IMPORTANCEDuring the past few decades, the incidence of breast cancer (BC) has been increasing rapidly in East Asia, and BC is currently the most common cancer in several countries. The rising incidence is likely related to changing lifestyle and environmental factors in addition to the increase in early diagnosis with BC awareness and screening. The understanding and management of BC are generally based on research and data from the West. However, emerging differences in BC epidemiology and tumor and host biology in Asian populations may be clinically relevant.OBSERVATIONS A higher proportion of premenopausal BCs occur in Asia, although this factor is possibly an age-cohort effect. Although the relative frequencies of different immunohistochemical subtypes of BC may be similar between the East and West, the higher prevalence of luminal B subtypes with more frequent mutations in TP53 may be confounded by disparities in early detection. In addition, Asian BCs appear to harbor a more immune-active microenvironment than BCs in the West. The spectra of germline mutations in BC predisposition genes and single-nucleotide polymorphisms contributing to BC risk vary with ethnicity as well. Differences in tolerability of certain cytotoxic and targeted agents used in BC treatment may be associated with pharmacogenomic factors, whereas the lower body mass of the average woman in East Asia may contribute to higher toxicities from drugs administered at fixed doses. Phenotypic characteristics, such as lower breast volume, may influence the type of surgery performed in East Asian women. On the other hand, increased breast density may affect the sensitivity of mammography in detecting BCs, limiting the benefits of screening mammography. CONCLUSIONS AND RELEVANCEBreast cancer has become a major health problem in Asia. The inclusion of more women from Asia in clinical trials and epidemiologic and translational studies may help unravel the interethnic heterogeneity of BCs and elucidate the complex interplay between environmental and intrinsic factors in its pathogenesis. These insights may help to refine prevention, diagnosis, and management strategies for BC in the setting of ethnic diversity.
Purpose: Whether diffuse large B-cell lymphoma (DLBCL) of primary central nervous system origin (PCNSL) is biologically different from DLBCL of peripheral nodal origin (NL) remains unclear. The purpose of this study was to compare the expression frequencies and prognostic significance of a panel of cell differentiation markers between these two disease entities. Experimental Design:This study included HIV-unrelated patients with PCNSL (n = 51) and NL (n = 72) treated at four hospitals inTaiwan for whom archival tumor tissue was available. Immunohistochemistry for CD10, BCL-6, MUM-1, vs38c, CD138, and BCL-2 was done. CD10, BCL-6, and MUM-1expression results were used to classify all cases into the germinal center B-cell (GCB) or the non-GCB subgroup. The prognostic significances of clinical and immunophenotypic markers were evaluated.Results: Nuclear MUM-1expression was significantly higher in PCNSL than in NL (P < 0.001; 84% versus 53%). PCNSL tumors were more frequently classified into the non-GCB subgroup than NL tumors (P = 0.020; 78% versus 62%). For patients with PCNSL, univariate analysis showed that patients with BCL-6 expression had a trend towards longer survival (P = 0.073; median survival, 25.3 versus 7.3 months), and multivariate analysis showed BCL-6 was an independent prognostic factor (P = 0.026). For patients with NL, both of univariate (P = 0.003) and multivariate analyses (P = 0.002) showed that GCB was significantly associated with favorable survival. Conclusion: The higher frequency of non-GCB subclassification, which was mainly contributed by nuclear MUM-1expression in PCNSL implies that it has a more differentiated cellular origin than NL. BCL-6 expression in patients with PCNSL and GCB subgroup in patients with NL were favorable prognostic factors.
Since BRCA mutations are only responsible for 10–20% of cases of breast cancer in patients with early-onset or a family history and since next-generation sequencing technology allows the simultaneous sequencing of a large number of target genes, testing for multiple cancer-predisposing genes is now being considered, but its significance in clinical practice remains unclear. We then developed a sequencing panel containing 68 genes that had cancer risk association for patients with early-onset or familial breast cancer. A total of 133 patients were enrolled and 30 (22.6%) were found to carry germline deleterious mutations, 9 in BRCA1, 11 in BRCA2, 2 in RAD50, 2 in TP53 and one each in ATM, BRIP1, FANCI, MSH2, MUTYH, and RAD51C. Triple-negative breast cancer (TNBC) was associated with the highest mutation rate (45.5%, p = 0.025). Seven of the 9 BRCA1 mutations and the single FANCI mutation were in the TNBC group; 9 of the 11 BRCA2, 1 of the 2 RAD50 as well as BRIP1, MSH2, MUTYH, and RAD51C mutations were in the hormone receptor (HR)(+)Her2(−) group, and the other RAD50, ATM, and TP53 mutations were in the HR(+)Her2(+) group. Mutation carriers were considered as high-risk to develop malignancy and advised to receive cancer screening. Screening protocols of non-BRCA genes were based on their biologic functions; for example, patients carrying RAD51C mutation received a screening protocol similar to that for BRCA, since BRCA and RAD51C are both involved in homologous recombination. In conclusion, we consider that multiple gene sequencing in cancer risk assessment is clinically valuable.
Background The incidence of breast cancer among younger East Asian women has been increasing rapidly over recent decades. This international collaborative study systemically compared the differences in age-specific incidences and pathological characteristics of breast cancer in East Asian women and women of predominantly European ancestry. Methods We excerpted analytic data from six national cancer registries (979 675 cases) and eight hospitals (18 008 cases) in East Asian countries and/or regions and, for comparisons, from the US Surveillance, Epidemiology, and End Results program database. Linear regression analyses of age-specific incidences of female breast cancer and logistic regression analyses of age-specific pathological characteristics of breast cancer were performed. All statistical tests were two-sided. Results Unlike female colorectal cancer, the age-specific incidences of breast cancer among East Asian women aged 59 years and younger increased disproportionally over recent decades relative to rates in US contemporaries. For years 2010–2014, the estimated age-specific probability of estrogen receptor positivity increased with age in American patients, whereas that of triple-negative breast cancer (TNBC) declined with age. No similar trends were evident in East Asian patients; their probability of estrogen receptor positivity at age 40–49 years was statistically significantly higher (odd ratio [OR] = 1.50, 95% confidence interval [CI] = 1.36 to 1.67, P < .001) and of TNBC was statistically significantly lower (OR = 0.79, 95% CI = 0.71 to 0.88, P < .001), whereas the probability of ER positivity at age 50–59 years was statistically significantly lower (OR = 0.88, 95% CI = 0.828 to 0.95, P < .001). Subgroup analyses of US Surveillance, Epidemiology, and End Results data showed similarly distinct patterns between East Asian American and white American patients. Conclusions Contrasting age-specific incidences and pathological characteristics of breast cancer between East Asian and American women, as well as between East Asian Americans and white Americans, suggests racial differences in the biology.
Metaplastic carcinoma of the breast (MCB) is a rare subtype of breast cancer. Anecdotal reports are available regarding its response to systemic chemotherapy. We reviewed the records of patients diagnosed with MCB at National Taiwan University Hospital between 1988 and 2009. A total of 46 MCB cases were identified from 8,695 breast tumor patients who underwent biopsy or resection. About 11 of 25 patients with initial bulky disease (T3-4) received neoadjuvant chemotherapy before surgery, and 2 (18.2%) exhibited a partial response. About 12 of 18 patients who developed distant metastasis received palliative systemic chemotherapy. Of them, only 1 (8.3%), 1 (10%), and none (0%) responded to first-, second-, or third- and beyond line chemotherapy, respectively. None of the patients who received anthracyline- (n = 13), vinorelbine- (n = 7), or cyclophosphamide-based (n = 18) chemotherapy responded, whereas 3 (17.6%) of 17 patients who received taxane-based chemotherapy exhibited a partial response. Tumor response to systemic chemotherapy remains generally poor for MCB patients. Taxanes may have modest activity, but need to be validated in further studies.
Substantial evidence indicates that exposure to bisphenol A (BPA) during early development may increase breast cancer risk later in life. The changes may persist into puberty and adulthood, suggesting an epigenetic process being imposed in differentiated breast epithelial cells. The molecular mechanisms by which early memory of BPA exposure is imprinted in breast progenitor cells and then passed onto their epithelial progeny are not well understood. The aim of this study was to examine epigenetic changes in breast epithelial cells treated with low-dose BPA. We also investigated the effect of BPA on the ERα signaling pathway and global gene expression profiles. Compared to control cells, nuclear internalization of ERα was observed in epithelial cells preexposed to BPA. We identified 170 genes with similar expression changes in response to BPA. Functional analysis confirms that gene suppression was mediated in part through an ERα-dependent pathway. As a result of exposure to BPA or other estrogen-like chemicals, the expression of lysosomal-associated membrane protein 3 (LAMP3) became epigenetically silenced in breast epithelial cells. Furthermore, increased DNA methylation in the LAMP3 CpG island was this repressive mark preferentially occurred in ERα-positive breast tumors. These results suggest that the in vitro system developed in our laboratory is a valuable tool for exposure studies of BPA and other xenoestrogens in human cells. Individual and geographical differences may contribute to altered patterns of gene expression and DNA methylation in susceptible loci. Combination of our exposure model with epigenetic analysis and other biochemical assays can give insight into the heritable effect of low-dose BPA in human cells.
BackgroundElevated vascular endothelial growth factor (VEGF) was associated with poor prognosis in leptomeningeal carcinomatosis and anti-angiogenic therapy was found to prolong the survival of mice in preclinical studies. This prospective pilot study investigated the efficacy of anti-VEGF therapy plus chemotherapy in patients with leptomeningeal carcinomatosis originating from breast cancer.MethodsEligible patients were scheduled to receive bevacizumab combined with etoposide and cisplatin (BEEP) every 3 weeks for a maximum of 6 cycles or until unacceptable toxicity. The primary objective was the central nervous system (CNS)-specific response rate, which was defined as disappearance of cancer cells in the cerebrospinal fluid (CSF) and an improved or stabilized neurologic status. The impact of VEGF inhibition on etoposide penetration into the CSF was analyzed.ResultsEight patients were enrolled. The CNS-specific response rate was 60% in 5 evaluable patients. According to intent-to-treat analysis, the median overall survival of the eight patients was 4.7 months (95% confidence interval, CI, 0.3–9.0) and the neurologic progression-free survival was 4.7 months (95% CI 0–10.5). The most common grade 3/4 adverse events were neutropenia (23.1%), leukopenia (23.1%), and hyponatremia (23.1%). The etoposide concentrations in the CSF were much lower than those in plasma, and bevacizumab did not increase etoposide delivery to the CSF.ConclusionsBEEP exhibited promising efficacy in breast cancer patients with leptomeningeal carcinomatosis. Additional studies are warranted to verify its efficacy and clarify the role of anti-angiogenic therapy in this disease.Trial registrationClinicalTrials.gov identifying number NCT01281696.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1290-1) contains supplementary material, which is available to authorized users.
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