The incidence of breast cancer is rising throughout the world. Breast cancer is slowly becoming more prevalent in countries which previously had low rates of cancer as well as becoming a leading cause of cancer death in some countries. Fortunately, a large number of these tumors are estrogen receptor (ER) positive and respond to anti-hormonal adjuvant therapy which until recently has been 5 years of tamoxifen treatment. Unfortunately, a significant number of patients develop recurrent cancers and the recurrent tumors are resistant to tamoxifen treatment. In addition, because of tamoxifen's selective estrogenic actions, there have been reports of venous thrombosis, endometrial cancer, and strokes in patients receiving tamoxifen therapy. Thus, there are other novel therapies such as aromatase inhibitors that block estrogen production in postmenopausal women or fulvestrant that destroys the estrogen receptor. This paper will summarize the therapeutic options for anti-hormonal therapy, the role of anti-hormonal agents in advanced breast cancer, and adjuvant therapy and the current status of chemoprevention with selective ER modulators.

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Recently, primary systemic chemotherapy has been used not only for locally advanced breast cancers but also for operable cases for which adjuvant chemotherapy is necessary^1-6). Moreover, various kinds of ablation therapies have been tried to treat early breast cancer non-surgically, such as radiofrequency ablation (RFA), interstitial laser surgery, cryosurgery and focused ultrasound surgery (FUS)^7-11). If pathological complete remisson (pCR) can be correctly assessed by magnetic resonance mammograpy (MRM) or ultrasonography (US), a non surgical approach can be used for treatment. MRM is now widely used to assess the effect of chemotherapy in the neoadjuvant setting^12-20). However, the ability of MRM to estimate pCR is not yet sufficient to allow a non-surgical approach to breast cancer¹³⁾.
Conversely, ultrasonography (US) might over-diagnose fibrous change as residual invasive cancer. If both MRM and US reveal no abnormal finding, there might be no residual cancer on pathological examination. However, such circumstances are encountered in only 2-3% of cases given the neoadjuvant treatment. Other cases, such as US showing residual disease in spite of pCR on MRM, have some potential for false positivity. Therefore, US-guided needle biopsy, especially vacuum-assisted breast biopsy, might be suitable to judge whether true pCR was achieved in the targeted lesion.

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Here we reviewed the recent progress of molecular targeting drugs, iuncluding trastuzumab, lapatinib, erlotinib and bevacituzumab. Fortunately, Her-2 positive cases of metastatic or relapsed cases, those with the worse prognosis, are responsive to trastuzumab-based chemotherapy. Lapatinib will likely be effective against trastuzumab-resistant cases and brain metastases. Furthermore, the introduction of bevacituzumab will improve VEGF-VEGFR- associated tumor growth.

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Trastuzumab (Herceptin ® ) has many benefits for metastatic breast cancer patients with HER2 overexpression/amplification. Trastuzumab alone or trastuzumab in combination with chemotherapy regimens are standard treatment worldwide as first line therapy for metastatic breast cancer patients with HER2 overexpression/amplification. Furthermore, an international collaboration for adjuvant trastuzumab trials showed last year that trastuzumab treatment improves disease-free and overall survival after or in combination with adjuvant chemotherapy. However, there are many uncertain issues concerning trastuzumab adjuvant and metastatic treatment, such as treatment beyond disease progression (PD), combination with hormone therapy, duration of adjuvant treatment, and cardiac safety of long term treatment.

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ErbB/HER receptor or its signal transduction pathway is an attractive therapeutic target for breast cancer. Lapatinib, an orally administered dual inhibitor of ErbB1 (EGFR) and ErbB2 (HER2) receptor tyrosine kinases has shown promising results for metastatic breast cancer (MBC). Lapatinib exhibited activity against trastuzumab-refractory MBC and showed an acceptable adverse event profile such as transient mild rash, diarrhea and nausea. The addition of lapatinib to capecitabine resulted in significantly prolonged time to progression. Large randomized trials using lapatinib following chemotherapy and surgery are ongoing for early stage HER2-overexpressing breast cancer. Various combinations with agents such as paclitaxel, aromatase inhibitors, or other molecular targeted agents are currently being investigated in clinical trials. If these approaches overcome the limitations of trastuzumab, lapatinib will become an effective treatment option for breast cancer in the near future.

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Cancer development requires neovascularization. The level of angiogenic activity in breast cancer has been shown to be a determinant of disease progression and survival. Vascular endothelial growth factor (VEGF) is a one of the most essential pro-angiogenic growth factors expressed by most cancer-cell types and certain tumor stromal cells. Blocking the action of VEGF appears to be a promising anti-angiogenic approach to treat multiple types of solid tumors including breast cancer, and clinical trials using agents which target VEGF were launched beginning in the late 1990s. The effort reached fruition in 2005 with the first report of a large, prospective randomized trial of anti-VEGF therapy in patients with metastatic breast cancer (MBC), which demonstrated the benefit of adding the monoclonal antibody bevacizumab to the chemotherapeutic agent paclitaxel. The success of this trial provided proof of principle that inhibition of angiogenesis has the potential to enhance the effectiveness of treatment of this disease. Adjuvant therapy trials are in development with bevacizumab and numerous other anti-VEGF agents are now being tested in patients with breast cancer in various settings. Nevertheless, since bevacizumab monotherapy has minimal activity, a question for future therapeutic development of these agents in breast cancer relates to the interaction between anti-angiogenic strategies and cytotoxic therapies. Further research is still needed for complete understanding of the exact role of VEGF and angiogenesis in health and disease, to take best advantage and avoid the adverse effects of anti-angiogenic therapy.

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In breast cancers, estrogen activates estrogen receptor (ER) through genomic and nongenomic pathways, which leads to nuclear and extranuclear processes that promote the proliferation of breast cancer cells. Growth factor receptor signaling pathways also activate ER via phosphorylation through the signal crosstalks between estrogen and growth factors. The intratumoral levels of estrogen and growth factors, therefore, profoundly influence ER activity, which are regulated by the tumor-stromal interactions in the microenvironment. In postmenopausal breast cancers, tumor cells activate stromal fibroblasts to express aromatase, a key enzyme in estrogen biosynthesis, resulting in intratumoral estrogen production. At present, aromatase inhibitors are used as a first-line endocrine therapy for breast cancers. We developed a comprehensive system to evaluate the ER-activating ability of stromal fibroblasts for individual patients, and found that it varied among individual cases. This system might be useful for predicting the individual response to endocrine therapy and analyzing the tumor microenvironment. In addition to estrogen production, tumor-associated fibroblasts lead to the progression of breast cancer via different pathways. A study to differentiate the microenvironmental regulation of estrogen-dependent and – independent breast cancer growth would also be useful to improve hormone therapy for breast cancer.

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A task force of the Japanese Breast Cancer Society has proposed a recommendation for adequate evaluation of hormone receptors in routine practice, in order to standardize handling of tissues, staining techniques and scoring systems. As a part of the study, several examinations were conducted to detect the effect of technical problems, including the influence of fixation time and other fixation and processing conditions, on the immunoreactivity for ERα.
There is little influence of prolonged fixation on the immunoreactivity for ERα, except for cases in which particularly over-fixed blocks are used. A delay in the onset of fixation could decrease the immunohistochemical findings of steroid receptors, compared with shorter or longer fixation, and the situation is similar to the fixation of a whole large surgical specimen in formalin in a big bucket. Incomplete fixation might be an important cause of heterogeneiety of immunoreactivity for ERα.
Manual and automated immunohistochemical (IHC) staining by DAKO (Glostrup, Denmark) and Biogenex (San Ramon, CA) and automated IHC staining by Ventana Medical Systems (Tucson, AZ) each employ different methods. Using a scoring system, in which the proportion of cells stained in each specimen was recorded as 0, less than 1%, 1% or more and less than 10%, and 10% or more, the intermethod variability of those IHC staining methods exhibited substantial multi-rater kappa values concerning the ER and PgR (kappa for ER according to the percentage of positive cells=0.67; PgR=0.72). Concerning intermethod consistency, the scoring system based on the percentage of positive cells was advantageous over other scoring systems, based on the intensity of nuclear staining.
Using double staining, patients with ER-positive and HER2-positive tumors can be classified as those with co-expressed tumors and those with differently expressed tumors. As such, the co-expressed tumor might be resistant to antiestrogen therapy in ERα-positive and HER2-positive breast cancer and double staining might lead to the development of new therapeutic strategies for hormone and HER2-positive breast cancer.

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The assessment of hormone receptor status in breast cancer is essential to decide whether endocrine therapy is indicated or not. Immunohistochemistry (IHC) is thought to be the best method for examination of estrogen receptor (ER) and progesterone receptor (PgR) in routine practice. However, the cutoff point of IHC is still controversial. The St. Gallen consensus meeting in 2005 demonstrated that in patients with more than 10% ER stained tumor cells, hormone therapy will be “ effective ” but in those with 1 to 10% ER stained tumor cells will have an “ uncertain ” response. Based on the cutoff value of the St. Gallen consensus meeting, a new scoring system (J-Score) which only evaluates the positivity cell rate without taking the staining intensity into account was established. In this paper, the ER status results of 486 patients evaluated by the J-Score and A-Score (Allred Scoring system) were compared. The “ uncertain ” patients with ER positive cells 1 to 10% (J-Score 2) composed only 0.9% and “ borderline ” cases (A-Score 3 to 4) including “ uncertain ” cases (J-Score 2) composed 3.2% of the total patients. Thus, the number of patients determined as “ uncertain ” by the J-Score is very small and the number considered “ borderline ” by the A-Score is slightly larger.
Although the J-Score system is thought to be easy and convenient for evaluating ER status in routine practice and the cutoff values adjusted to St. Gallen recommendation might be meaningful for clinical studies, many pathological and clinical studies are necessary before it is accepted as a standard method.

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The choice of endocrine therapy for breast cancer depends on the menopausal status and stage of disease. Endocrine therapy remains the first choice and most important component in the treatment of hormone sensitive non-life threatening advanced breast cancer. In premenopausal women with metastatic disease, the combination of a luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen is reasonable as first-line endocrine therapy. In postmenopausal patients with recurrent disease progressing after or during adjuvant tamoxifen, third-generation aromatase inhibitors (AIs) are the preferred first-line endocrine treatment. Many premenopausal and postmenopausal women with hormone responsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Recent clinical trials designs have been implemented, employing AIs as monotherapy in postmenopausal breast cancer patients, as first-line adjuvant therapy, and in sequence either 2-3 or 5 years, with initial tamoxifen. Emerging results from these trials indicate an advantage to patients for any of these strategies, and most international guidelines now suggest the use of an AI in the adjuvant setting in postmenopausal women. The use of endocrine treatment for metastatic and early breast cancer will be reviewed here.

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Breast cancer is a hormone-dependent cancer like prostate cancer and endometrial cancer. Estrogen plays important roles in the development and progression of breast cancer. Endocrine therapy is the treatment of choice for estrogen receptor- and/or progesterone receptor-positive breast cancer. Endocrine therapy has been used for several purposes, including chemoprevention, preoperative treatment, postoperative adjuvant treatment and treatment for recurrent diseases. A large number of clinical trials have provided evidence showing the clinical benefits of various endocrine therapies for the treatment of breast cancer. The current status and recent advances in endocrine therapy for breast cancer are reviewed based on the results of current clinical trials. Future perspectives of endocrine therapy are also discussed.

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Background: Intracystic abnormalities of the breast may result from debris, intracystic papilloma, or rarely breast cancer. Intracystic tumors cannot be diagnosed based on imaging examinations or fine needle aspiration alone, and therefore excisional biopsy must be performed. We have treated many cases who had nipple discharge with mammary ductoscopy since 1992, and we have used this method to diagnose intracystic tumors.
Methods: An endoscope was inserted into the cyst percutaneously, and the intracystic tumor was biopsied using forceps.
Results: Six intracystic tumors were biopsied with the endoscope. Four of six cases were cancer, and two were benign papillomas.
Conclusion: We were able to visualize and accurately biopsy intracystic tumors of the breast using mammary ductoscopy.

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Background: Percutaneous imaging-guided core needle biopsy (CNB) is being used increasingly as an alternative to surgical biopsy for the diagnosis of breast lesions that are suspicious or highly suggestive of malignancy. The purpose of this study was to evaluate ultrasonographically (US) guided 18-gauge automated CNB with post-fire needle position verification (PNPV) in the assessment of US visible breast lesions.
Methods: Biopsy of 235 US visible breast lesions was performed using US-guided 18-gauge core needles (18-GCN). After firing the biopsy needle, an image was obtained in the orthogonal plane to confirm the precise post-fire position of the needle track before removing the needle. Needle core diagnoses were compared with surgical diagnoses in 235 lesions subsequently surgically excised.
Results: The median size of the lesions was 14 mm (range, 5-60 mm). Agreement between needle core and surgical diagnoses in the 235 lesions was 92% including 192 cancers, 28 benign lesions, and 3 high-risk lesions. In the remaining 12 discordant lesions, 4 were high-risk lesions and 8 were benign lesions. In all 8 benign lesions, imaging-histological discordance was present. The sensitivity of US guided 18-GCNB for breast cancer was 96% (199 of 207). In 71% (167/235) of the cases only one core with PNPV was made. No complications occurred.
Conclusion: US-guided 18-GCNB for sonographically-demonstrated discrete mass lesions with PNPV is an accurate core needle biopsy technique of breast cancer. During the course of tissue sampling, evaluating the post-fire needle tip position by obtaining an orthogonal view with ultrasonographic guidance is the key to predicting the yield regardless of the size of the needle or the number of core samples.

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Purpose: To confirm which modality, ultrasonography (US) or mammography (MMG), is useful to detect breast cancer in women aged 30 to 39 years, and to compare the sensitivity and findings of these two modalities for invasive carcinoma and ductal carcinoma in situ (DCIS) in the diagnostic setting.
Methods: We retrospectively evaluated the sensitivity and findings of these two modalities in 165 patients aged 30 to 39 years, who underwent surgery at the Cancer Institute Hospital between 2001 and 2003. US or MMG were performed after obtaining information on the other modalities previously used and physical examination. The abnormal findings of US were defined as mass lesions and focal hypoechoic areas due to breast cancer. The abnormal findings of MMG were defined as category 3 to 5 (Japanese Mammography Guidelines) masses, calcifications, and other findings due to cancer.
Results: Of 165 patients, 147 patients (89%) mammographicaly showed dense breasts. Histologically, 146 (88%) were invasive carcinomas and 19 (12%) were DCIS. In all carcinomas, the sensitivity of US (95%) was higher than that of MMG (85%). The sensitivity of US for invasive carcinoma (99%) was higher than that of MMG (85%). On the other hand, the sensitivity of MMG for DCIS (89%) was much higher than that of US (68%).
Conclusions: US is more sensitive to detect breast cancers than MMG in this age range, especially for invasive carcinoma. On the other hand, MMG is useful for detecting DCIS, especially when it manifests with microcalcifications.

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We report a case of nipple adenoma incidentally found in a mastectomy specimen, and describe its unique histological appearance and the immunohistochemical distribution of Ki-67 positive tumor cells. A 45-year-old woman with no symptoms or sign related to the nipple had a left mastectomy for invasive breast cancer. A small nipple adenoma, 7 mm in size, was incidentally recognized in the nipple of the resected breast. Histologically, the tumor in the nipple was composed of numerous proliferative ducts with a tubular and florid papillomatous appearance. Many demarcations between squamous cells of the epidermis and tumor cells were recognized in the summit as well as the lateral wall of the nipple. A high Ki-67 labeling index (20.3%) was recognized in the tumor cells in the superficial region, and a low labeling index (0.7%) was seen in the deeper region of the tumor. Based on these proliferative patterns, the symptoms and clinical signs related to the nipple that are often found in patients with nipple adenoma are thought to be associated with the destruction of the epidermis of the nipple by the invasion of benign tumor cells with high proliferative activity.

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We report a case of primary giant cell malignant fibrous histiocytoma (GCMFH) of the breast. A 56-year-old Japanese woman presented with a firm mass in the right breast. Mammography and ultrasonography revealed a well-circumscribed and lobulated mass in the upper outer quadrant of the right breast, indicative of a benign breast tumor or mucinous carcinoma. Magnetic resonance imaging revealed a restricted breast tumor without intraductal spread. Computed tomography and bone scintigraphy found no sites of distant metastases. Fine needle aspiration biopsy showed several clusters of atypical cells associated with numerous multinucleated giant cells. Breast-conserving surgery with axillary lymph nodes dissection was performed. Histological examination showed primary GCMFH of the breast. No metastases were identified in any of the 15 left axillary lymph nodes resected and surgical margins were free from tumor cells. The tumor was negative for both estrogen and progesterone receptor. Neither adjuvant chemoendocrine therapy nor postoperative radiotherapy was given, and the patient has remained disease free for 30 months postoperatively. To our knowledge, only 30 cases of primary MFH of the breast have been reported in the literature.

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We report a case of angiosarcoma arising in the breast following breast-conserving surgery with radiation therapy for breast carcinoma. The patient, a 49-year-old postmenopausal woman, had undergone breast-conserving surgery for invasive ductal carcinoma of the left breast (pT2 pN0 M0 Stage IIA). Adjuvant radiotherapy (50 Gy with a booster dose to the tumor bed of 10 Gy) was then performed for the residual breast tissue and the patient was treated with hormone therapy (tamoxifen, 20 mg daily) for 5 years. She presented with skin erosion with bleeding 10 years after the initial operation. Incisional biopsy revealed angiosarcoma of the breast, and total mastectomy was subsequently performed. The patient was the treated with chemotherapy (weekly paclitaxel, 80 mg/m² × cycles) and has remained well without evidence of local or distant recurrence.

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We report a case of neuroendocrine carcinoma in a 40-year-old woman who presented with two lumps in her left breast. Mammography failed to reveal any lesions because she had so-called dense breasts, but ultrasonography showed 4 irregular hypoechoic masses. Magnetic resonance imaging also showed 4 homogeneous lobulated tumors with early contrast enhancement, suggesting malignancy. Core needle biopsy and subsequent immunohistochemical examination of the specimens was performed. Neuroendocrine carcinoma was diagnosed. The tumor cells were diffusely positive for chromogranin A and synaptophysin, and some were positive for CD56. We performed total mastectomy with sentinel lymph node biopsy, which showed no metastasis. Recurrence has not been detected at 36 months after surgery.

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