Factors Determining Anthracycline Use in Hormone Receptor Positive,Early-Stage Breast Cancer

BackgroundAnthracyclines are associated with significant toxicities whereas nonanthracyclines have proven to be better tolerated. A 21-gene assay allows clinicians to predict who will not benefit from adjuvant chemotherapy and avoid systemic toxicities. Physicians are using the recurrence score to guide chemotherapy selection, despite the lack of evidence. In this study we examined factors associated with prescribing patterns for an anthracycline-based chemotherapy in hormone receptor-positive stage I to III breast cancer.Materials and MethodsThis was a retrospective study using the Michigan Breast Oncology Quality Initiative data set (February 1, 2006 to December 31, 2015). Women with histologically confirmed stage I to III invasive breast cancer with estrogen receptor and/or progesterone receptor-positive, HER2/neu-negative receptor status were included. We used χ² analysis to determine associations of these characteristics with the 21-gene assay score and anthracycline use.ResultsA total of 17,788 patients were evaluated. Most tumors were stage I (60%). Most procedures were lumpectomy with radiation (66%). Anthracyclines were used more often in stage III patients (69%), younger patients (40% for patients younger than 65 years), and those with higher 21-gene recurrence scores. Patients with low recurrence scores were more likely to receive anthracyclines if lymph node-positive (10%) than if lymph node-negative (1%; P < .001). Patients with high recurrence scores and lymph node-positive status were just as likely to receive an anthracycline-based as a nonanthracycline-based regimen (47.5% vs. 49.2%; P = .89).ConclusionThese data indicate that medical oncologists might be anticipating the results of Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer study (TAILORx) and the Clinical Outcomes in ER+HER2-node-positive Breast Cancer Patients Who Were Treated According to the Recurrence Score Results: Evidence From a Large Prospectively Designed Registry (RxPonder) trials and are avoiding the potential serious complications associated with anthracycline treatment in patients least likely to receive benefit.     

激素受体阳性晚期乳腺癌内分泌治疗选择

激素受体阳性乳腺癌占所有乳腺癌的70%。内分泌治疗是这个亚型乳腺癌的主要治疗手段,最常见药物有他莫昔芬和芳香酶抑制剂如阿拉曲唑、来曲唑和依西美坦。全文重点总结新型内分泌治疗药物,如雌激素受体降解剂(Fulvestrant),以及新的靶向药物如mTOR抑制剂(Everolimus)、CDK4/6抑制剂(Palbociclib、Ribociclib和Abemaciclib)和PI3K抑制剂(Alpelisib、Buparlisib和Pictilisib)等。新的靶向药物联合内分泌治疗已经改变了临床实践,延长激素受体阳性晚期乳腺癌患者的生存期。     

Positive Expression of Insulin-Like Growth Factor-1 Receptor Is Associated with a Positive Hormone Receptor Status and a Favorable Prognosis in Breast Cancer

Purpose

Insulin-like growth factor 1 receptor (IGF-1R) is commonly expressed in primary breast cancers. Understanding the role of IGF-1R signaling in the different subtypes of breast cancer is important because each subtype has a different outcome and requires different treatment modalities. However, the precise biological significance of IGF-1R expression in cancer cells is still unclear. In this study, we examined the expression of IGF-1R in the different molecular subtypes of breast cancer. The effects of IGF-1R expression on the survival rates and outcomes of breast cancer were also examined.

Methods

IGF-1R expression was evaluated immunohistochemically in tissue microarray blocks constructed from 1,198 invasive breast cancer samples collected from six medical institutions. IGF-1R expression was interpreted according to the human epidermal growth factor receptor 2 (HER2)/neu immunohistochemistry scoring system. Scores of 2+ and 3+ were considered positive.

Results

Positive IGF-1R expression was observed in 65.4% of invasive breast cancer samples. IGF-1R expression was detected in all cancer subtypes (luminal A, 84.4%; luminal B, 75.9%; HER2, 21.2%; triple-negative, 46.6%) and was found to be associated with a positive hormone receptor status and the absence of HER2 amplification (p<0.001). Positive IGF-1R expression was significantly associated with high survival rates (p=0.014). However, a multivariate analysis revealed that the expression levels of IGF-1R did not achieve statistical significance. In the triple-negative cancer subtype, IGF-1R expression was found to be associated with a lower disease-free survival rate (p=0.031).

Conclusion

Positive IGF-1R expression is associated with a favorable prognosis in breast cancer. IGF-1R is frequently expressed in the luminal A/B subtypes of breast cancer, and its expression is related to the hormone receptor status.     

三阴乳腺癌与激素受体阴性、HER-2阳性乳腺癌的临床病理特征及预后对比分析

目的:在未接受针对HER-2靶点的分子靶向治疗的情况下,对比分析三阴乳腺癌与激素受体阴性、HER-2阳性乳腺癌的I临床病理特征和影响预后的因素.方法:收集2000年1月至2004年12月江西省肿瘤医院收治的222例激素受体阴性的乳腺癌,根据免疫组化法检测的HER-2状态,将其分为3组:三阴组(IHC0～+)、三阴待定组(IHC++)、HER-2阳性组(IHC+++).回顾性的分析3组患者的临床病理特征和生存情况.结果:统计显示,3组患者的临床病理特征无显著差异.5年DSF三阴组76.3%、三阴待定组74.7%、HER.2阳性组58.2%(P=0.019);5年0S分别为77.6%、75.9%和59.7%(P=0.011).结论:三阴乳腺癌与激素受体阴性、HER-2阳性乳腺癌的临床病理特征无显著差异.在未使用针对HER-2靶点的分子靶向治疗的情况下,激素受体阴性、HER-2阳性乳腺癌比三阴乳腺癌预后更差.     

Cancer Care Ontario Guideline Recommendations for Hormone Receptor Testing in Breast Cancer

Hormone receptor testing (oestrogen and progesterone) in breast cancer at the time of primary diagnosis is used to guide treatment decisions. Accurate and standardised testing methods are critical to ensure the proper classification of the patient's hormone receptor status. Recommendations were developed to improve the quality and accuracy of hormone receptor testing based on a systematic review conducted jointly by the American Society of Clinical Oncology/College of American Pathologists and Cancer Care Ontario's Program in Evidence-Based Care. Evidence-based recommendations were formulated to set standards for optimising immunohistochemistry in assessing hormone receptor status, as well as assuring quality and proficiency between and within laboratories. A formal external review was conducted to validate the relevance of these recommendations. It is anticipated that widespread adoption of these guidelines will further improve the accuracy of hormone receptor testing in Canada.     

Ixabepilone and Carboplatin for Hormone Receptor Positive/HER2-neu Negative and Triple Negative Metastatic Breast Cancer

Background

Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2^? metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial.

Clinical Characteristics and Outcomes of Single Versus Double Hormone Receptor–Positive Breast Cancer in 2 Large Databases

PurposeTo identify biologic and outcome differences between double hormone receptor (HR)-positive (dHR⁺, estrogen receptor (ER)⁺/progesterone receptor [PgR⁺]) and single HR-positive (sHR⁺, either ER⁺/PgR⁻ or ER⁻/PgR⁺) breast cancer; and to explore whether hormone therapy (HT) response in HER2-negative breast cancer correlates with HR status.Patients and MethodsThis retrospective study was conducted by using 2 large breast cancer databases: the Surveillance, Epidemiology, and End Results (SEER) database and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) clinical data set. Cox regression analysis was used to estimate overall survival (OS) and breast cancer–specific survival (BCSS) among sHR⁺ and dHR⁺ patients.ResultsIn the SEER database, dHR⁺ patients had significantly longer OS and BCSS than ER⁺/PgR⁻ patients in short-term follow-up (OS: hazard ratio = 0.620; 95% confidence interval [CI], 0.590, 0.652; P < .001; BCSS: hazard ratio = 0.493; 95% CI, 0.462, 0.526; P < .001). Meanwhile, ER⁻/PgR⁺ patients had younger age, larger tumor size, and higher disease grade than dHR⁺ and ER⁺/PgR⁻ patients. In patients who received HT, dHR⁺ patients had a more favorable OS than ER⁺/PgR⁻ patients (hazard ratio = 0.789; 95% CI, 0.635, 0.982; P = .034), and ER⁻/PgR⁺ patients had a worse OS than ER⁺/PgR⁻ patients at 10 years’ follow-up (hazard ratio = 7.991; 95% CI, 1.053, 60.644; P = .044). However, these groups had similar outcomes over longer periods.ConclusionIn HER2-negative breast cancer, sHR⁺ patients are associated with relatively worse characteristics and worse short-term outcomes than dHR⁺ patients. Additionally, the outcome of patients receiving HT may differ according to the HR status. However, further studies are needed to confirm these conclusions.     

HER2 Activating Mutations in Estrogen Receptor Positive Breast Cancer

Purpose of Review

HER2 activating mutations are a new, druggable mutation identified by next-generation DNA sequencing (NGS) of breast cancer. Here, we review the recent data on the diagnosis and treatment of HER2 mutated, metastatic breast cancer.

Recent Findings

Pre-clinical studies have shown that HER2 activating mutations accelerate tumor growth and can be inhibited by HER2 targeted drugs, including trastuzumab and the second-generation, pan-HER tyrosine kinase inhibitor, neratinib. HER2 mutations can be diagnosed by NGS testing on either a tumor biopsy or circulating tumor DNA obtained from peripheral blood. Case reports provided initial evidence that HER2 targeted therapies can effectively treat patients with HER2 mutated, metastatic breast cancer. Two phase II clinical trials, MutHER and SUMMIT, both demonstrate that neratinib monotherapy has clinical efficacy for these patients, with clinical benefit rate of 31–40%.

Summary

HER2 targeted therapies are effective for HER2 mutated breast cancer but emergence of drug resistance remains a problem. Clinical trials are now testing neratinib-containing drug combination regimens for HER2 mutated, metastatic breast cancer patients.

     

MicroRNA在雌激素受体阳性乳腺癌中的研究进展

MicroRNA(miRNA)能调节细胞生长、增殖、分化和凋亡等活动,与各种恶性肿瘤的发生发展息息相关,乳腺癌亦不例外.在乳腺癌中,雌激素受体(ER)阳性者占有相当大的比例,约75％,因此雌二醇(E2)、ER与miRNA的相互联系以及相互调节机制需予以重视,进而有助于探索miRNA对ER阳性乳腺癌的临床应用价值.全文就近年来的相关研究成果加以概述和总结,旨在为转化医学提供信息,将相关研究成果应用于临床.     

血浆性激素水平和绝经前女性患乳腺癌危险性的关系

目的评价血浆类固醇性激素水平与绝经前女性患乳腺癌危险性的关系。方法采用放射免疫法测定75例绝经前女性乳腺癌病例和78例匹配对照的血浆雌二醇(E₂)、孕酮(P)及睾酮(T)水平,并应用条件Logistic回归分析绝经前女性血浆E2、P、T水平与患乳腺癌危险性的关系。结果(1)病例组血浆E2和T水平均显著高于对照组;病例组血浆P水平低于对照组,但差异无统计学意义。（2）以下四分位数（P₂₅）为非暴露参考,血浆P上四分位数（P₇₅）水平调整OR（95%CI）为0.43（0.20~0.85）,趋势P=0.023;血浆T上四分位数（P₇₅）水平调整OR为3.63（1.82~7.45）,趋势P=0.015;血浆E₂上四分位数（P₇₅）水平调整OR为2.48（1.27~5.14）,但差异无统计学意义,趋势P=0.270。结论血浆T水平与绝经前女性患乳腺癌的危险性呈正相关,血浆P水平与绝经前女性患乳腺癌的危险性呈负相关。     

Hormone Receptor Expression and Clinicopathologic Features in Male and Female Breast Cancer

Background: Male and female breast cancers were investigated for variation in the clinicopathologiccharacteristics and expression of steroid hormone receptors in the northeast of Iran. Materials and Methods:Tumor specimens of 17 males and 338 females with breast cancer were collected at the hospitals of MashhadUniversity of Medical Sciences. Immunohistochemical expression of hormone receptors and clinicopathologicfeatures of breast cancer were compared between two groups. Results: The mean age in men was 15 years higherthan women (p=0.000). Males and females were mainly in stage II and III respectively (p=0.007). Although morethan 60% of male and female patients were grade II, the respective figures for grade I and III were 25% and12.5% in men but 7.1% and 27.2% in women respectively (p=0.025). ER was significantly more positive in menagainst women; 82.3% versus 53.4% (p=0.016). The related measures for PR was 58.8% and 50.3%, respectively(p=0.424). Males also showed significantly more ER expression than postmenopausal females; 82.3% versus48.9% (p=0.010). Conclusions: Breast cancer in males and females contrasted in age at diagnosis, histologicaltype, stage, grade and ER expression which emphasize they are separate diseases with different behaviors.     

Adverse Event Management of mTOR Inhibitors During Treatment of Hormone Receptor–Positive Advanced Breast Cancer: Considerations for Oncologists

Breast cancer (BC) is diagnosed in nearly 1 in 3 women with cancer in the United States; one third of these patients have regional lymph node metastases at the time of diagnosis. The 5-year survival rate of patients with metastatic BC is very low, and approximately 40,000 women were expected to die of the disease in 2013. About 75% of patients with BC have hormone receptor–positive (HR⁺) disease, which is often managed with endocrine therapy; however, most patients eventually have resistance to these therapies. Recently, the mammalian target of rapamycin (mTOR) inhibitor everolimus, in combination with exemestane, improved progression-free survival (PFS) of patients with advanced BC, leading to its approval by the US Food and Drug Administration. Because adverse events (AEs) associated with everolimus might differ from AEs that oncologists who treat patients with BC are more familiar with, everolimus AEs and their effective management are reviewed in this article. Possible dose adjustments of everolimus for patients with renal or hepatic impairment and strategies for minimizing potential interactions of everolimus with other drugs and food are also discussed.     

类固醇受体辅助活化因子SRC-1和SRC-3在乳腺癌组织中表达研究

[目的]探讨类固醇受体辅助活化因子SRC-1和SRC-3在乳腺癌与癌旁组织中的表达及意义。[方法]应用免疫组化SP法,检测43例乳腺浸润性癌、23例癌旁原位癌成分、9例癌旁导管上皮不典型增生及10例正常乳腺组织中SRC-1和SRC-3蛋白的表达情况。[结果]乳腺癌组织中SRC-1和SRC-3蛋白阳性表达率均高于原位癌、不典型增生和正常乳腺组织,差异有统计学意义（χ^2=10.981、10.065,P〈0.05）;且在不同组织间SRC-1和SRC-3蛋白表达强度不同,差异有统计学意义（H=5.731、5.646,PO.05）,但雌激素受体（ER）阳性组SRC-1和SRC-3蛋白阳性表达高于ER阴性组,差异有统计学意义（χ^2=5.217,P〈0.05;χ^2=12.675,P〈0.01）,且在乳腺癌组织中SRC-1和SRC-3表达与ER表达呈正相关（r=0.322,P〈0.05;r=0.455,P〈0.01）。[结论]SRC-1和SRC-3在乳腺癌的发生发展中可能起一定的作用。     

可手术乳腺癌内分泌受体状态对预测近期复发的意义

目的为了调查可手术乳腺癌病人术后近期复发与内分泌受体状态的相关性。材料和方法对1985-1988年间76例Ⅰ、Ⅱ期乳腺癌改良根治手术病人进行专人调查，注重询问术后36个月内的近期复发病人，探讨复发和未复发病例的雌激素受体（ER）和孕酮受体（PR）的状态。结果确认16例术后36个月内出现复发，近期复发率为21％（16／76）。16例复发的ER、PR同时呈（＋）和（-）的比率分别为29％和57％；而60例未复发的ER、PR同时呈（＋）和（-）的比率分别为50％和40％；两组之间具有显著差异（P＜0.01）。在复发组中单独PR呈（＋）和（-）的比率分别为36％和64％；而未复发组单独PR呈（＋）和（-）的比率分别为51．9％和48．1％，两组之间也具有显著差异（P＜0．05）。结论表明可手术乳腺癌内分泌状态ER、PR同时呈（-）病人较其同时呈（ ）者抑或单独PR呈（-）者具有近期易复发倾向，其预后更劣。因而作者认为PR状态是另一个主要的预后因素。提议：应把PR（-）肿瘤病人列入高危人群，并作为术后3年内定期复诊主要对象之一。     

表皮生长因子受体表达与乳腺癌激素受体水平和预后的关系

应用免疫组化ＡＢＣ方法研究７５例乳腺癌冰冻组织表皮生长因子受体（ＥＧＦＲ）的表达，结合临床资料和ＥＲ、ＰＲ测定结果进行分析，探讨ＥＧＦＲ表达与乳腺癌预后的关系。结果表明，ＥＧＦＲ阳性３０例（４０％），ＥＧＦＲ表达与肿瘤大小、腋淋巴结状况，临床分期和年龄无关，与ＥＲ、ＰＲ存在着显著的负相关（Ｐ＜０．００５）。全组中位随诊时间为６０个月，ＥＧＦＲ阳性组术后总生存率明显低于阴性组（Ｐ＜０．００１）。在无腋淋巴结转移的病例中，ＥＧＦＲ阳性组和阴性组术后生存情况也有显著差异（Ｐ＜０．０１），提示ＥＧＦＲ表达与乳腺癌不良的预后有关。调整分析乳腺癌有关的预后因素，各组病例中均以ＥＧＦＲ表达阳性组的预后为差，说明ＥＧＦＲ对乳腺癌预后具有独立的作用，不受其他因素的影响。经Ｃｏｘ模型多因素分析显示，ＥＧＦＲ和腋淋巴结受累与否是对乳腺癌术后生存情况有显著性影响的两个因素。     

Real-World Outcomes of Ribociclib and Aromatase Inhibitor Use in First Line Hormone Receptor Positive,HER2-Negative Metastatic Breast Cancer

BackgroundInternational guidelines recommend combining a CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Results from MONALEESA-2 demonstrate superior progression free survival (PFS) and overall survival (OS) with ribociclib (CDK4/6 inhibitor) and ET compared to ET alone. Real world outcomes have yet to be reported.Materials and MethodsKARMA is a non-interventional registry of Australian patients receiving first-line treatment with ribociclib and aromatase inhibitor (AI), obtained via a Medicine Access Program (MAP) for HR+, HER2- MBC. Outcomes were compared with the ribociclib/letrozole cohort in MONALEESA-2.ResultsData from 160 patients at 17 sites was analysed. Median follow-up is 36.5 months. Compared to MONALEESA-2, patients were numerically younger (54.3 vs. 62 years), with higher rates of bone-only metastases (31% vs. 21%). A total of 63 of 160 (39%) patients remain on treatment. A total of 56% of patients had at least 1 dose reduction, with neutropenia (68%) and abnormal liver enzymes (17%) the most common reasons. A total of 17 of 160 (11%) discontinued treatment due to toxicity, with no treatment related deaths. Median PFS was not reached (95% CI 29.9- NR), with PFS at 12 months and 18 months being 76% and 67% respectively versus 25.3 months, 73% and 63% in MONALEESA-2.ConclusionThe ribociclib and AI combination was well tolerated in this real-world setting. The KARMA registry cohort achieved a superior PFS (>36.5 months) to MONALEESA-2, potentially due to more favourable baseline disease characteristics. Less frequent assessment scheduling in this non trial setting may also contribute.