Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy.

BACKGROUND: Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment. PATIENTS AND METHODS: SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5). RESULTS: Intention-to-treat population included 4851 women in SOLE (n = 2425 in the intermittent and n = 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n = 78 in the intermittent and n = 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment. CONCLUSIONS: Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption.

Effects of molecular crowding environment on the acquisition of toxic properties of wild-type SOD1.

BACKGROUND: Mutants of Cu,Zn-superoxide dismutase (SOD1) exhibit cytotoxicity such as aggregation and pro-oxidation after denaturation, which is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). In the present study, we investigated the possibility of the acquisition of toxic properties for wild-type SOD1 (WT) in the demetalated (apo) form after denaturation. METHODS: Denaturation and subsequent pro-oxidant activity of SOD1 were confirmed by circular dichroism (CD) spectroscopy and fluorescence assay, respectively. The aggregation of SOD1 was investigated by native polyacrylamide gel electrophoresis (PAGE). Crowding environment was prepared by the addition of polyethylene glycol (PEG) into buffer solution. RESULTS: The structural stability of SOD1 is reduced by demetallation. Nevertheless, high temperatures around 45 °C are required to induce denaturation of apo-WT. The generated denaturated apo-WT exhibits pro-oxidant activity after the rebinding of Cu2+. In molecular crowding environment mimicked by PEG, apo-WT is found to exhibit denaturation even at physiological temperature. The denatured WT in molecular crowding environment has both the activities of pro-oxidation and aggregation. The acquisition of the pro-oxidant activity is accelerated for H43R, which is an ALS-related mutant, in molecular crowding environment. CONCLUSIONS: Apo-WT acquires the toxic properties at physiological temperature when subjected to molecular crowding environment. Molecular crowding environment also accelerates the induction of the toxicity for H43R. GENERAL SIGNIFICANCE: Molecular crowding environment in living cells becomes an instability factor inducing denaturation and subsequent toxicity for SOD1. Apo-WT also has the toxic properties in molecular crowding environment, which can be related to the pathogenesis of ALS.

Efficacy and safety of trastuzumab, lapatinib, and paclitaxel neoadjuvant treatment with or without prolonged exposure to anti-HER2 therapy, and with or without hormone therapy for HER2-positive primary breast cancer: a randomised, five-arm, multicentre, open-label phase II trial.

BACKGROUND: Dual blockade of HER2 promises increased pathological complete response (pCR) rate compared with single blockade in the presence of chemotherapy for HER2-positive (+) primary breast cancer. Many questions remain regarding optimal duration of treatment and combination impact of endocrine therapy for luminal HER2 disease. METHODS: We designed a randomised phase II, five-arm study to evaluate the efficacy and safety of lapatinib and trastuzumab (6 weeks) followed by lapatinib and trastuzumab plus weekly paclitaxel (12 weeks) with/without prolongation of anti-HER2 therapy prior to chemotherapy (18 vs. 6 weeks), and with/without endocrine therapy in patients with HER2+ and/or oestrogen receptor (ER)+ disease. The primary endpoint was comprehensive pCR (CpCR) rate. Among the secondary endpoints, pCR (yT0-isyN0) rate, safety, and clinical response were evaluated. RESULTS: In total, 215 patients were enrolled; 212 were included in the full analysis set (median age 53.0 years; tumour size = T2, 65%; and tumour spread = N0, 55%). CpCR was achieved in 101 (47.9%) patients and was significantly higher in ER- patients than in ER+ patients (ER- 63.0%, ER+ 36.1%; P = 0.0034). pCR with pN0 was achieved in 42.2% of patients (ER- 57.6%, ER+ 30.3%). No significant difference was observed in pCR rate between prolonged exposure groups and standard groups. Better clinical response outcomes were obtained in the prolongation phase of the anti-HER2 therapy. No surplus was detected in pCR rate by adding endocrine treatment. No major safety concern was recognised by prolonging the anti-HER2 treatment or adding endocrine therapy. CONCLUSIONS: This study confirmed the therapeutic impact of lapatinib, trastuzumab, and paclitaxel therapy for each ER- and ER+ subgroup of HER2+ patients. Development of further strategies and tools is required, particularly for luminal HER2 disease.

Change in the structure and function of lectin by photodissociation of NO.

We have shown here that the structure and sugar-binding activity of lectin can be changed by the photodissociation of NO. Intramolecular S-S bonds are photogenerated from SNO in the protein, which can be used to photo-control the structure and function of proteins.

Toxicity profile differences of adjuvant docetaxel/cyclophosphamide (TC) between Asian and Caucasian breast cancer patients.

AIM: For early-stage breast cancer, four cycles of docetaxel and cyclophosphamide (TC) was proven superior to doxorubicin plus cyclophosphamide in the US Oncology 9375 trial. Given primary prophylactic antibiotics, 5% febrile neutropenia was recorded in a population comprising 75.5% Caucasians. Smaller trials and retrospective studies reviewing TC use in Asian patients did not produce similar incidence rates. This study aims to discover the variable hematological toxicities with TC use in Caucasian and Asian patients. METHODS: Breast cancer data was retrospectively reviewed for patients receiving adjuvant docetaxel 60-75 mg/m2 plus cyclophosphamide 600 mg/m2 from six countries (China, Hong Kong, Japan, Taiwan, Italy, and United States). Similar number of patients with relatively balanced baseline characteristics were chosen for analysis of hematological and nonhematological toxicities and survival data. RESULTS: From March 2004 to July 2013, data of 227 patients (127 Asians and 100 Caucasian) patients were analyzed for treatment-related toxicities. During the four cycles of TC, Asians had a significantly higher rate of grade ≥2 neutropenia than Caucasians (45.7% vs 6.0%; P <0.001) and significantly more grade ≥3 neutropenia events were documented (respectively 30.7% vs 4.0%, P <0.001). The prophylactic use of G-CSF was similar; 26.0% in Asians and 28.0% in Caucasian (P = 0.764). There were no differences in nonhematological toxicities. No significant difference in disease-free survival was observed between Asians and Caucasians (log-rank P = 0.910). CONCLUSIONS: Ethnic differences in toxicity profile exist between Asian and Caucasian patients given adjuvant TC. Over 30% Asians but less than 5% Caucasians experienced grade ≥3 neutropenia.

A phase II study of metronomic paclitaxel/cyclophosphamide/capecitabine followed by 5-fluorouracil/epirubicin/cyclophosphamide as preoperative chemotherapy for triple-negative or low hormone receptor expressing/HER2-negative primary breast cancer.

PURPOSE: Better treatments for triple-negative breast cancer (TNBC) are needed. To address this need, we studied the effects of preoperative metronomic paclitaxel/cyclophosphamide/capecitabine (mPCX) followed by 5-fluorouracil (FU)/epirubicin/cyclophosphamide (FEC) as preoperative chemotherapy in TNBC patients. METHODS: Forty primary TNBC patients received four cycles of metronomic paclitaxel (80 mg/m(2) on Days 1, 8, and 15), cyclophosphamide (50 mg/body daily), and capecitabine (1,200 mg/m(2) daily), followed by four cycles of 5-FU (500 mg/m(2)), epirubicin (100 mg/m(2)), and cyclophosphamide (500 mg/m(2)) every 3 weeks. The primary end point was the pathological complete response (pCR) rate. RESULTS: Forty patients formed the intent-to-treat population. The median dose intensities of paclitaxel, cyclophosphamide, and capecitabine were 89.7, 92.1, and 89.8%, respectively. Five patients discontinued mPCX and two discontinued FEC, primarily because of adverse events, resulting in a per-protocol population (PPS) of 33 patients. The pCR (ypT0/Tis ypN0) rate was 47.5% (19/40) in the intent-to-treat population and 54.5% (18/33) in the PPS. The clinical response rates were 36/40 (90.0%) and 31/33 (93.9%) in the intent-to-treat and PPS, respectively. The breast conservation rate was 72.7% (24/33), and 5/13 patients underwent partial resection instead of pre-planned total mastectomy. Grade 3-4 adverse events included neutropenia (35%), leukopenia (25%), and hand-foot syndrome (8%). CONCLUSIONS: Metronomic PCX followed by FEC chemotherapy was associated with a high pCR rate and low toxicity in TNBC patients. Further studies of this regimen in larger numbers of patients are warranted.

Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study).

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85-90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36-5.21, P = 0.004 for cN2-3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15-2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22-3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43-4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16-4.20, P = 0.017 for cT3-4 vs. cT1-2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48-6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53-13.14, P = 0.005 for cN2-3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12-4.94, P = 0.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31-5.97, P = 0.006 and HR 3.86, 95 % CI 1.13-24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.

Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil­ epirubicin­cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy.

This randomized, multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide (FEC) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker. Patients were randomized to 4 cycles of docetaxel/capecitabine (docetaxel: 75 mg/m2 on day 1; capecitabine: 1,650 mg/m2 on days 1­14 every 3 weeks) or docetaxel alone (75 mg/m2 on day 1 every 3 weeks) after completion of 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks). The primary endpoint was the pathological complete response (pCR) rate. Predictive factor analysis was conducted using clinicopathological markers, including hormone receptors and Ki67 labeling index (Ki67LI). A total of 477 patients were randomized; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 %, respectively. There were no significant differences in the pCR rate (docetaxel/capecitabine: 23 %; docetaxel: 24 %; p = 0.748), disease-free survival, or overall survival. However, patients with mid-range Ki67LI (10­20 %) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone. Furthermore, multivariate logistic regression analysis showed pre-treatment Ki67LI (odds ratio 1.031; 95 % CI 1.014­1.048; p = 0.0004) to be a significant predictor of pCR in this neoadjuvant treatment setting. Docetaxel/capecitabine (after 4 cycles of FEC) did not generate significant improvement in pCR compared to docetaxel alone. However, exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer.

Predictions of the pathological response to neoadjuvant chemotherapy in patients with primary breast cancer using a data mining technique.

Nomogram, a standard technique that utilizes multiple characteristics to predict efficacy of treatment and likelihood of a specific status of an individual patient, has been used for prediction of response to neoadjuvant chemotherapy (NAC) in breast cancer patients. The aim of this study was to develop a novel computational technique to predict the pathological complete response (pCR) to NAC in primary breast cancer patients. A mathematical model using alternating decision trees, an epigone of decision tree, was developed using 28 clinicopathological variables that were retrospectively collected from patients treated with NAC (n = 150), and validated using an independent dataset from a randomized controlled trial (n = 173). The model selected 15 variables to predict the pCR with yielding area under the receiver operating characteristics curve (AUC) values of 0.766 [95 % confidence interval (CI)], 0.671-0.861, P value < 0.0001) in cross-validation using training dataset and 0.787 (95 % CI 0.716-0.858, P value < 0.0001) in the validation dataset. Among three subtypes of breast cancer, the luminal subgroup showed the best discrimination (AUC = 0.779, 95 % CI 0.641-0.917, P value = 0.0059). The developed model (AUC = 0.805, 95 % CI 0.716-0.894, P value < 0.0001) outperformed multivariate logistic regression (AUC = 0.754, 95 % CI 0.651-0.858, P value = 0.00019) of validation datasets without missing values (n = 127). Several analyses, e.g. bootstrap analysis, revealed that the developed model was insensitive to missing values and also tolerant to distribution bias among the datasets. Our model based on clinicopathological variables showed high predictive ability for pCR. This model might improve the prediction of the response to NAC in primary breast cancer patients.

Correlation between docetaxel-induced skin toxicity and the use of steroids and H2 blockers: a multi-institution survey.

Steroids and H(2) blockers are commonly used as supportive care for taxane-containing chemotherapy, but they also affect docetaxel's primary metabolizer, cytochrome P(450) 3A4. This retrospective observational study was performed to better understand the effects of these compounds on docetaxel-induced skin toxicities, specifically hand-foot syndrome (HFS) and facial erythema (FE), a relationship that is currently poorly understood. Member institutions of the Japan Breast Cancer Research Group were invited to complete a questionnaire on the occurrence of grade 2 or higher HFS and FE among patients treated between April 2007 and March 2008 with docetaxel as an adjuvant or neoadjuvant chemotherapeutic treatment for breast cancer. We obtained data for 993 patients from 20 institutions. Twenty percent received H(2) blockers, and all patients received dexamethasone. Univariate and multivariate analyses revealed that H(2) blockers are associated with a significantly higher incidence of both HFS and FE. The incidence of FE was significantly higher for the docetaxel + cyclophosphamide (TC) regimen than for non-TC regimens combined. Dexamethasone usage did not affect the incidence of either HFS or FE. In conclusion, use of H(2) blockers as premedication in breast cancer patients receiving docetaxel significantly increases the risk of both HFS and FE.

Update results of FEC followed by docetaxel neoadjuvant trials for primary breast cancer.

This study has been initiated to evaluate the safety, clinical and pathologic response as well as the relation of response (pCR or non-pCR) and survival (overall and relapse-free) of fluorouracil, epirubicin and cyclophosphamide (FEC) followed by docetaxel (DOC) as preoperative chemotherapy in patients with operable breast cancer. Japanese patients with primary breast cancer, Tlc-3N0M0 or T1-3NIM0, age 20-60, PS 0-1 were included in this study. Preoperative chemotherapy consisted of 4 cycles of FEC (500 mg/m(2), 100 mg/m(2), 500 mg/m(2)) every 3 weeks followed by 4 cycles of DOC (75 mg/m(2)) every 3 weeks. Since June 2002, 200 patients were enrolled in this study, and the time of this interim analysis, 80 patients were evaluable for safety and clinical efficacy. The overall clinical response rate was 71.4% (14% CR, 44% PR, 42% SD/PD), and the only G3,4 toxicities, neutropenia and febrile neutropenia were observed in 54% and 14% of patients, respectively. Eighty nine patients were evaluable for pathologic response by central review. Pathologic response was evaluated among invasive tumors on multiple cross-section specimens based on a modified version of the Japanese grading system for Japanese Breast Cancer Society. The pathologic response rate was 17%. In this ongoing trial, FEC followed by DOC was active and well tolerated.

Unargued issues on the pathological assessment of response in primary systemic therapy for breast cancer.

PURPOSE: The role of primary systemic therapy (PST) in the treatment of operable breast cancer is currently under intensive investigation in the hope of allowing greater conservation of the breast, and emerging evidence suggests that induction of a pathological complete response (pCR) is at least, to some extent, predictive of long-term clinical response. In this review, we highlight the issues of pathologic evaluation after PST. METHODS: We performed a computer-assisted MEDLINE search, and additional references were found in the bibliographies of these articles. RESULTS: So far, several grading classifications are used to assess pathologic responses after PST, and pCR rates vary from 1% to 54.7% according to the PST regimens employed. However, the term "pCR" has not been applied in a consistent, standardized manner, and the pCR rates appear to depend not only on the differences in the definition of pCR, but also on the extent of tissue sampling and the techniques used for pathologic examination. So far, only limited information is available about the reliability and validity of the definition of pathologic responses. CONCLUSION: Assessment of pCR needs to be standardized, and each grading system should be verified for reliability and validity. As a lack of standard for tumor processing and evaluation may result in considerable fluctuation of pCR rates between trials, we should take into account the differences in the definition of pathologic response when comparing the results of PST.

[Efficacy of weekly docetaxel therapy for advanced or recurrent breast cancer].

To evaluate the safety and efficacy of weekly docetaxel (weekly TXT) in cases of advanced or recurrent breast cancer, 31 patients were enrolled in this pilot study of weekly TXT given at 25 mg/m2/w. Each cycle consisted of 3 weeks of therapy followed by a 1-week treatment break in an outpatient setting. Patients received a median of 15 infusions with a median cumulative dose of 680 mg. The median time to treatment failure was 8 months. The overall response rate was 32.3%, and 22.6% of patients had stable disease for at least 6 months. The response rate was consistent regardless of prior chemotherapy with anthracycline. There was no grade 3 or 4 toxicity, and the regimen was generally well tolerated. Although 37.5% of patients had grade 1 or 2 nail change, myelosuppression, fatigue, nausea, vomiting and fluid retention were mild. Weekly TXT seems to be an effective and feasible treatment for advanced or recurrent breast cancer patients.

Clinical significance of plasma nucleosome levels in cancer patients.

The nucleosome is the primary repeating unit of DNA organization in chromatin, and cell death may lead to increased levels of circulating nucleosomes in plasma (PNLs) in various circumstances such as inflammation, pulmonary embolism, autoimmune disease, and cancer. Cell death can also be induced by chemotherapeutic agents. We investigated PNLs in 99 patients with primary breast cancer, 26 with recurrent disease, 11 with benign breast disease, and 27 with other histological types of cancer. In 18 patients with recurrent breast cancer who received docetaxel (D, 60 mg/m2) every 3 weeks as second line therapy after an anthracycline-based regimen, PNLs were investigated before and during the administration of D. One hundred and seventy-four healthy controls (111 females, 63 males) without any evidence of disease were also investigated. PNLs were detected using the cell death detection ELISAplus kit. PNLs were significantly higher in patients with primary breast cancer (mean +/- SD: 0.135 +/- 0.213) and in recurrent breast cancer (0.182 +/- 0.196) as compared with healthy female controls (0.010 +/- 0.012) (p < 0.01). In patients with primary breast cancer, no correlation was found between PNLs and clinicopathological characteristics. On the other hand, PNLs were decreased after mastectomy (p < 0.05). Patients with other histological types of cancer (0.244+/-0.383) also showed significantly higher PNLs as compared to healthy controls (p < 0.01), and PNLs were elevated independently of the histological type of cancer. In patients with recurrent breast cancer, PNLs showed a transient increase 24 h after the administration of D, and these increases correlated with the degree of subsequent leukopenia. In a follow-up study, pretreatment baseline PNLs decreased markedly when a response was obtained, whereas there was no decrease in either stable disease or progressive disease. Thus, increased PNLs were found in cancer patients, and PNLs seem to be a sensitive marker of cell death that could be predictive of both leukopenia and response to chemotherapy.

Circulating angiogenesis regulators in cancer patients.

BACKGROUND/AIMS: To date, numerous studies have demonstrated that several angiogenesis regulators circulate in the blood and may function as endocrine factors in cancer patients. This review aims to give a comprehensive insight into the possible clinical value of circulating angiogenesis regulators, mainly basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF), angiogenin, pleiotrophin, thrombospondin (TSP) and endostatin (ES) in cancer patients. METHODS: A computerized (MEDLINE) and a manual search based on the reference lists of the publications were performed to identify articles published on this topic. RESULTS: In a detailed literature search, approximately 100 publications were found up to the end of 1999. Circulating angiogenic factors such as bFGF, VEGF, HGF and angiogenin have been evaluated not only as diagnostic and/or prognostic factors but also as predictive factors in cancer patients. On the other hand, little is known about the clinical significance of negative regulators. Neither the source nor the mechanism of protein externalization has been clarified in detail. CONCLUSIONS: Although there are no known factors with established clinical utility, circulating angiogenesis regulators may be useful in several situations. They could be used to determine the risk of developing cancer, to screen for early detection, to distinguish benign from malignant disease, and to distinguish between different types of malignancies. In patients with established malignancies such factors might be used to determine prognosis, to predict the response to therapy, and to monitor the clinical course. Further investigations are warranted to assess the specific utility of each factor.

Circulating levels of endostatin in cancer patients.

Endostatin is a negative regulator of angiogenesis. We examined plasma endostatin levels (PESLs) in cancer patients and healthy controls. PESLs were detected by competitive enzyme immunoassay in 147 patients with primary breast cancer, 44 patients with other histological types of cancer, 26 patients with recurrent breast cancer, 17 patients with benign breast disease and 221 healthy controls. PESLs were elevated in those patients with cancer or benign breast disease. In patients with primary breast cancer, significantly higher PESLs were found in post-menopausal patients than in pre-menopausal patients (p<0.01), although there were no differences in the other clinicopathological characteristics evaluated. PESLs in primary breast cancer patients did not change after surgery, but they increased after administration of the adjuvant tamoxifen. When we applied an age-matched cut-off value as a mean of the values for the female controls, we found that node-negative breast cancer patients with high PESLs had a significantly more favorable relapse-free survival time than those with low PESLs (p<0.05, log-rank test). Our data demonstrate that PESLs are detectable in healthy controls, and that cancer patients have elevated PESLs. A larger study is warranted to clarify the clinical significance of circulating endostatin.

The predictive value of angiogenesis for adjuvant therapy in breast cancer.

Recent accumulated data have indicated that angiogenesis is a promising indicator to predict prognosis and response to treatment. In breast cancer, microvessel density (MVD), a semi-quantitative marker of neovascularization grade, has been suggested to provide independent prognostic value. In addition, the expression of both vascular endothelial growth factor (VEGF)and thymidine phosphorylase (TP), two angiogenesis regulatory molecules, were found to be closely associated with MVD, and with the effect of treatments. In particular, VEGF expression seems to be a phenotype resistant to endocrine therapy, whereas TP expression decreases sensitivity to chemotherapy containing fluorouracil. This review summarizes the current topics regarding the prognostic and predictive value of angiogenesis in primary breast cancer, and we discuss future applications of antiangiogenesis treatments in an adjuvant setting.