Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group.

We evaluated the efficacy and safety of sequential therapy with trastuzumab monotherapy (H-mono) followed by H plus docetaxel (D) after disease progression (H --> H + D) versus combination therapy with H + D as first-line therapy. Patients with human epidermal growth factor receptor type 2 (HER2)-positive metastatic breast cancer (MBC) and left ventricular ejection fraction >50% were randomly assigned to either (a) H --> H + D [H, once weekly 2 mg/kg (loading dose, 4 mg/kg); D, once every 3 weeks 60 mg/m(2)] or (b) H + D. Primary endpoints were progression-free survival (PFS) for the H-mono stage of the H --> H + D group and H + D group and overall survival (OS) for both groups. Secondary endpoints were overall response rate, time to treatment failure, second PFS and safety. The planned number of patients was 160 patients in total. Of 112 patients enrolled, 107 were eligible. After 112 patients were enrolled, the Independent Data Monitoring Committee recommended stopping enrollment because PFS and OS were greater in the H + D group than the H --> H + D group. Median PFS was 445 days in the H + D group versus 114 days for H-mono in the H --> H + D group [hazard ratio (HR), 4.24; P < 0.01]. OS was significantly longer in the H + D group (HR, 2.72; P = 0.04). H + D therapy is significantly superior to H --> H + D therapy as first-line therapy in patients with HER2-positive MBC, especially in terms of OS.

Phase II study of 4-weekly capecitabine monotherapy in advanced/metastatic breast cancer.

BACKGROUND: A multicenter, phase II study was conducted to evaluate the efficacy and safety of the Japanese intermittent 4-week regimen of capecitabine in patients with advanced/metastatic breast cancer. METHODS: Fifty patients who had received no more than one prior chemotherapy regimen for advanced/metastatic disease were enrolled from 23 centers and received at least two 4-weekly cycles of capecitabine (828 mg/m² orally twice daily for 3 weeks followed by a 1-week rest period). RESULTS: The overall response rate assessed by the Independent Review Committee (standard population, n = 46) was 28.3% (95% confidence interval 16.0-43.5%), including complete responses in 6.5%. Stable disease was observed in 20 patients and maintained for more than 6 months in 10 patients. The median duration of response in 13 evaluable responders was 5.3 months. Among evaluable patients (n = 47), median time to disease progression was 5.1 months. Median overall survival was 20.2 months. The most common treatment-related adverse events (all grades) were hand-foot syndrome (66%), nausea (26%), stomatitis (22%) and diarrhea (20%). Grade 3/4 treatment-related adverse events were seen in 23 patients (46%). The most common grade 3/4 adverse events were lymphocytopenia (22%), hand-foot syndrome (18%) and hyperbilirubinemia (10%). CONCLUSIONS: Although the target overall response rate was not reached, the Japanese intermittent 4-week regimen of capecitabine was shown to be an effective and well-tolerated first- or second-line therapy for advanced/metastatic breast cancer.

Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan.

BACKGROUND: To compare the cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and the anthracycline-containing regimen cyclophosphamide, epirubicin, and fluorouracil (CEF) to evaluate the efficacy and safety of the latter. METHODS: A total of 294 patients with axillary node-positive primary breast cancer of STAGE I-IIIa were randomly assigned to either CEF [cyclophosphamide (CPA) 500 mg/m(2) i.v. days 1 and 8; epirubicin (EPI) 60 mg/m(2) i.v. day 1; and 5-fluorouracil (5-FU) 500 mg/m(2) i.v. days 1 and 8] or CMF [CPA 500 mg/m(2) i.v. days 1 and 8; methotrexate (MTX) 40 mg/m(2) i.v. days 1 and 8; and 5-FU 500 mg/m(2) i.v. days 1 and 8]. Both treatment regimens were comprised of six cycles at 4-week intervals. Tamoxifen (TAM) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years. RESULTS: The overall 5-year survival was 77.1% for CEF and 71.4% for CMF [p = 0.24; hazard ratio 0.79 (95% CI 0.50-1.24)], and the 5-year disease-free survival was 55.7% for CEF and 48.9% for CMF [p = 0.15; hazard ratio 0.80 (95% CI 0.57-1.12)]. Although the log-rank test did not show a significant difference, both overall and disease-free survivals were higher for CEF according to the point estimates. Adverse drug reactions (ADRs) occurred more frequently in CEF. CONCLUSION: Whereas CEF had a good trend compare with CMF, it could not be proven statistically significant. The principal cause of the failure seems to be insufficient power, that is, the dose intensity (EPI: 60 mg/m(2)) set 10 years ago, when the trial began, was low, and the number of trial subjects was small because of the background of the times, which made the accumulation of cases extremely difficult. However, the trial should be considered to be meaningful, as it was the first, formally conducted controlled trial on chemotherapy in Japan.

Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208.

A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27-55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10-49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively (P = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival.

[Assessment of goserelin treatment in adjuvant therapy for premenopausal patients with breast cancer in Japan-zoladex breast cancer study group trial-B].

OBJECTIVE: Goserelin (GOS) therapy in an adjuvant setting for estrogen receptor(ER)-positive premenopausal patients with breast cancer was assessed in a randomised comparative study. METHODS: ER positive premenopausal patients with n + or n 0 and T > or = 3 cm received tamoxifen (TAM) 20 mg/day, GOS 3.6 mg/4 weeks or GOS + TAM for 2 years, and the clinical efficacy and safety of these regimens were assessed. RESULTS: In the data analysis of total 207 patients, hazard ratios of disease free survival (DFS) and overall survival (OS) in the GOS group compared to the TAM group were 0.87 and 2.10,respectively. The incidence of adverse drug reactions was similar (42-55%) in all three groups. Since the number of patients in this study did not reach the target number, the efficacy could not be assessed from a statistical aspect. Therefore,meta-analysis with similar foreign studies(ZIPP) was implemented. The results of meta-analysis showed that the hazard ratios of DFS and OS in the GOS group compared to the non-GOS group were 0.83 and 0.85, respectively. CONCLUSION: Although the analysis of 207 patients did not show any statistically significant difference between each of the treatment groups, the results of meta-analysis showed a significant prolongation of DFS in the GOS group. Also high tolerability of GOS was suggested. From these results, GOS was considered highly useful in adjuvant therapy for ER-positive premenopausal patients with breast cancer.

Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials.

PURPOSE: This article reports the results of a pooled analysis of six randomized trials conducted to study the efficacy of uracil and tegafur (UFT) in the adjuvant treatment of node-negative breast cancer patients. PATIENTS AND METHODS: Six randomized controlled trials on node-negative breast cancer patients were conducted from 1992 through 1995 in Japan that included the three, three-arm trials (control [no adjuvant], UFT, and tamoxifen [TAM] groups) and the three, four-arm trials (control, UFT, TAM, and UFT plus TAM groups). Pooled analysis was performed on the data obtained from these six trials (involving 2,934 patients). RESULTS: Overall survival was compared between the UFT group (including both the UFT group and the TAM plus UFT group) and the non-UFT group (control group and TAM group). A significant difference (P = .04) was observed in 5-year survival rates between the UFT (95.9%) and the non-UFT (94.0%) groups. Overall survival was also compared between the TAM group (TAM group and TAM plus UFT group) and the non-TAM group (control group plus UFT group). The 5-year survival rate (95.2%) in the TAM group was not significantly different from that (93.9%) in the non-TAM group, but the subset analysis showed a significant (P = .01) improvement in the estrogen receptor-positive subset. CONCLUSION: Adjuvant UFT improves the overall survival of node-negative breast cancer patients. Given that UFT has milder adverse effects, it is suggested that UFT can be a useful alternative to doxorubicin and cyclophosphamide, or cyclophosphamide, methotrexate, and fluorouracil in the adjuvant treatment for node-negative breast cancer.

A phase II study of S-1 in patients with metastatic breast cancer--a Japanese trial by the S-1 Cooperative Study Group, Breast Cancer Working Group.

BACKGROUND: S-1 is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoropyrimidine drug consisting of 1 M tegafur (FT), 0.4 M 5-chloro-2, 4-dihydroxypyrimidine (gimeracil), and 1 M potassium oxonate (oteracil), with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric, head and neck cancers. We investigated its clinical efficacy against metastatic breast cancer. METHODS: A non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n=111) were enrolled, and 108 patients were regarded as eligible. S-1 was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times. RESULTS: Among the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CR+PR) of 41.7% (95% confidence interval: CI, 32.3-51.5%). The incidences of toxicity (> or =grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group. CONCLUSION: S-1 was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.

[A late phase II clinical study of S-1 in patients with progressed, refractory breast cancer].

A late phase II clinical study of S-1 against advanced or refractory breast cancer was done by 37 institutes in Japan. S-1 was administered twice daily at 80, 100 or 120 mg/body/day consecutively for 28 days followed by 14 days of rest (1 course). Eighty-three patients were enrolled and 81 were eligible for the study. The response ratio was 42.0% with 6 CR and 28 PR and its 95% confidence interval for the response was 31.1 to 53.5%. The median survival period was 910 days (95% confidence interval was 493-1, 083 days). The observed major adverse reactions (> or = grade 2) were as follows: hematological toxicities: leukopenia 21.0% (17/81), neutropenia 28.4% (23/81), erythropenia 4.9% (4/81); gastrointestinal toxicities: anorexia 9.9% (8/81), nausea and vomiting 12.3% (10/81), diarrhea 8.6% (7/81), stomatitis 1.2% (1/81), and fatigue 8.6% (7/81). The severe adverse reactions (> or = grade 3) were as follows; hematological toxicities: neutropenia 8.6% (7/81), anorexia 4.9% (4/81), fatigue 3.7% (3/81), nausea and vomiting 1.2% (1/81), diarrhea 1.2% (1/81), stomatitis 1.2% (1/81). Grade 4 adverse reactions (neutropenia and fatigue) were observed only in 1 patient. The ratio without hospitalization was 87.7%. These results strongly suggest the superior efficacy and safety of S-1 against patients suffering from advanced, refractory breast cancer. Therefore, S-1 may be a new therapeutic agent to prolong the survival period of breast cancer patients due to its high antitumor activity and low toxicity.

Four cases of chylous fistula after breast cancer resection.

Chylous fistulas in cases treated surgically for breast cancer only, are rare. We encountered four chylous fistula cases after breast cancer operations out of a total of 851 cases, all of which involved the left breast. Chylous fistulas were confirmed by axillary white fluid and were unrelated to obesity, surgical method or the area of axillary lymph node dissection. All four cases of chylous fistulas were successfully treated conservatively, with no special dietary control and no surgical treatment.

Association of p53 codon Arg72Pro and p73 G4C14-to-A4T14 at exon 2 genetic polymorphisms with the risk of Japanese breast cancer.

BACKGROUND: The association between breast cancer risk and genetic polymorphisms of p53 at codon 72 (Arg72Pro) has been investigated by several studies, but the results are not consistent. The aim of this case-control study conducted in Nagoya, Japan, was to reconfirm the results of prior studies of polymorphisms of p53 Arg72Pro, and to test if polymorphisms of p73 G4C14-to-A4T14 at exon 2 (G4A) were also associated with breast cancer risk. METHODS: The cases were 200 breast cancer patients who visited Aichi Cancer Center Hospital. The controls were 282 local citizens who underwent a health check-up. All cases and controls were recruited from Chubu Japan. Genotyping was carried out by polymerase chain reaction with confronting two-pair primers. RESULTS: The p53 genotype distribution was 40.4% for Arg72 homozygous, 48.9% for heterozygous, and 10.7% for Pro72 homozygous in controls, and 32.0%, 50.0%, and 18.0% in cases, respectively. A comparison between cases and controls indicated a significantly increased risk for Pro72 homozygosity in cases (odds ratio=2.14; 95% confidence interval=1.21-3.79). The genotypic frequencies for p73 G4A were 54.3% for G/G, 39.7% for G/A, and 6.0% for A/A in controls; and 59.0%, 32.0%, and 9.0% in cases, respectively. There were no significant differences in p73 G4A frequency between cases and controls. CONCLUSIONS: This study implies an association of breast cancer risk with the p53 polymorphism Arg72Pro, but not with p73 G4A.

Dietary factors protective against breast cancer in Japanese premenopausal and postmenopausal women.

Since components of the Japanese diet that might be responsible for the relatively low breast cancer incidence rates observed in Japan have not been clarified in detail, a case-referent study with reference to menopausal status was conducted using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). In total, 2,385 breast cancer cases were included, and 19,013 women, confirmed as free of cancer, were recruited as the reference group. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined by multiple logistic regression analysis. There were reductions in risk associated with high intake of milk and green-yellow vegetables (green leafy vegetables, carrots and pumpkins) among both pre- and postmenopausal women. The protective effects of the Japanese diet were more prominent among postmenopausal than premenopausal women. The adjusted OR of fish consumption (5 or more times per week vs. fewer than 3 times per month) was 0.75 (95% CI 0.57-0.98, p(trend) = 0.01) for postmenopausal breast cancer. A significant decrease in postmenopausal breast cancer risk was also observed for increasing intake of fruit (OR = 0.61, 95% CI 0.41-0.91). Thus, traditional Japanese dietary factors may protect against breast cancer development, especially among postmenopausal women.

Physical exercise reduces risk of breast cancer in Japanese women.

To evaluate the effects of physical exercise on breast cancer risk, a large-scale case-referent study of 2376 incident breast cancer cases and 18,977 non-cancer referents was conducted using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). To adjust appropriately for possible confounders, we examined the effects within subgroups of the study population. The multivariable-adjusted odds ratio (OR) was 0.81 (95% confidence interval (CI): 0.69-0.94) for twice a week or more regular exercise. We observed a decreased risk of breast cancer for women who regularly exercised for health twice a week or more, irrespective of menopausal status, and were able to detect greater risk reductions within particular subgroups, including women who were parous, without a family history or non-drinkers. Among premenopausal women, a particularly strong protective effect of physical exercise was observed (OR=0.57, 95%CI: 0.28-1.15) for those women whose body mass index (BMI) was high (BM > or = 25). In contrast, risk reduction was found (OR=0.71, 95%CI: 0.50-1.01) among postmenopausal women whose BMI was medium (BMI: 22-25). Stratification of history of stomach cancer screening to adjust modifying effects of healthy consciousness allows a more precise assessment of the protective effect of exercise twice a week or more, independent of stomach cancer screening history. This study provides evidence that physical exercise, especially exercise twice a week or more, reduces the risk of breast cancer among Japanese women.

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.

Impact of established risk factors for breast cancer in nulligravid Japanese women.

BACKGROUND: The mechanism by which pregnancy impacts breast cancer risk remains poorly understood. There is a need for detailed quantification of risk in nulliparous women. We therefore have undertaken a case-referent study of breast cancer employing data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan, examining the impact of reproductive and anthropometric factors on breast cancer risk among nulligravid women compared with their parous counterparts. METHODS: In total, 2032 breast cancer cases were included, and 17848 women, confirmed as free of cancer, were recruited as a reference group. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by multiple logistic regression analysis. RESULTS: A protective effect of later age at menarche was observed among parous women, but it did not alter risk in nulligravid cases. The risk increment with a family history appeared to be most pronounced among premenopausal cases with no history of pregnancy (OR=2.68, 95% CI: 1.41-5.11). Among postmenopausal women, positive associations with height and current body mass index (BMI) in the nulligravid group were similar to those observed in the parous group. The present study indicated that age at menopause, family history in premenopausal women, and height and obesity in postmenopausal women seemed to exert more influence in nulligravid women. Formal tests for interaction between maternity status and these factors, however, did not prove statistically significant. CONCLUSION: Our findings suggest that established risk factors for breast cancer have an additive impact with nulligravid status. Thus, it is implied that obesity control for all women, including nulliparous individuals, is important from a practical viewpoint for primary breast cancer prevention.

Transforming growth factor B1 T29C polymorphism and breast cancer risk in Japanese women.

BACKGROUND: A cohort study for Caucasians aged 65 years or older demonstrated a marked breast cancer risk reduction for those with the CC genotype of transforming growth factor B1 (TGF B1) T29C polymorphism. This is a prevalent case-control study to examine the reported risk reduction for Japanese women. PATIENTS AND METHODS: A total of 232 histologically diagnosed breast cancer patients who visited Aichi Cancer Center Hospital between June 1999 and March 2000 were enrolled. The controls were 172 female outpatients without cancer at the same hospital. DNA was extracted from peripheral blood, and TGF B1 genotype was determined by PCR-CTPP. RESULTS: The genotype frequency was 23.7% for TT, 49.2% for TC, and 27.1% for CC among controls, and 28.9%, 46.1%, and 25.0%, respectively, among cases. Age-adjusted odds ratio (OR) relative to the TT genotype was 0.81 (95% confidence interval, 0.50-1.31) for the TC genotype and 0.77 (0.45-1.34) for the CC genotype. For premenopausal women, the CC genotype was significantly associated with reduced risk of breast cancer in comparison with the TT genotype (OR=0.45, 0.20-0.98). The association was not observed for postmenopausal women (OR=1.40, 0.64-3.08). CONCLUSION: The present study showed risk reduction for Japanese premenopausal women with the CC genotype, but not for postmenopausal Japanese women.

[Axillary lymph node dissection in clinically node-positive breast cancer].

Many Japanese surgeons think that clinically node-positive breast cancer is already a systemic disease. However, about 60% of surgeons believe that the survival rate increases with axillary lymph node dissection. Furthermore, 64% of surgeons change the area of axillary lymph node dissection based on the intraoperative diagnosis of lymph node metastases. We analyzed axillary lymph node dissection in clinically node-positive breast cancer using evidence-based medicine. We recommend that the level I and II axillary dissection be the preferred procedure and that the removal of level III axillary nodes is not necessary for staging. However, if grossly positive nodes are identified intraoperatively, a level III dissection should be carried out to maximize local control.

Combination of subareolar blue dye and peritumoral RI for sentinel lymph node biopsy.

BACKGROUND: The identification rate of sentinel lymph nodes (SLNs) is variable because numerous different methods employing different tracers have been used for sentinel lymph node detection. The aim of this study was to determine the optimal technique for sentinel lymph node biopsy (SLNB). METHODS: From May 1999 to December 2001, SLNB was performed for 376 patients with T1-3 and N0-1 primary breast cancer using blue dye alone, radioisotope (RI) alone and combination of RI and blue dye. Two hundred sixty-eight patients underwent SLNB using blue dye alone. They were divided into 4 groups (Group A: n=50; peritumoral injection, Group B: n=83; the first half to receive subareolar injection, Group C: n=83; the second half to receive subareolar injection, and Group D: n=52; small incision according to an axillary skin landmark). One hundred eight patients underwent SLNB using RI. Tin colloid was used in 49 cases (Tin Colloid Group) and phytate in 59 cases (Phytate Group). Among them, 29 patients underwent injection of RI alone and 79 patients received a combination of RI and blue dye. RESULTS: The identification rates of SLN using blue dye alone were 60%, 82%, 92% and 79% in Groups A, B, C and D, respectively. The identification rates of SLN in patients receiving RI alone and in those receiving combination of RI and blue dye were 40% and 89%, respectively, in Tin Colloid Group, and 92% and 94%, respectively, in Phytate Group. CONCLUSION: When using blue dye alone, subareolar injection provided a better identification rate than peritumoral injection. The combination of peritumoral phytate and subareolar blue dye provided the best identification rate (94%) in all the groups. The combination of intraparenchymal phytate and subareolar blue dye was the most efficient technique for sentinel node biopsy in breast cancer patients.

Significant reduction in breast cancer risk for Japanese women with interleukin 1B -31 CT/TT relative to CC genotype.

OBJECTIVE: The present case-control study aimed to examine the associations between breast cancer risk and three functional polymorphisms (Interleukin (IL) -1A C-889T, IL-1B C-31T and IL-1RN 86-bp variable number tandem repeat) related to expression of IL-1beta, which combines estrogen receptor. METHODS: Cases were 231 patients with breast cancer who had been diagnosed 1 month to 6 years before their enrollment in 1999-2000 at Aichi Cancer Center Hospital. Controls were 186 non-cancer outpatients recruited during the same period at the digestive tract, breast surgery and gynecology clinics. RESULTS: There were no differences in the genotype distributions of the IL-1A and IL-1RN polymorphisms, but individuals harboring a IL-1B C-31T T allele (high expression allele) were less frequent among cases (74.3%) than among controls (84.9%). The age-adjusted odds ratio (OR) relative to CC genotype was 0.52 (95% confidence interval, 0.30-0.88) for CT genotype, 0.58 (0.32-1.02) for TT genotype and 0.54 (0.33-0.90) for CT/TT genotype. Subgroup analysis showed that the preventive effect was significantly stronger for postmenopausal women than for premenopausal women (interaction 0.30, 0.11-0.84). CONCLUSIONS: Although this is the first report on the association between breast cancer risk and IL-1B C-31T, the observed association seems plausible in a biological sense.

[Phase I single-dose administration study of exemestane in postmenopausal women].

A single-dose administration study of a new type of aromatase inactivator, exemestane, was performed in normal healthy postmenopausal Japanese women. The study was conducted to investigate the safety, effect on serum and urinary estrogen concentrations, and pharmacokinetics of exemestane at 25 or 50 mg. A crossover study using a single dose (25 mg) was also conducted in order to study the effect of meals on these parameters. Adverse events, in which a causal relationship with the study drug could not be excluded, were as follows: hot flushes (2/4), sleepiness (1/4), and glycogeusia (1/4), all of which were mild and transient. There were no clinically significant laboratory test or physical finding abnormalities with either dose, except for one patient in the 50 mg group who had an increase in levels of GPT, ALP and gamma-GTP. Maximal suppression of serum estrogen concentration (22-37% suppression) was achieved 3-4 days after single-dose administration of exemestane (25 mg or 50 mg), and almost no suppression was observed 2 weeks later. A significant decrease in the amount of urinary estrogen excretion occurred on day 4 and day 8 after exemestane administration. The level of urinary estrogen excretion almost returned to baseline levels in the 25 mg group and returned to 65% of baseline levels in the 50 mg group 2 weeks after drug administration. Both serum estrogen concentration and the amount of urinary estrogen excreted decreased in a similar fashion under both fasting and fed conditions, suggesting no effect of meals on the suppression of estrogen concentrations. Exemestane was adsorbed immediately after single-dose administration, and this was followed by a gradual decrease in serum concentrations in a multiphase pattern. An increase in Cmax and AUC0-tz values was observed after meals compared with those values obtained under fasting conditions, yet the increase was not statistically significant, suggesting that the increase was not clinically relevant. The results of this study verified the safety and the estrogen suppressive effects on serum and urinary concentrations of estrogen of a single dose of exemestane up to 50 mg. Furthermore, results suggest that the suppression of serum and urinary estrogen concentrations and pharmacokinetics of exemestane were not affected by food.