The primary aim of this study was to compare the effectiveness of oral uracil-tegafur (UFT) with that of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) given as postoperative ...adjuvant treatment to women with node-negative, high-risk breast cancer.
Women with node-negative, high-risk breast cancer were randomly assigned to receive either 2 years of UFT or six cycles of CMF after surgery. The primary end point was relapse-free survival (RFS). Overall survival (OS), toxicity, and quality of life (QOL) were secondary end points. The hypothesis was that UFT was not inferior to CMF in terms of RFS.
Between October 1996 and April 2001, a total of 733 patients were randomly assigned to receive either treatment. The median follow-up time was 6.2 years. The RFS rates at 5 years were 88.0% in the CMF arm and 87.8% in the UFT arm. OS rates were 96.0% and 96.2%, respectively. The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS (95% CI, 0.66 to 1.45; P = .92) and 0.81 for OS (95% CI, 0.44 to 1.48; P = .49). The toxicity profiles differed between the two groups. The QOL scores were better for patients given UFT than those given CMF.
RFS and OS with oral UFT were similar to those with classical CMF. Given the higher QOL scores, oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.
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.
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.
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.
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.
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.
ABSTRACT Breast cancer has attracted increasing attention recently, because the number of breast cancer patients has increased, and breast cancer has affected some famous people. In Japan, however, ...the rate of screening examinations for breast cancer remains low and has shown little increase. Various innovations have been introduced to raise the examination rate, but the existence of some kinds of psychosocial problems in examinees may be one reason for the limited effect of these efforts. Here we report a study on the mental health and mental fatigue level of adult women that could affect their behavior of undergoing examinations. Questionnaires on breast cancer screening examination behavior were distributed to 5,321 adult women from March to September 2014, and responses were obtained from 1,752 (32.9%). After excluding women under 40 years old and questionnaires with clearly inadequate responses, the subjects of the investigation were 1,047 women. Past experience of undergoing breast cancer screening and levels of mental health and mental fatigue using the WHO subjective well-being inventory (SUBI) were investigated. The SUBI consists of two scales for positive affect and negative affect that make up subjective well-being, with 11 subscales (General Well-Being Positive Affect, Expectation-Achievement Congruence, Confidence in Coping, Transcendence, Family Group Support, Social Support, Primary Group Concern, Inadequate Mental Mastery, Perceived Ill-Health, Deficiency in Social Contacts, and General Well-Being Negative Affect). It is used to assess levels of mental health and mental fatigue. 802 people (51.6 +- 7.97) had undergone examinations in the past, and 245 (49.3 +- 7.29 years old) had not. The group that had never undergone examinations tended to be significantly younger (P < 0.0001). The score for mental health level was significantly higher in the group that had undergone examinations (P = 0.013), but no significant difference was seen in mental fatigue level (P = 0.847). Subjects with poor mental health (score < 31) were significantly less likely to undergo screening examinations (odds ratio (OR) 1.61, 95% confidence interval (CI) 1.112-2.331, P = 0.012). The results of a multivariate analysis of the 11 subscales showed trends of women being less likely to undergo screening examinations with higher scores for Confidence in Coping (OR 1.175, 95% CI 1.026-1.346, P = 0.019), and more likely to undergo screening examinations with higher scores for Family Group Support (OR 0.872, 95% CI 0.777-0.979, P = 0.020). Low mental health level was found to be an impediment to the behavior of undergoing breast cancer screening examinations. Among the mental health items, family support and excessive confidence affected the behavior of undergoing examinations. Thus, approaches that raise mental health with that in mind are thought to be necessary.
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.
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.
Recent studies have indicated that a complex machinery of transactivation of target genes by estrogen or antiestrogen through estrogen receptor (ER) exists. However, the substantial roles of ER-beta, ...coactivators, and corepressors in the development and progression of breast cancer remain to be elucidated. To obtain some clue to these roles, we screened the expression levels of ER-alpha, ER-beta, coactivators (SRC-1, TIF2, AIB1, CBP, and P/CAF) and corepressors (N-CoR and SMRT) in 6 normal mammary glands, 6 intraductal carcinomas, 22 invasive ductal carcinomas, and 7 breast cancer cell lines using a multiplex reverse transcription-PCR. ER-alpha mRNA expression levels significantly correlated with ER-alpha protein levels measured by enzyme immunoassay in the breast cancer tissues and cell lines. A significant correlation of expression levels was observed between ER-alpha and TIF2, AIB1, P/CAF, and N-CoR, and between ER-beta and AIB1 and CBP in the tissue samples. A significant correlation was also observed between ER-alpha and ER-beta and between ER-beta and CBP in the cell lines. The expression levels of ER-alpha, TIF2, and CBP were significantly higher in the intraductal carcinomas than those in the normal mammary glands. In addition, the expression levels of ER-alpha and N-CoR were significantly higher in the intraductal carcinomas than those in the invasive ductal carcinomas. These findings suggest a positive correlation of expression levels among ER-alpha and cofactors and among ER-beta and cofactors, an up-regulation of expression levels of ER-alpha and cofactors during the development of intraductal carcinomas from normal mammary glands, and a decrease in their expression levels during the progression of breast cancer.
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.
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.
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.
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).
Although further studies to assess Src activity are necessary, investigation of Src inhibitors for breast cancer including in-vivo models should be encouraged more.
Vascular endothelial growth factor (VEGF)‐A is known to play an important role in tumor angiogenesis. Three additional members of the VEGF family, VEGF‐B, ‐C and ‐D, have recently been discovered. ...VEGF‐C and VEGF‐D are ligands for VEGF receptor‐3, which is expressed in the endothelium of lymphatic vessels. The expression of VEGF‐C is known to be associated with the development of lymphatic vessels. Therefore, it is conceivable that VEGF‐C and VEGF‐D might play a role in the development of lymphatic vessels in solid tumors. To obtain some clue as to this role, we developed a semi‐quantitative reverse transcription‐polymerase chain reaction method to investigate the mRNA expression levels of each VEGF family member in breast cancer. All the VEGF family members were expressed at different levels in seven human breast cancer cell lines explored. Although VEGF‐A and VEGF‐B expressions were detected in both node‐positive and node‐negative breast tumors, VEGF‐C expression was detected only in node‐positive tumors. VEGF‐D expression was detected only in an inflammatory breast cancer and a tumor which developed an inflammatory skin metastasis. These findings suggest a possible relationship between the expression level of VEGF‐C and/or VEGF‐D and the development of lymphatic tumor spread.
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