Fumine Tsukamoto

Quantitative analysis of estrogen receptor‐α and ‐β messenger RNA expression in breast carcinoma by real‐time polymerase chain reaction

Estrogen action is mediated not only through a classic estrogen receptor (ER) (ER‐α) but also through a second ER (ER‐β) that has a structure and function similar to ER‐α. A correlation between ER‐β mRNA expression with ER and progesterone receptor (PR) protein levels as well as prognostic factors remains to be established in breast carcinoma.

Immunohistochemical Detection of P-glycoprotein in Breast Cancer and Its Significance as a Prognostic Factor.

Overexpression of P-glycoprotein (Pgp) in tumors is one of the major mechanisms which mediates the multidrug resistance (MDR) phenotype. To evaluate the prognostic significance of Pgp in breast cancer, Pgp expression was examined in paraffin-embedded tissue sections of 94 breast cancer specimens by immunohistochemistry. Tissue specimens were obtained by mastectomy without preoperative chemotherapy. UIC2 monoclonal antibody which recognizes an extracellular epitope of human Pgp was employed. Of the 94 breast cancer specimens, 35 (37.2%) were positive for Pgp expression. Pgp expression had no correlation with menopausal or hormone receptor status, axillary lymph node involvement or tumor size. However, a significant correlation was observed between Pgp expression and disease relapse (p = 0.0322). Pgp-positive patients showed a significantly shorter disease-free survival period than Pgp-negative patients by the Kaplan-Meier method (p = 0.0433). These results suggest that immunohistochemical detection of Pgp in breast cancer tissue may have prognostic value after radical operation.

Section 5. Breast: Overview: video-assisted breast surgery

Since 1992, video-assisted surgery for the breast has been developed mainly in the field of plastic surgery, notably in breast augmentation surgery. Today, video-assisted surgery, indicating partial or total endoscopic surgery, can be performed for the treatment of both benign and malignant breast tumors to improve the cosmetic outcome. Although, in some respects, this kind of surgery for malignant tumors is still experimental, it is feasible enough for clinical use, and is expected to become one of the standard operations for breast cancer.Abstract Since 1992, video-assisted surgery for the breast has been developed mainly in the field of plastic surgery, notably in breast augmentation surgery. Today, video-assisted surgery, indicating partial or total endoscopic surgery, can be performed for the treatment of both benign and malignant breast tumors to improve the cosmetic outcome. Although, in some respects, this kind of surgery for malignant tumors is still experimental, it is feasible enough for clinical use, and is expected to become one of the standard operations for breast cancer.

Laparoscopic adrenalectomy: lateral transabdominal approach vs posterior retroperitoneal approach

Laparoscopic adrenalectomy has been used to remove a wide variety of adrenal neoplasms. Although several laparoscopic approaches to the adrenal gland have been described, the lateral transabdominal approach has several advantages when compared with other approaches for laparoscopic adrenalectomy. From October 1995 to July 1999, we performed laparoscopic adrenalectomies on 16 patients, including eight posterior retroperitoneal approaches and eight lateral transabdominal approaches. Sixteen patients, ranging in age from 23 to 69 years, were treated for the following conditions: non-functioning adenoma, four patients; aldosteronoma, seven patients; pheochromocytoma, three patients; Cushings adenoma, two patients. The average tumor size was 2.5 +/- 0.5 cm (1.8-3.0 cm, median 2.4 cm) in the lateral transabdominal approach, 1.2 +/- 0.8 cm (0.8-3.2 cm, median 1.75 cm) in the posterior retroperitoneal approach. Average operative time of lateral transabdominal approach was significantly shorter than that of the posterior retroperitoneal approaches (mean 129 min vs 269 min, P = 0.0005). Conversion to laparotomy was required in one patient in the posterior approach. Postoperative complication occurred in one pneumothorax in the lateral transabdominal approach and two subcutaneous emphysemas in the posterior retroperitoneal approach. There was no statistical difference in blood loss during the operation in the two groups. There was no mortality in either group. The lateral transabdominal approach is a safe and efficient technique for the removal of the adrenal neoplasms. Compared with other approaches, this technique has a wider working space and also good exposure for removing the adrenal gland.

Leiomyosarcoma of the breast: A case report and review of the literature about therapeutic management

We experienced a leiomyosarcoma of the breast in an 18-year-old female. No specific treatment has been established. In order to clarify appropriate therapeutic management methods, the limited data available from our and previous case reports were assessed. A leiomyosarcoma of the breast must be excised with a negative margin. If the tumor size is large and an adequate margin, greater than 3-cm margin around the excised tumor, is not achieved due to anatomical constraints, radiotherapy may be indicated.

Phase II Trial in Japan of Sequential Administration of Weekly Paclitaxel Followed by FEC as Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer [KBCSG0206 Trial: Kinki Breast Cancer Study Group (KBCSG)]

Objective: We conducted a phase II trial in Japan to evaluate the efficacy and tolerability of weekly paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) as neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC). Methods: Patients with clinical stage IIIA–IIIB breast cancer received NAC consisting of 12 once-a-week cycles of paclitaxel followed by 4 once-every-third-week cycles of FEC. Results: Fifty patients with LABC were enrolled, 47 of whom were administered paclitaxel followed by FEC as NAC. The clinical response rate for all chemotherapies was 85.1%, and the pathological complete response rate was 27.7%. Regarding toxicity, grade 3–4 neutropenia was observed in 10% of patients. No serious toxicities requiring the discontinuation of treatment were encountered. The rate of breast conservation surgery was 31.9%, median survival had not been reached at the time of conclusion of this study, and the 3-year survival rate was 85.1%. Median disease-free survival was 40.2 months, and the 3-year disease-free survival rate was 62.1%. Conclusions: Weekly paclitaxel followed by FEC demonstrated efficacy and tolerable toxicity in a neoadjuvant setting for LABC.

The cell cycle profiling-risk score based on CDK1 and 2 predicts early recurrence in node-negative, hormone receptor-positive breast cancer treated with endocrine therapy.

The Cell Cycle Profiling - Risk Score (C2P-RS) based on CDK1 and CDK2 specific activities was significantly associated with relapse in breast cancers. We evaluated the prognostic value of the C2P-RS classification using a Japanese cohort including node-negative, hormone receptor-positive breast cancers treated with adjuvant endocrine therapy alone as systemic therapy. Of 266 patients, 22 (8.3%) relapsed within 5 years after surgery. The distribution of each C2P-RS group was 71.8% in the low group, 12.0% in the intermediate group, and 16.2% in the high group. The 5-year relapse-free survival rate in the low C2P-RS group (97.3%) was significantly higher than that in the intermediate C2P-RS group (84.3%) or the high C2P-RS group (74.4%) (P < 0.001). The univariate analysis demonstrated that age, tumor size, histologic grade, and HER2 had no significant correlations with relapse but the C2P-RS classification (P < 0.001) and Ki-67 (P = 0.009) were significantly associated with relapse. Multivariate analysis showed only that the C2P-RS classification was a significant independent prognostic indicator. The C2P-RS classification might be a significant predictor of earlier recurrence in node-negative, hormone receptor-positive breast cancers treated with endocrine therapy.

Randomized phase III study of trastuzumab monotherapy followed by docetaxel and trastuzumab versus the combination of trastuzumab and docetaxel as first-line treatment in patients with HER2 positive metastatic breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #3132 Introduction: Treatment with trastuzumab (H) is a standard therapy for the patients with HER2 positive metastatic breast cancer (MBC) and both the combination with H and chemotherapy (CT) and H alone are very popular. However, it is unknown which is better; sequential H alone followed by combination of CT and H at disease progression or the combination with H and CT as first-line therapy. Therefore, we conducted phase III randomized trial compared them in HER2 positive MBC. Methods: Eligible patients were HER2 positive MBC patients (pts) with measurable tumour based on RECIST, ECOG Performance status 0 or 1 and left ventricular ejection fraction (LVEF) >50%. Patients with prior CT for MBC, adjuvant H, and Docetaxel (DTX) were excluded. They were randomly assigned to sequential weekly H 2 mg/kg (loading 4 mg/kg) alone followed by combination of DTX (60 mg/m2, q3wks) and H at disease progression (arm A) or concurrent combination of H and DTX (arm B). Primary endpoints were time to progression (TTP) of H alone (arm A) and combination of H and DTX (arm B) and overall survival (OS). Secondary endpoints were overall response rate (ORR), TTP and safety in arm A and B. Results: Of the 108 pts registered, 105 pts were eligible. Baseline characteristics of all pts in two groups were well-balanced. Median age was 57/55 years, prior adjuvant CT 38/45% and single metastatic site 30/31% in arm A and B, respectively. Median TTP in arm A was 137 days compared to 445 days in arm B (hazard ratio=4.15; P<0.0001). ORRs were 15% and 71% in arm A and B, respectively. Median OS has not been reached yet, however, the number of deaths were 11 pts in arm A and 4 pts in arm B (hazard ratio=3.36; P=0.028). Adverse event incidence of grade 3 or 4 was 51/85% in each arm. An Efficacy and Safety Evaluation Committee recommended stopping this trial based on the results of TTP and OS. Discussion: These results suggested that the combination of H and CT is superior to sequential H alone followed by DTX and H as first-line therapy in HER2 positive MBC pts despite the number of pts did not reach to the planned sample size. We will continue further investigation based on extended follow-up period. The updated data will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3132.

Abstract P2-10-18: Cell Cycle Profiling – risk score (C2P-RS) based on the specific activity of CDK1 and CDK2 predicts relapse in node-negative, hormone receptor-positive breast cancer treated with endocrine therapy

Background: We have previously reported on the Cell Cycle Profiling (C2P) assay for determining the specific activity (SA, activity/expression) of cyclin-dependent kinases (CDKs). The C2P-risk score (C2P-RS) based on CDK1 and CDK2 SAs was significantly associated with “tumor growth speed” in xenograft models and relapse in early breast cancer. This study was conducted to confirm the prognostic performance of C2P-RS classification in node-negative and hormone receptor (HR)-positive (ER− and/or PR-positive) breast cancers. Methods: This multicenter and blinded retrospective study included patients with node-negative, HR-positive tumors treated with endocrine therapy alone. Patients treated with adjuvant chemotherapy or trastuzumab or any kind of neoadjuvant treatments were excluded. C2P-RS was determined via the C2P assay (Sysmex Corporation, Kobe, Japan) using frozen samples obtained during surgery. C2P-RS classification based on C2P-RS and CDK1 SA classified patients into three groups (low, intermediate, and high C2P-RS groups) using the same cut-off values as previously reported. ER, PR, HER2, and Ki-67 expressions were centrally evaluated with immunohistochemistry. The primary endpoint was the 5y-relapse-free survival (RFS) rate. Results: Of 317 patients enrolled in this study, 266 (24–85 y) were eligible: menopausal status: pre- 44%, post- 56%; histologic grade: I 24%, II 58%, III16%; ER: positive 93%; PR: positive 82%; HER2: negative 96%. 22 (8.3%) patients relapsed within 5 y after surgery (median follow-up period, 73 mo). The distribution of each C2P-RS group was 71.8% in the low group, 12.0% in the intermediate group, and 16.2% in the high group. The Kaplan-Meier method showed that the 5y-RFS rate in the high C2P-RS group (74.4%) was significantly lower than that in the intermediate (84.3%) or the low C2P-RS groups (97.3%) (P Conclusion: C2P-RS is unique in that it reflects the tumor growth speed, and C2P-RS classification was able to select patients with favourable or unfavourable prognosis from among those with node-negative, HR-positive tumors treated with endocrine therapy alone. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-18.

Abstract LB-276: A novel approach using the telomerase-selective adenoviral marker (OBP-401) for detection of circulation tumor cells in breast cancer patients

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: The detection of circulating tumor cells (CTCs) is a potential method to predict survival of metastatic breast cancer patients as well as outcomes of early breast cancer patients. However, no method for CTCs has yet proven to be the golden standard. We developed a new approach for detecting CTCs using the telomerase-selective adenoviral marker (OBP-401, Oncolys Biopharma). This marker contains the replication cassette, in which the human telomerase reverse transcriptase promoter drives expression of E1 genes, and the green fluorescent protein (GFP) gene for monitoring viral replication. Thus, OBP-401 infects viable cancer cells and replicates in them under the telomerase activity, and we can detect viable CTCs as GFP-positive cells. Methods: This system is consisted of the following steps; (1) virus-infection for 7.5 ml whole blood (incubated with 4 × 10sup8 Plaque Forming Unit OBP-401 virus for 24 hours at 37 Celsius), (2) dead cell staining using [L23102][1] (invitrogen), (3) virus-inactivation and RBC elimination, and (4) detection of GFP expressing cells using fluorescence microscopy. In a preclinical study, the sensitivity of this system was assessed using cell lines. Next, we conducted feasibility studies for CTCs detection in 80 healthy individuals, 70 metastatic, and 27 early breast cancer patients. In metastatic and early breast cancer patients, we compared the sensitivity of this system with that of CellSearch® (Veridex). GFP-positive cells (viable CTCs) and [L23102][1] expressing cells measuring ≥ 20 m in diameter (dead CTCs) were considered as CTCs in this system. Preliminary data: The sensitivity of this system, which was determined by a serial dilution of MDA-MB-468 cells against healthy volunteers blood, was 1 cell per 7.5 ml. Neither viable nor dead CTCs were detected in any of healthy controls. Of 50 metastatic patients, 12% were primary breast cancers with stage IV disease, 24% were in the 1st line chemotherapy setting, and 42 % were heavily pretreated with chemotherapy. The sensitivities of tumor markers (CEA and CA15-3), CellSearch, and OBP-401 were 78%, 54%, and 66%, respectively. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-276. [1]: /lookup/external-ref?link_type=GEN&access_num=L23102&atom=%2Fcanres%2F70%2F8_Supplement%2FLB-276.atom