Toshinari Yamashita

One-carbon metabolism-related gene polymorphisms and risk of breast cancer.

Environmental exposures and/or genetic background in Japanese population, which might contribute to the relatively low breast cancer incidence rates in Japan, have not been clarified in detail. Folate plays an essential role in DNA methylation and synthesis, and thus may be involved in the development of breast cancer. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS), influence folate metabolism, but epidemiological studies have yielded inconsistent findings. We therefore conducted a case-control study to clarify their associations with breast cancer risk. A total of 456 breast cancer cases and 912 age-matched and menopausal status-matched non-cancer controls were genotyped for the polymorphisms. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic models adjusted for potential confounders and gene-environment interactions between the polymorphisms and folate consumption were also evaluated. We observed an increased risk of postmenopausal breast cancer with the MTHFR 677TT genotype (OR = 1.83, 95% CI: 1.08-3.11) with a menopausal status-based analysis. In combination analysis, a significantly elevated OR was found among postmenopausal women with the MTHFR 677TT genotype and lower intake of dietary folate compared with those with 677CC genotype and adequate folate consumption (OR = 2.80, 95% CI: 1.11-7.07). In addition, interaction between the MTRR A66G polymorphism and folate intake for risk of postmenopausal breast cancer was observed (interaction P = 0.008). Our findings indicated that the MTHFR and MTRR polymorphisms were associated with individual susceptibility to breast cancer among postmenopausal women.

Microsatellite instability in sporadic human breast cancers

Human breast‐cancer specimens from 100 patients were analyzed for microsatellite instability (referred to as replication error; RER) at 12 genomic loci on 7 chromosomes, and results were correlated with clinicopathologic characteristics. In 42 of 100 breast‐cancer patients, we investigated whether RER was associated with the amplification of oncogenes and/or suppression of tumor‐suppressor genes. Of the 100 patients, 8 (8%) were RER‐positive at one or more chromosomal loci. The majority of RER‐positive patients had early‐stage disease with ER‐positive tumors, suggesting that RER occurs early in breast tumorigenesis. However, no significant correlation was observed between RER and oncogenes or tumor‐suppressor genes. Thus, the mechanism of RER in sporadic human breast cancer may be independent of the multi‐step carcinogenesis caused by the alterations of oncogenes and tumor‐suppressor genes.

Predictors of response to exemestane as primary endocrine therapy in estrogen receptor–positive breast cancer

Endocrine therapy is the most important treatment of choice for estrogen receptor (ER)‐positive breast cancer. Potential mechanisms for resistance to endocrine therapy involve ER‐coregulatory proteins and cross‐talk between ER and other growth factor–signaling networks. However, the factors and pathways responsible for endocrine therapy resistance, particularly resistance to aromatase inhibitors, have not been clearly established. Sixteen postmenopausal patients with ERα‐positive primary breast cancer were treated daily with 25 mg of exemestane (an aromatase inhibitor) for 6 months. Expressions of ERα, ERβ, progesterone receptor (PgR), androgen receptor (AR), amplified in breast cancer 1 (AIB1), aromatase, epidermal growth factor receptor, human epidermal growth factor receptor type 2, Ki67, cyclin D1, p53, Bcl2, signal transducer and activator of transcription 5 (Stat5), and insulin‐like growth factor binding protein 5 (IGFBP5), and phosphorylations of ERα serine (Ser) 118, ERα Ser167, Akt Ser473, and p44/42 MAPK threonine (Thr) 202/tyrosine (Tyr) 204, were examined by immunohistochemistry on pretreatment tumor biopsies and post‐treatment surgical specimens. Analyses were made to test for correlations with response to exemestane. Of the 16 patients, seven responded and nine retained stable disease. High‐level expression of AIB1 and phosphorylation of Akt Ser473 were significantly associated with a better response to exemestane, suggesting that these factors could be considered as predictors of exemestane response. Expressions of ERα, ERβ, PgR, aromatase, Ki67, cyclin D1, and p53, and phosphorylations of ERα Ser118, ERα Ser167, and p44/42 MAPK Thr202/Tyr204, were decreased, whereas expressions of Stat5 and IGFBP5 were increased in post‐treatment specimens compared to the values in pretreatment biopsies. Thus, the analysis of factors involved in the estrogen‐dependent growth‐signaling pathways may be useful in identifying patients responsive to exemestane. (Cancer Sci 2009)

Clinical significance of bcl-2 gene expression in human breast cancer tissues

The expression of estrogen receptor (ER) and bcl-2(Bcl-2), an apoptosis protective oncogene, in normal andcancerous breast duct epithelia was immunohistochemically examined infresh frozen tumor tissues from 142 Japanese breastcancer patients. The clinico-pathological characteristics and the diseasefree survival of the patients were analyzed. Theexpression of both the proteins was also observedin intraductal components of breast cancer. Although lessthan 1% of normal duct epithelia expressed ER,Bcl-2 was diffusely expressed. The expression of boththese proteins in breast cancer significantly correlated witheach other. Their expression significantly correlated negatively withtumor size but not with lymph node status.The papillo-tubular sub-type of invasive ductal carcinoma expressedBcl-2 significantly more frequently than the solid-tubular sub-type.Patients with Bcl-2 expressing tumors survived without recurrencesignificantly more than those with tumors exhibiting reducedexpression. Papillary-cribriform type intraductal componentsexpressed both those proteins more often than the solid-comedo type.

Effect of soybean on breast cancer according to receptor status: a case-control study in Japan.

The possible association of high soy food consumption with low incidence of breast cancer in Asian countries has been widely investigated, but findings from epidemiologic studies have been inconsistent. Breast cancers defined by receptor status, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) may have distinct etiologic factors. Here, we conducted a case–control study to clarify associations between intake of soybean products and breast cancer risk according to receptor status. A total of 678 breast cancer cases and 3,390 age‐ and menopausal status‐matched noncancer controls were included. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic models adjusted for potential confounders. On analysis according to receptor status, we observed a significantly reduced risk of ER‐positive (ER+) (top tertile OR = 0.74; 95% CI, 0.58–0.94; trend p = 0.01) and HER2‐negative (HER2−) tumors (top tertile OR = 0.78; 95% CI, 0.61–0.99; trend p = 0.04). Further, when the 3 receptors were jointly examined, a reduced risk was observed only in patients with ER+/PR+/HER2− tumor (top tertile OR = 0.73; 95% CI, 0.54–0.97; trend p = 0.03). These findings indicate that the protective effect of soy against breast cancer risk differs by receptor status.

Analysis of Oncogenes and Tumor Suppressor Genes in Human Breast Cancer

Oncogenes (c‐erbB‐2, c‐myc, and some genes linked to the 11q13 lesion), tumor suppressor genes (retinoblastoma gene, p53) and an antimetastatic gene (nm23/nucleoside diphosphate kinase) play important roles in breast cancer progression. Amplification of c‐erbB‐2, c‐myc, and int‐2, and expression of RB, p53 (mutant), and NDP kinase were determined in 77 primary breast cancer specimens. nm23‐H1 allelic loss was also studied. c‐erbB‐2 and c‐myc amplification, loss of RB expression, p53(mutant) expression, and nm23‐H1 allelic loss were also found in non‐invasive carcinoma, int‐2 amplification was significantly correlated with lymph node status (P=0.02) and a significant association was found between p53(mutant) expression and tumor size (P=0.04). c‐erbB‐2 amplification was strongly associated with disease‐free and overall survival in multivariate analysis (P=0.002). All of the c‐erbB‐2 amplified cases and all but one of the int‐2 amplified cases in node‐positive patients had relapsed within 2 years post resection. The cancer cells may acquire new proliferative pathways sequentially as a result of multiple genetic alterations which enable them to bypass the estrogendependent proliferation.

A case of HER2-positive male breast cancer with lung metastases showing a good response to trastuzumab and paclitaxel treatment

We present a case of advanced HER2-positive male breast cancer, which showed a good response to a combined treatment of trastuzumab and paclitaxel. A 78-year-old man was diagnosed with invasive ductal carcinoma (T4d N3 M1, stage IV). He had advanced breast cancer consisting of multiple tumors with skin involvement and redness over the entire left chest region. A computed tomography (CT) scan of the chest revealed a metastatic tumor in the left lung. Histologically, both the primary breast cancer and the metastatic lung tumor were identified as invasive ductal carcinoma that was estrogen receptor-negative (ER)(−) and progesterone receptor-negative (PgR)(−), with a HER2 score of 3+ (IHC). The patient received a combination chemotherapy using trastuzumab and paclitaxel. Two months later, a follow-up chest CT scan showed that the left lung tumor had disappeared, suggesting a good response to trastuzumab and paclitaxel. During trastuzumab treatment, no severe adverse events above grade 3 were observed. This is the first reported case of advanced HER2-positive male breast cancer in which a good response to trastuzumab and paclitaxel was demonstrated at both primary breast cancer and metastatic sites.

Contribution of problem-solving skills to fear of recurrence in breast cancer survivors

Although fear of recurrence is a major concern among breast cancer survivors after surgery, no standard strategies exist that alleviate their distress. This study examined the association of patients’ problem-solving skills and fear of recurrence and psychological distress among breast cancer survivors. Randomly selected, ambulatory, female patients with breast cancer participated in this study. They were asked to complete the Concerns about Recurrence Scale (CARS) and the Hospital Anxiety and Depression Scale. Multiple regression analyses were used to examine their associations. Data were obtained from 317 patients. Patients’ problem-solving skills were significantly associated with all subscales of fear of recurrence and overall worries measured by the CARS. In addition, patients’ problem-solving skills were significantly associated with both their anxiety and depression. Our findings warrant clinical trials to investigate effectiveness of psychosocial intervention program, including enhancing patients’ problem-solving skills and reducing fear of recurrence among breast cancer survivors.

Clinical value of enzyme immunoassay of epidermal growth factor receptor in human breast cancer

SummaryEpidermal growth factor receptor (EGFr) levels were analyzed in 140 primary breast cancer specimens by immunohistochemical assay (ICA), competitive binding assay (BA), or enzyme immunoassay (EIA). Thirtynine of 118 specimens (33.1%) were scored as positive by ICA, 30 of 116 (25.9%: cut-off level 10 fmol/mg protein) by BA, and 31 of 80 (38.9%: cut-off level 5 fmol/mg protein) by EIA. Agreement on EGFr status was 72.3% (68/94) between ICA and BA, 77.0% (57/74) between BA and EIA, and 73.8% (59/80) between EIA and ICA. These discrepancies are based on assay differences and the heterogeneous distribution of cancer cells within specimens. Regardless of the assay method used, EGFr status had a significantly negative correlation with estrogen receptor status. Although EGFr-ICA and BA status had no relationship with prognosis, patients with medium and high EGFr-EIA level tumors (over 5 fmol/mg protein) had shorter relapse-free periods than those with low level tumors. However, the prognostic value of positive EGFr-EIA status was weaker than that ofc-erbB-2 overexpression.

Psychometric Properties of the Japanese Version of the Concerns About Recurrence Scale (CARS-J)

OBJECTIVE Although the fear of recurrence is a major concern among breast cancer survivors after their surgery, there are no instruments to evaluate their distress in Japan. This study examines the psychometric properties of the Japanese version of the concerns about recurrence scale, which was originally developed in the USA. METHODS The forward and backward translation method was used to develop Concerns About Recurrence Scale. Randomly selected ambulatory female patients with breast cancer participated in this study. They were asked to complete Japanese version of the concerns about recurrence scale and Hospital Anxiety and Depression Scale. The validity and reliability of Japanese version of the concerns about recurrence scale were evaluated statistically. RESULTS Data were obtained from 375 patients. A novel four-factor solution was found (Health and Death Worries, Womanhood Worries, Self-valued Worries and Role Worries) that accounted for 59.2% of the total variance. Correlation coefficients between the Japanese version of the concerns about recurrence scale subscale scores and the anxiety score measured by Hospital anxiety and depression scale ranged from 0.39 to 0.60. Cronbachs alpha coefficients, which are measures of the internal consistency of the subscales, ranged from 0.86 to 0.94. CONCLUSIONS The results suggest that Japanese version of the concerns about recurrence scale is a reliable and valid clinical research tool to evaluate the fear of recurrence among patients with breast cancer in Japan, although there may be cross-cultural differences regarding factor structures between Western and Japanese breast cancer patients.