Impact of serum vitamin D on the response and prognosis in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Several studies have recently reported that the relationships between serum vitamin D and the prognosis or the pathological response to neoadjuvant chemotherapy (NAC) in breast cancer. However, there are no data regarding the clinical impacts of the vitamin D in Japanese breast cancer patients so far. PATIENTS AND METHODS: In the present study, a total of 250 patients with clinical Stage I-III primary breast cancer who were treated with NAC and subsequently underwent definitive surgery were included. Serum 25-hydroxvitamin D (25(OH)D) levels were evaluated using blood samples obtained before NAC. RESULTS: The serum 25(OH)D was positively associated with age, and the serum 25(OH)D was significantly higher in postmenopausal women than that in pre/peri-menopausal women. Serum 25(OH)D level was not associated with the achievement of pathological complete response (pCR) in this cohort. The low 25(OH)D levels were significantly associated with shorter time to distant recurrence (TTDR). According to the univariate analysis, high clinical stage before NAC (cStage III) and low serum 25(OH)D level were significantly associated with the shorter TTDR, and pCR was significantly associated with the longer TTDR. According to a multivariate analysis, low serum 25(OH)D level were independent poor prognostic factors for TTDR. CONCLUSIONS: The low 25(OH)D levels were significantly associated with poorer prognosis in Japanese women with operable breast cancer patients treated with NAC.

Long-term survival analysis of addition of carboplatin to neoadjuvant chemotherapy in HER2-negative breast cancer.

PURPOSE: Addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) has improved pathological complete response (pCR) rates in previous studies. We present long-term survival outcomes (disease-free survival [DFS], pre-planned secondary endpoint; overall survival [OS], post hoc exploratory endpoint) of our randomized study of the addition of CBDCA to NAC for HER2-negative breast cancer. METHODS: Patients with stage II/III, HER2-negative breast cancer (N = 179) were randomly assigned to receive CP-CEF (four 3-week cycles of CBDCA [area under the curve, 5 mg/mL/min, day 1] and weekly paclitaxel [wPTX, 80 mg/m2, day 1, 8, 15] followed by four 3-week cycles of cyclophosphamide, epirubicin, and 5-fluorouracil [CEF, 500/100/500 mg/m2]) or P-CEF (four cycles of wPTX followed by four cycles of CEF) as NAC. DFS and OS were analyzed at each population of pCR status and assigned treatment arm. RESULTS: Of 179 patients, 154 were available for long-term follow-up. At a median follow-up of 6.6 years (range, 0.7-8.0 years), patients who achieved pCR [n = 42, 23.5% (CP-CEF: n = 28, P-CEF: n = 16)] had longer DFS and OS than non-pCR patients [DFS; HR 0.15 (0.04-0.61), P = 0.008, OS; log-rank P = 0.003]. Addition of carboplatin to NAC significantly improved DFS and OS in the subset of patients with TNBC [DFS: HR, 0.22 (0.06-0.82), P = 0.015; OS: HR, 0.12 (0.01-0.96), P = 0.046], but not in the subset of patients with hormone receptor-positive disease or among all patients. CONCLUSIONS: Addition of carboplatin to neoadjuvant chemotherapy significantly improved DFS and OS in patients with TNBC but not in those with hormone receptor-positive, HER2-negative breast cancer.

FANCJ expression predicts the response to 5-fluorouracil-based chemotherapy in MLH1-proficient colorectal cancer.

PURPOSE: Fanconi anemia protein, FANCJ, directly interacts with MLH1, a key protein involved in DNA mismatch repair. Deficient mismatch repair, or microsatellite instability, is a potent marker for the ineffectiveness of 5-fluorouracil (5-FU) in colorectal cancer (CRC). We investigated the significance of FANCJ expression in CRC, focusing on the effects of 5-FU-based adjuvant chemotherapy. METHODS: Clinicopathologic features and immunohistochemical expression of FANCJ and MLH1 were studied in 219 patients with CRC. We also analyzed 5-FU sensitivity in CRC cell lines with varying levels of FANCJ expression. RESULTS: FANCJ expression was elevated in tumor tissues compared with normal epithelial tissue. High expression of FANCJ was significantly associated with 5-FU resistance measured by the SDI test (P < 0.05) and poor recurrence-free survival (RFS) (P < 0.05). Among patients with stage II/III tumors who received 5-FU, patients with tumors exhibiting high FANCJ expression had significantly worse RFS than did patients with tumors exhibiting low FANCJ expression (P < 0.01). Among patients who did not receive adjuvant chemotherapy, FANCJ expression was not correlated with RFS (P = 0.76). High FANCJ expression was correlated with 5-FU resistance in tumors with normal MLH1 expression (P < 0.05) but not in tumors not expressing MLH1 (P = 0.9). In vitro, FANCJ overexpression was correlated with 5-FU resistance in MLH1-proficient HCT116 3-6 cells but not in MLH1-deficient HCT116 cells. CONCLUSIONS: FANCJ could be a useful biomarker to predict the response to 5-FU and prognosis of CRC, particularly in tumors with normal MLH1 expression.

[A randomized controlled trial to evaluate the effect of adjuvant oral fluoropyrimidine derivative therapy after curative resection for stage II/III rectal cancer-adjuvant chemotherapy trial of S-1 for rectal cancer (ACTS-RC):].

We are conducting a prospective randomized trial to evaluate the survival benefit of adjuvant chemotherapy with S-1 (tegafur, gimeracil, oteracil potassium) and UFT (uracil-tegafur) after curative surgery for patients with Stage II and III rectal cancer. Patients are randomized to either administration of UFT (control) or S-1. UFT was orally administered for 5 days (400 mg/m2/day) followed by two days rest for a year. S-1 was orally administered for 4 weeks (80 mg/m2/day) followed by two weeks rest for a year. The primary endpoint is relapse-free survival (RFS) rate, and the secondary endpoints are overall survival time (OS) and frequency or level of adverse events. We aim to include 400 patients in each of the treatment groups and assume that the registration period will last until 2009.

S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance.

Inducible nitric-oxide synthase (iNOS) has been implicated in many human diseases including insulin resistance. However, how iNOS causes or exacerbates insulin resistance remains largely unknown. Protein S-nitrosylation is now recognized as a prototype of a redox-dependent, cGMP-independent signaling component that mediates a variety of actions of nitric oxide (NO). Here we describe the mechanism of inactivation of Akt/protein kinase B (PKB) in NO donor-treated cells and diabetic (db/db) mice. NO donors induced S-nitrosylation and inactivation of Akt/PKB in vitro and in intact cells. The inhibitory effects of NO donor were independent of phosphatidylinositol 3-kinase and cGMP. In contrast, the concomitant presence of oxidative stress accelerated S-nitrosylation and inactivation of Akt/PKB. In vitro denitrosylation with reducing agent reactivated recombinant and cellular Akt/PKB from NO donor-treated cells. Mutated Akt1/PKBalpha (C224S), in which cysteine 224 was substituted by serine, was resistant to NO donor-induced S-nitrosylation and inactivation, indicating that cysteine 224 is a major S-nitrosylation acceptor site. In addition, S-nitrosylation of Akt/PKB was increased in skeletal muscle of diabetic (db/db) mice compared with wild-type mice. These data suggest that S-nitrosylation-mediated inactivation may contribute to the pathogenesis of iNOS- and/or oxidative stress-involved insulin resistance.