Exclusion of Patients With Brain Metastases in Published Phase III Clinical Trials for Advanced Breast Cancer

Metastatic HER2-positive (HER2+) and triple-negative breast cancer (TNBC) confer a 30% or higher risk of developing brain metastases (BrM), but BrM is typically an exclusion criteria for clinical trials, which limits the generalizability of trial results to these patients. We therefore analysed trends in the enrollment of patients with BrM, as well as the use of outcomes specific to the central nervous system (CNS), in phase III clinical trials evaluating systemic therapy for patients with advanced HER2+ and/or TNBC. Notably, 10 of the 34 trials (29%, 95% confidence interval = 15.1%-47.5%) evaluated CNS-specific outcomes and trials that completely excluded patients with BrM were significantly less likely to meet their primary endpoint (n = 6/17, 35%) than those that permitted conditional enrollment (n = 13/15, 87%) (P = .005), suggesting that enrollment of patients with BrM is not detrimental to trial success.     

Care of Seniors with Breast Cancer – Treatment Received and Refining Decision Making

AimsTreatment decisions for older patients with breast cancer are complex and evidence is largely extrapolated from younger populations. Frailty and comorbidity need to be considered. We studied the baseline characteristics and treatment decisions in older patients in Christchurch with breast cancer and assessed survival outcomes and prognostic/discriminatory performance of several tools.Materials and methodsWe searched the Canterbury Breast Cancer Registry and identified patients aged 70 years or older at diagnosis with invasive, non-metastatic breast cancer between 1 June 2009 and 30 June 2015. We retrieved demographics, treatment and outcome information. Overall survival and breast cancer-specific survival were estimated. Tools analysing performance status and comorbidity were assessed for their prognostic and discriminatory power.ResultsIn total, 440 patients were identified. Primary surgery was carried out for 362 patients (82.3%): breast-conserving surgery in 114 (of whom 88.6% received radiation therapy); mastectomy in 248 (of whom 24.6% received radiation). Hormone therapy was given for 265 (71.1%) patients with oestrogen receptor-positive cancers. Two hundred and seventy-four (62.3%) patients received full standard treatment, which was associated with significantly improved 5-year survival and 5-year breast cancer-specific survival. The median estimated overall survival was 8.2 years (95% confidence interval 7.3–9.1 years). Of those who died, 71.3% of deaths were due to causes other than breast cancer or unknown causes. The comorbidity-adjusted life expectancy (CALE) showed partial prognostic accuracy. CALE, Charlson and Eastern Cooperative Oncology Group tools all showed discriminatory value.ConclusionIn this population-based series of older patients with breast cancer, showing high levels of primary and adjuvant treatment, patients were more likely to die of causes other than breast cancer. Performance status and comorbidity tools showed prognostic and discriminatory potential in this population supporting their use in treatment decision making. CALE showed the most potential to improve treatment decisions but requires validation in this population to improve prognostic accuracy.     

基于生物信息学筛选早发性乳腺癌差异表达基因

目的筛选并分析与早发性乳腺癌发生、发展相关的靶基因。 方法(1)在美国国立生物技术信息中心的公共基因芯片数据库(GEO)中检索早发性乳腺癌样本及非早发性乳腺癌样本相关基因芯片数据。对上述数据使用GEO2R、R4.1.2及Venn软件筛选出相关差异表达基因(DEGs)，并运用在线分析工具(Web Gestalt)对DEGs，进行相关功能和信号通路富集分析。(2)同时，通过String在线数据库构建DEGs编码的蛋白质-蛋白质相互作用(PPI)网络，并利用Cytohubba插件对该网络中的基因进行评分，筛选出枢纽基因。将枢纽基因导入Kaplan-Meier生存分析工具(Kaplan-Meier Plotter)，评估枢纽基因在早发性乳腺癌的预后价值。(3)将肿瘤基因组图谱(TCGA)数据库中的肿瘤组织以年龄为标准进行分组，分析枢纽基因在各年龄组中的表达，并与正常组织中的表达进行比较，对得到的枢纽基因进行验证。DEGs表达量的多组间比较使用Kruskal-Wallis H检验，使用Bonferroni法进行两两比较。 结果(1)筛选出编号为GSE89116、GSE109169、GSE36295的基因芯片数据集，共得到80个差异表达基因，其中上调差异表达基因17个，下调差异表达基因63个。富集分析显示：DEGs主要富集在脂质代谢和氧化还原过程以及PPAR信号通路、AMPK信号通路上。(2)在PPI中发现主要的关键基因为PPARG、ADIPOQ、LIPE、PCK1、PDK4、ACACB、PLIN1、CAV1、CD36、ANGPTL4。ACACB、ADIPOQ、CAV1、LIPE、PLIN1、PPARG基因的低表达与乳腺癌患者的不良OS相关(HR＝0.69、0.84、0.76、0.88、0.78、0.82；95%CI：0.59~0.80、0.76~0.93、0.67~0.83、0.79~0.97、0.70~0.86、0.73~0.90；P均<0.050)。(3)ACACB、ADIPOQ、LIPE、PLIN1、CAV1及PPARG这6个与预后相关的基因在正常组织中的表达量均远高于各年龄组肿瘤组织中的表达量(χ²＝104.03、179.57、161.85、189.87、118.56、103.62，P均<0.001)，早发性乳腺癌组(21~40岁)的LIPE、PLIN1表达量低于41~60岁、61~80岁年龄组，差异具有统计学意义(LIPE: Z＝21.07、23.12, P均<0.050; PLIN1：Z＝16.89、18.76, P均<0.050)。 结论早发性乳腺癌与非早发性乳腺癌存在差异基因表达谱，LIPE、PLIN1可能是早发性乳腺癌发生、发展的关键基因。     

Assessment of the uterine dose in digital mammography and digital breast tomosynthesis

IntroductionDigital Mammography (DM-2D) and more recently Digital Breast Tomosynthesis (DBT), are two of the most effective imaging modalities for breast cancer detection, often used in screening programmes. It may happen that exams using these two imaging modalities are inadvertently performed to pregnant women. The objective of this study is to assess the dose in the uterus due to DM-2D and DBT exams, according to two main irradiation scenarios: in the 1st scenario the exposure parameters were pre-selected directly by the imaging system, while in the 2nd scenario, the maximum exposure parameters were chosen.MethodsThe mammography equipment used was a Siemens Mammomat Inspiration. A physical anthropomorphic phantom, PMMA plates (simulating a breast thickness of 6 cm) and thermoluminescent dosimeters (TLDs) were used to measure entrance air kerma values on the phantom's breast and abdomen in order to successively estimate the mean glandular dose (MGD) and the dose in the uterus. For the two irradiation scenarios chosen, two-breast imaging modalities were selected: 1) DBT in Cranio-Caudal (CC) view (with 28 kV and 160 mAs as exposure parameters), 2) DBT and DM in Medio Lateral-Oblique (MLO) and CC views (with 34 kV and 250 mAs as exposure parameters).ResultsIn the 1st scenario, the TLD measurements did not detect significant dose values in the abdomen whereas the MGD estimated using the D.R. Dance model was in close agreement with data available in the literature. In the 2nd scenario, there was no significant difference in MGD estimation between the different views, whereas the air kerma values in the abdomen (in DBT mode, CC and MLO) were 0.049 mGy and 0.004 mGy respectively. In CC DM-2D mode the abdomen air kerma value was 0.026 mGy, with no significant detected value in MLO view.ConclusionsFor the dose in the uterus, the obtained values seem to indicate that DM-2D and DBT examinations inadvertently performed during pregnancy do not pose a significant radiological risk, even considering the case of overexposure in both breasts.Implications for practiceThe accurate knowledge of the doses in DM-2D and DBT will contribute to raise the awareness among medical practitioners involved in breast imaging empowering them to provide accurate information about dose levels in the uterus, improving their radiation risk communication skills and consequently helping to reduce the anxiety of pregnant women undergoing this type of examinations.     

T1~T2期乳腺癌保乳术后化疗后程同步大分割放疗前瞻性Ⅰ期临床研究

目的 前瞻性评估T1~T2期乳腺癌保乳术后化疗后程大分割放疗的不良反应和耐受性，以及在缩短治疗时间、减轻患者经济负担等方面的价值。方法 共入组20例T1~T2期乳腺癌保乳术后患者，所有患者于末次多西他赛化疗前开始大分割放疗。观察急性放射反应、治疗完成率及无病生存率、住院时间及住院费用等。结果 治疗完成率100%。主要不良反应为血液学毒性（白细胞减少）及皮肤反应，患者均可耐受。中位随访时间为30.1个月，随访率100%。美容效果良好率100%。平均总治疗时间为4周，总住院治疗费用节省约1万元。21个月无病生存率为100%。结论 T1~T2期乳腺癌保乳术后可耐受同步大分割放化疗，局部控制好，美容效果佳，且具有较高的卫生经济学价值。     

Cellular immunotherapy in breast cancer: The quest for consistent biomarkers

Breast cancer is the most common malignancy in women worldwide, with a relatively high proportion of patients experiencing resistance to standard treatments. Cellular immunotherapy (CI), which is based on the extraction, modification, and re-infusion of the patient’s immune cells, is showing promising results in these patients. Among CI possible approaches, adoptive cell therapy (ACT) and dendritic cell (DC) vaccination are the most comprehensively explored in both primary/translational research studies and clinical trials. ACT may include the use of tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR)-, or chimeric antigen receptor (CAR)-engineered T-cells. There are indications suggesting that a biomarker-based approach might be beneficial in effectively selecting breast cancer patients for CI. Here, we sought to provide the current knowledge of CI in breast cancer, focusing on candidate biomarkers, ongoing clinical trials, limitations, and immediate future perspectives.     

Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders

In this review we summarize the impact of the various modalities of breast cancer therapy coupled with intrinsic patient factors on incidence of subsequent treatment-induced myelodysplasia and acute myelogenous leukemia (t-MDS/AML). It is clear that risk is increased for patients treated with radiation and chemotherapy at younger ages. Radiation is associated with modest risk, whereas chemotherapy, particularly the combination of an alkylating agent and an anthracycline, carries higher risk and radiation and chemotherapy combined increase the risk markedly. Recently, treatment with granulocyte colony-stimulating factor (G-CSF), but not pegylated G-CSF, has been identified as a factor associated with increased t-MDS/AML risk. Two newly identified associations may link homologous DNA repair gene deficiency and poly (ADP-ribose) polymerase inhibitor treatment to increased t-MDS/AML risk. When predisposing factors, such as young age, are combined with an increasing number of potentially leukemogenic treatments that may not confer large risk singly, the risk of t-MDS/AML appears to increase. Patient and treatment factors combine to form a biological cascade that can trigger a myelodysplastic event. Patients with breast cancer are often exposed to many of these risk factors in the course of their treatment, and triple-negative patients, who are often younger and/or BRCA positive, are often exposed to all of them. It is important going forward to identify effective therapies without these adverse associated effects and choose existing therapies that minimize the risk of t-MDS/AML without sacrificing therapeutic gain.

Implications for Practice

Breast cancer is far more curable than in the past but requires multimodality treatment. Great care must be taken to use the least leukemogenic treatment programs that do not sacrifice efficacy. Elimination of radiation and anthracycline/alkylating agent regimens will be helpful where possible, particularly in younger patients and possibly those with homologous repair deficiency (HRD). Use of colony-stimulating factors should be limited to those who truly require them for safe chemotherapy administration. Further study of a possible leukemogenic association with HRD and the various forms of colony-stimulating factors is badly needed.

     

Evidence from a BreastScreen cohort does not support a longer inter-screen interval in women who have no conventional risk factors for breast cancer

ObjectivesTo determine screening outcomes in women who have no recorded risk factors for breast cancer.MethodsA retrospective population-based cohort study included all 1,026,137 mammography screening episodes in 323,082 women attending the BreastScreen Western Australia (part of national biennial screening) program between July 2007 and June 2017. Cancer detection rates (CDR) and interval cancer rates (ICR) were calculated in screening episodes with no recorded risk factors for breast cancer versus at least one risk factor stratified by age. CDR was further stratified by timeliness of screening (<27 versus ≥27 months); ICR was stratified by breast density.ResultsAmongst 566,948 screens (55.3%) that had no recorded risk factors, 2347 (40.9%) screen-detected cancers were observed. In screens with no risk factors, CDR was 50 (95%CI 48–52) per 10,000 screens and ICR was 7.9 (95%CI 7.4–8.4) per 10,000 women-years, estimates that were lower than screens with at least one risk factor (CDR 83 (95%CI 80–86) per 10,000 screens, ICR 12.2 (95%CI 11.5–13.0) per 10,000 women-years). Compared to timely screens with risk factors, delayed screens with no risk factors had similar CDR across all age groups and a higher proportion of node positive cancers (26.1% vs 20.7%). ICR was lowest in screens that had no risk factors nor dense breasts in all age groups.ConclusionsMajority of screens had no recorded breast cancer risk factors, hence a substantial proportion of screen-detected cancers occur in these screening episodes. Our findings may not justify less frequent screening in women with no risk factors.