Numerous genes are controlled by complex regulatory networks and involved in the development and progression of breast cancer, and these genes are the key factors determining each characteristic of the tumor. Gene expression profiling, a large scale analysis of gene expression, has created new possibilities for the molecular characterization of cancer. Systematic analysis of expression patterns of thousands of genes in tumor cells using DNA microarrays and correlation of these patterns to specific features of phenotypic variation may provide the basis for an improved taxonomy of cancer. These profiles have the potential to explain the genetic heterogeneity of breast cancer and allow treatment strategies to be planned in accordance with their probability of success in individual patients.

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Gene therapy for advanced breast cancer is anticipated to be a useful therapeutic approach. Strategies in ongoing clinical protocols can be divided into four groups:(1)suppression of oncogenes or transfer of tumor-suppressor genes;(2)enhancement of immunological response;(3)transfer of suicide genes;(4)protection of bone marrow using drug resistance genes. We have started a clinical study of multidrug resistance(MDR1)gene therapy. Advanced breast cancer patients received high dose chemotherapy and autologous peripheral blood stem cell transplantation(PBSCT)with MDR1-transduced hematopoietic cells, and then were treated with docetaxel. Two patients have been treated so far, and in vivo enrichment of MDR1-transduced cells with docetaxel treatment has been seen. Both patients are in complete remission and had no apparent adverse effects from the MDR1 gene transfer.

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The genomic information obtained through the human genome project has been accelerating the analysis of the functions of various disease relevant genes. The high molecular weight biomolecules, including oligonucleotides, antisense nucleotides, small interference RNA and peptides, as well as genes (cDNA) and proteins, are becoming increasingly important for the development of molecular therapies. However, the potential of such information-rich macromolecules for therapeutic use has been limited by the poor permeability across the lipid bilayer of the cellular plasma membrane. Over the past decade, a unique activity of oligopeptides, known as protein transduction domains (PTDs) or cell penetrating peptides (CPPs), has made it possible to transduce biologically active macromolecules into living cells in vitro by conjugating a PTD to the desired macromolecule. Furthermore, this activity has also enabled the systemic delivery of bioactive macromolecules to all tissues in living animals. However, we are now confronted with the next difficulty delivering the macromolecules specifically to the therapeutic targets in vivo. In this review, we focus on the application of PTD to develop antitumor macromolecules and introduce several representative strategies to discriminate between tumor and normal tissue. In addition, we discuss the unique characteristics of breast cancer, which are expected to facilitate the application of PTD to develop novel protein therapy for breast cancer.

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A fundamental obstacle in systemic therapy for metastatic breast cancer patients is specific targeting of therapy directly to a solid tumor. Hypoxic or necrotic regions are characteristic of solid tumors in many murine and human tumors, including the majority of primary tumors of the breast. A strain of anaerobic bacteria such as Bifidobacterium or Clostridium selectively localizes to and proliferates in solid tumors after systemic application. Another approach uses attenuated Salmonella strains that need tumor-specific nutrients to selectively proliferate and is a potential gene delivery system. We constructed a plasmid, pBLES100-S-eCD, which included the cytosine deaminase gene. Transfected Bifidobacterium longum produced cytosine deaminase in the hypoxic tumor. Enzyme/pro-drug therapy was confirmed to be effective for systemic administration.

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The widespread use of screening mammography has resulted in increased detection of nonpalpable breast lesions here in Japan. For the histopathologic work-up of these lesions, stereotactic core biopsy is essential as a minimally invasive diagnostic procedure. However, the number of facilities that provide this procedure cannot keep up with the increasing demand from patients.
Another issue is interpreting the results of the biopsy. With a histological diagnosis using needle samples, there is always a risk of underestimation or a false-negative result. To avoid missing cancers after stereotactic biopsy, it is important to check for sampling errors and for discrepancies between the radiologic and pathologic findings.
We are pushing for the rapid spread of an ideal form of stereotactic breast core biopsy (using prone-type units, digital methods, and vacuum-assisted breast biopsy devices) throughout Japan so that every patient can undergo this examination.

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Background: Emerging evidence suggests that induction of pathologic complete response (pCR) after primary systemic therapy (PST) is, at least to some extent, predictive of survival. However, standards for processing surgical specimens and for histopathologic evaluation of the pathologic response to therapy appear to be lacking.
Methods: To perform a systematic review of representative articles on this topic, a computerized (MEDLINE) search was undertaken followed by a manual search based on the reference lists of the publications identified.
Results: Several classification systems have been used to assess pathologic response to PST, the term pCR has not been applied in a consistent standardized manner, and only limited information is available about the reliability and validity of these classification systems. However, definitions of pCR can be summarized as follows: near pCR, only focal invasive tumor residues in the removed breast; quasi pCR, total or near total disappearance of invasive tumor in the removed breast; pCRinv, only in situ tumor residual in the removed breast; comprehensive pCR, no evidence of residual invasive tumor in the removed breast; strict pCR, disappearance of all tumor cells in the removed breast; comprehensive pCR _br+n, no evidence of residual invasive tumor in the breast and axillary nodes; strict pCR _br+n, no malignant tumor cells in the removed breast and axillary nodes. Comparison of the use of the term “ pCR ” in various trials reveals that it is not applied equivalently in these studies.
Conclusion : Assessment of pCR needs to be standardized, with verification for reliability and validity. For now, the non-equivalency in the definition of pCR should be taken into account when comparing the results of PST.

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Background : A pilot phase II study was conducted to evaluate the efficacy and safety of the Japanese intermittent regimen of capecitabine (Xeloda ^®) in patients with advanced or recurrent breast cancer.
Methods : A total of 23 patients who had received no more than one prior chemotherapy regimen received oral 828 mg/m2 capecitabine twice daily for 3 weeks followed by a 1-week rest period. The response to capecitabine was evaluated in 22 patients (one patient ineligible).
Results : The overall response rate was 45.5% (95% CI, 24.4-67.8%), including 1 complete response (4.5%) and 9 patients with partial response (40.9%). A further 7 patients (31.8%) had stable disease. The median duration of response was 7.2 months (range, 3.0-15.8 months) and the median time to progression was 6.4 months (95% CI, 4.1-15.1 months). Treatment-related adverse events ≥ grade 3 were observed in 7 patients (30.1%).
Conclusion : Intermittent capecitabine therapy (828 mg/m² twice daily for 3 weeks followed by a 1-week rest period) was shown to be effective and well tolerated as second-line treatment for advanced or recurrent breast cancer. The Japanese regimen is worthy of further study in larger numbers of patients in phase II / III clinical trials.

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Background : Invasive micropapillary carcinoma (IMPC) of the breast is a special subtype of invasive ductal carcinoma (IDC), which is known to have a high potential to metastasize to the axillary lymph node. However, it is sometimes difficult to differentiate IMPC from conventional IDC showing an IMPC-like pattern due to artifact (pseudo-IMPC). In the present study, we investigated the usefulness of immunohistochemical expression of MUC1 for distinguishing IMPC from pseudo-IMPC, and analyzed several clinicopathological parameters of IMPC and pseudo-IMPC cases.
Methods : Eighty cases showing IMPC or IMPC-like pattern were selected from our surgical files of 1240 cases of IDC. We examined the expression of MUC1, D2-40 and CD34 by immunohistochemistry.
Results : Eighty cases were classified into 9 cases (0.7%) of pure-IMPC, 31 cases (2.5%) of mixed-IMPC, and 40 cases of pseudo-IMPC, according to the expression pattern of MUC1. In pure-IMPC cases, MUC1 expression was found at the reversed apical membrane of neoplastic cell clusters, while in pseudo-IMPC, MUC1 expression was present in the whole cytoplasmic membrane and/or cytoplasm. There were no significant differences among the three groups in patient age, tumor size and nuclear grade of neoplastic cells. However, lymphatic invasion and lymph node metastasis in the pure-IMPC or mixed-IMPC cases were higher than those in pseudo-IMPC cases with statistically significant values. Pure-IMPC has a higher recurrence rate and lower overall survival compared to pseudo-IMPC [P=0.0165(DFS) P=0.025(OS)].
Conclusions : This study demonstrated that immunohistochemistry of MUC1 is useful for the diagnosis of IMPC. The pure-IMPC cases had higher incidences of lymphatic invasion and lymph node metastasis, and also showed a poorer prognosis.

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Background : There is little evidence regarding associations between magnetic resonance imaging (MRI) features and other important histopathological prognostic factors of breast cancer. The purpose of our study was to investigate the relationship between rim enhancement on MRI and common histopathological prognostic factors of breast cancers.
Methods : We reviewed the contrast-enhanced MR images of 106 consecutive women with histopathologically verified invasive breast carcinomas. Three radiologists assessed the images of each lesion for the presence of rim enhancement on early and delayed images, which were classified into four patterns. Statistical analyses were performed to explore the associations of these patterns with common histopathological prognostic factors and patient age.
Results : Positive ratios of lymph node metastasis and blood vessel invasion and negative ratios of hormone receptors were higher in the invasive cancers with rim enhancement than those without rim enhancement. Rim enhancement was more frequent in invasive ductal cancers with a higher histological grade and larger invasive cancers. The pattern of rim enhancement with centripetal progression showed a significantly increased risk of lymph node metastasis and was associated with a larger size of invasive lesion when compared with the other patterns. Invasive cancers with rim enhancement and little change between the early and delayed images and with centrifugal progression showed significantly less hormone receptor positivity than those without rim enhancement.
Conclusions : Rim enhancement patterns of breast cancers on contrast-enhanced MRI are related to common histopathological prognostic factors and these patterns may be valuable in the preoperative evaluation of breast cancers.

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Background: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer has been emphasized, however, there is no general agreement as to how immunohistochemical assays should be evaluated. It is critical to evaluate hormone receptor status when considering response to endocrine therapy.
Methods : Estrogen receptor (ER) and progesterone receptor (PgR) expression was examined by immunohistochemistry using Allred's score for primary breast tumors from 75 metastatic breast cancer patients who received first-line treatment with endocrine therapy (56 patients received tamoxifen, 11 patients received aromatase inhibitors, and 8 patients received LH-RH agonist or other endocrine reagents) on relapse. Correlation between hormone receptor status and response to endocrine therapy as well as post-relapse survival was analyzed.
Results : The most significant correlation between positive ER expression and response to any endocrine therapy (p=0.011) or tamoxifen only (p=0.030) occurred when the cutoff score was set at 10%. When the evaluation was based on Allred's score (TS), a cutoff point of TS≥4 showed a more significant association between positive ER expression and response to all kinds of endocrine therapy (p=0.020) or tamoxifen only (p=0.047). When evaluated at a cutoff point of 1% positive cells, there were fifteen patients with both ER- and PgR-negative tumors, and three patients (20.0%) responded to the therapy. Patients with 1% or more ER or PgR positive cells had better survival after relapse (p=0.0005 and p=0.0008, respectively).
Conclusions : The proportion score alone might be enough to predict hormone responsiveness and post-relapse survival in metastatic breast cancer. The cutoff might be set low, for example 1%, especially for metastatic disease.

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We experienced a very rare case of intracystic papilloma in a 57-year-old man who came to our hospital complaining of a left subareolar mass and nipple discharge. The patient had a history of chronic schizophrenia, necessitating long-term treatment with phenothiazines. His serum prolactin levels were elevated. Mammography demonstrated a well defined mass with microcalcifications. Ultrasonography revealed a cyst with an intracystic component. The inner lesion of the mass enhanced on contrast-enhanced computed tomography. The carcinoembryonic antigen concentration of the cyst fluid was 400 ng/mL and no malignant cells were found by aspiration biopsy cytology. Excisional biopsy was performed under local anesthesia. Pathological examination revealed the intracystic component to be intracystic papilloma. There are ten reports of male intracystic papilloma including ours. We report the second case of a patient given long-term phenothiazine therapy, which is known to increase serum prolactin levels.

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We report on an exceedingly rare case of noninvasive ductal carcinoma arising in malignant phyllodes tumor of the breast. The patient was a 75-year-old woman who presented with a chief complaint of an indolent tumor mass of the left breast. Papillotubular carcinoma was diagnosed by aspiration cytology, and mastectomy with preservation of the pectoral muscle was subsequently performed (Bt+Ax+Ic, R2). Histopathological examination showed proliferation of monotonous, uniform tumor cells in a cribriform pattern amid atypical and spindle-shaped cells. Neither stromal invasion of the epithelial tumor cells nor clear transition between epithelial tumor cells and non-epithelial tumor cells was seen. Immunohistochemical staining revealed that the epithelial component was positive for antibodies such as CEA, EMA and keratin, while the non-epithelial component was negative for the same antibodies. Malignant phyllodes tumor with a noninvasive ductal carcinoma was diagnosed rather than true carcinosarcoma of the breast. No metastasis was detected in the axillary lymph nodes, and the patient was classified as stage II A (T2N0M0). Although neither chemoendocrine therapy nor irradiation was employed postoperatively, no recurrence was observed two years and two months after the surgery. There is little consensus on the treatment or prognosis of the disease. Careful observation of the present case is therefore important.

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We report a case of an adenoma of the nipple in a 33-year-old Japanese woman who presented with a 2-year history of itching, eczema, and discharge from the left nipple. Examination revealed a firm, well defined and erosive tumor measuring 10×11 mm that was sore, crusted, and indurated. There was a slight serosanguineous discharge from the tumor. Cytological material from the tumor obtained from the discharge and by fine needle aspiration (FNA) and scraping showed a papillary cell cluster thought to be a benign papilloma.
We performed a tumor resection with preservation of the nipple. The histological diagnosis was adenoma of the nipple. The patient was left with a cosmetically well-preserved nipple. No recurrent tumor has been observed for two years after surgery.

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A 30-year-old woman presented with a right breast tumor. Mucinous carcinoma was diagnosed by core needle biopsy (T2: 5 cm N1 M0). Despite receiving a neoadjuvant anthracycline and taxane regimen, the patient demonstrated no clinical response (NC). Based on the patient's strong preference, we performed breast-conserving surgery. On histological examination, we observed widespread mucus and a few viable malignant cells, a Grade 2 therapeutic response. Neither optimal management procedures nor guidelines for chemotherapy for primary mucinous carcinoma of the breast have been established. It is a reasonable assumption, however, that discordance between the clinical response and therapeutic response to neoadjuvant chemotherapy may occur in cases of mucinous carcinoma.

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A patient with intraductal papilloma who had abnormal bloody discharge from Montgomery's areolar tubercle underwent mammary ductography, mammary ductoscopy from the tubercle, and microdochectomy.
A 43-year-old woman who was being followed-up for left breast cancer noticed bloody discharge from Montgomery's areolar tubercle of the right breast. Because the discharge continued for 2 months, further examinations were conducted. Mammary ductoscopy of Montgomery's areolar tubercle showed a normal internal duct structure. The presence of yellowish superficial lesions suggested intraductal inflammation or superficial hyperplasia of the duct epithelium. Lavage cytology revealed benign papillary lesions. Since the discharge continued and we could not completely exclude malignancy, microdochectomy was performed. Histologically a lactiferous duct was connected to Montgomery's areolar tubercle and an intraductal papilloma was seen in part and considered to have caused the bloody discharge.
Bloody discharge from Montgomery's areola tubercles is extremely rare, the present case was our first experience with ductoscopy of Montgomery's areolar tubercle out of 641 cases of mammary ductoscopy performed on patients with bloody nipple discharge from 1998 to 2004. In our case, Montgomery's areolar tubercles were connected to a lactiferous duct. Although there are a few breast carcinomas that cause bloody discharge and eruption of areola, areolar preservation should be performed with the knowledge that disease may also involve the areola through the lactiferous ducts.

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A case of ductal carcinoma in situ (DCIS) with microinvasion arising in a radial scar of the breast is presented. A 57-year-old woman visited our hospital with bloody discharge from her left nipple. There were no abnormal findings on cytology, carcinoembryonic antigen (CEA) level of nipple discharge was<500 ng/ml, and mammograms were normal. After 2 years of careful periodic follow-up, spiculation without a central core appeared on mammograms. The CEA level of the nipple discharge increased to 1000 ng/ml. Ductgraphy showed a connection between the duct with the discharge and the center of the spiculation. Since these findings suggested malignancy, she underwent segmentectomy of the breast, and pathological examination showed a radial scar and DCIS with microinvasion in the ducts within the radiating bands of fibrous tissues. We discuss the characteristics of a radial scar and its relationship to breast cancer based on our experience and a review of the literature.

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Adenoid cystic carcinoma (ACC) of the breast is a rare variant of breast malignancy and is known to have an excellent prognosis. We report two cases of ACC diagnosed by preoperative fine-needle aspiration cytology (FNAC), which proved to be very useful in determining the appropriate treatment. The patients were a 57-year-old woman (case 1) and a 71-year-old woman (case 2). On physical examinations and imaging studies both tumors were recognized as lobulated tumors that measured 3.0 × 2.3 cm (case 1) and 3.9 × 3.4 cm (case 2) respectively. FNAC materials showed clusters of malignant cells surrounding globules of mucus, therefore, ACC was diagnosed. Considering the characteristics of ACC, breast-conserving surgeries with axillary dissection and adjuvant radiotherapy were performed instead of primary chemotherapy or mastectomy. Histologically, a distinctive biphasic pattern was observed that consisted of true laminae and pseudocystic spaces. Tumor sizes were 4.0 × 3.3 cm (case 1) and 4.6 × 3.8 cm (case 2), respectively, and surgical margins were negative on microscopic examination. Lymph node metastasis was not present in either case. Even though ACC is very rare, preoperative diagnosis can be made based on its characteristic features. Preoperative diagnosis is extremely useful for determining appropriate treatment.

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