Tomoko Umeda

Cellular localization of urokinase-type plasminogen activator, its inhibitors, and their mRNAs in breast cancer tissues

The plasminogen activation (PA) system may participate in cancer invasion and metastasis. A series of breast cancer tissue specimens was analysed using in situ hybridization and immunohistochemistry. Urokinase‐type plasminogen activator (u‐PA) mRNA was detected in cancer cells and fibroblasts adjacent to them and its expression was found to be more intense in invasive than in intraductal regions. In invasive but not in intraductal regions, especially those with abundant stroma, plasminogen activator inhibitor‐1 (PAI‐1) mRNA was observed in cancer cells, fibroblasts, macrophages, and endothelial cells, and PAI‐2 mRNA was present in cancer cells, and fibroblasts, macrophages, and lymphocytes around them. These PAI‐1‐ and PAI‐2‐positive cancer cells were localized at the periphery of the invasive front. Immunohistochemistry yielded basically similar results. A retrospective study of surgically resected breast cancers from 73 patients revealed significant clinical differences associated with u‐PA and PAI‐2 expression in cancer cells, associated with a poor and a good prognosis, respectively. These findings indicate that breast cancer cells and fibroblasts express u‐PA initially and then its inhibitors, and that this process is related to invasion. Expression of u‐PA and PAI‐2 in cancer cells themselves may serve to up‐regulate and limit PA‐mediated invasion and metastasis, respectively.

Indocyanine green fluorescence imaging system for sentinel lymph node biopsies in early breast cancer patients.

PurposeThis study presents a new method that enables the detection of sentinel lymph nodes (SLN) with high sensitivity using indocyanine green (ICG) fluorescence imaging.MethodsThis study enrolled 128 patients with clinically node-negative breast cancer. Fluorescence imaging was obtained after ICG was injected into the areola. Subcutaneous lymphatic channels were immediately visible.ResultsLymphatic channels and SLN were successfully visualized in all patients. One lymphatic channel was 60%, two channels were 24%, and three channels were 16%. The number of fluorescence SLN ranged from 1 to 6, and blue-dyed SLN ranged from 0 to 3. In the latter, SLN were not identified in 44 patients. Nineteen patients had pathologically identified lymph node metastases. All of them were recognized by fluorescence imaging, but 8 patients had lymph nodes with metastases were not identified by dye method.ConclusionThis ICG fluorescence imaging technique is feasible and safe for detecting SLN in a less invasive manner than conventional mapping, with real-time observations.

The Kampo Medicine Goshajinkigan Prevents Neuropathy in Breast Cancer Patients Treated with Docetaxel

BACKGROUND Goshajinkigan (GJG) is used for the treatment of several neurological symptoms. We investigated the efficacy of GJG and mecobalamin (B12) against neurotoxicity associated with docetaxel (DOC) in breast cancer patients. MATERIALS AND METHODS Sixty breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG and 27 patients (B12 group) received oral administration of 1500 μg/day B12. Neuropathy was evaluated according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (NCI-CTC) ver. 3.0, and a visual analogue scale (VAS). This study employed a randomized open design. RESULTS The incidence of neuropathy was 39.3% in the GJG group, and 88.9% in the B12 group (p<0.01). In the GJG group, grade 1 DEB-NTC was observed in 2 cases, grade 2 in 5 cases and grade 3 in 5 cases. Grade 1 NCI-CTC was observed in 7 cases, grade 2 in 6 cases, and VAS was 2.7 ± 2.2. In the B12 group, grades 1, 2 and 3 DEB-NTC were observed in one case, 12 cases and 12 cases, respectively; and grades 1, 2 and 3 NCI-CTC were observed in 11 cases, 12 cases and one case, and VAS was 4.9 ± 2.4. CONCLUSIONS Concomitant administration of GJG is useful in preventing neuropathy in breast cancer patients treated with a DOC regimen.

Breath Alcohol Concentration in Japanese Breast Cancer Patients Following Alcohol-Containing Chemotherapeutic Agent Infusion

Background: Preparations containing dehydrated ethanol as an additive, due to its water-insoluble properties, have been frequently used for chemotherapeutic agents, such as paclitaxel (PTX), docetaxel (DOC) and eribulin. When selecting these drugs, the influence of alcohol on the central nervous system (CNS) must be considered. In this study, we measured the breath alcohol concentration (BAC) in Japanese breast cancer patients treated with these agents. Method: Japanese patients with breast cancer receiving outpatient chemotherapy with alcohol-containing agents were registered. The BAC was measured immediately after drip infusion and 30 and 60 minutes later. Result: Thirty-one female patients were enrolled in this study. Breath alcohol was detected in 18 patients (58%) immediately after administration: 6 patients (75%) with PTX, 10 (50%) with DOC and 2 (67%) with eribulin. After 30 minutes, no patient had BAC over 0.15 mg/L, but breath alcohol under 0.1 mg/L was detected in 1 patient with PTX and 1 with DOC after 60 minutes. Conclusion: The influence of alcohol may disappear 60 minutes or more after administration, making it possible to travel home safely at this time.

Mucinous carcinoma occurring in the male breast

Male breast carcinoma is an uncommon neoplasm, accounting for 0.6% of all breast carcinomas. Invasive ductal carcinoma of no special type is the most common type of male breast carcinoma, and mucinous carcinoma occurring in the male breast is extremely rare. In the present study, we report a case of mucinous carcinoma of the male breast and discuss the clinicopathological features of this type of tumor. A 63-year-old Japanese male presented with a gradually enlarged nodule in the right breast. The resected breast specimen revealed pure mucinous carcinoma and immunohistochemical analyses demonstrated that tumor cells were positive for estrogen receptor (ER), but negative for progesterone receptor (PgR). In addition, HER2 expression was not amplified. Pure mucinous carcinoma is generally associated with a low incidence of lymph node or distant metastases, and excellent disease-free survival in females. However, certain cases of this type of tumor with axillary lymph node metastasis in the male breast have been reported. In addition, the immunoprofiles of mucinous carcinoma in males are fundamentally the same as those in females. More than 90% of cases show positive immunoreactivity for ER and/or PgR, and HER2 expression is not amplified. However, it has been reported that breast cancer in males is more frequently positive for ER than in females, and has less HER2 overexpression. The high rate of hormone receptor-positive breast cancer in males is considered to be due to similar conditions as those in breast cancer in postmenopausal women. The pathogenesis of male breast carcinoma, including mucinous carcinoma, remains unclear; therefore, additional clinicopathological studies are required.

Feasibility Study of Docetaxel and Cyclophosphamide Six- Cycle Therapy as Adjuvant Chemotherapy for Japanese Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Patients

BACKGROUND We compared treatment completion rates and safety of docetaxel and cyclophosphamide six- cycle therapy (TC6) with docetaxel followed by 5FU, epirubicin and cyclophosphamide (T-FEC) therapy in Japanese patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. MATERIALS AND METHODS We administered TC6 q3w or T-FEC q3w to HER2-negative breast cancer patients. The primary endpoint of this trial was toxicity. As second endpoints, the treatment completion rate and relative dose intensity were evaluated. RESULTS The TC6 and T-FEC group consisted of 22 and 21 patients, respectively. Concerning hematological toxicity, grade 3 or higher adverse reactions included neutropenia and febrile neutropenia. As non-hematological adverse events, exanthema and peripheral neuropathy were frequently reported in the TC6 group, whereas more patients of the T-FEC group reported nausea and vomiting. In TC6, the treatment completion rate was 86.4% and the relative dose intensity of docetaxel was 93.2%. In T-FEC, the values were 95.2% and 98.9%, respectively. CONCLUSIONS These results suggest that TC6 is tolerable in Japanese, and that this regimen can also be performed in outpatient clinics. However, with the TC6 regimen, the compliance was slightly lower than with the T-FEC regimen, and supportive therapy needs to be managed appropriately.

Abstract P1-15-11: The Kampo medicine Goshajinkigan prevents docetaxel-related peripheral neuropathy in breast cancer patients

Background: Although taxanes have become a key chemotherapeutic drug in breast cancer treatment. Taxanes inhibit the growth of cancer cells by disrupting the functioning of their microtubules; however, the microtubules of nerve cells are also affected by this process, which can cause neurological disorders. The Kampo medicine Goshajinkigan (GJG) is a traditional Japanese medicine that is used for the treatment of several neurological symptoms including pain and numbness, GJG is comprised of 10 herbs, each of which contains numerous active ingredients. Recently, GJG has been reported to prevent anticancer drug-induced peripheral neuropathy in colorectal cancer. We performed the present prospective randomized study to confirm the effects of GJG and mecobalamin (B12) against docetaxel (DOC)-associated peripheral neurotoxicity in breast cancer patients. Patients and method: Between May 2007 and April 2011, 60 breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG and 27 patients (B12 group) received oral administration of 1500 μg/day B12. The patients were treated with TC (75mg/m 2 docetaxel and 600 mg/m 2 cyclophosphamide) every 3 weeks for 4 cycles, docetaxel alone (100mg/m 2 ) every 3 weeks for 4 cycles, and XT (900mg/m 2 capecitabine administered orally twice a day on days 1–14 plus 60 mg/m 2 docetaxel) every 3 weeks for 6 cycles. Peripheral neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (NCI-CTC) ver.3.0, and a visual analogue scale (VAS). Results: The median age of the GJG group was 58 years old (35 to 70 years old), the B12 group was 55 years old (33 to 69 years old), and they were all females. For the regimens, in the GJG group, TC, DOC only, and XT were administered in 19 cases, 13 cases and 1 case, respectively. In the B12 group, they were 15 cases, 11 cases and 12 cases, respectively. The cumulative dose of DOC was 338.5 mg/m2 in the GJG group, and 340 mg/m2 in the B12 group. Peripheral neuropathy occurred significantly less frequently in the GJG group (39.3%) than the B12 group (88.9%) (p Conclusion: The present study is the first prospective control study to prove the efficacy of GJG against docetaxel-induced peripheral neuropathy in breast cancer patients. Our findings suggest that DOC-associated peripheral neurotoxicity can be suppressed by the administration of GJG. It will be necessary to confirm the usefulness of GJG in larger prospective studies. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-11.

Cetuximab as salvage monotherapy in chemotherapy‑refractory metastatic colorectal cancer: A single‑center report

In July 2008, cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), was approved in Japan for clinical use against chemotherapy-refractory metastatic colorectal cancer (mCRC). At Shiga University of Medical Science, between December 2007 and April 2012, a total of 24 EGFR-positive mCRC cases were administered immunohistochemistry with cetuximab as salvage monotherapy. The safety, side-effects and clinical efficacy of the treatment, including response rate, time to treatment failure, progression-free and overall survival, K-ras mutation status and impact on outcome, were investigated. The patient tumor growth control rate (TCR) was 38%, the mean time to progression (TTP) was 9.8 weeks [95% confidence interval (CI), 7.2–12.4] and the mean overall survival (OS) was 49.4 weeks (95% CI, 30.1–68.8). The most common adverse reactions reported were skin reactions, including acne (67%), hand-foot syndrome (16.7%) and paronychia (16.7%), followed by hypocalcemia (50%), hypomagnesemia (16%), stomatitis (20%) and gastrointestinal disorders (12%). The results of the present single-center study demonstrated that cetuximab monotherapy is beneficial for the treatment of chemotherapy-refractory patients with mCRC and that it has an acceptable level of safety and manageable side-effects.

Safety Assessment of Intravenous Administration of Trastuzumab in 100ml Saline for the Treatment of HER2-Positive Breast Cancer Patients

BACKGROUND The infusion rate is considered to affect incidence and severity of infusion reactions (IRs) caused by protein formulations. Trastuzumab (TRS) is approved for 90-minute infusion as the initial dose followed by 30-minute infusion with 250 ml saline. In the study, we evaluated the safety of TRS intravenously administered over 30 minutes with 100 ml saline to reduce burden of patients, safety of infusion with 250 ml saline already being established. MATERIALS AND METHODS Women with HER2 positive breast cancer, ≥18 years and ≥55% left ventricular ejection fraction (LVEF), were registered in the study. Patients received 8mg/kg of TRS 250 ml over 90 minutes followed by 6mg/kg of TRS 100ml over 30 minutes in a three-week cycle. RESULTS A total of 31 patients were recruited, 24 for adjuvant therapy and seven with metastases. The median age was 59 years (range 39 to 82). The total number of TRS doses ranged from 5 to 17 with the median of 15. Mild IR occurred in two patients at the first dose. However, no IR was observed after reducing to 100 ml saline. No decrease of LVEF, increase of serum brain natriuretic peptide or any other adverse events were reported. CONCLUSIONS Intravenous infusion of TRS with 100 ml saline over 30 minutes in breast cancer patients can be considered safe based on results from the study. It can be given on an outpatient basis as with the currently recommended dilution in 250 ml saline.

Progression Potential of Ductal Carcinoma in situ Assessed by Genomic Copy Number Profiling

Background: Ductal carcinoma in situ (DCIS) of the breast is heterogeneous in terms of the risk of progression to invasive ductal carcinoma (IDC). To treat DCIS appropriately for its progression risk, we classified individual DCIS by its profile of genomic changes into 2 groups and correlated them with clinicopathological progression factors. Methods: We used surgically resected, formalin-fixed, paraffin-embedded tissues of 22 DCIS and 30 IDC lesions. We performed immunohistochemical intrinsic subtyping, array-based comparative genomic hybridization, and unsupervised clustering. Results: The samples were divided into 2 major clusters, A and B. Cluster A showed a greater number of gene and chromosome copy number alterations, a larger IDC/DCIS ratio, a higher frequency of nonluminal subtype, a lower frequency of luminal subtype, and a higher nuclear grade, when compared with cluster B. However, there was no difference in the frequencies of lymph node metastasis between clusters A and B. We identified 9 breast-cancer-related genes, including TP53 and GATA3, that highly contributed to the discrimination of A and B clusters. Conclusion: Classification of breast tumors into rapidly progressive cluster A and the other (cluster B) may contribute to select the treatment appropriate for their progression risk.