaling pathway. The intracellular signaling pathway of HER2 is thought to involve ras-MAPK, MAPK-independent S6 kinase and phospholipase C-gamma signaling pathways. However, the biological consequences of the activation of these pathways are not yet completely known. Amplification of the HER2 gene and overexpression of the HER2 protein induces cell transformation and has been demonstrated in 10% to 40% of human breast cancer. HER2 overexpression has been suggested to associate with tumor aggressiveness, prognosis and responsiveness to hormonal and cytotoxic agents in breast cancer patients. These findings indicate that HER2 is an appropriate target for tumor-specific therapies. A number of approaches have been investigated: (1) a humanized monoclonal antibody against HER2, rhuMAbHER2 (trastuzumab), which is already approved for clinical use in the treatment of patients with metastatic breast cancer; (2) tyrosine kinase inhibitors, such as emodin, which block HER2 phosphorylation and its intracellullar signaling; (3) active immunotherapy, such as vaccination; and (4) heat shock protein (Hsp) 90-associated signal inhibitors, such as radicicol derivatives, which induce degradation of tyrosine kinase receptors, such as HER2.

Serum carcinoembryonic antigens (CEA), CA 15-3, and tissue polypeptide antigens (TPA) have been used in monitoring the clinical course of patients with breast cancer. However, recent reports have suggested that the serial levels of these markers during therapy do not always correlate with the response to therapy. To clarify the usefulness of the serial combination assay of these markers in monitoring the clinical course of patients during therapy, we investigated the relationship between the initial changes and the kinetic patterns of the markers after therapy and the objective responses. When an increase or decrease of over 20% in these markers is taken to be significant, then the initial changes in all three markers significantly correlated with the therapeutic responses (P < 0.01). Five distinct kinetic patterns in the marker levels were observed. A paradoxical kinetic pattern of CEA and CA 15-3 levels--that is, an "initial surge and subsequent drop"--was seen in one-third of the responders. The TPA levels tended to exhibit a "steady decline" pattern in those responders. The sensitivity and specificity of the kinetic patterns to predict the clinical courses were significantly higher than those obtained from the analysis of initial changes. These findings thus suggest that adequate knowledge of the unique kinetics of each marker may help to make a more accurate prediction of the therapeutic responses.