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Aims: This meta-analysis explores the relationship between the everolimus minimum (Cmin) and maximum (Cmax) exposure and the risk for pulmonary adverse events (AEs) in Japanese versus non-Japanese patients. Methods: Patient-level data from patients treated with daily everolimus in advanced solid tumor trials were evaluated using a Cox regression model, stratified by cancer type or treatment arm, with log-transformed time-averaged Cmin or Cmax as a time-varying covariate. Kaplan-Meier analysis was used to evaluate the relationship between pulmonary AEs and pharmacokinetic parameters. Results: Thirty studies were identified. In the Cmin population (n = 1,962), all-grade pulmonary AE incidence was significantly higher in Japanese versus non-Japanese patients (19.9 vs. 9.4%). Pharmacokinetic parameters were similar between Japanese and non-Japanese patients. A 2-fold increase in everolimus Cmin significantly increased the risk for the first any-grade pulmonary AE in Japanese (risk ratio: 1.824; 95% CI: 1.141-2.918) and non-Japanese patients (risk ratio: 1.406; 95% CI: 1.156-1.710). Conclusions: The risk for pulmonary AEs is related to everolimus exposure. Local monitoring and reporting differences might account for the significantly higher reported incidence of low-grade everolimus-associated pulmonary AEs in Japanese versus non-Japanese patients. Patients should be carefully monitored for early signs of pulmonary AEs, and appropriate medical management should be implemented.

Purpose: We recently developed the one-step methylation-specific PCR (OS-MSP) assay which can detect methylated DNA (met-DNA) in serum with high sensitivity. To examine its prognostic value, we applied this new assay to the detection of met-DNA in serum of breast cancer patients. Methods: Serum samples taken before surgery from 336 primary invasive breast cancer patients were subjected to the OS-MSP assay for the promoter regions of GSTP1, RASSF1A, and RARβ2. The assay outcome was considered positive when methylation was detected in at least one of these three genes. Total DNA content in serum was also determined. Results: Of the 336 stage I/II patients, 33 (10%) were positive for met-DNA in serum and showed a significantly worse overall survival (OS) rate at 100 months (78 vs. 95%; p = 0.002) than those with negative findings (n = 303). Patients with high total DNA in serum (n = 112) also showed a significantly worse OS rate at 100 months (86 vs. 97%; p = 0.001) than those with low total DNA in serum (n = 224). Moreover, patients both positive for met-DNA and with high total DNA in serum (n = 18) showed a much worse OS rate at 100 months (65 vs. 94%; p < 0.001) than the others (n = 318). Conclusions: Met-DNA in serum detected with the OS-MSP assay constitutes a significant and independent prognostic factor, and its combination with total DNA in serum seems to be even more effective for prediction of prognosis for breast cancer patients.

One of the etiologic factors involved in local recurrence after breast-conserving surgery may be malignant seeding of the wound during the lumpectomy procedure. A total of 340 patients with stage I and II breast cancer were entered into the study. Of these, 270 patients received breast-conserving surgery (BCS group), and the other 70 patients underwent mastectomy (control group). After resection, lavage cytology was performed at the surgical wound. There were 55 patients (20.4%) who showed positive lavage cytology in the BCS group. In the control group, there were only 3 patients (4.3%) with positive cytology. Positivity was significantly higher in the former group (p = 0.00064). Patients with evidence of cutting across cancer lesions showed significantly higher positive rates in lavage cytology (p < 0.00001). Positivity in lavage cytology was significantly higher in patients with positive surgical margins evaluated by frozen sections (p = 0.0017), touch cytology (p < 0.0001) and formalin-fixed, paraffin-embedded sections (lateral or medial margin; p = 0.0036, anterior and posterior margin: p = 0.0210). The positivity was also significantly higher in patients with an extensive intraductal component (p < 0.0001), and less than or equal to 50 (p = 0.0061) years of age. Multivariate analysis revealed that the highest relative risk factor for positive cytology was evidence of cutting across cancer lesions (relative risk = 8.166; p < 0.00001).

Objective: The aim of this study was to elucidate the clinicopathological characteristics of breast ductal carcinomas in situ (DCIS) with aldehyde dehydrogenase 1 (ALDH1)-positive cancer stem cells (CSCs). Methods: DCIS (n = 194) were subjected to immunohistochemical staining and results were examined for associations with various clinicopathological parameters. The ALDEFLUOR assay for breast cancer cell lines was also performed to determine the proportion of CSCs according to intrinsic subtype. Results: DCIS with ALDH1-positive CSCs were significantly (p < 0.05) more likely to be estrogen receptor-α (ER)-negative, progesterone receptor (PgR)-negative, Ki67-positive and HER2-positive tumors. Luminal A subtype (8.6%) showed a significantly (p < 0.001) lower ALDH1 positivity than the other subtypes [luminal B (50.0%), luminal HER2 (36.8%), HER2 (35.3%) and triple-negative subtype (26.7%)]. Double immunostaining revealed that ALDH1-positive CSCs did not overlap with ER-, PgR- or Ki67-positive tumor cells but did overlap with HER2-positive tumor cells. The percentage of ALDEFLUOR-positive CSCs was lower in the luminal A cell lines (0.02% for T-47D and 0.4% for MCF7) than in the luminal HER2 (9.1% for BT-474 and 9.5% for MDA-MB-361), HER2 (13.9% for AU565 and 33.2% for SK-BR-3) and triple-negative cell lines (28.4% for MDA-MB-231 and 30.7% for MDA-MB-468). Conclusions: Our results suggest that most CSCs in DCIS are in the G0 phase (Ki67 negative) and do not express ER or PgR, but they do express HER2 in HER2-positive tumors.

Aromatase inhibitor (AI) is widely used as an endocrine treatment in postmenopausal patients with hormone receptor-positive breast cancer. To identify useful prognostic factors for patients with metastatic breast cancer treated with AI therapy, we investigated the association between several hormone receptor-related factors and prognosis. The expressions of estrogen receptor-α (ERα), ERβ, progesterone receptor, the phosphorylation of ERα serine 118 (Ser118) and ERα Ser167 were examined using immunohistochemical techniques for the primary tumors of 41 patients with metastatic breast cancer who received first-line AI therapy after relapse. To assess the associations of protein expression and phosphorylation levels with progression-free survival (PFS), the levels of each factor were categorized into low and high values at optimal cutoff points. In univariate analysis, high ERα expression and high ERα Ser167 phosphorylation correlated with longer PFS (p = 0.016 and 0.013, respectively). In multivariate analysis, low ERβ expression and high ERα Ser167 phosphorylation correlated with longer PFS (p = 0.031 and 0.004, respectively). Patients with both low ERβ expression and high ERα Ser167 phosphorylation had longer PFS than the others (p = 0.0107). These data suggest that the expression of ERβ and phosphorylation of ERα Ser167 may be useful prognostic factors in patients with metastatic breast cancer who received first-line AI therapy.

Objective: Predictors of pathologic complete response (pCR) to neoadjuvant chemotherapy for breast cancers have been studied extensively. Here, we focused on reduction rate after paclitaxel administration for prediction of pCR to paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC). Methods: This study included 115 patients with tumors ≥3.0 cm or with node-positive disease who were treated preoperatively with paclitaxel (80 mg/m2, once a week, 12 cycles) followed by FEC (500/75/500 mg/m2, every three weeks, 4 cycles). Reduction rate was measured with magnetic resonance imaging. Results: Tumor size (≤5.0 cm) (p = 0.014), estrogen receptor (ER) negativity (p = 0.013), and human epidermal growth factor receptor 2 positivity (p = 0.020), but not histologic type, histologic grade, or progesterone receptor, were significantly associated with pCR, while association of reduction rate ≥80% was highly significant (p = 0.0003). Multivariate analysis identified negative ER (p = 0.022) and reduction rate (p = 0.003) as independent predictors of pCR. Finally, patients with reduction rate ≥80% showed a significantly higher favorable outcome (p = 0.014) than others. Conclusions: Good response (reduction rate ≥80%) to paclitaxel seems to be a clinically useful predictor of pCR as well as a favorable prognosticator for patients treated preoperatively with paclitaxel followed by FEC.

Objective: Since preoperative differentiation between follicular thyroid adenoma (FTA) and carcinoma (FTC) remains very difficult, the purpose of this study was to identify the genes differentially expressed in FTA and FTC in order to construct a diagnostic system based on such genes for differentiation of FTA and FTC. Methods:Gene expression profiles of 45 FTAs and 22 FTCs were analyzed by means of adapter-tagged competitive polymerase chain reaction (ATAC-PCR) with 2,516 genes (learning set). The genes differentially expressed in FTAs and FTCs were then used to construct a diagnostic system based on the weighted-voting algorithm. In addition, a validation study of this diagnostic system was conducted using 12 FTAs and 6 FTCs (validation set). Results: The diagnostic system for differentiation of FTA and FTC, constructed with the aid of the learning set samples, was based on 60 genes differentially expressed in FTA and FTC, which included several genes previously identified as overexpressed in FTC (DPP4, KRT19 and IGFBP3) or FTA (trefoil factor 3 and thyroid peroxidase).The leave-one-out cross-validation study showed that the accuracy of this diagnostic system was as high as 90% (sensitivity: 77.3% and specificity: 95.6%), and was confirmed by the validation study (diagnostic accuracy: 83.3%; 95% confidence interval: 62.8–95.4%, sensitivity: 66.7% and specificity: 91.2%). Conclusions: This diagnostic system using the ATAC-PCR assay is expected to be clinically useful for preoperative differentiation between FTA and FTC since ATAC-PCR can be used for the small amount of RNA obtained from fine needle aspiration biopsy.

Objective: To evaluate the efficacy and toxicity of concurrent administration of doxorubicin and docetaxel, without prophylactic use of granulocyte colony-stimulating factor, as first-line chemotherapy in patients with metastatic breast cancer (MBC). Methods: This multi-institutional study enrolled 40 women; 37 were assessable for efficacy and all 40 patients were evaluated for toxicity. Treatment consisted of 50 mg/m2 doxorubicin and 60 mg/m2 docetaxel on day 1 every 3–4 weeks. Results: Patients received a total of 251 cycles of chemotherapy (median, 5 cycles; range, 1–13 cycles). Of the 37 patients assessable for efficacy, 2 had a complete response and 24 had partial responses, which accounted for a 70% objective response rate (95% confidence interval, 53–84%). The median time to treatment failure was 30.1 weeks (range, 3.3–80.7 weeks). Grade 4 neutropenia was observed in 88% of patients and was the most frequent haematological toxicity. Febrile neutropenia was seen in 40% of patients, but no severe infections were observed. Non-haematological toxicity was generally tolerable. There were 2 grade 4 adverse events, which included 1 bleeding duodenal ulcer and 1 hypersensitivity reaction, but grade 3 episodes were infrequent. None of the patients developed congestive heart failure or asymptomatic decrease of left ventricular ejection fraction to less than 50%. Fluid retention syndrome ≤ grade 2 was observed in 25% of patients at a median cumulative dose of docetaxel of 270 mg/m2. Conclusion: Concurrent administration of 50 mg/m2 doxorubicin and 60 mg/m2 docetaxel is active with a manageable toxicity profile as first-line chemotherapy for MBC.

Objectives: We have conducted a quantitative analysis of estrogen receptor-α (ER-α) and -β (ER-β) mRNA expression in normal thyroid and tumor tissues. Methods: Normal thyroid tissues (n = 10) and tumor tissues [(follicular adenoma (n = 14), follicular carcinoma (n = 8), papillary carcinoma (n = 14), anaplastic carcinoma (n = 3) and medullary carcinoma (n = 6)] were obtained at surgery from 45 female patients. ER-α and ER-β mRNA expression has been studied by a quantitative polymerase chain reaction. Results: ER-α mRNA levels in the normal thyroid were not significantly different from those in follicular adenomas, papillary carcinomas and medullary carcinomas but were marginally (p = 0.08) higher than those in follicular and anaplastic carcinomas. ER-β mRNA levels in the normal thyroid tissues were not significantly different from those in any other tumor tissues. ER-β to ER-α mRNA ratios were significantly (p < 0.05) higher in the normal thyroid tissues than in follicular adenomas. Proportions of ER-β mRNA variants (ER-β 1, 2, 5, and 5′) did not significantly differ among the normal and tumor tissues. Conclusions: A downregulation of ER-α mRNA in follicular and anaplastic carcinomas seems to suggest that estrogens are unlikely to play an important role in the carcinogenesis and progression of these carcinomas. On the other hand, a significant decrease in ER-β to ER-α mRNA ratios in follicular adenomas suggests a possible involvement of estrogens in the pathogenesis of this disease since the same phenomenon has been reported on estrogen-dependent breast cancers.

Prognostic factors for distant metastases in patients with local recurrence after breast-conserving treatment (BCT) were studied. Fifty-six patients who developed local recurrence after BCT were recruited from 18 key hospitals/institutes in Japan. All 10 patients whose primary tumors were DCIS fared well without evidence of distant failure for a median follow-up period of 57 months (range 41–72) after the local recurrence. Inflammatory local recurrence was observed in 5 patients whose prognosis was grave: 3 with concomitant distant metastases and 1 developing them 7 months later. In the remaining 41 patients with noninflammatory local recurrence, various clinicopathological factors including age, disease-free interval, histology of the primary and recurrent tumors, axillary lymph node status, estrogen and progesterone receptor, immunohistochemical staining of erbB2 and p53 protein were evaluated as prognostic factors. Only the p53 immunostaining status of the primary tumor was found to be a significant prognostic indicator for distant metastases; distant disease-free survival at 5 years after the local recurrence was 92% for patients with p53-negative cancers and 51% for those with p53-positive cancers (p < 0.05).

A case-control study was conducted on 143 case-control sets recruited from the 18 key hospitals/ institutes in Japan to identify risk factors for local recurrences and distant metastases after breast-conserving surgery in breast cancer patients: (1) positive surgical margin was a risk factor for local recurrences (relative risk (RR) = 16.70, p0.001) but not for distant metastases, (2) positive p53 immunostaining was a risk factor for both local recurrences (RR = 5.62, p = 0.003) and distant metastases (RR = 3.11, p = 0.034), (3) lymph node metastasis was a risk factor for distant metastases (RR = 9.28, p = 0.001) but not for local recurrences, (4) radiation therapy reduced local recurrences (RR = 0.13, p = 0.004) and (5) adjuvant chemotherapy (RR = 0.27, p = 0.120), endocrine therapy (RR = 0.21, p = 0.037), and chemoendocrine therapy (RR = 0.05, p = 0.013) reduced local recurrences.

pS2 protein expression is induced by estrogen through estrogen receptors (ER), and is known to be inhibited by antiestrogen in the breast cancer cell line MCF-7. The present study was undertaken to determine whether pS2 expression may be inhibited by the antiestrogen tamoxifen (TAM) human breast cancer. pS2 expression was immunohistochemically investigated in 22 patients treated preoperatively with TAM and in 45 without TAM treatment (control group). Immunostaining was considered positive when 10% of tumor cells showed cytoplasmic staining. We found that 94% of the pS2-positive tumors were ER-positive (ER+), and there was a significant association between the two proteins (p < 0.0001). In ER+ tumors, pS2 expression was seen in only 21% (3 of 14) of the TAM+ group, compared to 70% (16 of 23) of the control group. Statistical analysis of these data indicated a high likelihood (p = 0.006) of TAM treatment being associated with inhibition of pS2 expression in human breast cancers.

To estimate cell kinetics of intraductal carcinoma present outside the invasive ductal carcinoma of the breast, an argyrophil stain for proteins associated with nucleolar organizer regions (Ag-NOR) was applied on paraffin sections of 28 breast cancers with an extensive intraductal component. The patients chosen for study were comparable to those eligible for breast-conserving surgery in our institute. The mean numbers of Ag-NOR in the nucleus were: normal duct 1.2 +/- 0.2 (mean +/- SD), normal lobule 3.1 +/- 1.2, main tumor 10.7 +/- 4.1 and intraductal lesion 7.7 +/- 2.6. A significant difference of Ag-NOR numbers was observed not only between the normal epithelium and main tumor (p0.01) but also between the main tumor and intraductal lesion (p0.01). As for intersite variation in individual cases, the Ag-NOR number of the intraductal lesion was lower than that of the main tumor in 25 out of 28 cases (89%). These results demonstrate that an intraductal lesion is less aggressive than the main tumor.

The influence of 1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on the development and steroid hormone receptor contents of 7,12-dimethylbenzanthracene (DMBA)-induced rat ma

The influence of adjuvant chemotherapy (ACT) for operable breast cancer on the results of systemic therapy at relapse was retrospectively studied in 62 patients with recurrent disease. 32 had been treated with ACT [ACT (+) group] and the others had not [ACT (-) group]. The response rate (CR + PR) to the first treatment was 22% in the ACT (+) group and 43% in ACT (-) group. It is suggested that relapsing patients with a history of ACT respond poorly to the treatment as compared to those not receiving it.

From 1976 to 1984, 135 recurrent breast cancer patients were treated with chemotherapy and/or additive endocrine therapy and their initial therapies and survival time were analyzed. Survival from the time of recurrence in these patients was longer than historical control patients (median 26 vs. 14 months). There was no statistical difference amongst the four groups which were subdivided by initial therapies after recurrence (tamoxifen alone, tamoxifen + tegafur, tamoxifen + other chemotherapy and chemotherapy). Therefore, the type of initial therapy did not affect the survival among these patients.