After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).

To investigate the significance of immunohistochemical molecular subtyping, we evaluated outcomes of subtypes based on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67. Using tissue microarrays, 1006 breast cancer patients between November 1999 and August 2005 were categorized into four subtypes: luminal A (ER+ and/or PR+, HER2-, Ki-67 < 14%), luminal B (ER+ and/or PR+, HER2-, Ki-67 ≥ 14% or ER+ and/or PR+, HER2+), HER2-enriched (ER-, PR-, HER2+), and triple-negative breast cancer (TNBC) (ER-, PR-, HER2-). Demographics, recurrence patterns, and survival were retrospectively analyzed using uni-/multivariate analyses. Luminal A, luminal B, HER2-enriched, and TNBC accounted for 53.1%, 21.7%, 9.0%, and 16.2% of cases, respectively. Luminal A presented well-differentiation and more co-expression of hormone receptors comparing to luminal B. HER2-enriched showed larger size and higher nodal metastasis. TNBC demonstrated younger age at diagnosis, larger size, undifferentiation, higher proliferation, and frequent visceral metastases. The peak of recurrence for luminal A was at 36 months postoperatively, while that for HER2-enriched and TNBC peaked at 12 months. The relapse risk of luminal B was mixed. Luminal A showed the best survival, but no difference was observed between the other three subtypes. When matched by nodal status, however, TNBC showed the worst outcomes in node-positive patients. In multivariate analyses, luminal A remained a positive prognostic significance. Immunohistochemically-defined subtypes showed different features, recurrence patterns, and survival. Therefore, molecular subtypes using four biomarkers could provide clinically useful information of tumor biology and clinical behaviors, and could be used for determining treatment and surveillance strategies.

Expression of the HER2 oncogene is increased in ϳ30% of human breast carcinomas and is closely correlated with the expression of fatty acid synthase (FASN). In the present study, we determined the mechanism by which FASN and acetyl-CoA carboxylase ␣ (ACC␣) could be induced by HER2 overexpression. SK-BR-3 and BT-474 cells, breast cancer cells that overexpress HER2, expressed higher levels of FASN and ACC␣ compared with MCF-7 and MDA-MB-231 breast cancer cells in which HER2 expression is low. The induction of FASN and ACC␣ in BT474 cells were not mediated by the activation of SREBP-1. Exogenous HER2 expression in MDA-MB-231 cells induced the expression of FASN and ACC␣, and the HER2-mediated increase in ACC␣ and FASN was inhibited by both LY294002, a phosphatidylinositol 3-kinase inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. In addition, the activation of mTOR by the overexpression of RHEB in MDA-MB-231 cells increased the synthetic rates of both FASN and ACC␣. On the other hand, FASN and ACC␣ were reduced in BT-474 cells by a blockade of the mTOR signaling pathway. These changes observed in their protein levels were not accompanied by changes in their mRNA levels. The 5-and 3-untranslated regions of both FASN and ACC␣ mRNAs were involved in selective translational induction that was mediated by mTOR signal transduction. These results strongly suggest that the major mechanism of HER2-mediated induction of FASN and ACC␣ in the breast cancer cells used in this study is translational regulation primarily through the mTOR signaling pathway.Because OA-519, a poor prognostic marker found in breast cancer cells, was shown to be a fatty acid synthase (FASN) 3 (1),a number of studies have demonstrated abnormally high levels of FASN in many human epithelial cancers and preneoplastic lesions (2, 3). FASN, a lipogenic enzyme, catalyzes the biosynthesis of palmitic acid that is used for the synthesis of triacylglycerol as a storage fuel molecule as well as membrane lipids including phospholipids and sphingolipids (4). In breast cancer cells, the expression of FASN is closely related to the aggressiveness of cancers as well as to the development, maintenance, and cell cycle progression of human cancers (5-7). Breast cancer cells that overexpress FASN undergo apoptosis when treated with small interfering RNAs (siRNAs) against FASN or FASN inhibitors, such as C75 and cerulenin (8 -11). Under physiological conditions, the activities of lipogenic enzymes, including FASN, are tightly regulated by nutritional and hormonal parameters at the transcription level. Sterol regulatory element-binding proteins (SREBP-1a, SREBP-1c, and SREBP-2) are the major transcription factors that mediate this regulation (12). SREBPs reside in endoplasmic reticulum membranes as inactive precursors. To become active, the NH 2 -terminal segments of SREBPs are released from the endoplasmic reticulum by proteolytic cleavage and enter the nucleus where they activate their target genes. SREBP-1 preferentially activates the genes in...

We investigated the impacts of breast cancer diagnosis and treatment on employment status and the ability to perform occupational and housekeeping tasks. We performed a cross-sectional study to compare Korean breast cancer survivors (n = 1,594) who had been working before cancer diagnosis with a group of 20 to 60-year-old women from the general Korean population (n = 415). Employment decreased from 47.6% to 33.2% after cancer treatment. It was significantly smaller relative to the general population (52.1%) [adjusted odds ratio (aOR) = 1.68; 95% confidence interval (CI): 1.35-2.11). There was an inverse association between employment and low levels of education, low household income, multiple comorbidities, disease stage, and mastectomy. In addition, women who lived with a spouse were more likely to quit working after treatment compared to women who had no spouse. Fatigue and exhaustion were the most frequent difficulties encountered during occupational work (by 46.8% of cancer survivors) and housework (64.6%). Our findings suggest that breast cancer has a greater impact on employment among Korean women than among women in previously studied Western populations. Our data suggest that socio-cultural factors, as well as certain clinical characteristics, influence the decisions of Korean women to return or to not return to work after surviving breast cancer.

Monoclonal antibodies specific for the p185HER2/neu growth factor receptor represent a significant advance in receptor-based therapy for p185HER2/neu-expressing human cancers. We have used a structure-based approach to develop a small (1.5 kDa) exocyclic anti-HER2/neu peptide mimic (AHNP) functionally similar to an anti-p185HER2/neu monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185HER2/neu with high affinity (KD=300 nM). This results in inhibition of proliferation of p185HER2/neu-overexpressing tumor cells, and inhibition of colony formation in vitro and growth of p185HER2/neu-expressing tumors in athymic mice. In addition, the mimetic sensitizes the tumor cells to apoptosis when used in conjunction with ionizing radiation or chemotherapeutic agents. A comparison of the molar quantities of the Herceptin antibody and the AHNP mimetic required for inhibiting cell growth and anchorage-independent growth showed generally similar activities. The structure-based derivation of the AHNP represents a novel strategy for the design of receptor-specific tumor therapies.

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor–positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease–free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

PurposeThe present study aims to evaluate the prevalence of unmet needs among breast cancer survivors, to assess the relationships between unmet needs and depression and quality of life, and to explore the extent to which unmet needs of breast cancer patients relate to the time elapsed since surgery.Materials and MethodsAmong 1,250 eligible patients who participated in the study, 1,084 cases (86.7%) were used for analysis. Clinicopathological and social parameters were reviewed and the Supportive Care Needs Survey, Functional Assessment of Cancer Therapy-Breast cancer instrument, and Beck Depression Inventory were administered. The frequency of unmet needs, the association between unmet needs and depression and/or quality of life (QOL) and the impact of the time elapsed since surgery on the patients' unmet needs were analyzed.ResultsThe highest levels of unmet needs were found to be in the health system and information domain. Patients with a survival duration of less than 1 year since surgery showed significantly higher unmet needs in all need domains except the sexuality domain (p<0.001) than participants in the other groups. Patients with a survival duration of 1-3 years also experienced significantly higher psychological and information needs than long-term survivors (>5 years). In addition, unmet needs were significantly associated with depression (p<0.001) and QOL (p<0.001).ConclusionThe present study demonstrated that long-term breast cancer survivors had a significantly lower level of unmet needs than patients with survival duration of less than 3 years after surgery and patients with survival duration of less than 1 year since surgery suffered the greatest unmet needs. QOL might be enhanced if interventions are made for specific unmet needs of each patient group.

As with mammography, placing sonographic lesions into BI-RADS categories is useful for predicting the presence of malignancy.