Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER ...degrader that demonstrated activity in early studies.
This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable
mutations.
Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238).
mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88;
= .002) and patients with
mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77;
= .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively).
Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with
mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs ...into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1-8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%-41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%-75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%-48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.
Recent studies have identified a small population of highly tumorigenic cells with stem cell properties in human breast and other solid tumors that are considered to be the source of tumor initiation ...and maintenance; these cells are referred to as cancer stem cells (CSCs). Preclinical data suggest that current breast cancer treatment strategies lead to CSC enrichment, contributing to chemotherapy and radiotherapy resistance, although a strong correlation with clinical parameters and prognosis is yet to be established. Importantly, overcoming treatment failure by effective targeting of CSCs may be an appealing approach, potentially leading to improved clinical outcomes for patients with breast cancer. Several preclinical studies provide promising results that support this hypothesis. The purpose of this review is to summarize the role of CSCs in breast cancer recurrence and resistance and to discuss current attempts of CSC targeting.
摘要
最近在人类乳腺和其他实体瘤的研究中发现了一小群具有干细胞特性的高度致瘤细胞，并认为这些细胞是肿瘤发生和发展的起源；这些细胞被称作癌症干细胞（CSC）。临床前数据提示目前的乳腺癌治疗策略导致了CSC的不断出现，促使了化疗和放疗耐药的发生，尽管CSC与临床参数和预后之间具有较强的相关性尚有待明确。重要的是，通过有效靶向CSC来克服治疗失败可能是一种具有吸引力的方法，有可能改善乳腺癌患者的临床结局。几项临床前研究提供的颇具前景的研究结果支持这一假说。该综述的目的是小结CSC在乳腺癌复发和耐药中的作用并讨论目前CSC靶向治疗的尝试。
This review summarizes the role of cancer stem cells in breast cancer recurrence and resistance, as well as current efforts toward potential cancer stem cell‐directed therapies.
Hormonal therapy for advanced breast cancer (ABC) has evolved significantly since the introduction of tamoxifen more than 40 years ago. The availability of selective antiestrogen therapies has ...further improved treatment options for women with hormone receptor‐positive (HR+) ABC. However, with the development of resistance to hormonal therapies, a new treatment paradigm has emerged based on our understanding of biological pathways involved in HR+ breast cancer and mechanisms of resistance to hormonal therapy. Recent drug development efforts have focused on combining hormonal treatment with agents that target mammalian target of rapamycin serine‐threonine kinases and cyclin‐dependent kinases. In parallel with the evolution of hormonal and targeted therapies, our understanding of the utility of clinical endpoints has deepened. Progression‐free survival (PFS) is a primary endpoint well‐understood by clinicians and is increasingly accepted as a surrogate for overall survival (OS) by the U.S. Food and Drug Administration. Yet the perceived clinical benefit of PFS to patients is less well understood. Patients may not grasp the implications of prolonged PFS, highlighting the reality that patient preference in treatment selection encompasses factors that extend beyond drug activity. This presents an opportunity for clinicians to discuss PFS with patients in the context of their treatment plans, clinical outcomes, and quality‐of‐life measures. The objective of this review is to explore the clinical validity of the PFS and OS endpoints and the clinical relevance of PFS and OS to patients, especially in light of drivers that led to a range of treatment options for patients with HR+ ABC.
Implications for Practice:
Advances in drug development during the past two decades have provided numerous options for treatment of advanced breast cancer that include monotherapy with endocrine modulating agents and dual therapy that combines endocrine therapy with an inhibitor targeting the mammalian target of rapamycin serine‐threonine kinase or cyclin‐dependent kinase pathways known to be involved with resistance. Clinical trial endpoints for breast cancer have evolved as well. Communication of progression‐free survival, overall survival, and other outcomes with patients should incorporate the context of the individual's treatment plan and include discussion of response rate, side effects, and quality of life.
This review explores drivers that led to advances in treatment options, the validity of progression‐free survival (PFS) and overall survival (OS) endpoints in clinical studies, and the clinical relevance of PFS and OS to patients with hormone receptor‐positive advanced breast cancer.
We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were ...more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.
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•We build the genomic and transcriptomic landscape of 465 primary TNBCs•Chinese TNBC cases demonstrate more PIK3CA mutations and LAR subtype•Transcriptomic data classify TNBCs into four subtypes•Multi-omics profiling identifies potential targets within specific TNBC subtypes
Jiang et al. characterize primary Chinese triple-negative breast cancer (TNBC) and classify it into four subtypes. They find that these TNBCs have more frequent PIK3CA mutations and chromosome 22q11 copy-number gains than non-Asian TNBCs and that the LAR subtype has more ERBB2 somatic mutations and CDKN2A loss.
Opinion statement
Since the 2013 Supreme Court declaration, panel testing for hereditary cancer syndromes has evolved into the gold standard for oncology germline genetic testing. With the advent of ...next-generation sequencing, competitive pricing, and developing therapeutic options, panel testing is now well integrated into breast cancer management and surveillance. Although many established syndromes have well-defined cancer risks and management strategies, several breast cancer genes are currently classified as limited-evidence genes by the National Comprehensive Cancer Network (NCCN). Follow-up for individuals with mutations in these genes is a point of contention due to conflicting information in the literature. The most recent NCCN guidelines have stratified management based on gene-specific cancer risks indicating that expanding data will allow for better recommendations as research progresses. The evolving management for these genes emphasizes the clinicians’ need for evidence-based understanding of low penetrance breast cancer genes and their implications for patient care. This article reviews current literature for limited evidence genes, detailing cancer risks, association with triple-negative breast cancer, and recommendations for surveillance. A brief review of the challenges and future directions is outlined to discuss the evolving nature of cancer genetics and the exciting opportunities that can impact management.
Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among ...diabetes, metformin use, and breast cancer in postmenopausal women participating in Women's Health Initiative clinical trials.
In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes.
Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio HR, 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2.
Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.
Metastatic breast cancer (MBC) results in substantial morbidity and mortality for women afflicted with this disease. A majority of MBCs are hormone‐responsive and estrogen receptor‐positive, making ...endocrine therapy (ET) an integral component of systemic therapy. With a primary goal of minimizing the effects of estrogen on hormone‐responsive MBC, ETs are among the first targeted treatments that aim to inhibit the influence of estrogen receptor activation on tumor proliferation. Several biochemical mechanisms have been the focus of drug development for treatment, including selective estrogen‐receptor modulation, aromatase inhibition, and selective estrogen‐receptor degradation. Treatments that exploit these mechanisms have improved survival and quality of life for women with MBC. However, in many cases, resistance to ET limits their effectiveness. Elucidation of the complex cellular signal cascades involved in the development of acquired resistance to ET and the interrelationship of growth factor signaling and estrogen responsiveness have characterized components of these pathways as attractive targets for drug development. Based on these insights and with the aim of overcoming hormone resistance, targeted therapies are emerging as useful treatments for MBC. This article reviews current endocrine treatments of MBC as well as recent and ongoing study of combination treatments and targeted therapies that interfere with cellular proliferation pathways as means of overcoming resistance.
Implications for Practice
This review provides medical oncologists and other oncology health care providers with a current understanding of the rationale for endocrine therapy in estrogen receptor‐positive metastatic breast cancer and the efficacy and safety profile of available treatment options. Additionally, current concepts regarding the development of treatment resistance and the treatment strategies for overcoming resistance are discussed. Enhancing the current information and the understanding of these topics will assist clinicians in evaluating optimal treatment options for their patients.
摘要
转移性乳腺癌（MBC）在女性人群中的发病率较高, 大量患者因此死亡。MBC以激素反应性和雌激素受体阳性类型居多, 这就使得内分泌治疗（ET）成为全身治疗中不可或缺的一部分。激素反应性MBC的首要治疗目标是尽可能降低雌激素对肿瘤的影响, 在这一背景下, ET成为首批旨在抑制雌激素受体激活对肿瘤增殖影响的靶向治疗方法之一。治疗药物的开发热点集中于数种生化机制, 包括选择性调节雌激素受体、抑制芳香化酶和选择性降解雌激素受体。基于以上机制的治疗方法改善了MBC女性患者的生存期和生活质量。但在诸多病例中, ET耐药限制了治疗的有效性。现已阐明ET获得性耐药形成过程中涉及的复杂细胞信号级联反应以及生长因子信号传导与雌激素反应性之间的相互关系, 由此确定以上通路的组成因素是药物开发的理想靶点。基于以上深入了解, 兼以克服激素耐药为目的, 靶向治疗正逐渐成为MBC的有效治疗方法。本文综述了MBC的现有内分泌治疗, 以及近期完成和正在进行的通过干扰细胞增殖通路来克服耐药性的联合治疗和靶向治疗研究。
对临床实践的提示：本综述为肿瘤内科医生和其他肿瘤学卫生保健人员提供了以下方面的现有信息：内分泌治疗用于雌激素受体阳性转移性乳腺癌的依据；现有治疗方案的疗效和安全性特征。此外, 还讨论了关于耐药性形成和克服耐药性的治疗策略的现有概念。强化现有信息和对以上主题的理解将有助于临床医生评价患者的最佳治疗选择。
Endocrine therapy is an integral component of systemic therapy for metastatic breast cancer. In addition, targeted therapies are emerging as useful treatments. This article reviews current endocrine treatments of metastatic breast cancer, as well as studies of combination treatments and targeted therapies that interfere with cellular proliferation pathways, as a means of overcoming resistance.
According to a systematic review of 52 publications conducted by Begtrup et al, fish oil exposure in surgical patients does not increase bleeding or blood transfusion requirements either during or ...after surgery. 3 The study ultimately concluded that fish oil supplements were effective in reducing platelet aggregation in individuals. For the purpose of this study, we hypothesized that obese postmenopausal patients with ER+ breast cancer undergoing breast surgery who consume omega-3 supplements 30 days prior to their surgery will experience a decrease in wound healing complications as well as surgical site infections (SSIs) compared to individuals who do not supplement with omega-3 prior to their procedures. ...we believe that it is of importance to research the effect of preoperative omega-3 fatty acid supplementation on alterations to the tumor microenvironment in obese postmenopausal individuals with ER + breast cancer, and this study is on-going.
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