Tetsuya Taguchi

We undertook a prospective phase II study to evaluate the efficacy of S-1 plus trastuzumab combination regimen for human epidermal-growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC). HER2-positive MBC patients received oral administration of S-1 (80 mg/m2/day, days 1 to 28, every 6 weeks) and intravenous weekly trastuzumab (2 mg/kg), according to the results of a prior Phase I trial of our group. A total of 28 patients were enrolled and received a median of 3.5 (range 1-10) cycles of treatment. Overall response rate and clinical benefit rate were 53.6% and 75.0%, respectively. Progression-free survival was 30 weeks. With regard to grade 3 and 4 adverse effects, leucopenia, neutropenia, increase in serum alanine aminotransferase, and diarrhea were observed. Combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control in this trial.

As there are no reports of S-1 in combination with trastuzumab in clinical settings, we evaluated the safety and efficacy of S-1 in combination with trastuzumab for human epidermal-growth factor receptor (HER2)-positive metastatic breast cancer (MBC) and determined the recommended dose (RD). Patients with HER2-positive MBC received trastuzumab (a fixed initial dose of 4 mg/kg/day, then 2 mg/kg every week) plus S-1 (4 weeks followed by a 2-week rest) every 42 days. The dosage of S-1 was set of three levels (1: 80 mg/m², 2: 65 mg/m², 3: 50 mg/m²). The purposes of this study were the determination of the RD and safety. Dose-limiting toxicity (DLT) data were continually monitored to assess S-1 dose decreases. Twelve patients were treated at level 1. Because no patients experienced DLT, the RD of S-1 plus trastuzumab therapy was 80 mg/m² S-1 and 4 mg/kg followed by 2 mg/kg trastuzumab. The overall response rate and disease control rate were 33.3% and 83.3%, respectively. S-1 plus trastuzumab could be safely and effectively used for the treatment of HER2-positive MBC. The RD for a phase II study of this regimen was determined to be 80 mg/m² S-1 and 2 mg/kg trastuzumab every week (loading dose, 4 mg/kg).

Objective: We conducted a phase II trial in Japan to evaluate the efficacy and tolerability of weekly paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) as neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC). Methods: Patients with clinical stage IIIA–IIIB breast cancer received NAC consisting of 12 once-a-week cycles of paclitaxel followed by 4 once-every-third-week cycles of FEC. Results: Fifty patients with LABC were enrolled, 47 of whom were administered paclitaxel followed by FEC as NAC. The clinical response rate for all chemotherapies was 85.1%, and the pathological complete response rate was 27.7%. Regarding toxicity, grade 3–4 neutropenia was observed in 10% of patients. No serious toxicities requiring the discontinuation of treatment were encountered. The rate of breast conservation surgery was 31.9%, median survival had not been reached at the time of conclusion of this study, and the 3-year survival rate was 85.1%. Median disease-free survival was 40.2 months, and the 3-year disease-free survival rate was 62.1%. Conclusions: Weekly paclitaxel followed by FEC demonstrated efficacy and tolerable toxicity in a neoadjuvant setting for LABC.

Clinical studies of WT1-targeted cancer vaccine are being performed. However, WT1-specific Th response in cancer patients remains unclear. Using quantitative real-time RT-PCR, we investigated IFN-gamma and IL-10 mRNA expression from Th cells by stimulation with helper peptide WT1(332). Seventeen patients, of whom 10 had achieved stable disease and the remaining 7 had progressive disease, were weekly vaccinated with WT1 CTL epitope (modified WT1(235)) and examined for WT1(332)-specific Th response. A clear correlation between WT1(332)-specific Th response and clinical response was observed at 4 weeks post-vaccination. In patients who responded, a clear inverse correlation between IL-10-type and IFN-gamma-type WT1(332)-specific Th response was detected at pre- and 4 weeks post-vaccination, and the shift of the Th response from IL-10-type dominancy at early phase to IFN-gamma-type dominancy at late phase was observed. From this study we concluded that occurrence of WT1(332)-specific Th response could predict good clinical response of WT1 CTL epitope vaccination.

Recently, some new anticancer agents and hormonal agents can be used to treat breast cancer, and more patients are administering combinations of these drugs in clinical practice. Tegafur and Uracil (UFT) have been widely used for the postoperative chemotherapy of breast cancer, and often combined with hormonal agents. However, due consideration has not been given to safety and compliance of the combined use of UFT and aromatase inhibitor (AI). We therefore studied the safety and compliance with UFT alone and in combination with the hormonal agents tamoxifen or anastrozole as postoperative therapy in postmenopausal women with breast cancer. Our results confirmed that longterm postoperative therapy with UFT alone was feasible, provided that early adverse events are carefully monitored. Combined therapy was not associated with a significant increase in the incidence of adverse events or a decrease in compliance, even in older adult patients. Therefore, we consider UFT plus a hormonal agent (especially anastrozole) to be a treatment option for patients with HER2-negative highly or incompletely endocrine responsive disease who require relatively moderate chemotherapy or for older adult patients who require treatment with low toxicity.

Paclitaxel (PTX) is frequently used for a chemotherapy of breast cancer and gynecologic cancer. Besides a bone-marrow depression and hypersensitive reaction, the peripheral neuropathy is one of the serious adverse events of PTX. The mechanism of peripheral neuropathy has not been clarified, and few agents have been reported to be effective for the treatment and the prevention of that. Recently, it has been reported that Gosya-jinki-gan is useful for the PTX induced peripheral neuropathy, so we carried a retrospective study(n=82)to evaluate the effectiveness of Gosya-jinkigan with the medical records. It is suggested that peripheral neuropathy developed more rapidly in sequential administration of PTX every week than in administration in 4 weeks cycles consisting of 3 weeks on and 1 week off(5.4w vs. 9.4w). We have also found that Gosya-jinki-gan was possibly effective for the treatment and the prevention of peripheral neuropathy. Additionally Gosya-jinki-gan might be more effective for peripheral neuropathy when it is administered from the beginning of chemotherapy including PTX.

Purpose: The reason why chemotherapy induces resistance to subsequent hormonal therapy remains to be clarified in postmenopausal breast cancers. We hypothesized that chemotherapy might down-regulate the intratumoral biosynthesis of estrogens. Thus, we have studied the influence of chemotherapy (docetaxel) on intratumoral aromatase mRNA expression because aromatase is a key enzyme for intratumoral biosynthesis of estrogens. Experimental Design: The mRNA levels of aromatase and its inducers [tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and cyclooxygenase 2 (COX-2)] were determined by a real-time polymerase chain reaction assay in breast cancer tissues obtained before and after neoadjuvant chemotherapy with docetaxel (four cycles of 60 mg/m² every 3 weeks) in 16 postmenopausal patients with estrogen receptor (ER)- and/or progesterone receptor (PR)-positive breast cancers. ER and PR levels in tumor tissues were also determined by enzyme immunoassay before and after chemotherapy. Results: The intratumoral aromatase mRNA levels decreased significantly (P < 0.05) after chemotherapy from 0.84 ± 0.28 (mean ± SE) to 0.47 ± 0.28. The intratumoral TNF-α mRNA levels also decreased significantly (P < 0.05) after chemotherapy from 2.40 ± 0.52 to 0.95 ± 0.25. On the contrary, the intratumoral IL-6 and COX-2 mRNA levels showed a marginally significant increase (P = 0.07) and a significant increase (P < 0.05), respectively, after chemotherapy. PR levels showed a marginally significant decrease (P = 0.08) after chemotherapy, whereas ER levels were almost constant before and after chemotherapy. Conclusions: Antitumor activity of docetaxel is mediated, at least in part, through a down-regulation of aromatase expression in tumor tissues, resulting in the suppression of intratumoral estradiol synthesis. Aromatase expression seems to be regulated mostly by TNF-α, but not IL-6 and COX-2.

Adiponectin is a peptide hormone secreted from the adipose tissue, affecting the proliferation and insulin sensitivity of various types of cells. Because association of obesity with breast cancer risk is well established, it is possible that adiponectin plays some role in the development of breast cancer. Thus, in the present study, the association of the serum adiponectin levels with breast cancer risk was investigated. A case-control study was conducted on 102 breast cancer patients (cases) and 100 healthy women (controls). The serum adiponectin levels of cases and controls were examined in their association with breast cancer risk after adjustment for the various classical risk factors (family history, age at menarche, parity, body mass index, and so forth). In addition, the relationship between the serum adiponectin levels and the various clinicopathological characteristics of breast cancers was studied. Women in the low tertile of serum adiponectin levels were associated with a significantly (P < 0.005) increased risk for breast cancer compared with women in the high tertile [odds ratio (OR), 3.63; 95% confidence interval (CI), 1.61-8.19]. Such an association was observed both in the premenopausal women (OR, 3.46; 95% CI, 0.89-13.50) and in the postmenopausal women (OR, 3.90; 95% CI, 1.23-12.44). The frequency of large (>2 cm) tumors and that of high histological grade (2+3) tumors were significantly (P < 0.005 and P < 0.05, respectively) higher in breast cancer patients in the low tertile of the serum adiponectin levels than those in the high and intermediate tertiles. These results suggest that the low serum adiponectin levels are significantly associated with an increased risk for breast cancer and that tumors arising in women with the low serum adiponectin levels are more likely to show a biologically aggressive phenotype. The association between obesity and breast cancer risk might be partly explained by adiponectin.

The relationship of intratumoral mRNA levels of class I and III beta-tubulin isotypes with clinical response to docetaxel has been studied in breast cancer patients. Expression of class I and class III beta-tubulin mRNA levels was determined by a real-time PCR in breast cancer tissues obtained from 39 patients with locally advanced breast cancers (n = 26) or locally recurrent breast cancers (n = 13) before docetaxel treatment. Class I beta-tubulin mRNA levels of responders [6.58 +/- 1.43 (x10(2)), mean +/- SE] were significantly (P = 0.002) lower than those of nonresponders [14.97 +/- 2.95 (x10(2))], and class III beta-tubulin mRNA levels of responders (1.38 +/- 0.40) were also significantly (P = 0.003) lower than those of nonresponders (7.43 +/- 2.77). Breast cancers were divided into four groups according to the expression status of class I and class III beta-tubulin isotype mRNA, i.e., the class I-high/class III-high group (n = 13), the class I-high/class III-low group (n = 7), the class I-low/class III-high group (n = 7), and the class I-low/class III-low group (n = 12). The class I-high/class III-high group showed a very low response rate (15%), whereas the class I-low/class III-low group showed a very high response rate (75%). The class I-high/class III-low group and the class I-low/class III-high group showed intermediate response rates of 57% and 43%, respectively. These results demonstrate that high expression of class I and class III beta-tubulin isotype mRNA is significantly associated with docetaxel resistance, and determination of class I and class III beta-tubulin isotype mRNA levels would be useful in the prediction of response to docetaxel.

Several reports have demonstrated the association between high serum estrogens levels and breast cancer risk in postmenopausal women. It is hypothesized that breast cancers arising in postmenopausal women with high serum estrogens levels are more likely to be estrogen receptor (ER)-positive. Thus, we have investigated whether or not high serum estrone (E(1)) levels are associated with ER-positive breast cancer risk in postmenopausal women. A case-control study was conducted on 71 cases (postmenopausal breast cancer patients) and 73 controls (postmenopausal healthy women). Serum E(1) levels were examined in their association with breast cancer risk after adjustment for the various epidemiological risk factors. In addition, clinicopathological characteristics of breast cancers arising in the women with high E(1) levels were investigated. Women in the high tertile of E(1) levels had a significantly (P < 0.01) increased risk of breast cancer as compared with women in the low tertile [odds ratio (OR), 4.14; 95% confidence interval (CI), 1.44-11.87]. Subset analysis according to the ER status showed that women in the high tertile of E(1) levels had a significantly increased risk for ER-positive breast cancer (OR, 23.79; 95% CI, 3.50-161.59) but not for ER-negative breast cancer (OR, 1.45; 95% CI, 0.41-5.15) as compared with women in the low tertile. Tumor size and lymph node status were not significantly different between women in the high tertile and those in the intermediate and low tertiles. But the frequency of low-histological-grade tumors and ER-positive tumors (88 and 67%, respectively) showed a greater trend toward an increase (P = 0.06 and P = 0.07, respectively) in women in the high tertile than those (69 and 46%, respectively) in the intermediate and low tertiles. In addition, ER levels in ER-positive tumors were significantly (P < 0.05) higher in women in the high tertile (245.3 +/- 37.1 fmol/mg protein) than those in the intermediate and low tertiles (134.0 +/- 31.3 fmol/mg protein). Postmenopausal women with high serum E(1) levels have a significantly increased risk for ER-positive, but not ER-negative, breast cancer. Breast cancers arising in women with high E(1) levels show a high ER positivity as well as high ER content. Measurement of serum E(1) levels would be clinically useful in the selection of postmenopausal women who can benefit from prophylactic use of tamoxifen because tamoxifen can prevent ER-positive, but not ER-negative, breast cancer.