Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.     

TSC22D1 and PSAP predict clinical outcome of tamoxifen treatment in patients with recurrent breast cancer

Purpose Two genes, TSC22 domain family, member 1 (TSC22D1) and prosaposin (PSAP) were identified in an in vitro functional screen for genes having a causative role in tamoxifen resistance. These genes were also present in our previously established 81-gene signature for resistance to first-line tamoxifen therapy. The aim of this study was to investigate the predictive value of these genes for tamoxifen therapy failure in patients with recurrent breast cancer. Experimental Design The mRNA levels of TSC22D1 and PSAP were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in 223 estrogen receptor-positive primary breast tumors of patients with recurrent disease treated with first-line tamoxifen therapy. The main objective of this study was the length of progression-free survival (PFS). Results High mRNA levels of TSC22D1 and PSAP were significantly associated with shorter PFS and both were independent of the traditional predictive factors (HR = 1.30, 95% CI = 1.04–1.64 P = 0.023; and HR = 1.40, 95% CI = 1.03–1.88, P = 0.029, respectively). In multivariate analysis, patients with high mRNA levels of both genes associated significantly with no clinical benefit (OR = 0.19, 95% CI = 0.06–0.62, P = 0.006) and had the shortest PFS (HR = 2.05, 95% CI = 1.29–3.25, P = 0.002). Conclusion These results confirm our previous in vitro and tumor-related findings and are indicative for the failure of tamoxifen treatment in breast-cancer patients. Both TSC22D1 and PSAP are associated with clinical outcome and may have a functional role in therapy resistance. Danielle Meijer and Maurice P.H.M. Jansen contributed equally to this work.     

乳腺癌患者CYP2D6基因多态性与他莫昔芬代谢相关性研究

目的 探究乳腺癌患者CYP2D6基因多态性与他莫昔芬药物代谢产物浓度之间的关系。方法 收集2010年1月—2012年12月我院乳腺癌患者的外周血样本,检测CYP2D6基因上rs16947,rs1065852和rs28371725三种单核苷酸多态性(Single nucleotide polymorphism,SNP)位点的基因型及他莫昔芬代谢产物在血液中的浓度。应用非参数检验中的独立样本Kruskal-Wallis检验进行统计学分析。结果 CYP2D6基因上rs16947位点不同基因型携带者间他莫昔芬代谢产物4-OH-N-D-TAM和4'OH-N-D-TAM在血液中的浓度具有统计学差异(P=0.049),表明CYP2D6基因上的rs16947位点影响他莫昔芬药物在人体内的代谢。结论 乳腺癌患者CYP2D6基因rs16947位点的基因型与部分他莫昔芬代谢产物的血液浓度有关。     

One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer

PurposeWe report the long-term results of a randomised trial comparing tamoxifen with tamoxifen plus cyclophosphamide, methotrexate and fluorouracil (CMF) in postmenopausal high-risk breast cancer patients. In addition, we analyse the prognostic and predictive value of centrally assessed subtypes.MethodsPostmenopausal patients with breast cancer and positive nodes, deep invasion or size exceeding 5 cm were randomly assigned to 1 year of tamoxifen, or cyclophosphamide 600 mg/m², methotrexate 40 mg/m² and fluorouracil 600 mg/m² intravenously on day 1 every 4 weeks for nine cycles plus tamoxifen (CMFT). Tissue microarrays were constructed retrospectively and oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and proliferation-related Ki-67 antigen (Ki67) status were assessed.ResultsFrom October 1982 through March 1990 we randomised 1445 patients and 969 (67%) were eligible for the biomarker analysis. At 10-years 936 women had suffered a disease-free survival (DFS) event (tamoxifen, 495 events in 686 patients; CMFT, 441 events in 642 patients). The addition of CMF to tamoxifen significantly improved DFS (adjusted hazard ratio 0.82; 95% confidence interval (CI) 0.71–0.93; P = 0.003) but not overall survival (adjusted hazard ratio 0.95; 95% CI 0.85–1.08; P = 0.44). DFS was superior in Luminal A tumours (ER or PgR positive, HER2 negative and Ki67 ?14%) when compared to Luminal B or non-luminal (ER and PgR negative) tumours. There was no statistical evidence of heterogeneity by subtype in the benefit from CMF (P_interaction = 0.45).ConclusionCMF added to 1 year of tamoxifen reduces the risk of a DFS event. The benefit from CMF was not significantly different in Luminal A and B subtypes.     

Prognosis of uterine corpus cancer after tamoxifen treatment for breast cancer

Tamoxifen increases the risk of uterine corpus cancer. Since only few, mostly small, studies have examined prognosis of uterine corpus cancer following tamoxifen, we conducted a large retrospective cohort study to further investigate this. We examined histopathologic and immunohistochemical characteristics of 332 patients with uterine corpus cancer following breast cancer, according to tamoxifen use. Survival was examined in the same patients combined with 309 patients from a previous study with updated follow-up. Histological review of all cancers was performed. Long-term tamoxifen users showed a higher proportion of non-endometrioid tumors than non-users (32.7% vs. 17.4%, P = 0.004), especially serous adenocarcinomas and carcinosarcomas. An increased proportion of FIGO stage III and IV tumors was also observed (20.0% vs. 11.3%, P = 0.049). Within FIGO stage I, both short-term and long-term tamoxifen users showed a higher proportion of tumors limited to the endometrium than non-users (35.7% vs. 22.9%, P = 0.049 and 0.004 respectively). Uterine corpus cancers in long-term tamoxifen users were more often steroid receptor-negative (ERα, PRA and PRB, P < 0.05) and P53-positive (P = 0.015). Three-year uterine corpus cancer-specific survival was worse for long-term tamoxifen users than for non-users (82% vs. 93% P = 0.0001). The survival difference remained after adjustment for histopathologic and immunohistochemical characteristics (hazard ratio (HR) for ≥2 years tamoxifen = 2.4; 95% CI = 1.2–4.6). In conclusion, this large study clearly shows that tamoxifen-associated tumors have less favorable histological features and a worse survival. Our results can be applied when weighing risks and benefits of tamoxifen versus other hormonal agents used in the prevention and treatment of breast cancer. TAMARISK (Tamoxifen Associated Malignancies: Aspects of Risk)-group of the Comprehensive Cancer Centers (CCC): O. Visser (CCC Amsterdam), R. A. M. Damhuis (CCC Rotterdam), W. J. Louwman (CCC South Netherlands), J. A. A. M. van Dijck (CCC East Netherlands), Y. Westerman (CCC Middle Netherlands), M. J. M. Dirx (CCC Limburg), M. L. E. A. Jansen-Landheer (CCC West), L. de Munck (CCC Northern Netherlands), S. Siesling (CCC Stedendriehoek Twente).     

Thymidine phosphorylase is regulated by tamoxifen in T47D breast cancer cell line

BACKGROUND: Thymidine phosphorylase (TP) has diverse functions within cells, including increasing the sensitivity of cancer cells to cytotoxic drugs including 5-fluorouracil (5-FU) and methotrexate. However, the regulators of TP still remains largely unknown. METHOD: In this study, we examined whether tamoxifen has specific effects on TP expression in the T47D breast cancer cell line. We studied the TP expression in the T47D cell line before and after tamoxifen treatment using Western blot analysis and ELISA. RESULTS: We found that TP expression is significantly up-regulated in tamoxifen-treated cells compared with control. CONCLUSIONS: Our findings suggest that tamoxifen may increase chemotherapy sensitivity through TP up-regulation for treatment regimens including doxifluridine, capecitabine, and/or methotrexate.     

HER2 status in hormone receptor positive premenopausal primary breast cancer adds prognostic, but not tamoxifen treatment predictive, information

BACKGROUND: Overexpression of human epidermal growth factor receptor 2 (HER2) or amplification of its gene is a prognostic factor in primary breast cancer and a predictor for tamoxifen treatment efficacy in oestrogen receptor (ER) positive disease. In the present study we explored a defined cohort of breast cancer patients included in a randomised trial in order to assess prognostic and tamoxifen treatment information yielded by HER2 status. METHODS: Premenopausal breast cancer patients with stage II tumours (n = 564) were included and allocated to 2 years of adjuvant tamoxifen treatment versus no adjuvant treatment. ER, progesterone receptor (PR) status and HER2 status was determined by immunohistochemistry using a tissue microarray. HER2 amplification was analysed by fluorescent in situ hybridisation and tumours being amplified and/or HER2 3+ were considered HER2+. HER2 status was evaluable in 83% of the patients and 12.6% were HER2+. In untreated patients, HER2 was a negative prognostic factor in ER+ patients, HR 2.95; 95% CI: 1.61-5.38, p < 0.001, but not in ER- patients, HR 0.67; 95% CI: 0.28-1.61, p = 0.4, and a significant interaction between the two markers was found, p < 0.01. HER2 status was not related to tamoxifen treatment efficacy in ER+ patients (term of interaction p = 0.95). When stratifying for PR status, similar results were achieved. DISCUSSION: HER2+ and ER+ breast cancer constituted a subgroup of tumours with poor prognosis in premenopausal breast cancer, whereas no treatment interaction was found between HER2 status and tamoxifen in ER+ tumours. The poor prognosis in HER2+ and ER+ patients may interfere with the interpretation of HER2 data in non-randomised trials of adjuvant tamoxifen.     

乳腺癌他莫昔芬耐药机制的研究进展

他莫昔芬(Tamoxifen,TAM)对于治疗雌激素受体(ER)阳性的乳腺癌是一种重要的治疗策略.然而TAM耐药是内分泌治疗失败的一个主要原因.TAM耐药的潜在机制是多因素的,其中大部分仍是未知的.本文介绍了近年来有关乳腺癌TAM耐药机制的研究进展,为阐明TAM耐药机理及克服耐药性提供有价值的信息和思路.     

Vitamin D and breast cancer: Emerging concepts

The benefit of vitamin D in cancer prevention and to certain extent therapy has been well recognized. The active form of vitamin D, 1,25-dihydroxycholecalciferol (1,25(OH)2 D3) is a natural ligand for vitamin D receptor (VDR). Since 1,25(OH)2D3 exerts toxic effects at a concentration that is beneficial, nearly 1500 analogs of vitamin D have been synthesized and evaluated for their efficacy in a variety of carcinogenesis and human cancer models both in vitro and in vivo. Among these only a handful of them have been approved for evaluation in clinical trials for leukemia, breast, prostate and colon cancers. The mechanism of vitamin D action is mediated by the nuclear VDR and the signaling cascade for its action is extensively reported. In this review we focus on the newer concepts for vitamin D action. These include (1) differential effects of vitamin D in maintaining cell proliferation when the cells are under stress but suppressing cell growth when the cells are transformed; (2) functional significance of VDR polymorphism in potential vitamin D responsiveness; (3) regulation of constitutive splicing of vitamin D target gene, CYP24a, by the hormone and its significance; and (4) regulation of microRNA by vitamin D in breast cancer. It is anticipated that the new work in these selective areas would expand the understanding of vitamin D in breast cancer prevention and therapy.     

Vitamin D receptor variants and breast cancer risk in the Polish population

The aim of the study was to determine whether four VDR gene single nucleotide polymorphisms (SNPs: rs1544410, rs731236, rs10735810 and rs4516035) are associated with breast cancer risk in Polish population. Two independent series of female patients were employed: 960 consecutive breast cancer cases, and 800 unselected early onset cases diagnosed under the age of 51. The control group for the consecutive breast cancer cases consisted of 960 healthy, age-matched women with a negative cancer family history. 550 healthy women, aged 51 or less, with negative cancer family history were selected as the independent controls for the early onset breast cancer cases. The frequencies of the VDR polymorphisms in the unselected cases when compared to the respective control population failed to reveal any association between the individual SNPs and disease. Examination of the group of early-onset patients, revealed an association between rs10735810 and increased breast cancer risk. Heterozygous carriers for the change had an OR = 1.73 (95% CI 1.33–2.26, P < 0.0001) and homozygous carriers OR = 2.34 (95% CI 1.71–3.21, P < 0.0001). The remaining three examined SNPs failed to show any association with disease risk. In summary, this study has identified an association between the VDR gene and early onset breast cancer risk in the Polish population.     

Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: Systematic review and meta-analysis of prospective cohort studies

AimTo estimate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and survival among colorectal and breast cancer patients.MethodsWe performed a comprehensive literature search of prospective cohort studies assessing the association of serum 25(OH)D levels with survival in colorectal and breast cancer patients. Study characteristics and results were extracted and dose–response relationships were graphically displayed in a standardised manner. Meta-analyses using random effects models were performed to estimate pooled hazard ratios.ResultsThe systematic search yielded five studies including 2330 colorectal cancer patients and five studies including 4413 breast cancer patients all of which compared mortality across two to five categories of 25(OH)D levels. Among colorectal cancer patients, pooled hazard ratios (95% confidence intervals) comparing highest with lowest categories were 0.71 (0.55–0.91) and 0.65 (0.49–0.86) for overall and disease-specific mortality, respectively. For breast cancer patients, the corresponding pooled estimates were 0.62 (0.49–0.78) and 0.58 (0.38–0.84), respectively. No significant evidence of heterogeneity between studies was observed.ConclusionHigher 25(OH)D levels (>75 nmol/L) were associated with significantly reduced mortality in patients with colorectal and breast cancer. Randomised controlled trials are needed to evaluate whether vitamin D supplementation can improve survival in colorectal and breast cancer patients with low vitamin D status (25(OH)D < 50 nmol/L) at diagnosis and before treatment.     

Evaluation of vitamin D deficiency in breast cancer patients on bisphosphonates

BACKGROUND: Bisphosphonates are very effective in treating osteoporosis and metastatic bone disease; however, unfavorable outcomes can occur when they are given to patients with occult vitamin D deficiency. No clear consensus exists on the assessment of vitamin D status in cancer patients undergoing bisphosphonate therapy. This study examines the prevalence of vitamin D deficiency among breast cancer patients treated with bisphosphonates for osteoporosis or metastatic bone disease, and observes the use of calcium and vitamin D supplementation in these patients. METHODS: This retrospective study reviewed the electronic records of 321 breast cancer patients treated with bisphosphonates. Information on age, race, and serum levels of 25-hydroxyvitamin D (25-OHD), parathyroid hormone, and calcium were collected, and intakes of calcium and vitamin D supplements were queried in an outpatient pharmacy database. RESULTS: Of the 321 patients treated with bisphosphonates, 209 (65.1%) had their 25-OHD levels checked at least once. Of these patients, 57 (27.3%) had a serum 25-OHD level <20 ng/ml. Of the 209 patients with a known 25-OHD level, only eight (3.8%) received >600 IU of vitamin D per day, and 41 (19.6%) patients received 400-600 IU of vitamin D daily. CONCLUSION: Especially in the setting of metastatic bone disease in breast cancer patients, we advocate routine 25-OHD concentration screening for vitamin D deficiency in general. Clear guidelines for the diagnosis of vitamin D deficiency in cancer patients would be extremely beneficial to have, as would identification of the proper dose of vitamin D supplementation. We recommend 1,000 IU daily to our metastatic cancer patients.     

乳腺癌辅助他莫昔芬治疗与后续白内障发生的相关性分析

背景与目的：他莫昔芬是绝经前激素受体阳性乳腺癌辅助内分泌治疗的标准药物,也是绝经后患者的重要选择。目前,他莫昔芬治疗与后续白内障发生的相关性争议较大,需进一步证实。方法：分析复旦大学附属肿瘤医院乳腺外科前瞻性维护的病例数据库中的相关信息,结合门诊随诊数据,共纳入3 034例可用患者。其中无内分泌治疗患者806例,含他莫昔芬治疗1 065例,仅接受芳香化酶抑制剂治疗1 163例。对无内分泌治疗与含他莫昔芬治疗两组,根据后续发生白内障与否进行关联分析,并进行年龄（≤40岁、40~50岁、＞50岁）与他莫昔芬用药时长（用药5年内、超过5年）的亚组研究。结果：无内分泌治疗组（806例）与含他莫昔芬治疗组（1 065例）两组间白内障发生率没有显著差异（HR=1.1,95% CI：0.8~1.5;P=0.70）。但在不同年龄亚组中有不同情况：≤40岁组与40~50岁组,他莫昔芬的使用与白内障发病没有显著关联;在＞50岁组,使用他莫昔芬后发生白内障的概率（15.4%）是未使用组（9.0%）的1.8倍（95% CI：1.1~3.1;P=0.024）。不仅如此,多因素分析揭示,长期使用他莫昔芬（超过5年）的患者也相对于5年内使用患者有更高的白内障发生风险。结论：虽然在整体人群中白内障与他莫昔芬无显著相关,但在中老年等绝经后患者及长时间他莫昔芬用药患者中,白内障的发病风险显著提高。提示选择他莫昔芬治疗时,要重视各类不良反应风险的评估和白内障高危人群的鉴别。     

Endometrial K-ras mutations in postmenopausal breast cancer patients treated with adjuvant tamoxifen or toremifene

Purpose Long-term use of tamoxifen is associated with a two- to threefold increased risk of endometrial cancer in postmenopausal women. Toremifene is another triphenylethylene antiestrogen, which is as effective as tamoxifen in postmenopausal breast cancer. Thus far, its use has not been associated with an increased risk of endometrial cancer. K-ras codon 12 mutations seem to be important in endometrial carcinogenesis, and these mutations have been found in endometrial samples of patients on tamoxifen. The present study was undertaken to investigate if there is any difference in the frequency of endometrial K-ras mutations among patients treated with tamoxifen or toremifene.Methods Endometrial samples were taken from 23 postmenopausal breast cancer patients (tamoxifen, n=11; toremifene, n=12) before and after 36 months of treatment. DNA was isolated from formalin-fixed paraffin-embedded samples using a routine proteinase K digestion protocol. K-ras mutations in codon 12 were screened using real-time PCR and melting curve analysis in LightCycler equipment. Wild-type PNA oligomer was used to increase the sensitivity of the assay.Results All baseline samples contained wild-type K-ras, while 10/23 (43%) of the follow-up samples carried a codon 12 mutation. Mutations were identified in 3 of the 11 in the tamoxifen group and in 7 of the 12 in the toremifene group. Seven were transitions (GA), and three were transversions (two GT, one GC). One of the mutations in the toremifene group was associated with a polypoid endometrium. All the other mutations were found in an atrophic (n=6) or proliferative (n=3) endometrium.Conclusions Both tamoxifen and toremifene induce endometrial K-ras codon 12 mutations. The significance of this finding to endometrial carcinogenesis remains to be elucidated.     

Vitamin D and breast cancer

In addition to its role in calcium homeostasis and bone health, vitamin D has also been reported to have anticancer activities against many cancer types, including breast cancer. The discovery that breast epithelial cells possess the same enzymatic system as the kidney, allowing local manufacture of active vitamin D from circulating precursors, makes the effect of vitamin D in breast cancer biologically plausible. Preclinical and ecologic studies have suggested a role for vitamin D in breast cancer prevention. Inverse associations have also been shown between serum 25-hydroxyvitamin D level (25(OH)D) and breast cancer development, risk for breast cancer recurrence, and mortality in women with early-stage breast cancer. Clinical trials of vitamin D supplementation, however, have yielded inconsistent results. Regardless of whether or not vitamin D helps prevent breast cancer or its recurrence, vitamin D deficiency in the U.S. population is very common, and the adverse impact on bone health, a particular concern for breast cancer survivors, makes it important to understand vitamin D physiology and to recognize and treat vitamin D deficiency. In this review, we discuss vitamin D metabolism and its mechanism of action. We summarize the current evidence of the relationship between vitamin D and breast cancer, highlight ongoing research in this area, and discuss optimal dosing of vitamin D for breast cancer prevention.     

A Cancer Research (UK) randomized phase II study of idoxifene in patients with locally advanced/metastatic breast cancer resistant to tamoxifen

Idoxifene is a novel selective oestrogen receptor modulator (SERM) which had greater binding affinity for the oestrogen receptor (ER) and reduced agonist activity compared with tamoxifen in preclinical studies. In a randomized phase II trial in 56 postmenopausal patients with progressive locally advanced/metastatic breast cancer we assessed whether idoxifene showed evidence of activity compared with an increased 40 mg/day dose of tamoxifen in patients who had previously demonstrated resistance to the standard 20 mg/day dose of tamoxifen. Of 47 patients eligible for response (25 idoxifene, 22 tamoxifen), two partial responses and two disease stabilizations (SD) for >6 months were seen with idoxifene (overall clinical benefit rate 16%, 95% CI 4.5–36.1%). The median duration of clinical benefit was 9.8 months. In contrast, no objective responses were seen with the increased 40 mg/day dose of tamoxifen, although two patients had SD for 7 and 14 months (clinical benefit rate 9%, 95% CI 1.1–29.2%). Idoxifene was well tolerated and the reported possible drug-related toxicities were similar in frequency to those with tamoxifen (hot flushes 13% vs 15%, mild nausea 20% vs 15%). Endocrine and lipid analysis in both groups showed a similar significant fall in serum follicle-stimulating hormone and luteinizing hormone after 4 weeks, together with a significant rise in sex hormone binding globulin levels and 11% reduction in serum cholesterol levels. In conclusion, while idoxifene was associated with only modest evidence of clinical activity in patients with tamoxifen-resistant breast cancer, its toxicity profile and effects on endocrine/lipid parameters were similar to those of tamoxifen.This work is presented on behalf of the Cancer Research UK Phase I/II Committee.     

The role of vitamin D in breast cancer

The biological role of vitamin D outside of calcium homeostasis is still under evaluation. The ability of vitamin D to inhibit cell proliferation and induce differentiation makes it a potential modifier of neoplastic transformation. Vitamin D affects the cell cycle, apoptosis, hormone receptors, angiogenesis, and hypoxia, all of which are related to the breast cancer growth, progression and metastasis. A large percentage of the industrial-world population is deficient in vitamin D. Epidemiological evidence suggests that vitamin D deficiency increases the risk of breast cancer. Vitamin D may have synergistic, additive, or antagonistic effects when combined with other therapeutic agents against breast cancer. Vitamin D appears to depress aromatase inhibitor by acting through cytochrome P 450. This evidence along with pre-clinical and clinical studies, justify the inclusion of vitamin D in future clinical trials related to breast cancer in order to determine its efficacy as a part of the breast cancer therapeutic armament.     

可手术乳腺癌新辅助化疗364例临床分析

目的：探讨新辅助化疗对可手术乳腺癌的治疗作用、方案、周期数以及生物学指标与疗效的关系。方法：364例新辅助化疗的乳腺癌患者,治疗前肿瘤穿刺活检或术后标本均检测生物学指标ER、PR、C-erbB-2、Ki-67、p53。患者采用FAC、TE、NP方案化疗,每3～4周1次,共1～4个周期,化疗结束后10～14天手术。疗效按UICC实体瘤疗效评定标准进行评价,并统计患者5年生存率。结果：TE方案有效率及病理缓解率高于FAC方案及NP方案（P〈0．05）,其5年生存率也高于后两方案（P〈0．05）;新辅助化疗2周期以上的有效率高于2个周期（P〈0．05）,但平均生存时间无显著差异（P〉0．05）;C-erbB-2阴性、p53阳性、ER／PR阴性患者的有效率高（P〈0．05）;Ki-67表达结果不影响治疗的有效率（P〉0．05）;以上生物学指标表达的不同情况5年生存率之间无显著差异（P〉0．05）。结论：可手术乳腺癌术前应给予2个周期以上TE方案化疗;生物学指标中C-erbB-2阴性、p53阳性、ER／PR阴性的患者有效率高。     

Increased expression of miR-126 and miR-10a predict prolonged relapse-free time of primary oestrogen receptor-positive breast cancer following tamoxifen treatment

BackgroundAdjuvant tamoxifen is a valid treatment option for women with oestrogen receptor (ER)-positive breast cancer. However, up to 40% of patients experience distant or local recurrence or die. MicroRNAs have been suggested to be important prognosticators in breast cancer. This study aims to identify microRNAs with the potential to predict tamoxifen response.Patients and methodsWe performed a global microRNA screen (1105 human microRNAs) in primary tumours of six matched pairs of postmenopausal, ER-positive breast cancer patients treated with tamoxifen, who were either recurrence free or had developed a recurrence (median follow up: 8.84 years; range: 1.28–12.7 years). Patients of this discovery set and the 81 patients of the validation set (median follow up: 8.64 years; range: 0.21–19.85 years) were treated at the Robert Bosch Hospital, Stuttgart, Germany, between 1986 and 2005.ResultsOut of the top 20 deregulated microRNAs (12 up-regulated, eight down-regulated) miR-126 (Hazard Ratio (HR) = 0.56, 95% confidence interval (CI): 0.38–0.83; Holm-adj. P = 0.022) and miR-10a (HR = 0.53, 95% CI: 0.33–0.85; Holm-adj. P = 0.031) were identified as significant predictors of tamoxifen outcome by multivariate Cox regression analysis in the independent validation set of 81 postmenopausal, ER-positive patients. Kaplan–Meier survival analyses based on cut-offs determined by receiver operating characteristics curves confirmed that a higher expression of miR-126 and miR-10a in the patients tumour was associated with longer relapse-free time (log-rank P = 0.037, P < 0.0001, respectively).ConclusionsOur data suggest that miR-126 and miR-10a are independent predictors for tumour relapse in early postmenopausal breast cancer patients treated with adjuvant tamoxifen.