Prognostic value of phosphorylated HER2 in HER2-positive breast cancer patients treated with adjuvant trastuzumab.

BACKGROUND: Adjuvant trastuzumab has been routinely used in HER2-positive operable breast cancer patients. Prognostic factors remain to be well characterized in these patients and might correlate with primary and/or acquired resistance to trastuzumab. PATIENTS AND METHODS: The study subjects were 78 HER2-positive operable breast cancer patients treated with adjuvant chemotherapy followed by 1-year trastuzumab between 2005 and 2010 in our institute. All breast tumors showed a HercepTest score of 3+ or that of 2+ and positive fluorescence in situ hybridization. Expression levels of HER1, phosphorylated HER2 (pY1248), HER3, HER4, and p53 were assessed by immunohistochemistry. Prognostic factors were investigated with univariate and multivariate analyses using the Kaplan-Meier/log-rank test and Cox proportional hazards model, respectively. RESULTS: The median age and follow-up period of the patients were 54 years and 39 months, respectively. The mean tumor size was 2.1 cm and the node-positive rate was 42 %. Eight patients had recurrent diseases but no patient died of cancer. Univariate analysis revealed that pHER2 positivity was only a significantly worse prognostic factor for relapse-free survival (RFS) (P = 0.049). A HercepTest score of 2+ and high expression level of p53 showed a trend. Multivariate analysis revealed three biological markers: pHER2 positivity [hazard ratio (HR) = 11.6, 95 % confidence interval (CI) 1.3-111.1, P = 0.031], p53 positivity (HR = 6.4, 95 % CI 1.0-40.0, P = 0.047) and a HercepTest score of 2+ (HR = 8.6, 95 % CI 1.6-45.2, P = 0.011) to be worse prognostic factors for RFS. Notably, three out of five patients with breast tumors expressing HER2 at a score of 2+ and pHER2 had recurrent diseases. Interestingly, the expression level of pHER2 significantly correlated with the expression levels of HER2 and HER3 in HER2-positive breast tumors. CONCLUSIONS: This retrospective cohort study suggests that a lower expression level of HER2 and high expression levels of pHER2 and p53 may indicate a worse prognosis in HER2-positive breast cancer patients treated with trastuzumab and chemotherapy. Further studies are needed to evaluate pHER2 expression in HER2-positive breast cancer as a prognostic and/or predictive marker.

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.

Antitumor and anticancer stem cell activity of a poly ADP-ribose polymerase inhibitor olaparib in breast cancer cells.

BACKGROUND: Although the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitor olaparib is known to have potent antitumor activity in BRCA-related breast cancer cells, a limited number of preclinical and clinical studies have shown antitumor activity of olaparib in non-BRCA-related breast cancer. We investigated antitumor activity of olaparib in breast cancer cell lines derived from patients with nonfamilial sporadic breast cancer. METHODS: Effects of olaparib alone or in combination with five different chemotherapeutic agents on cell growth, cell cycle progression, apoptosis, and proportion of cancer stem cells using the mammosphere assay and CD44/CD24/ESA cell surface marker assay were investigated in a panel of six sporadic breast cancer cell lines. Extracellular-signal-regulated kinase (ERK) phosphorylation was also investigated to elucidate action mechanisms of olaparib. RESULTS: Olaparib inhibited the growth of two estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell lines and two ER-negative and HER2-negative breast cancer cell lines (50% growth inhibitory concentrations 1.3-3.0 µM) associated with G2/M accumulation and induction of apoptosis. In contrast, two HER2-positive cell lines were resistant to olaparib. Interestingly, olaparib significantly decreased the proportion of putative cancer stem cells in either sensitive or resistant cell lines. In addition, olaparib increased expression of p-ERK. Combined treatments of olaparib with a mitogen-activated protein kinase kinase (MEK) inhibitor U0126 completely suppressed expression of p-ERK. These treatments also inhibited the G2/M accumulation and apoptosis induction by olaparib. Among five chemotherapeutic agents commonly used for breast cancer treatment, only an irinotecan metabolite SN38 showed additive antitumor activity with olaparib. Importantly, the combined treatment enhanced the increase in G2/M accumulation and apoptosis induction as well as a decrease in the proportion of cancer stem cells. CONCLUSIONS: This study has indicated for the first time that the PARP inhibitor olaparib has substantial antitumor and anticancer stem cell activity in breast cancer cell lines of nonfamilial origin. Upregulation of p-ERK might explain, at least in part, antitumor and anticancer stem cell activity of olaparib. Combined treatment of olaparib with irinotecan might be effective in treatment of non-BRCA-related breast cancer.

Marked lymphovascular invasion, progesterone receptor negativity, and high Ki67 labeling index predict poor outcome in breast cancer patients treated with endocrine therapy alone.

PURPOSE: Whether postoperative chemotherapy should be added to endocrine therapy or not is an important issue in patients with hormone receptor-positive and human epidermal growth factor receptor (HER)2-negative breast cancer. To identify patients who should be treated with additional chemotherapy, prognostic factors were investigated in breast cancer patients postoperatively treated with endocrine therapy alone. PATIENTS AND METHODS: Tumor samples and clinicopathological data were collected from patients who underwent curative surgery and were postoperatively treated with endocrine therapy alone between 1999 and 2003 in three different institutes. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and HER2 in primary tumors were centrally retested. Patients with ER-negative and/or HER2-positive tumors and/or with unknown nodal status were excluded from the study subjects. Immunohistochemical analysis of Ki67, HER1, insulin-like growth factor-1 receptor, and aldehyde dehydrogenase-1 was also performed. Prognostic factors were investigated by univariate and multivariate analyses. RESULTS: A total of 261 patients were the subjects of this study. The median age was 59 years old, the mean tumor size was 1.9 cm, the node-positive rate was 20 %, and 65 % received tamoxifen alone. Distant metastases were observed in 11 patients at a median follow-up of 98 months, and four patients had died of breast cancer at a median follow-up of 99 months. Univariate analysis showed that marked lymphovascular invasion (LVI), PgR negativity, high Ki67 labeling index (LI), and high nuclear grade were significantly worse prognostic factors for distant metastasis. Multivariate analysis revealed that marked LVI [hazard ratio (HR) 21.8] and PgR negativity (HR 10.3) were independently worse prognostic factors for distant metastasis, respectively. Multivariate analysis also revealed that marked LVI (HR 287.3), PgR negativity (HR 25.1), and high Ki67 LI (HR 19.6) were independently worse prognostic factors for breast cancer-specific death, respectively. CONCLUSIONS: The results of this multi-institute cohort study indicated that endocrine therapy alone could not prevent distant metastasis in breast cancer patients with PgR-negative tumors and/or with tumors showing marked LVI or high cell proliferation. These patients may need postoperative adjuvant chemotherapy in addition to endocrine therapy.

Long-term outcome of hypofractionated radiotherapy to the whole breast of Japanese women after breast-conserving surgery.

BACKGROUND: In Japan, there are still no reports of long-term outcome for hypofractionated radiotherapy to the whole breast after breast-conserving surgery (BCS). We report our institution's results from evaluation of the efficacy and safety of hypofractionated radiotherapy for Japanese women. METHODS: Data in the medical records of 327 patients were retrospectively reviewed. The patients were treated with hypofractionated radiotherapy between January 2003 and December 2006 at the Kawasaki Medical School Hospital and were followed for more than 3 years. The median age was 54 years old (the age range was 28-80 years). The whole breast was irradiated with a total dose of 42.56 Gy/16 fx with boost irradiation to positive margins. Adjuvant therapy consisted of chemotherapy and/or hormone therapy and was administered to 300 patients, based on their stage or pathological findings. RESULTS: Follow-up periods ranged from 21 to 92 months; the median follow-up period was 60 months. At 5-year follow-up, overall survival, cause-specific survival, relapse-free survival, and local control were 96.0, 97.5, 95.3, and 99.7% respectively. Grade 2 radiation pneumonitis occurred in five patients. Grade 2 radiation dermatitis occurred in 17 patients. Severe late complications were not observed. CONCLUSIONS: In our study, hypofractionated radiotherapy led to good results without severe toxicity. We believe hypofractionated radiotherapy after BCS is safe and efficient treatment for Japanese women.

[A pilot study of the reduced effects of adverse events caused by oral morphine and oxycodone after rotating to fentanyl patch in patients with metastatic breast cancer].

BACKGROUND: It has been confirmed by several clinical trials that the fentanyl patch causes less adverse events than sustained-release oral morphine, and after rotation. However, there has been no evidence comparing the fentanyl patch with controlled-release oral oxycodone in terms of adverse events. PURPOSE: We prospectively investigated the reduced effects of adverse events caused by sustained-release oral morphine and controlled-release oxycodone after rotating to the fentanyl patch in patients with metastatic breast cancer. METHOD: Metastatic breast cancer patients requiring sustained-release oral morphine or controlled-release oral oxycodone(n=9, 2 taking oral morphine, 7 taking oral oxycodone, mean age, 57. 5 years)were recruited. Those experiencing adverse events from oral morphine or oral oxycodone were administered a fentanyl patch. RESULTS: The pain score was reduced significantly at the 4th week. The fentanyl patch was associated with significantly less nausea, vomiting, constipation, sleepiness and dizziness over the study period. CONCLUSION: This study suggested that the fentanyl patch can reduce adverse events caused by sustained-release oral morphine as well as controlled-release oral oxycodone.

Current trends in TSH suppression therapy for patients with papillary thyroid carcinoma in Japan: results of a questionnaire distributed to councilors of the Japanese Society of Thyroid Surgery.

PURPOSE: To clarify the current trends in TSH suppression therapy for Japanese papillary carcinoma patents, a questionnaire survey was conducted among hospitals employing councilors of the Japanese Society of Thyroid Surgery. METHODS: The questionnaire consisted of 11 clinical questions divided into two sections. RESULTS: One hundred and seventy-two questionnaires were mailed, and 89 hospitals (51.7%) responded and were included in the analyses. Total thyroidectomy (38.4%) was less common compared with non-total thyroidectomy. TSH suppression therapy was performed in 72 hospitals (80.7%). In 30 hospitals (41.7%), all patients were treated with TSH suppression therapy. The patients with advanced disease (33.3%), at high risk (28.6%) and with total thyroidectomy (19.0%) were selected at the remaining 42 hospitals. The majority of responding hospitals did not have a standard policy regarding the serum level of TSH for each patient (70.0%). The common criterion for the adjustment of serum TSH was the risk classification (73.9%). The duration of TSH suppression therapy was not specified in most hospitals (75.8%). CONCLUSIONS: Our survey demonstrated that TSH suppression therapy is a common adjuvant therapy, but that the criteria for adjustment, the indications for and the duration of this therapy have not been standardized in Japan.

[Specialists in endocrine and thyroid surgery].

It was common for specialists in endocrine and thyroid surgery to join both the Japan Association of Endocrine Surgeons (with membership of approximately 1,000 surgeons and urologists) and the Japanese Society of Thyroid Surgery (with membership of approximately 1,000 surgeons and otolaryngologists), which was established in 2008. On January 1, 2009, the category of specialist in endocrine and thyroid surgery was created, and as of January 2012, 358 specialists were listed. The first specialist examination (written and oral) will be conducted in October 2012, allowing specialists to be certified. There are now total of 127 authorized and associated institutions. This report gives an outline of this system and future issues to be addressed.

The cell cycle profile test is a prognostic indicator for breast cancer patients treated with postoperative 5-fluorouracil-based chemotherapy.

OBJECTIVE: The cell cycle profile test is suggested to be an independent prognostic indicator for breast cancer patients. To further clarify the prognostic value, we applied this to breast cancer patients treated with postoperative 5-fluorouracil-based chemotherapy. METHODS: A total of 153 breast cancer patients, who were treated with postoperative 5-fluorouracil-based chemotherapies, were randomly selected. Specific activities of cyclin-dependent kinases 1 and 2 in the tumor samples were analyzed. Patients were divided into three categories (low, intermediate or high risk) based on cell cycle profile analysis. RESULTS: The proportions of the cell cycle profile categories were 39% for low risk, 10% for intermediate risk and 45% for high risk, respectively. Although the cell cycle profile test did not show a significant predictive power for relapse-free survival (high vs. low risk; P = 0.052), the cell cycle profile categories were significant prognostic factors in a subgroup of 98 patients with fewer than three involved nodes (high vs. low risk, P = 0.004). Multivariate analyses also indicated that a cell cycle profile parameter (high vs. low risk) was an independent prognostic indicator from the number of involved nodes and clinical stage in this subgroup (hazard ratio = 2.46, P = 0.01). Interestingly, the prognostic power of the cell cycle profile test was significant in 75 patients treated with oral 5-fluorouracil derivatives alone (hazard ratio = 6.29 for high vs. low risk, P = 0.02). CONCLUSIONS: These findings suggest that the cell cycle profile test is useful for predicting a higher risk of relapse in patients treated with postoperative 5-fluorouracil-based chemotherapy.

Clinicopathological significance of Y416Src and Y527Src expression in breast cancer.

AIMS: To elucidate the clinicopathological significance of Y416Src and Y527Src expression in breast cancer, and to evaluate their usefulness as potential predictive markers for Src inhibitors. BACKGROUND: c-Src is a non-receptor tyrosine kinase; the active form of c-Src can catalyse tyrosine phosphorylation. The expression and activity of c-Src correlates with cell adhesion, survival, angiogenesis, migration, invasion and osteoclast function. There are limited clinicopathological data on Src expression and breast cancer characteristics. METHODS: An immunohistochemical study was performed to determine the expression of c-Src, Y416Src, and Y527Src in 215 consecutive breast cancer cases. The correlation of their expression with various clinicopathological factors was analysed statistically. RESULTS: c-Src was expressed in all 215 cases (100%). Y416Src was expressed in 174 cases (80.9%) and was highly expressed in 30 cases (14.0%). Y527Src was expressed in 138 cases (64.2%) and was highly expressed in 11 cases (5.1%). High expression of Y416Src was significantly associated with metastatic disease (p=0.0327), whereas high expression of Y527Src was significantly associated with metastatic disease (p=0.0004), clinical stage (p=0.0062), as well as HER2 status (p=0.0149). High expression of either Y416Src or Y527Src was significantly correlated with poor overall survival (p=0.0049 and p<0.0001, respectively). In the 192 curatively operated cases, Y416Src expression was significantly associated with poor disease-free survival (p=0.0088). CONCLUSION: Although further studies to assess Src activity are necessary, investigation of Src inhibitors for breast cancer including in-vivo models should be encouraged more.

New diagnostic method for breast cancer based on clinical mammographic data and its clinical validation.

BACKGROUND: Recently, the numbers of patients with breast cancer have increased rapidly in Japan, and about 40,000 people contract the disease annually today. Therefore, secondary prevention by breast cancer screening has become an important issue. Presently, mammography is used frequently for the diagnosis of breast cancer, but the reading of mammograms is difficult, and physicians must attend training classes specified by the Central Committee on Quality Control of Mammographic Screening and obtain a license to perform screening. Assessment categories are used for the evaluation of mammograms. Although they provide a scale for the diagnosis of breast cancer, the interpretation of mammograms is dependent on the physician's subjective judgment, and the advent of an objective evaluation method is awaited. METHODS: We scored the size, shape, density, margin, border, and internal structure of mammographic images and evaluated the relationships of these scores with lesion categorization. RESULTS: Since lesions could not be categorized by the analysis of any single item of mammographic images, the items were paired, and a new diagnostic system for breast cancer was prepared. When this system was applied, the diagnostic accuracy was very satisfactory, with a sensitivity of 100% (37/37) and a specificity of 92.9% (65/70) for category 5; 83.6% (51/61) and 97.8% (45/46), respectively, for category 4; and 88.9% (8/9) and 94.9% (93/98), respectively, for category 3. CONCLUSION: In this study, findings concerning the margin and internal structure were important for the discrimination of category 5, and those concerning the size, shape, and density made major contributions to the discrimination of category 3.

Analysis of clinical outcome of patients with poorly differentiated thyroid carcinoma.

Background. We retrospectively analyzed whether poor differentiation is the independent prognostic factor for thyroid carcinoma or not. Methods. The subjects were 29 patients with PDTC who were treated between April 1996 and March 2006 to compare with those of well-differentiated papillary carcinoma patients (n = 227). Results. The relapse free (RFS), distant relapse-free survival and cause-specific survival, rates were significantly lower in patients with PDTC (P < .0001, P < .001, and P < .05). After classification into focal (<10%) and diffuse type (over 10%) of PDTC, there were no significant differences in RFS and cause-specific survival due to component type or proportion of poorly differentiated component. On multivariate analysis, poor differentiation (P < .0005, RR = 4.456, 95% CI; 1.953-10.167) and extrathyroidal infiltration (P < .05, RR = 2.898, 95% CI; 1.278-6.572) showed a significant impact on DFS, and poor differentiation (P < .05, RR = 9.343, 1.314-66.453) and age (P < .005, RR = 1.306, 1.103-1.547) significantly impacted cause-specific survival. Conclusion. Poor differentiation was an independent factor for survival. Distant relapse was significantly more common among PDTC patients, and systemic therapy might be warranted.

[A case of HER2 overexpressing advanced breast cancer with CTF therapy [cyclophosphamide, pirarubicin (THPADM), fluorouracil] showed long-term effectiveness after paclitaxel shock].

A 53-year-old woman with left breast tumor was diagnosed as bilateral breast cancer(left; T3N3M0, Stage III C/right; T2N0M0, Stage II )in our hospital, both of which were revealed as invasive ductal carcinoma shown to be ER-negative, PgR negative and HER2-positive by core needle biopsy. In December 2004, paclitaxel and trastuzumab combination therapy was tried, but she went into shock just during administration of paclitaxel, and this therapy was discontinued. After that the triweekly CTF therapy was tried as an anthracycline containing regimen, and the lymph node metastases obtained a complete response after a month and a 38. 5% reduction of left primary breast tumor, which was the best response observed after three months. Time to progression was prolonged to 7 months(9 cycles). Although febrile neutropenia occurred in the first cycle, the therapy could be continued safely thereafter as an outpatient. Anthracycline-containing regimens are likely to be avoided because of the difficulty of combining with trastuzumab in the treatment of HER2 overexpressing advanced/metastatic breast cancer. But the CTF therapy of less cardiotoxicity and less alopecia, can expect longer use and better QOL as an alternative for HER2 overexpressing advanced/metastatic breast cancer patients.

Preferential antitumor effect of the Src inhibitor dasatinib associated with a decreased proportion of aldehyde dehydrogenase 1-positive cells in breast cancer cells of the basal B subtype.

BACKGROUND: Recent studies have suggested that the Src inhibitor dasatinib preferentially inhibits the growth of breast cancer cells of the basal-like subtype. To clarify this finding and further investigate combined antitumor effects of dasatinib with cytotoxic agents, a panel of breast cancer cell lines of various subtypes was treated with dasatinib and/or chemotherapeutic agents. METHODS: Seven human breast cancer cell lines were treated with dasatinib and/or seven chemotherapeutic agents. Effects of the treatments on c-Src activation, cell growth, cell cycle, apoptosis and the proportion of aldehyde dehydrogenase (ALDH) 1-positive cells were examined. RESULTS: The 50%-growth inhibitory concentrations (IC50s) of dasatinib were much lower in two basal B cell lines than those in the other cell lines. The IC50s of chemotherapeutic agents were not substantially different among the cell lines. Dasatinib enhanced antitumor activity of etoposide in the basal B cell lines. Dasatinib induced a G1-S blockade with a slight apoptosis, and a combined treatment of dasatinib with etoposide also induced a G1-S blockade in the basal B cell lines. Dasatinib decreased the expression levels of phosphorylated Src in all cell lines. Interestingly, dasatinib significantly decreased the proportion of ALDH1-positive cells in the basal B cell lines but not in the other cell lines. CONCLUSIONS: The present study indicates that dasatinib preferentially inhibits the growth of breast cancer cells of the basal B subtype associated with a significant loss of putative cancer stem cell population. A combined use of dasatinib with etoposide additively inhibits their growth. Further studies targeting breast cancers of the basal B subtype using dasatinib with cytotoxic agents are warranted.

Molecular morphological approach to the pathological study of development and advancement of human breast cancer.

Since the concept of gene profile-based intrinsic subtypes was proposed, various studies on pathological characteristics have been performed. Particularly, triplenegative (TN) breast cancer, which is negative for all hormone receptors [estrogen receptor (ER) and/or progesterone receptor (PgR) and human epidermal growth factor 2 (HER2)], has been attracting attention because effects of endocrine and targeting therapies cannot be anticipated and thus selecting a treatment method is difficult. TN cancer accounts for about 10%-15% of all invasive breast cancer cases in Japanese, which is significantly lower than the incidence reported in the United States. Cytokeratin (CK) 5/6 or epidermal growth factor receptor (EGFR) is positive in 80%, being classified as basal-like carcinoma, but it should be understood that TN breast cancer and basal-like carcinoma are not necessarily the same. Criteria for positivity judgment of ER, PgR, and HER2 were established to select treatment in cases positive for each marker, and greater importance is attached to strict accuracy control. Inversely, the level of negative findings to judge TN varies among the judgment criteria. In any case, the prognosis of TN breast cancer is poor. Pathologically, TN breast cancer shows certain morphological characteristics, such as high grade and a pushing margin, and abnormalities of BRCA1 and p53 are frequently noted. At present, as no effective therapeutic strategy has been established for TN breast cancer, further clarification of the molecular biological characteristics of such cancers is needed. In addition, the incidence of TN-type ductal carcinoma in situ (DCIS) is low, suggesting that TN does not remain preinvasive DCIS for a prolonged period and that it transforms to invasive cancer in an early stage. Because mammary gland basal cells have characters of progenitor or stem cells that differentiate into both luminal epithelium and myoepithelial cells, these cells may be utilized for the differential diagnosis of the benignity or malignancy of intraductal lesions in routine pathological practice. As proliferation markers, such as Ki-67, and multiple gene arrays for gene signature are also utilized to select adjuvant therapy, analysis may progress further in the future.

Dose-escalation phase I study in metastatic breast cancer patients with combination of paclitaxel and tegafur·uracil.

The study present the results of the dose-setting study of concomitant weekly administration of paclitaxel and tegafur·uracil (UFT) for metastatic breast cancer. Eligible patients who entered the study underwent two or more courses of weekly paclitaxel + UFT therapy as the protocol therapy. The initial dose (level 1) was paclitaxel, 80 mg/m(2) and UFT, 400 mg/day. At level 2, paclitaxel remained the same, but UFT was increased to 600 mg/day. At level 3, only paclitaxel was increased to 90 mg/m(2). Twelve patients were enrolled in this study between September 2000 and September 2002. Three patients were assigned to level 1. Grade 3 liver dysfunction (increased aspartate aminotransferase and alanine aminotransferase) was noted in one patient and grade 4 neutropenia was noted in one patient, showing that dose-limiting toxicity was detected in 2/3 patients. In accordance with the protocol, UFT was fixed at 400 mg/day and paclitaxel was decreased to 60 mg/m(2) at level -1, and then increased to 70 mg/m(2) at level 0. The overall effective rate after completion of two courses was 33% (3/9) including one case of complete response and two cases of partial responses. The remaining patients presented with stable diseases and no patient had progressive disease. In this study, weekly paclitaxel with concomitant UFT was administered. The recommended doses of paclitaxel and UFT were determined to be 70 mg/m(2) and 400 mg/day, respectively. As the toxicity profile shows, the highest toxicity level of this regimen was neutropenia and liver dysfunction, and dose-limiting toxicity was neutropenia.

Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer.

PURPOSE: Our previous study indicated that concurrent administration of 4-OH-tamoxifen (TAM) and 5-fluorouracil (5-FU), but not doxorubicin (Dox), resulted in additive antitumor effects on endocrine-responsive breast cancer cells. We further clarified the effects of combined administration of endocrine therapy with chemotherapeutic agents in this study. METHODS: Concurrent treatment with 4-OH-TAM and paclitaxel (Ptx) was investigated in estrogen receptor (ER)-positive breast cancer cells. Additionally, the combined effects of estrogen depletion from culture medium mimicking estrogen ablative therapy with 5-FU, Dox, and Ptx were investigated. RESULTS: Concurrent treatment with 4-OH-TAM and Ptx yielded less than additive antitumor effects in ER-positive breast cancer cells, as observed with Dox in our previous study. More interestingly, estrogen depletion with 5-FU, but with neither Dox nor Ptx, yielded additive antitumor effects on these cells. We also performed preliminary experiments to elucidate the mechanisms of action responsible for the combined antitumor effects observed. Ptx upregulated the level of expression of one of the molecules related to TAM resistance, Eph-A2, as observed with Dox in our previous study. Estrogen depletion down-regulated the level of expression of one of the molecules related to 5-FU resistance, thymidylate synthase, as observed with 4-OH-TAM in our previous study. CONCLUSIONS: These findings, together with those of our previous study, suggest that concurrent treatment with endocrine therapy, administration of TAM, or estrogen ablative therapy and 5-FU but neither Dox nor Ptx may yield additive antitumor effects on endocrine-responsive breast cancer.

Preoperative dynamic lymphoscintigraphy predicts sentinel lymph node metastasis in patients with early breast cancer.

BACKGROUND: Preoperative lymphoscintigraphy is commonly used in sentinel lymph node biopsy (SLNB) for patients with early breast cancer; however, its significance to predict SLN metastasis remains to be determined. PATIENTS AND METHODS: Sixty patients were enrolled in a feasibility study of SLNB. Patients with clinically node-negative breast cancer were eligible for this study. Dynamic lymphoscintigraphy was performed before SLNB. All patients underwent SLNB followed by axillary lymph node dissection. RESULTS: A dual mapping procedure using isotope and dye injections was performed. SLNs were identified in 59 of 60 patients (98.3%), with a node-positive rate of 41.7% and a false-negative rate of 1.7%. No SLN was identified in 4 of 60 patients (6.7%) on preoperative lymphoscintigraphy. Interestingly, abnormal accumulation of the radiotracer close to hot spots was observed in 29 of 56 patients (51.8%). Lymph node metastases were detected in 18 of 29 patients (62.0%) with this pattern and 5 of 27 patients (18.5%) without this pattern (P < 0.05). Micrometastases were more frequently detected in node-positive patients without this pattern than in those with this pattern (80 vs. 16.7%). Diagnostic parameters of this pattern to predict SLN metastases, including micrometastases, were 62.1% for sensitivity, 81.5% for specificity, and 71.4% for accuracy. CONCLUSIONS: Abnormal accumulation of the radiotracer close to radioactive spots may indicate SLN metastasis. When dynamic lymphoscintigraphy shows this pattern, surgeons should consider the presence of SLN metastasis and carefully remove additional lymph nodes surrounding radioactive lymph nodes so as not to leave metastatic SLNs behind.

Pedunculated polyp of early sigmoid colon cancer with invasive micropapillary carcinoma.

A 64-year-old man was admitted to Dongo Hospital (Nara, Japan) with colonic cancer, following the onset of abdominal pain, diarrhea and fever. A pedunculated polyp was detected in the sigmoid colon by colonoscopy, and laparoscopy-assisted sigmoidectomy with regional lymph node resection was performed. Histopathologically, the tumor exhibited massive invasion of the submucosa, and multiple lymph node metastases were detected. The tumor mainly consisted of a micropapillary component. Immunohistochemically, MUC1 was expressed at the stromal edge of the micropapillary component and showed the characteristic 'inside-out' pattern of a micropapillary carcinoma. The multiple lymph node metastases were predominantly composed of carcinoma with a micropapillary pattern. Our case suggests that when a micropapillary component is identified in a pre-operative biopsy specimen, even for a pedunculated early colorectal cancer, the extent of surgical resection should be carefully considered due to the high potential for nodal metastasis.

[Evaluation of irinotecan hydrochloride (CPT-11) and trastuzumab combination therapy as salvage treatment in patients with HER2 overexpressing metastatic breast cancer].

BACKGROUND: Though irinotecan hydrochloride(CPT-11)was approved in Japan in 1994, there have been few reports since that evaluated the efficacy of CPT-11. The position of this agent in the treatment of patients with metastatic breast cancer(MBC)is not definite. In addition, no report has been published to date about CPT-11 and trastuzumab combination therapy. PURPOSE: To evaluate retrospectively the efficacy of CPT-11 and trastuzumab combination therapy as salvage treatment in patients with human epidermal growth factor receptor 2 (HER2)overexpressing MBC. PATIENTS AND METHOD: We examined ten cases who received this therapy against MBC since February 2002 till March 2007 in our hospital. Overall response rate, change of tumor markers, time to treatment failure (TTF), time to progression( TTP), overall survival (OS)after start of CPT-11 and adverse events were examined for efficacy and tolerability. RESULTS: Median age was 57 (40-67)and median number of prior chemotherapies was 5(2-9). Though the overall response rate was 20%, some tumor reduction was observed totally in seven cases. CEA and CA15-3 were decreased in 78%(7/9)and 63%(5/8) of cases, respectively. Median TTF, TTP and OS were 3, 4, and 6 months, respectively. Adverse events included three cases of severe neutropenia, one of whom died of treatment-related sepsis. Slight diarrhea occurred in seven and severe nausea occurred in two cases. Dose modification of CPT-11 was necessary in 5 cases, and three discontinued CPT-11 administration, mainly due to easy fatigability, nausea and neutropenia. During the therapy, four cases were all inpatients, and 6 eventually became outpatients. DISCUSSION: This therapy for patients with HER2 overexpressing metastatic cancer resistant to multi-agents demonstrated a good result in terms of antitumor effect. But high tolerability could not be documented by our experience with this therapy. It was supposed that the risk management with prediction of adverse events and preparation of better supportive therapy could make for the higher tolerability of this therapy for more effective clinical use.