Not all hormone receptor (HR)-positive tumors respond to hormone therapy, although hormone therapy has brought significant benefits to breast cancer patients. In order to improve the efficacy of hormone therapy, a variety of new approaches are currently being tested in such as extended adjuvant therapy, selection of responders using array-based techniques and combination therapy with signal transduction inhibitors. It is therefore necessary to distinguish between highly hormone responsive tumors and relatively less hormone sensitive tumors. Through reviewing recent outcomes of clinical trials, these issues are summarized and discussed in this review.

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Hormonal therapy is a rapidly progressing molecular-targeted therapy for breast cancer, using drugs such as LH-RH agonists, SERMs and aromatase inhibitors. Basic research for estrogen signaling and hormone sensitivity in breast cancer cells strongly contributes to the progression of clinical treatment of breast cancer. However, further problems remain unresolved, for example the accurate prediction of individual response to each hormonal therapy. Moreover, novel combinations with other molecular-targeted therapies might be advance the effectiveness of hormonal therapies. To address these issues, we are developing several new tools such as focused microarray and a GFP-reporter cell system. We first identified estrogen-responsive genes by comprehensive expression profiling of estrogen receptor (ER)-positive breast cancer cells, and produced a custom-made estrogen-responsive microarray of a narrowed-down subset. Using this microarray, we studied several basic issues regarding estrogen signaling and expression analysis of estrogen-responsive genes in breast cancer tissues. Furthermore, expression of several candidate genes selected from the contents of the customarray was also analyzed by real-time RT-PCR and by immunohistochemical techniques, to find new predictive factors for responsiveness to hormone therapy for primary breast cancer patients. We found that the expression of several genes such as HDAC6 significantly correlated with disease-free and overall survival of ER-positive patients. Furthermore, we are developing a new tool for analyzing the estrogen-related microenvironment on individual breast cancer patients using ERE-GFP-indicator cells. This system enables visualization of tumor-stroma interactions and the effects of aromatase inhibitors in an individual breast cancer sample. We believe that these approaches could provide not only new clues to elucidate the estrogen-dependent mechanisms of cancer, but also clinical benefits to patients by predicting individual response to hormonal therapy.

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Intratumoral metabolism and synthesis of estrogens as a result of the interactions of various enzymes are considered to play very important roles in the pathogenesis and development of hormone dependent breast carcinoma. Among these enzymes, intratumoral aromatase plays as important role converting serum androgens to estrogens in situ, and servies as a source of estrogen, especially in postmenopausal patients with breast carcinoma. However, other enzymes such as the 17β-hydroxysteroid dehydrogenase (17β-HSD) isozymes, estrogen sulfatase (STS) and estrogen sulfotransferase, also play pivotal roles in intratumoral estrogen production. The 17β-hydroxysteroid dehydrogenase (17β-HSD) isozymes catalyze the interconversion of estradiol (E2) and estrone (E1), and thereby serve to modulate the tissue levels of bioactive E2 in human breast carcinoma. 17β-HSD type 1 catalyzes primarily the reduction of estrone (E1) to estradiol (E2), whereas 17β-HSD type 2 catalyzes primarily the oxidation of E2 to E1. In human breast desease, 17β-HSD type 1 is expressed in proliferative disease without atypia, atypical ductal hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma. 17β-HSD type 2 has not been detected in any of these breast lesions. In addition, 17β-HSD type 1 coexpression is significantly correlated with estrogen receptor status in invasive ductal carcinoma cases. These results indicate that breast carcinoma can effectively convert E1, produced as a result of in situ aromatization, to E2, a biologically potent estrogen, which exerts estrogenic actions on tumor cells through estrogen receptor, especially the α subtype in carcinoma cells. Therefore, inhibiting intratumoral 17β-HSD type 1 is also considered to contribute to inhibition of cell proliferation by decreasing intratumoral estradiol. Estrogen sulfotransferase (EST;SULT 1E1orSTE gene) sulfonates estrogens to inactive estrogen sulfates, while steroid sulfatase (STS) hydrolyzes estrone sulfate (E1-S) to estrone. EST immunoreactivity was recently demonstrated to be significantly associated with a decreased risk of recurrence or improved prognosis by both uni- and multivariate analyses. STS immunoreactivity was significantly associated with an increased risk of recurrence by univariate analysis. These findings also suggest that EST and STS plays important roles in regulation of in situ estrogen production, and EST especially is a potent prognostic factor in human breast carcinoma. Therefore, the inhibition of intratumoral STS might also serve as an endocrine therapy in postmenopausal patients. It is also important to note that the status of intratumoral aromatase, 17β-HSD type 1, EST and STS in human breast cancer tissues is variable and not necessarily correlated with each other, which suggests different potential sources of intratumoral estrogens among individual patients with breast cancer. These findings indicate that there are patients who could benefit more from inhibition of these intratumoral enzymes rather than aromatase inhibition as an endocrine therapy. Therefore, it will become very important to examine the intratumoral levels of 17β-HSD type 1 and STS in the resected specimens of human breast carcinoma as potential targets of novel endocrine therapy in the near future.

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Akt is a serine/threonine kinase that has been demonstrated to play an important role in survival when cells are exposed to different apoptotic stimuli. Recent studies show that aberrant activation of Akt in breast carcinoma is associated with a poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway is currently attracting considerable attention as a new target for effective therapeutic strategies. We investigated the incidence of Akt activation in 252 primary breast carcinomas and relationships among the activation of Akt, HER2 overexpression, hormone receptor expression, and alteration of the PTEN gene. Eighty-four cases (33.3%) were positive for pAkt expression. pAkt was significantly associated with HER2 overexpression (p<0.0001) and LOH at the PTEN gene locus (p<0.01). There was an inverse correlation between pAkt and PR (p<0.05). We also retrospectively examined the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer. Of these 36 metastatic breast cancer cases, 12 cases (33.4%) were considered to show positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated worse efficacy than in pAkt-negative patients (p<0.01). In addition, the clinical benefit was the smallest in the patients positive both for HER2 and pAkt (p<0.01). The clinical benefit rate of estrogen deprivation therapy with AI or LH-RH agonist was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (p<0.05), and there was a tendency for the clinical benefit of SERM to be smaller in the pAkt-positive patients (p=0.09). These findings therefore suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings indicate that the activation of Akt in the downstream pathway of HER2 plays an important role in resistance to endocrine therapy for breast cancer. Our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.

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In patients with breast cancer, surgical intervention combined with preoperative chemotherapy improves breast conservation rates, and the long-term clinical results of patients undergoing preoperative chemotherapy is comparable to those receiving postoperative chemotherapy. The sequential administration of anthracycline (A) and taxanes (T) is now thought to be the most effective treatment regimen. We treated 296 patients with A and T sequentially and examined the clinical and pathological results. A total of 14% of the patients achieved a clinical complete response (cCR) and 9.5% achieved a pathological complete response (pCR). Tumor classification determined by imaging did not predict pCR, but CT findings helped determine appropriate resection margins. One hundred thirteen patients (38%) received lumptectomy following chemotherapy, and 24.7% (28/113) had positive tumor margins and the malignant cells tended to remain in invasive components. Prognosis was not associated with clinical stage and clinical response, but histopathological findings were closely related to prognosis. Future studies should attempt to develop an optimal chemotherapy regimen, set an appropriate resection margin, and find an effective treatment for patients with extensively calcified lesions.

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Background: The most important issue in breast-conserving surgery is avoidance of ipsilateral breast tumor recurrence (IBTR). We have investigated the factors related to the period between surgery and recurrence and the measures taken.
Subject and methods: From April 1989 to December 2004, 888 cases (excluding cases who underwent neoadjuvant chemotherapy) of breast-conserving surgery were performed. IBTR occurred in 56 of these cases. We investigated the timing of these recurrences. Furthermore, the rate of recurrence before and after 1999 when postoperative adjuvant therapy (such as CEF and Taxanes) was started as standard treatment was investigated.
Results: The mean period to recurrence in the 56 patients that experienced IBTR was 41.3 months; early recurrence within two years occurred in 21 (37.5%) patients. On the other hand, recurrence from the fifth year onwards post-surgery occurred in 11 patients (19.6%). Of the factors related to the timing of recurrence, a significant difference was seen in tumor proliferative activity, ER (estrogen receptor) status, lymphatic invasion (ly), and whether the lesion was inside or outside the mammary gland tissue. Furthermore, patients experiencing an early recurrence including inflammatory type breast recurrence had a complicated course with distant metastases and their prognosis was poor. Therefore, there was delayed onset of recurrence in the ER positive and ly negative patients with decreased tumor proliferation. With regard to the timing of operation in relation to adjuvant therapy, there was an increase in the conservation rate for the patients in the later phase of the study (1999 onwards), and the number of significantly large and surgical margin positive patients that were at risk of a recurrence was high. However, early recurrence was significantly low, and standard therapy was found to inhibit recurrence.
Conclusions: Although tumor proliferative activity, ER status and ly caused differences in timing of recurrence, standard adjuvant therapy, particularly chemotherapy for early recurrence, was effective in inhibiting recurrence.

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Background: To evaluate the efficacy and toxicity of vinorelbine (VNB) with doxorubicin/cyclophosphamide (AC) combination chemotherapy, a phase I-II study was carried out in patients with advanced or recurrent breast cancer.
Methods: The phase I part of this study was carried out to determine the treatment schedule and acceptable dose of VNB for the phase II study. In phase I, VNB was initially given as a short infusion on days 1, 8 and 15, every 4 weeks. The initial dose of vinorelbine was 15 mg/m². In the AC regimen, 20 mg/m² of doxorubicin (ADM) was given intravenously (i.v.) on days 1 and 8, and 100 mg/body of cyclophosphamide (CPA) was administered orally from days 1 to 14. Subsequently, a phase II study was carried out at the maximum acceptable dose (MAD).
Results: Twenty-three patients were entered into this study. In patients receiving VNB at a dose of 15 mg/m², neutropenia (≥grade 3) frequently occurred on day 15. The treatment schedule of this study was therefore changed to VNB given IV on days 1 and 8 with AC combination chemotherapy. In this treatment schedule, grade 4 neutropenia lasting for more than 4 days occurred in patients given VNB at a dose of 20 mg/m² with AC more frequently than in those given 15 mg/m² of VNB. Therefore, the MAD of VNB was determined to be 20 mg/m² in this regimen. At this recommended dose, there were 1 complete (CR) and 8 partial responses (PRs) in 15 patients, with an overall response rate of 60.0%. No treatment-related death occurred.
Conclusions: These data indicate that VNB plus AC combination chemotherapy was effective and well tolerated for breast cancer patients. A randomized trial of VNB plus AC vs. AC combination chemotherapy may be required to ascertain the benefit of this regimen for advanced or recurrent breast cancer patients.

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Background: Pre-clinical and clinical studies indicate that a combination of docetaxel and trastuzumab may effectively treat patients with human epidermal growth factor receptor-2 (HER-2) overexpressing metastatic breast cancer. We evaluated the efficacy and safety of this combination in a multicenter, open-label phaseII study in Japan.
Methods: Women with metastatic breast cancer whose tumors overexpressed HER-2, as assessed by immunohistochemistry and by fluorescence in situ hybridisation, received 2 to 6 cycles of docetaxel (70 mg/m², every 3 weeks) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). The primary endpoint was tumor response. Secondary endpoints were time to disease progression and adverse events.
Results: Of the 40 women enrolled in the study, 27 (68%) completed 6 cycles of treatment. Three patients discontinued the study before the second cycle. Median follow-up was 20.8 months (range, 0.6 to 30.9 months). The overall response rate was 65% (26/40; 95% CI, 48% to 79%). The median time to progression was 6.8 months (range, 0.6 to 21.2 months). Of the 40 patients, 35 (88%) had grade 3 or 4 leukopenia, and 33 (83%) had grade 3 or 4 neutropenia. Most instances of leukopenia and neutropenia were manageable by reducing the dose of docetaxel or by treatment with granulocyte colony-stimulating factor. In 4 patients, left ventricular ejection fraction decreased by more than 10% from baseline.
Conclusions: The combination of docetaxel and trastuzumab was as effective as reported in other similar studies and was well tolerated in these patients.

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Background: Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Although the survival of patients with IBC has been greatly improved by the use of combined treatment modalities, women with IBC still have lower survival rates. We have summarized a single-center experience involving IBC patients. Our objectives are to clarify molecular alterations of HER-2/neu and p53 in IBC and to investigate the prognostic factors.
Methods: Between January 1990 and December 2000, 57 patients with IBC were referred to the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The incidence of IBC among primary breast cancers was 1.0% (57/5,757) in our hospital. Forty-six patients meeting Haagensen’s criteria for inflammatory breast carcinoma were evaluated. All patients had biopsy-proven carcinomas but no distant metastases at referral. The median age at diagnosis for IBC was 51.8 (range, 28 to 70). All patients underwent a mastectomy. Chemotherapy was performed pre- or post-operatively. Three-year and 5-year survival rates were 56.5%, and 40.7%, respectively. Expressions of HER-2/neu and the p53 protein were determined retrospectively by immunohistochemical (IHC) staining of thin paraffin-embedded sections of primary tumors.
Results: Of 46 patients, 23 (50.0%) with tumors testing positive for HER-2/neu fared somewhat worse than those with negative tumors, but the differences were not significant for either overall survival (OS) or disease-free survival (DFS). Of 46 patients, 19 (41.3%) whose tumors were positive for p53 fared somewhat better than patients with negative tumors, with no significant differences in either OS or DFS. Patients presenting with less than ten pathologically involved axillary lymph nodes showed significantly better OS and DFS.
Conclusions: Overexpression of HER-2/neu and the p53 protein were not significant prognostic factors in inflammatory breast cancer. However, the increased incidence of HER-2/neu and the poor outcome of IBC may be of clinical interest, suggesting the need for clinical trials of antibody therapy targeted to HER-2/neu. Moreover, a high prevalence of p53 may be useful in determining the specific use of chemotherapy.

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Background: Combined use of blue dye and radiocolloid is considered to be useful for sentinel lymph node (SLN) biopsy of breast cancer. Whether both techniques together is superior to either alone was analyzed.
Patients and Methods: A consecutive series of 308 cases of breast cancer who underwent SLN biopsy using the combination technique was used. The frequency of a blue node or hot node was analyzed in all cases and only node-positive cases. Furthermore, the frequency of a blue node and hot node together, or either alone, and the highest radiocount of the SLNs in each case were examined for correlation with 8 clinicopathologic features. Three types of SLN containing both blue dye and radioactivity (blue-hot node), blue dye alone (blue-only node) and radioactivity alone (hot-only node), and the SLN radiocounts were analyzed for correlation with metastatic tumor.
Results: Of 308 cases, a blue node was present in 298 (97%), a hot node in 295 (96%), and either a blue or hot node in 306 (99%). The presence of a blue node or hot node was similarly affected by previous surgical biopsy and body mass index (BMI), and the presence of a hot node was also affected by age and tumor location. However, the presence of either a blue node or hot node was not affected by any of these characteristics. Of 77 node-positive cases, 8 (10%), 15 (19%) and 6 (8%) were considered to be node-negative based on blue node, hot node and either blue node or hot node positivity, respectively. The frequency of positivity for SLN metastasis decreased in order from blue-hot, blue-only to hot-only nodes. Of 62 cases with metastatic hot nodes, six (10%) were negative when the hottest node was examined, but the second-hottest node was positive.
Conclusions: The added value of the presence of blue node or hot node was confirmed in the SLN biopsy using the combination technique, which suggests that all blue nodes and hot nodes need to be harvested.

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Background: Lymphatic mapping and sentinel lymph node (SN) biopsy has rapidly replaced axillary lymph node dissection for clinically node-negative breast cancers. Because of a short follow-up period when the procedure was new, there were few reports of the clinical recurrence rate in breast cancer patients treated with SN biopsy. The present study attempts to clarify the occurrence of distant failure after SN biopsy, especially in breast cancer patients with SN micrometastasis.
Methods: The subjects consisted of 375 cases with clinically node-negative breast cancer, who had undergone SN biopsies. Chemotherapy and/or hormonal therapy was recommended based on the pathological primary tumor characteristics. The patients with SN micrometastasis also received adjuvant therapy equal to node-positive patients.

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Background: Asians are generally regarded to tolerate cytotoxic drugs less well than their Caucasian counterpart. A substantial proportion of patients receive suboptimal doses of chemotherapy for fear of severe toxicity. This retrospective study aims to evaluate the adverse events, especially hematological, of docetaxel in Chinese patients with breast cancer.
Patients and Methods: Fifty-nine patients, age ranged from 33 to 70 (median=47) years, were assigned to receive 3 to 6 (median=4) cycles of Docetaxel 100 mg/m² every 21 days as neoadjuvant (n=3), adjuvant (n=26), neoadjuvant plus adjuvant (n=3), or active therapy for metastatic or relapsed breast cancer (n=27).
Results: A total of 56 (95%) patients completed the assigned whole regimen and only 3 (5%) patients discontinued due to either poor tolerance to the drug's side effects or worsening of disease leading to death. On average, the received dose intensity (RDI) was 0.86 for docetaxel 100 mg/m² in this study. Among all the clinical adverse events, hematological toxicities were not excessively higher. Of the total 59 patients, major adverse events of all grades were leukopenia (22%), neutropenia (20%), fever (19%), and febrile neutropenia (14%). Only 12% and 14% of patients experienced grade 3 or 4 leukopenia and neutropenia, respectively.
Conclusion: In view of the increasing breast cancer incidence and the acceptable toxicity profile of docetaxel among Chinese patients, a dosage of 100 mg/m² can be recommended for use among Asians.

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Purpose: The present study aimed to determine the prevalence of subjective symptoms of late complications mainly caused by radiotherapy in breast-conserving therapy (BCT), and to identify patients and treatment factors that may predict such complications.
Materials and Methods: A cross-sectional survey was conducted on 247 patients who had had early breast cancer and who were free of recurrence after BCT. Self-administered questionnaires were mailed to the 247 patients. Patient and treatment factors were analyzed.
Results: Responses were received from 193 of the 247 patients. Common perceptions of late complications included shrinking in size (85%), pain (73%), firmness (65%), thickening of the arm (34%), and changes in skin color (19%). However, high-grade toxicity (above Grade 2) was perceived in only 0.52-7.8% of patients. In multivariate models, shrinking in size was associated with age (P=0.020), pain was associated with additional boost irradiation (P=0.015), and firmness was associated with time after surgery (P=0.004).
Conclusions: Late complications as perceived by the patient herself after BCT are common, but tend to be of minimal severity. Most predictive factors are inevitably associated with late complications. However, the boost irradiation may not be indicated for every patient from a QOL perspective.

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Paraneoplastic syndromes are the rarest neurological complications in patients with breast cancer. Here, we present a case of occult breast cancer presenting as paraneoplastic sensory neuropathy. A 47-year-old woman developed progressive upper and lower extremity weaknesses with paresthesia and gait ataxia. Multiple cerebrospinal fluid (CSF) analyses and magnetic resonance image (MRI) scans of her brain and spine offered no diagnosis. Although no paraneoplastic antibodies were found, paraneoplastic neurological syndrome was suspected after examination by the neurologist eliminated other possibilities. Her mammogram demonstrated pleomorphic calcifications. Although local and systemic therapies were given, no significant improvement in the neurologic condition was found.

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Diabetic mastopathy is an uncommon tumor-like proliferation of fibrous tissue of the breast that usually occurs in a patient who has suffered from type I diabetes mellitus of long duration. Here we report a rare case of diabetic mastopathy that occurred in type II non-insulin dependent diabetes mellitus. This patient was a 63-year-old postmenopausal woman. Mammography, ultrasonography and MR imaging could not distinguish it from breast cancer. Although the core needle biopsy specimen showed fibrosis without evidence of malignancy, excisional biopsy was performed. Histological findings demonstrated typical diabetic mastopathy with keloid-like fibrosis, perivascular lymphocytic infiltration, and lymphocytic lobulitis without evidence of malignancy. These lymphocytes were composed predominantly of B-cells. Five months after surgical biopsy, a nodular formation approximately 4 cm in diameter recurred adjacent to the resected end of the biopsy.

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A 48-year-old Japanese woman underwent [F-18] fluorodeoxyglucose positron emission tomography (FDG-PET) as part of her medical examination. A small hot spot was detected in her right breast. Quadrantectomy with sentinel lymph node (SN) biopsy using an endoscope was performed, and ductal carcinoma in-situ of the breast was diagnosed. The tumor size was 0.9 cm in its greatest diameter, and there were no cancer cells detected in the SN on frozen hematoxylin-eosin staining and cytokeratin immunohistochemical staining. We reported this rare case of ductal carcinoma in-Situ detected by FDG-PET as past of a medical checkup.

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We report a case of a 49-year-old Japanese woman diagnosed with breast carcinoma with osseous and cartilaginous metaplasia with a poor outcome. Histological examination revealed invasive ductal carcinoma with undifferentiated sarcomatous components including chondrosarcomatous areas. Osseous metaplasia was also noted in a very limited area. Neither axillary lymph node metastases nor vessel invasion were observed. Immunohistochemical examination was negative for estrogen receptor, progesterone receptor and HER2 overexpression. Stage II A T2N0M0 carcinoma was diagnosed postoperatively. Five months after the operation, she developed lung metastases. Although she received systemic chemotherapy, the lesions increased in number and grew rapidly. She died of pulmonary distress 5 months after relapse.

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We present a patient with pulmonary metastasis from breast cancer who received S-1 (TS-1) and maintained complete response for approximately 10 years after recurrence. A 51-year-old woman underwent modified radical mastectomy for left breast cancer in November 1991. Her cancer was postoperatively classified as pT2 pN0 M0 Stage IIA. As postoperative adjunctive treatment, tamoxifen and hexylcarbamoyl 1-5-FU (HCFU) were given. During the administration period (30 months after surgery), a solitary pulmonary metastasis occurred. Three months after the start of S-1 (100 mg/body/day), the tumor disappeared on images. Thereafter she took S-1 orally for approximately 10 years, and the pulmonary metastatic focus maintained complete response. In addition, no recurrent focus was observed. The adverse events observed during S-1 treatment were nausea, low-grade neutropenia and pigmentation of fingers. All were mild, and S-1 could be continued. Our case illustrates two important characteristics of S-1. First, S-1 was effective even though this patient had a lung metastasis during adjuvant treatment with HCFU. S-1 is a combined formulation containing 5-chloro-2, 4-dihydroxypyrimidine (CDHP; gimestat), which inhibits an enzyme that metabolites 5-FU, dihydropyrimidine dehydrogenase (DPD). Therefore, high 5-FU concentrations are maintained with S-1, and S-1 may be effective in the patients who do not respond to other fluoropyrimidine agents. Second, since S-1 toxicity was mild, long-term treatment for approximately 10 years was possible. Since S-1 contains potassium oxonate (OXO; otastat), gastrointestinal toxicities, the main adverse events of 5-FU agents, could be reduced. The purpose of treatments for metastatic breast cancer is to maintain favorable quality of life (QOL), as well as to improve survival. S-1 could be a valuable agent for breast cancer treatments, since it showed clinical efficacy and mild toxicity, and can be given orally.

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Breast cancer metastasis to pancreas is rarely seen. There have been only 6 cases described in the literature. We present the seventh case of a 54-year-old woman with breast cancer that metastasized to the tail of the pancreas 4 years and 4 months after radical mastectomy. Although the serum levels of CA15-3 and TPA had gradually increased without symptoms, it was difficult to establish the diagnosis before contrast-enhanced abdominal CT scan was performed.
Immunohistochemical staining using E-cadherin was positive, proving that the breast cancer was ductal rather than lobular in origin. CA15-3 immunohistochemically stained positive in the resected pancreas lesion. Positive monoclonal staining by GCDFP-15 (gross cystic disease fluid protein-15) in the pancreas tumor also confirmed it breast cancer origin.
Investigation of chemokine/chemokine receptors may clarify a new mechanism of metastasis to the pancreas from breast cancer.

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