乳腺癌生物标记

癌生物标记已经成为癌症研究的主要焦点。乳腺癌生物标记对乳腺癌的早期诊断、治疗方案的制定、治疗效果和预后评估有重要意义。现综述乳腺癌生物标记的相关研究进展。     

乳腺癌生物标记

癌生物标记已经成为癌症研究的主要焦点。乳腺癌生物标记对乳腺癌的早期诊断、治疗方案的制定、治疗效果和预后评估有重要意义。现综述乳腺癌生物标记的相关研究进展。     

Circulating Biomarkers in Breast Cancer

Breast cancer management has progressed immensely over the decades, but the disease is still a major source of morbidity and mortality worldwide. Even with enhanced imaging detection and tissue biopsy capabilities, disease can progress on an ineffective treatment before additional information is obtained through standard methods of response evaluation, including the RECIST 1.1 criteria, widely used for assessment of treatment response and benefit from therapy.⁶ Circulating biomarkers have the potential to provide valuable insight into disease progression and response to therapy, and they can serve to identify actionable mutations and tumor characteristics that can direct therapy. These biomarkers can be collected at higher frequencies than imaging or tissue sampling, potentially allowing for more informed management. This review will evaluate the roles of circulating biomarkers in breast cancer, including the serum markers Carcinoembryonic antigen CA15-3, CA27-29, HER2 ECD, and investigatory markers such as GP88; and the components of the liquid biopsy, including circulating tumor cells, cell free DNA/DNA methylation, circulating tumor DNA, and circulating microRNA.     

Biomarkers of Therapeutic Resistance in Breast Cancer

Despite improvements in early detection and adjuvant treatment, a significant fraction of women with early stage breast cancer will eventually develop a recurrence. While improvement in outcomes in metastatic disease has been achieved with new therapeutic options almost all patients eventually develop tumor progression due to drug resistance. We review the mechanisms of resistance to commonly used endocrine, chemotherapeutic, and targeted agents in breast cancer and the interplay of the biomarkers therein.     

Breast Ductal Lavage for Assessment of Breast Cancer Biomarkers

Lavage of the ductal systems of the breast provides fluid (DLF) containing hormones and products of hormone actions that may represent more accurately the composition of the breast than samples collected from blood or urine. The present study was undertaken to assess the presence of potential cancer biomarkers, their variation among individuals at high risk for breast cancer, and differences associated with menopause and tamoxifen treatment. Seventy seven tamoxifen-eligible subjects with a 5-year breast cancer risk estimate (Gail > 1.6%)(N = 53) or recently diagnosed breast cancer (N = 24) were offered tamoxifen therapy; those not accepting tamoxifen were under observation only. After six months, all subjects underwent ductal lavage (DL) in an unaffected breast. Estradiol (E2), estrone sulfate, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate, progesterone, cathepsin D and epidermal growth factor (EGF) were measured in DLF by immunoassays. Data were expressed as the mass of analyte per mg of protein in DLF and normalized by natural log transformation. With the exception of DHEA, none of the analytes measured were significantly lower in postmenopausal women than in premenopausal women. The mean log(e) concentration difference in estradiol was 10.9%. Tamoxifen treatment for 6 months did not result in a significantly greater concentration of E2 or in any of the other analytes in DLF of pre- or postmenopausal women. The between-duct variance of the concentration of free steroids within the same breast averaged 51% less than that between subjects, and was similar to that of non-diffusible proteins. The maintenance of estradiol concentrations in the breast after menopause demonstrates the importance of local biosynthesis. The fact that DLF E2 does not reflect the high serum concentrations of E2 during tamoxifen treatment indicates that breast concentrations of estradiol may be under feedback control. Unlike studies of low risk populations, progesterone concentrations were not significantly less in postmenopausal than in premenopausal women. The similarity in variance of free steroids and protein analytes between ducts of a breast indicates little transfer of steroids between lobules.     

Breast Cancer Biomarkers: Utility in Clinical Practice

Breast cancer is a heterogeneous disease. For the past decades, new technical tools have been developed for biomarkers at the DNA, RNA, and protein levels to better understand the biology of breast cancer. This progress is essential to classify the disease into clinically relevant subtypes, which may lead to new therapeutic opportunities. Novel biomarker development is paramount to deliver personalized cancer therapies. Further, tumor evolution, being natural or under treatment pressure, should be monitored and “liquid biopsies” by detecting circulating tumor cells or circulating free tumor DNA in blood samples will become an important option. This article reviews the new generation of biomarkers and the current evidence to demonstrate their analytical validity, clinical validity and clinical utility.     

三阴性乳腺癌的分子生物标记的研究进展

Notch、Wnt和Hh信号通路均参与了三阴性乳腺癌的发生发展。Aurora激酶A、Chkl、miR-93等在三阴性乳腺癌中存在过表达,并与其预后相关．为其治疗提供了新靶点。     

Biomarkers in Breast Cancer and the Implications of Their Discordance

The analysis of biomarkers in breast cancer has made a large impact in treatment decisions and determining prognosis. Information gained from the phenotypic and molecular profile helps both in prognostic stratification as well as treatment selection. With the advent of newer more efficacious chemotherapeutic and biological agents in the management of metastatic breast cancer, most women with this disease are exposed to multiple lines of therapy. Discordance in the receptor status between the primary and metastatic sites is frequently encountered and may play an important role in deciding subsequent therapy. In this review, we look at the role of current biomarkers in the management of breast cancer, which are promising and the therapeutic and prognostic implications of their discordance during the natural course of disease progression.     

乳腺癌患者血清蛋白质芯片检测

背景与目的:乳腺癌的早期诊断是取得满意治疗效果的关键,目前临床常用的乳腺癌检查方法有近红外线乳腺扫描,乳腺X线钼靶及数字化摄片、针吸细胞学检查、乳腺穿刺活检、外科手术活检或冰冻切片检查等,但这些方法的检测出来的多数已非早期肿瘤.本研究就是应用蛋白质芯片技术,分析乳腺癌患者与乳腺非癌患者和正常妇女、Ⅰ期、Ⅱ期和Ⅲ期乳腺癌之间血清蛋白质表达的差异.方法:我们选择IMAC3和WCX2两种芯片,对64例乳腺癌、52例乳腺非癌患者及12名正常妇女血清进行研究.统计学分析采用Ciphergen ProteinChip3.0和Biomark Wizard软件分析乳腺癌、乳腺非癌患者和正常人血清的蛋白质谱差异.结果:在WCX-2蛋白芯片,分子量为9 116Da、8 905 Da、8 749 Da、9 470 Da和9 692 Da的5个位点,在乳腺癌患者与乳腺非癌患者及正常妇女血清之间WCX-2蛋白峰表达有差异,乳腺癌患者蛋白质峰的表达较乳腺非癌和正常妇女表达高,敏感性为54.7%～92.2%;特异性为53.1%～81.3%;分子量为9 405Da和6 424Da的2个位点,Ⅰ期乳腺癌与Ⅲ期乳腺癌患者血清蛋白峰表达有差异,敏感性为73.7%～78.9%,特异性为61.9%～71.4%.在IMAC3蛋白芯片,分子量分别为5 236 Da、7 823 Da、7 464 Da、5 213 Da、5 334 Da、5 063 Da、5 374 Da、7 756 Da和7 623 Da有9个位点位置,乳腺癌患者与乳腺非癌患者及正常妇女血清蛋白峰表达有差异,蛋白质峰的表达乳腺癌患者较乳腺非癌和正常妇女表达低,敏感性为56.3%～82.8%;特异性为48.4%～78.1%;分子量为7 922Da、4641Da和5 910Da位置,Ⅰ期乳腺癌与Ⅲ期乳腺癌患者血清蛋白峰表达有差异,敏感性为63.2%～84.2%,特异性为47.6%～66.7%.结论:乳腺癌患者与乳腺非癌及正常妇女血清蛋白峰表达存在差异,这些差异蛋白有可能成为新的乳腺癌分子标志物,有助于乳腺癌的早期诊断及术后的随访.     

乳腺癌免疫治疗生物标志物的研究进展

摘 要：免疫检查点抑制剂作为研究的热点已被应用于多种实体瘤中,然而,研究发现部分肿瘤对免疫抑制剂不敏感,同时接受免疫治疗的患者也会出现特殊的、致命的不良反应。研究发现PD?鄄L1、肿瘤突变负荷、微卫星不稳定性以及肿瘤细胞浸润可以预测乳腺癌免疫治疗的反应、评估治疗疗效与预后。骨髓源性抑制细胞、循环肿瘤DNA和LAG3也表现出作为预测标志物的潜力。全文对乳腺癌免疫治疗相关预测生物标志物的最新研究进展作一综述。     

乳腺癌脑转移的潜在生物标志物研究进展

摘 要：脑转移是乳腺癌病情严重化和预后恶化的重要因素之一。近年来，越来越多的研究集中在寻找乳腺癌脑转移的潜在生物标志物，以便更好地理解其发生及进展机制，并为预防、诊断和治疗提供新的靶点。全文对近年来乳腺癌脑转移的潜在生物标志物进行了综述，重点讨论循环肿瘤细胞、细胞外囊泡以及蛋白质等生物标志物，以期为早期诊断乳腺癌脑转移提供参考依据。     

Emerging Prognostic and Predictive Biomarkers for Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is associated with a poor prognosis especially in the advanced setting and continues to pose a challenge for oncologists worldwide. Several biomarkers for this disease have been described. Recently the heterogeneity of TNBC has changed our perspective toward this disease. Differential response of TNBC to chemotherapy, poor prognosis of patients with residual disease following neoadjuvant chemotherapy, and the immunogenicity underlying TNBC make the management of this disease even more complex. Multiple signaling pathways and dynamic pathway programming are the hallmarks of TNBC. Newer trials for this disease therefore, need to be innovative and include biomarker enrichment and adaptive designs. This article highlights the emerging prognostic and predictive biomarkers for TNBC and discusses possible targets for future therapeutic strategies.     

Expression of LRP Gene in Breast Cancer Patients Correlated with MRP1 as Two Independent Predictive Biomarkers in Breast Cancer

Background: Breast cancer is the most common malignancy in women. Multidrug resistance (MDR) is still a greatobstacle of breast cancer chemotherapy. We have previously shown that multidrug resistance-associated protein 1 (MRP1)is associated with response to neoadjuvant chemotherapy. The lung resistance-related protein (LRP) is identified asa prognostic marker and response to treatment factor which has been studied mainly in hematological malignancy andleukemia. In this study, we aimed to analyze LRP expression and possible correlation between the expression level ofthis gene with MRP1 as a candidate marker for chemotherapy resistance. Materials and Methods: We collected 54breast tumors and adjacent normal tissues from Iranian breast cancer patients and Real time RT-PCR was employed tomeasure the gene expression level in our samples. Results: MRP1 and LRP expression level were significantly lowerin tumor tissues of the patients responding to chemotherapy compared to non-responding patients. No relation betweenthe expression level of either of these genes and clinicopathology markers was found. Conclusion: Our results suggestthat LRP gene expression is correlated to MRP1 in human breast cancer cells and may affect the clinical response totreatment.     

Identification of Novel Diagnostic Biomarkers in Breast Cancer Using Targeted Metabolomic Profiling

IntroductionBreast cancer (BC) is the most common cancer in women, with a high disease burden, especially in the advanced disease stages. Our study investigated the metabolomic profile of breast cancer patients’ serum with the aim of identifying novel diagnostic biomarkers that could be used, especially for early disease detection.Materials and MethodsUsing targeted metabolomic serum profiling based on high-performance liquid chromatography mass spectrometry, women with BC (n = 39) and a control group (n = 21) were examined for 232 endogenous metabolites.ResultsThe top performing biomarkers included acylcarnitines (ACs) and 9,12-linoleic acid. A combined panel of the top 4 biomarkers achieved 83% sensitivity and 81% specificity, with an area under the curve (AUC) of 0.839 (95% confidence interval, 0.811-0.867). Individual markers also provided significant predictive values: AC 12:0, sensitivity of 72%, specificity of 67%, and AUC of 0.71; AC 14:2, sensitivity of 74%, specificity of 71%, and AUC of 0.73; AC 14:0: sensitivity of 67%, specificity of 81%, and AUC of 0.73; and 9,12-linoleic acid, sensitivity of 69%, specificity of 67%, and AUC of 0.71. The individual markers, however, did not reach the high sensitivity and specificity of the 4-biomarker combination.ConclusionUsing mass spectrometry-targeted metabolomic profiling, ACs and 9,12-linoleic acid were identified as potential diagnostic biomarkers for breast cancer. Additionally, these identified metabolites could provide additional insight into cancer cell metabolism.     

Discovery and Validation of Breast Cancer Early Detection Biomarkers in Preclinical Samples

Despite the widespread use of mammography for breast cancer screening, breast cancer remains the most common cause of cancer-related mortality among women worldwide. The identification of blood-based biomarkers useful for the early detection of breast cancer could have a major impact on reducing breast cancer disease burden by identifying cancers early when they are most treatable. We conducted a series of large-scale proteomic discovery and validation studies using preclinical samples from the Women’s Health Initiative Observational Study prospective cohort. Of the 503 proteins quantified in experiments conducted on samples from ER⁺ breast cancer patients and matched controls, 57 differentiated cases from controls. The seven candidates were assessed in an independent validation set with a commercially available ELISA assay. We confirmed that one of these candidates, epidermal growth factor receptor (EGFR), was elevated in cases versus controls. Compared to women in the lowest EGFR quartile, those in the highest quartile has a 2.90-fold (p?=?0.0005) increased risk of developing breast cancer. An interaction with use of menopausal hormone therapy was observed such that among current estrogen plus progestin users, those in the highest EGFR quartile had a 9.04-fold (p?=?0.0004) increased risk of developing breast cancer. While the performance of EGFR in terms of sensitivity and specificity is insufficient for it to be used on its own clinically, the formal validation of EGFR suggests that there may indeed be changes in the plasma proteome prior to the clinical diagnosis of breast cancer that are detectable and of potential clinical utility.     

钼靶X线钙化征象与乳腺癌分子标志物相关性

[目的]探讨钢靶X线提示的钙化灶与雌激素受体（ER）、孕激素受（PR）、人表皮生长因子相关基因（Her-2／neu）、细胞增殖抗原标志物Ki-67间的关系。[方法]术前做过钼靶X线并且术后病理确诊为乳腺癌的患者83例，术后病理标本均行常规的ER、PR、Her-2／neu、Ki-67的免疫组化检测，回顾性分析钙化灶与上述分子标志物间的相关性。[结果]乳腺癌钙化灶与ER、PR表达无相关性（P〉0．05），而乳腺癌钙化灶与Her-2／neu、Ki-67的表达有相关性（P〈0．05）;Her-2／neu在杆状钙化组中的阳性表达率明显高于其他组（P=0．047）。[结论]铜靶X线钙化征象在一定程度上反映乳腺癌组织中Her-2／neu及Ki-67的表达状况．     

Serum Biomarkers for Chemotherapy Cardiotoxicity Risk Detection of Breast Cancer Patients

Objective: This study aimed to investigate level fluctuations of serum biomarkers that are associated with cardiotoxicity risk, such as high-sensitivity C-reactive protein (hs-CRP) and apolipoprotein-B (Apo-B) in response to chemotherapy treatment for breast cancer. Method: The serum levels of hs-CRP and Apo-B were evaluated in 56 breast cancer patients with main inclusion criteria: HER2 negative and who received adjuvant chemotherapy AC [A: Adriamycin, C: Cyclophosphamide] or AC→T [A: Adriamycin, C: Cyclophosphamide, T: Taxane] regimes at early II (n = 26) and late IV (n = 30) clinical stages by using particle enhanced turbidimetric assay. Results: The results of this study suggest that a high level of pre-treatment hs-CRP is a good prognostic marker in comparison to Apo-B. Moreover, the AC-T chemotherapy regime treatment in both early and late stages exhibited a significantly higher level of hs-CRP compared to that in the AC regime. Hs-CRP was significantly elevated in the early stage in comparison to the late stage among cancer patients, meanwhile Apo-B behaved inversely. Furthermore, the results showed that hs-CRP levels were significantly higher in late-stage cancer patients compared with those in early-stage in both chemotherapy regimens groups. On the other hand, Apo-B showed no significant differences. Conclusion: Monitoring hs-CRP level changes in comparison to Apo-B can be used to assist the side effect risk difference among different chemotherapy regimens, and staging reflecting a positive correlation between them more notable in the late stage.     

miR-140 and miR-196a as Potential Biomarkers in Breast Cancer Patients

Objective: MiR-140 and miR-196a were known to be correlated with cancer diagnosis and prognosis. The current study aimed at the analysis of miR-140 and miR-196a expression patterns and their clinical significance for breast cancer (BC) patients. Methods: Differentially expressed miR-140 and miR-196a were examined via quantitative PCR in 110 cases of BC and their adjacent non-tumor (ANT) tissues. Results: The results indicated that miR-140 and miR-196a, respectively, notably decreased and increased expression in BC samples in comparison with ANT (p<0.001). Reduced miR-140 expression was also related to Lymph node metastasis (LNM, P= 0.023) and stage (P = 0.009). Additionally, Receiver Operating Characteristics (ROC) analysis illustrated that miR-140 had a significant diagnostic accuracy for stage and LNM of BC patients. We also discovered a strong negative correlation between miR-196a expression with histological grade (P = 0.038), LNM (P = 0.012) and stage (P = 0.001). Conclusion: Overall, exploring the miR-140 and miR-196a profiles not only can statistically different among BC and ANT samples, but it is also expected to become potential BC biomarkers.     

The Hypoxic Response Expression as a Survival Biomarkers in Treatment-Naive Advanced Breast Cancer

Objective: Hypoxia-associated biomarkers profiling may provide information for prognosis, staging, and subsequent therapy. We aim to evaluate whether the quantitative gene and protein expression of hypoxic response tumor markers - carbonic anhydrase IX (CAIX) and hypoxia- inducible factor 1 alpha (HIF1A) — may have a role in predicting survival in advanced breast cancer of Indonesian population. Methods: Tumor tissues and peripheral blood samples were collected from treatment - naïve locally advanced (LABC) or metastatic breast cancer patients (MBC) at Wahidin Sudirohusodo General Hospital (Makassar, South Sulawesi) and its referral network hospitals from July 2017 to March 2019. The level of mRNA (of blood and tumor tissue samples) and soluble protein (of blood samples) of CAIX and HIF1A were measured by RT-qPCR and ELISA methods, respectively, besides the standard histopathological grading and molecular subtype assessment. The CAIX and HIF1A expression, patients’ age, tumor characteristics, surgery status, and neoadjuvant chemotherapy drug classes were further involved in survival analyses for overall survival (OS) and progression-free survival (PFS). Results: Forty (30 LABC, 10 MBC) eligible patients examined were 21 hormone-receptors positives (15 Luminal A, 6 Luminal B) and 19 hormone-receptors negatives (10 HER2-enriched, 9 triple-negative). The CAIX blood mRNA and CAIX soluble protein levels in hormone-receptors negative patients were higher than in hormone-receptor-positive patients (p < 0.05). In univariate analysis, both CAIX and HIF1A levels predict OS (except HIF1A protein) with CAIX tissue mRNA has the highest hazard ratio (HR 8.04, 95%CI:2.45-26.39), but not PFS. Cox proportional hazard model confirmed that CAIX tissue mRNA is the independent predictor of OS (HR 6.10, 95%CI: 1.16-32.13) along with surgical status and tumor advancement type (LABC or MBC). Conclusions: CAIX mRNA expression of tumor tissue in treatment-naïve advanced breast cancer has a predictive value for OS.