Molecular Profiles of Breast Cancer in a Single Institution.

BACKGROUND/AIM: Historically, breast cancer has been treated according to an evaluation of biomarkers, such as the estrogen receptor and HER2 status. Recently, molecular profiling has been used to detect driver mutations and select anti-cancer treatment strategies. In addition to detecting pathogenic mutations, the total mutation count (tumor mutation burden) has been considered as another biomarker. MATERIALS AND METHODS: We performed molecular profiling of 143 breast cancer tissues obtained from resected tissues via surgical operation. RESULTS: Suspected germline mutations were detected in 10% of the patients with a higher somatic mutation ratio. CONCLUSION: As hypermutated breast cancers are more likely to benefit from certain anti-cancer treatment strategies, molecular profiling can be used as a biomarker.

Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients: extended follow-up of JBCRG-cohort study 01.

BACKGROUND: Previous large trials of trastuzumab (TZM) demonstrated improved outcomes in patients with HER2-positive early breast cancer. However, its effectiveness and safety in Japanese patients is not yet clear. Recently, new anti-HER2 agents were developed to improve treatment outcomes, but the patient selection criteria remain controversial. PURPOSE: The aim of this study was to evaluate the long-term effectiveness of TZM therapy as perioperative therapy for HER2-positive operable breast cancer in daily clinical practice and to create a recurrence prediction model for therapeutic selection. METHODS: An observational study was conducted in Japan (UMIN000002737) to observe the prognosis of women (n = 2024) with HER2-positive invasive breast cancer who received TZM for stage I-III C disease between July 2009 and June 2011. Moreover, a recurrence-predicting model was designed to evaluate the risk factors for recurrence. RESULTS: The 5- and 10-year disease-free survival (DFS) rates were 88.9 (95% CI 87.5-90.3%) and 82.4% (95% CI 79.2-85.6%), respectively. The 5- and 10-year overall survival (OS) rates were 96% (95% CI 95.1-96.9%) and 92.7% (95% CI 91.1-94.3%), respectively. Multivariate analysis revealed that the risk factors for recurrence were an age of ≥ 70 years, T2 or larger tumors, clinically detected lymph node metastasis, histological tumor diameter of > 1 cm, histologically detected lymph node metastasis (≥ n2), and the implementation of preoperative treatment. The 5-year recurrence rate under the standard treatment was estimated to be > 10% in patients with a score of 3 or greater on the recurrence-predicting model. CONCLUSION: The recurrence-predicting model designed in this study may improve treatment selection of patients with stage I-III C disease. However, further studies are needed to validate the scores generated by this model.

Association between SLCO1B1 rs4149056 and tegafur-uracil-induced hepatic dysfunction in breast cancer.

Aim: The aim of this study was to identify pharmacogenomic biomarkers to predict tegafur-uracil (UFT)-induced liver dysfunction. Patients & methods: A total of 68 patients, who were administered UFT, were evaluated using a two-step pharmacogenomics analysis. Results: The first screening revealed the association between five SNPs and UFT-induced hepatic dysfunction. In the second step, SLCO1B1 (rs4149056) was found to be the only SNP associated with UFT treatment-related elevation of aspartate aminotransferase (odds ratio: C/C vs T/T = 7.8, C/T vs T/T = 5.7; p = 0.037) and alanine transaminase (odds ratio: C/C vs T/T = 12.2, C/T vs T/T = 4.1; p = 0.034) levels. Conclusion: The SLCO1B1 polymorphisms are possible predictors of UFT treatment-related hepatic dysfunction.

Synchronous and bilateral oncocytic carcinoma of the breast: A case report and review of the literature.

Synchronous bilateral breast cancer is rare, and oncocytic carcinoma is an even rarer breast cancer histological subtype. In general, oncocytic tumors are defined as neoplasms with eosinophilic granular cytoplasm and have been reported in various organs. Oncocytic carcinoma of the breast was first documented by Gadaleanu and Craciun in 1987, and 48 cases have since been reported. The present study reports a case of synchronous bilateral breast oncocytic carcinoma. The patient was a 78-year-old woman. Although she exhibited no symptoms, chest computed tomography revealed three multinodular breast tumors: Two in the right breast and one in the left. Core needle biopsy was performed on the three tumors, and the patient was diagnosed with invasive ductal carcinoma with potential apocrine carcinoma. A bilateral modified radical mastectomy was performed. Surgical specimens of the three tumors revealed cord- or nest-forming tumor cells with eosinophilic granular cytoplasm. Immunohistochemically, the tumor cells were markedly positive for mitochondria. Electron microscopy of the tumor samples additionally revealed numerous mitochondria filling the cytoplasm. Based on these findings, the tumors were diagnosed as oncocytic carcinoma. The pathogenesis of oncocytic carcinoma remains to be fully elucidated; thus, additional clinicopathological studies are required.

Radiation recall dermatitis occurring 6 years and 4 months after breast-conserving surgery: A case report.

Currently in Japan, breast-conserving therapy, consisting of breast-conserving surgery and post-operative radiation therapy, is performed frequently for the treatment of invasive breast cancer. It has been demonstrated that radiation therapy not only prevents recurrence in the preserved breast, but that it also contributes to improved patient survival. The present study describes the case of a 37-year-old woman with radiation recall dermatitis that occurred 6 years and 4 months after breast-conserving surgery. Erythema with a relatively distinct border was observed at the irradiated site on the left breast; eczema was diagnosed by a dermatologist. Inflammatory breast cancer was ruled out, since chest X-ray, abdominal ultrasound and bone scintigraphy were negative. Following ~1 month of topical corticosteroid application and oral second generation antihistamine treatment, the erythema was alleviated and the subjective symptoms also disappeared. Only a few cases of radiation recall dermatitis have been described in the fields of radiology and dermatology, but not yet in the surgical field. In the future, the incidence of radiation recall dermatitis is predicted to increase due to the increasing number of patients undergoing breast-conserving therapy. Whether in the surgical, radiological or dermatological field, if erythema is detected at the irradiated site during post-operative follow-up, routine care should be provided, keeping in mind the possibility of radiation recall dermatitis and inflammatory breast cancer.

Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients.

BACKGROUND: Previous large trials with trastuzumab (TZM) showed improved outcome in patients with HER2-positive early-stage breast cancer. However, the efficacy and safety of TZM in Japanese patients have not been fully evaluated. We have therefore conducted an observational study in Japan. METHODS: This was a retrospective and a prospective observational study in which data on women with histologically confirmed HER2-positive invasive breast cancer who received TZM for stage I-IIIC disease were collected from 56 institutions that participated in the Japan Breast Cancer Research Group and the efficacy of each treatment regimen analyzed. RESULTS: A total of 2,024 patients treated between July 2009 and June 2011 were initially enrolled in this study; in August 2013, the patient cohort comprised 2,009 patients. Of these, 142 (7.5 %) were aged ≥70 years, 1,097 (58.1 %) had clinically node-negative (cN0) breast cancer, and 883 (47.4 %) were estrogen receptor-positive. Treatment options were neoadjuvant therapy (662 patients) and adjuvant therapy with TZM (1,228 patients). Three-year overall survival (OS) rates in the entire cohort and in the neoadjuvant and adjuvant cohorts, respectively, were 98.9 [95 % confidence interval (CI) 98.2-99.3], 98.3 (95 % CI 96.8-99.1 %), and 99.2 % (95 % CI 98.4-99.6), respectively. Three-year disease-free survival (DFS) rates in the entire cohort and in the neoadjuvant and adjuvant cohorts, respectively were 94.2 (95 % CI 93.0-95.2), 94.8 (95 % CI 93.0-95.9), and 93.1 (95 % CI 90.7-94.9 %), respectively. Multivariate analysis showed that age and nodal status negatively correlated with DFS. Age was the only factor which correlated with OS rate. Adverse events (AEs) associated with TZM and grade 3/4 AEs were reported in 356 (18.8 %) and 14 (0.6 %) patients, respectively. Grade 3/4 cardiac toxicities were reported in 11 patients. CONCLUSION: Based on data from our patient cohort of Japanese women with HER2-positive early-stage breast cancer, the efficacy and safety of systemic therapy with TZM are comparable to data from previously conducted large trials. Progress in anti-HER2 therapy for patients aged ≥70 years who have a poorer prognosis is needed.

Efficacy of lapatinib monotherapy on occult breast cancer presenting with cutaneous metastases: A case report.

The case of a 72-year-old female who identified a lymph node enlargement in the left axilla is reported in the present study. A lymph node biopsy revealed a metastatic adenocarcinoma of the axillary lymph node. Following various assessments, the patient was diagnosed with occult breast cancer and lymph node metastases, for which treatment was initiated. Trastuzumab monotherapy was administered as the patient was elderly, positive for the hepatitis B virus and exhibited the following immunostaining/immunohistochemical analysis results: Estrogen receptor (ER) negative (-), progesterone receptor (PgR) negative (-) and human epidermal growth factor receptor 2 (HER2) positive (3+). Breast ultrasonography was performed 10 months after the initial trastuzumab administration and the left axillary lymph node enlargement had reduced in size and severity. However, a skin rash (erythema) was observed encompassing the left breast and extending into the axilla. As determined by the result of a skin biopsy of this area, the patient was diagnosed with occult breast cancer with cutaneous metastases. The immunohistochemical analysis results obtained from the skin biopsy were similar to those obtained from the lymph nodes: ER (-), PgR (-) and HER2 (3+). Therefore, the patient was switched from trastuzumab to lapatinib monotherapy. The erythema completely disappeared after two months of treatment. At present (34 months following lapatinib monotherapy initiation) no new lesions or severe side-effects have been observed.

The relevance of the intrinsic subtype to the clinicopathological features and biomarkers in Japanese breast cancer patients.

BACKGROUND: Breast cancer is a disease rich in diversity, and it can be categorized into the immunohistochemical intrinsic subtypes : ER/PR + and HER2-, ER/PR + and HER2+, HER2 type, basal-like and unclassified. METHODS: In this study, in addition to the clinicopathological features potentially associated with the intrinsic subtypes, protein expression and genetic mutations of key molecules associated with breast cancer prognosis and treatment sensitivity were analyzed. The distribution of subtypes in the patient population and the differences in marker distribution across the subtypes were investigated. RESULTS: The immunohistochemical features of 471 consecutive surgical cases of women with primary breast cancer, treated in a single institution, were examined. There were 306 patients who were ER/PR + HER2- (65%); 41 who were ER/PR + HER2+ (8.7%); 59 with HER2 type (12.5%); 37 with basal-like (7.9%); and 28 patients whose breast cancer was unclassified (5.9%). There were no significant differences between the subtypes regarding age, menopausal status, disease stage, lymphatic invasion, blood vessel invasion and lymph node metastasis. Statistically significant differences were found for histological type and grade. Regarding protein expression and genetic mutation, significant differences were found in the distribution within each subtype for six out of 12 molecules investigated. CONCLUSIONS: This study revealed that subtypes differ not only in their clinical pathological profiles, such as histological types and histological grades, but also in molecular expression. The molecular expression patterns observed for each intrinsic subtype may help the selection of an optimal treatment strategy.

Granular cell tumors: a report of six cases.

Granular cell tumor is a soft tissue neoplasm that originates in the nervous system and arises at virtually any body site, but is mainly found in the skin, oral cavity or digestive tract. Most are benign and reportedly malignant cases are rare, occurring in only 1% or 2% of cases. We report on our findings in six patients who developed granular cell tumor in the mammary gland, esophagus, subcutaneous tissue and muscle. Of six patients, two had granular cell tumor located in the breast, two in the submucosa of the esophagus, and the other two under the skin of the left axillary cavity and in the right latissimus dorsi muscle, respectively. One of the two patients with tumor in the submucosa of the esophagus also had esophageal cancer. Patients' age ranged from 41 to 70 years (average, 59.1 years). Two patients with tumor in the submucosa of the esophagus were men, and the others were women. All of them were given a diagnosis of granular cell tumor by tissue biopsy and examination of excised specimens, but no evidence of malignancy was found. No recurrence has been noted in the patients who underwent surgical tumor removal.

Routine clinical use of the one-step nucleic acid amplification assay for detection of sentinel lymph node metastases in breast cancer patients: results of a multicenter study in Japan.

BACKGROUND: The objective of this study was to confirm, by means of a multicenter study conducted in Japan, the reliability and usefulness of the one-step nucleic acid amplification (OSNA) assay in routine clinical use for sentinel lymph node biopsy (SLNB) of breast cancer patients. METHODS: Patients with Tis-T2N0M0 breast cancer who underwent SLNB before systemic chemotherapy comprised the study cohort. A whole sentinel lymph node (SLN) was examined intraoperatively with the OSNA assay except for a 1-mm-thick, central slice of the lymph node, which underwent pathologic examination after the operation. For patients who underwent axillary dissection, non-SLNs were examined with routine pathologic examination. RESULTS: In total, 417 SLNBs from 413 patients were analyzed. SLN metastases were detected with greater sensitivity by the OSNA assay than by pathologic examination (22.5% vs 15.8%; P < .001), as expected from the difference in size of the specimens examined. Patients who had SLN metastases assessed with the OSNA assay proved to harbor non-SLN metastases with an overall risk ratio of 33.7%. The risk of non-SLN metastasis was significantly lower for patients who had positive SLNs assessed as OSNA+ than for those who had SLNs assessed as OSNA++ (17.6% vs 44%; P = .012). CONCLUSIONS: The OSNA assay can be used for routine clinical SLNB, and its assessment for volume of metastasis may be a powerful predictive factor for non-SLN metastasis. Further studies with more patients are needed to confirm the usefulness of this assay for selection in the clinical setting of patients who do not need axillary dissection.

Sentinel lymph node biopsy for breast cancer patients using fluorescence navigation with indocyanine green.

BACKGROUND: There are various methods for detecting sentinel lymph nodes in breast cancer. Sentinel lymph node biopsy (SLNB) using a vital dye is a convenient and safe, intraoperatively preparative method to assess lymph node status. However, the disadvantage of the dye method is that the success rate of sentinel lymph node detection depend on the surgeon's skills and preoperative mapping of the sentinel lymph node is not feasible. Currently, a vital dye, radioisotope, or a combination of both is used to detect sentinel nodes. Many surgeons have reported successful results using either method. In this study we have analyzed breast lymphatic drainage pathways using indocyanine green (ICG) fluorescence imaging. METHODS: We examined the lymphatic courses, or lymphatic vessels, in the breast using ICG fluorescence imaging, and applied this method to SLNB in patients who underwent their first operative treatment for breast cancer between May 2006 and April 2008. Fluorescence images were obtained using a charge coupled device camera with a cut filter used as a detector, and light emitting diodes at 760 nm as a light source. When ICG was injected into the subareola and periareola, subcutaneous lymphatic vessels from the areola to the axilla became visible by fluorescence within a few minutes. The sentinel lymph node was then dissected with the help of fluorescence imaging navigation. RESULTS: The detection rate of sentinel nodes was 100%. 0 to 4 states of lymphatic drainage pathways from the areola were observed. The number of sentinel nodes was 3.41 on average. CONCLUSIONS: This method using indocyanine green (ICG) fluorescence imaging may possibly improve the detection rate of sentinel lymph nodes with high sensitivity and compensates for the deficiencies of other methods. The ICG fluorescence imaging technique enables observation of breast lymph vessels running in multiple directions and easily and accurately identification of sentinel lymph nodes. Thus, this technique can be considered useful.

[Efficacy and safety of oral chemo-endocrine therapy for elderly patients with breast cancer].

We often encounter elderly patients who are difficult to treat with standard treatment (e. g. anthracycline, taxane or operation) because of complication, age and so on, though there are no standard treatments for such elderly patients. We analyzed retrospectively the efficacy and safety of oral chemo-endocrine therapy for patients more than 65 years old who were difficult to treat with standard chemotherapy or operation because of complications and other reasons. Seventeen patients were analyzed. The response rate (RR) was 76.5%, and the clinical benefit rate (CBR) was 94.1%. The two-year survival rate from the start of treatment was 91.7%, and the median progression free survival (PFS) was 1, 230 days. Grade 1 anorexia and grade 1 Hand-Foot Syndrome were observed in only one patient, and it was remarkable that patients could continue to receive treatment for such a long time. In conclusion, oral chemo-endocrine therapy is effective for elderly patients difficult to treat with standard treatment, because it has better anti-tumor effect and tolerability.

Primary leiomyosarcoma of the breast treated by partial resection of the breast including nipple and areola: report of a case.

A 46-year-old female patient presented with a tumor measuring 0.5 cm in diameter under the areola of the breast. Because no definite malignancy was found with inspection and palpation, imaging analysis, or with a fine-needle aspiration cytology examination, follow-up observation was recommended. When the patient visited the hospital 6 months later, the mass was 0.9 cm in diameter. The tumor was excised and histopathologically diagnosed as a leiomyosarcoma. Subsequently, the patient underwent a partial resection of the breast, including the nipple and areola. A follow-up examination revealed no evidence of distant metastasis or local recurrences 8 years 4 months after the surgery. Primary leiomyosarcoma of the breast is extremely rare. Only 33 cases, which are reviewed in the present study, have been previously reported in the literature.

A comparison of HER2/neu gene amplification and its protein overexpression between primary breast cancer and metastatic lymph nodes.

OBJECTIVE: Breast cancer is a heterogeneous disease. The aim of this prospective study, in which fluorescence in situ hybridization was used to determine human epidermal growth factor receptor 2 status in primary breast cancers and in the lymph node metastases, was to verify the stability of human epidermal growth factor receptor 2 status in the following steps of neoplastic progression of breast cancer, which is fundamental for an appropriate therapeutic approach. METHODS: From patients with primary breast cancer, for whom, after January 2003, surgery was performed and involved metastatic lymph nodes were found, we randomly selected four groups of 15 patients, whose human epidermal growth factor receptor 2 score by immunohistochemistry was either 0, 1+, 2+ or 3+, respectively, totaling to 60. For each of those patients, their primary tumors and all of the metastatic lymph nodes were examined. Primary tumors and metastatic lymph nodes in each patient were examined by fluorescence in situ hybridization. RESULTS: Of 18 patients with fluorescence in situ hybridization-positive primary tumors, 15 (83.3%) were fluorescence in situ hybridization-positive and 2 (11.1%) were fluorescence in situ hybridization-negative in all of their metastatic lymph nodes, and 1 (5.5%) patient had mixed (fluorescence in situ hybridization-positive or -negative) metastatic lymph nodes. Of 42 patients with fluorescence in situ hybridization-negative primary tumors, 40 (95%) were fluorescence in situ hybridization-negative and 2 (5%) fluorescence in situ hybridization-positive in all of their metastatic lymph nodes. CONCLUSIONS: This study revealed that fluorescence in situ hybridization resulted in a high concordance of 83.3% between the human epidermal growth factor receptor 2 manifestation (fluorescence in situ hybridization-positive status) in primary tumors and that in metastatic lymph nodes, demonstrating that it is appropriate to determine whether and how to apply treatment by trastuzumab based on the results of evaluation of human epidermal growth factor receptor 2 expression.

[Radiofrequency ablation of liver metastasis from breast cancer].

As the hepatic metastasis from breast cancer has a tendency to have an extrahepatic lesion, systemic therapy therefore becomes acclimatization. However, local therapy is regarded as one of the choices if there is no extrahepatic lesion. We present three cases of liver metastasis from the breast treated by radiofrequency ablation (RFA). Case 1: A 65-year-old woman was treated by left mastectomy in 1997. Radiation exposure was performed for lung metastasis, and a weekly paclitaxel therapy was administered in 2001. We performed RFA percutaneously for liver metastasis of 2.8 cm in 2002. The aggravation spread to the lung lesion and she died after RFA within one year. The liver metastasis finally enlarged to 4 cm in size. Case 2: A 36-year-old woman was treated by left mastectomy (Stage IIIa), and was followed by chemotherapy in 2000. We performed RFA for metastasis of 2 cm of liver (S7) percutaneously in 2001, and didn't recognize a recurrence to date for 3 years and 8 months. Case 3: A 43-year-old woman was treated by left mastectomy (Stage IIIa), and followed by chemotherapy in 2003. We performed RFA for a liver metastasis of 3.5 x 4 cm under laparotomy in 2004. She has been disease free for 15 months.

Outcome of breast-conserving therapy in the Tokyo Women's Medical University Breast Cancer Society experience.

BACKGROUND: The results of BCT in Japanese women have not been fully evaluated. The Tokyo Women's Medical University Breast Cancer Society initiated BCT protocols in 1987. Here, we present a retrospective analysis of BCT outcomes and identify prognostic factors. METHODS: The study population comprised 348 patients (353 breasts) with UICC clinical stage 0,I or II breast cancer, for whom wide excision (n= 294), quadrantectomy (n= 56) and tumorectomy (n= 3) were performed. The final pathological margin states were positive in 102 breasts (cancer cells remained within 5 mm of the surgical margin). The whole breast was irradiated to a total dose with 44 Gy/20 fractions or 46 Gy/23 fractions in the patients with negative surgical margins. The patients with positive or close margins received 48.4 Gy/22 fractions or 50 Gy/25 fractions irradiation to the whole breast. All but 2 patients received a radiation boost to the tumor bed and all tumor beds were irradiated to more than 53 Gy. Adjuvant therapy was administered in 240 cases. The median follow-up time was 4.3 years. RESULTS: The 5-year overall, cause-specific and disease-free survival rates were 95.8%, 97.3% and 92.5%, respectively. Recurrence was observed in 29 patients including 11 patients with loco-regional recurrence. Local recurrence was observed in 6 patients, 5 of whom were premenopausal. The 5-year local control and loco-regional control rates were 98.9% and 96.6%, respectively. T status (T1 to T2) was the only significant prognostic factor for disease-free survival. No severe morbidity has been observed. Cosmetic results were excellent or good in 73% of patients. CONCLUSION: Our BCT protocols provide a high rate of local control and good cosmetic outcome. Pathologic margin status was not a major prognostic factor for local recurrence. Long term follow-up is required to reach a definite conclusion on optimal BCT protocols.