激素受体阳性/人表皮生长因子受体2阳性晚期乳腺癌的多靶向治疗研究进展

在乳腺癌患者中,约20％的患者存在肿瘤细胞人表皮生长因子受体2(HER2)过表达,使得肿瘤侵袭性更强,预后更差.针对这一特点,有靶向治疗方案以控制疾病进展.进一步研究发现,有将近50％的HER2阳性乳腺癌患者同时表达激素受体(HR),HER2与HR在下游通路存在交互作用,而这一特性也与乳腺癌患者的内分泌耐药及抗HER2治疗耐药相关.临床试验证实,针对HR+/HER2+这一亚组,靶向治疗联合内分泌治疗可为患者带来更大的生存获益,目前化疗仍然为该亚组患者的首选治疗方案.本文总结了针对HR+/HER2+晚期乳腺癌治疗的相关文献,探讨靶向治疗联合内分泌治疗是否可作为该亚组治疗的另一优选方案.     

HR+/HER2+晚期乳腺癌药物治疗方案选择的研究进展#br#

激素受体阳性/人表皮生长因子受体2阳性乳腺癌是一种具有独特特征的乳腺癌亚型。国内外指南建议,无论HR状态如何,含抗HER2治疗的联合方案(如曲妥珠单抗和帕妥珠单抗)应作为HER2+晚期乳腺癌的一线治疗。内分泌治疗可作为不能耐受化疗或化疗后患者的维持治疗。既往研究表明,HR通路与HER2通路相互作用,内分泌联合靶向治疗可有效避免肿瘤耐药。因此,内分泌联合靶向治疗是HR+/HER2+患者替代化疗的首选治疗方案。文章对HR+/HER2+乳腺癌的生物学特征、诊疗现状及未来研究方向进行综述。     

乳腺癌芳香化酶抑制剂耐药的研究进展

乳腺癌是女性常见的恶性肿瘤,约70%的患者为雌激素受体（estrogen receptor,ER）和（或）孕激素受体（progesterone receptor,PR）阳性,内分泌治疗是激素受体（hormone receptor,HR）阳性乳腺癌的主要治疗方式之一。近几十年来,内分泌治疗药物不断发展并应用于临床,乳腺癌患者的复发转移风险显著降低,预后得到长足改善。芳香化酶抑制剂（aromatase inhibitor,AI）在乳腺癌内分泌治疗中发挥重要作用,然而绝大部分患者会发生原发性或继发性耐药,因此克服内分泌治疗药物耐药对进一步提高临床疗效至关重要。从遗传学、表观遗传学及细胞内信号转导通路等方面对HR阳性乳腺癌患者AI治疗后耐药的机制及最新的研究进展进行综述,以期为临床诊疗及科研提供参考。     

乳腺癌内分泌治疗加时代

激素受体（HR）阳性乳腺癌对内分泌治疗有效但也会产生耐药,以内分泌治疗为基础的联合治疗克服了耐药并提高了内分泌治疗的效果。乳腺癌的治疗已进入内分泌治疗加时代,这包括乳腺癌内分泌治疗联合分子靶向药物、血管生成抑制剂、磷脂酰肌醇-3激酶（PI3K）抑制剂、哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂、细胞周期素依赖激酶（CDK)4/6抑制剂、抗HER2剂和表观遗传调节剂。本文系统总结乳腺癌内分泌联合治疗的临床研究结果和潜在药物。     

雄激素受体在乳腺癌他莫昔芬耐药中的作用和机制研究进展

他莫昔芬(tamoxifen,TAM)为人工合成的非甾体类抗雌激素药物,被普遍的应用于雌激素受体(estrogen receptor,ER)阳性的乳腺癌患者中。但大约一半的ER阳性的患者会出现耐药。可见内分泌耐药是当前临床迫切需要解决的问题。随着对耐药机制的深入研究:发现雄激素受体(androgen receptor,AR)在 72.9%的原发性乳腺癌病例中表达,并在约65%的乳腺癌中与ER同时表达。有研究显示:AR/ER越高预示着TAM治疗率越低;AR与人类表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）之间所形成的正反馈循环能够增加TAM耐药;AR、髓样细胞白血病-1蛋白(myeloid cell leukemia-1,Mcl-1)与TAM耐药有可能相关。所以探讨AR在TAM耐药中的作用和机制是非常有意义的。为乳腺癌的靶向治疗掀开了新的一页。     

CDK4/6抑制剂联合内分泌治疗晚期乳腺癌

内分泌治疗因疗效显著并具有安全性,是激素受体阳性(HR+)晚期乳腺癌患者的主要治疗方法。近年来内分泌领域发展迅速,如何延迟或逆转内分泌耐药及内分泌治疗新药物成为临床研究关注的焦点。研究发现,内分泌治疗耐药可能与CDK-RB-E2F通路有关,针对该通路的细胞周期蛋白依赖性激酶(CDK)4/6抑制剂可显著延缓HR+晚期乳腺癌患者内分泌耐药。CDK4/6抑制剂与内分泌药物联合使用,可提高HR+晚期乳腺癌患者的治疗客观缓解率,并可显著改善无进展生存期(PFS)。现就CDK4/6抑制剂的作用机制、药物有效性和安全性及相关临床试验做一综述。     

乳腺癌内分泌耐药的临床研究进展

内分泌治疗是激素受体阳性乳腺癌的重要系统治疗手段,但原发性与继发性耐药是当前内分泌治疗的难题.雌激素受体通路与其他受体通路的交互效应是耐药机制之一.抑制磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(Akt)-哺乳动物雷帕霉素靶蛋白(mTOR)、表皮生长因子受体(EGFR)等分子通路逆转内分泌耐药的临床研究已取得一定的成果.     

乳腺癌激素受体表达对新辅助化疗后病理完全缓解的影响

[目的]探讨乳腺癌激素受体表达对新辅助化疗后病理完全缓解(pathological complete response,pCR)的影响。[方法]回顾性分析2019年11月至2021年10月于武汉大学人民医院首诊为乳腺癌行新辅助化疗并手术108例患者的临床病理资料。依据激素受体(hormone receptor,HR)和人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)表达将患者进行分组,单因素分析采用χ^(2)检验或Fisher精确概率法,两两比较采用Bonferroni校正。多因素分析采用Logistic回归。[结果]多因素分析显示雌激素受体(estrogen receptor,ER)及HER2为新辅助化疗后p CR的独立预测因子,ER阴性(OR=13.134,P<0.001)及HER2阳性(OR=0.200,P=0.003)的患者p CR率更高,HR+/HER2-组pCR率最低(2.4%)。亚组分析pCR率观察到统计学差异,差异存在于HR+/HER2-组与其他三组[Bonfeffoni校正,P均<0.0083(0.05/6)]。[结论]不同激素受体表达的乳腺癌患者对新辅助化疗的反应不同。ER阴性、HER2阳性的乳腺癌患者新辅助化疗的效果更好,更易达到pCR。     

mTOR抑制剂在激素受体阳性乳腺癌治疗中的研究进展

靶向激素受体（hormone receptor,HR）和人类表皮生长因子（human epidermal growth factor receptor 2,HER-2）对激素受体阳性乳腺癌的治疗至关重要,然而原发或继发内分泌治疗耐药及后续的疾病进展仍不可避免。人哺乳动物雷帕霉素位点（mammalian target of rapamycin,mTOR）是细胞生长和分化的关键调节因子,参与细胞不可控性生长。目前许多研究表明mTOR通路的激活可能与乳腺癌内分泌治疗耐药相关,阻断此通路有助于消除耐药,维持药物的敏感性。许多靶向mTOR通路的药物均表现出强大的抗肿瘤效应,在乳腺癌治疗中具有良好前景,且已有许多临床试验结果表明mTOR抑制剂联合内分泌治疗可显著提高患者的生存率。本文对mTOR信号通路及其抑制剂在内分泌治疗耐药的乳腺癌中的新进展进行综述。      

三阳性乳腺癌内分泌治疗联合靶向治疗的研究进展

三阳性乳腺癌(triple-positive breast cancer,TPBC)是指雌激素受体、孕激素受体和人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)表达均为阳性的乳腺癌,占所有乳腺癌病理学类型的5%～10%。TPBC是Luminal B型乳腺癌亚型的一种特殊类型,既可以接受内分泌治疗,又可以接受靶向治疗。目前国内外指南推荐TPBC的治疗首选抗HER2靶向治疗联合化疗,但TPBC新辅助治疗的病理学完全缓解率却低于激素受体阴性/HER2阳性乳腺癌,且雌激素受体表达>30%的患者从抗HER2靶向治疗联合化疗中获益较小。目前随着多种抗HER2靶向药物不断问世,以及细胞周期蛋白依赖性激酶4和6抑制剂的临床应用,使得临床上对于高选择的患者首选靶向治疗联合内分泌治疗成为可能。本文就TPBC内分泌治疗联合靶向治疗的最新研究进展进行综述。     

Activation of PI3K/Akt signaling and hormone resistance in breast cancer

Akt is a serine/threonine kinase that has been demonstrated to play an important role in survival when cells are exposed to different apoptotic stimuli. Recent studies show that aberrant activation of Akt in breast carcinoma is associated with a poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway is currently attracting considerable attention as a new target for effective therapeutic strategies. We investigated the incidence of Akt activation in 252 primary breast carcinomas and relationships among the activation of Akt, HER2 overexpression, hormone receptor expression, and alteration of the PTEN gene. Eighty-four cases (33.3%) were positive for pAkt expression. pAkt was significantly associated with HER2 overexpression (p<0.0001) and LOH at the PTEN gene locus (p<0.01). There was an inverse correlation between pAkt and PR (p<0.05). We also retrospectively examined the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer. Of these 36 metastatic breast cancer cases, 12 cases (33.4%) were considered to show positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated worse efficacy than in pAkt-negative patients (p<0.01). In addition, the clinical benefit was the smallest in the patients positive both for HER2 and pAkt (p<0.01). The clinical benefit rate of estrogen deprivation therapy with AI or LH-RH agonist was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (p<0.05), and there was a tendency for the clinical benefit of SERM to be smaller in the pAkt-positive patients (p=0.09). These findings therefore suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings indicate that the activation of Akt in the downstream pathway of HER2 plays an important role in resistance to endocrine therapy for breast cancer. Our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.     

The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2

Approximately half of breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) also express hormone receptors (HRs). Although HR positivity predicts efficacy of endocrine agents, preclinical and clinical data suggest that HER2 overexpression confers intrinsic resistance to hormonal treatment. In addition, HER2 overexpression is an independent adverse prognostic factor regardless of the hormonal status of the tumor, indicating that patients with HR+/HER2+ breast tumors might not derive a benefit from single-agent hormonal therapy. These data provided a strong rationale for exploring the targeting of both HR and HER2 signaling pathways in HR+/HER2+ breast tumors to optimize hormonal therapy and overcome resistance to anti-estrogen therapy. Results from a randomized clinical trial that combined hormonal treatment with targeted anti-HER2 therapy in postmenopausal women with HR+/HER2+ advanced breast cancer indicate that this novel dual-targeting strategy significantly improves outcomes compared with endocrine treatment alone. Nonetheless, other data suggest that it might achieve an inferior outcome compared with anti-HER2 therapy plus chemotherapy. Therefore, targeting both the HR and HER2 signaling pathways upfront might not be the most-effective therapeutic strategy in the management of HR+/HER2+ breast cancer. We discuss the clinical implication of resistance to endocrine therapy, and describe new insights into the management of HR+/HER2+ advanced breast cancer.     

The association between Akt activation and resistance to hormone therapy in metastatic breast cancer

In this retrospective study, the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer was investigated. Thirty-six metastatic breast cancer patients, treated with endocrine therapy, were evaluated for the activation of Akt by an immunohistochemical assessment of the expression of phosphorylated Akt at Ser 473 (pAkt). The relationship between the efficacy of endocrine therapy and Akt activation, HER2 status and hormone receptor expression was also investigated. Of these 36 cases, 12 cases (33.4%) were considered to show a positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated a worse efficacy than in pAkt-negative patients (P<0.01). pAkt positivity was also associated with a poorer objective response (P<0.05). The clinical benefit rate was lower in HER2 positive groups than in HER2 negative group (P<0.05). In addition, the clinical benefit was the smallest in both the HER2 and pAkt-positive patients (P<0.01). Regarding the endocrine agents, the clinical benefit of estrogen deprivation therapy with aromatase inhibitor or luteinising hormone-releasing hormone agosists was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (P<0.05). In addition, there was a tendency for clinical benefit of selective estrogen receptor modulator to be smaller in the pAkt-positive patients (P=0.09). These findings, therefore, suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings suggest that the activation of Akt in the downstream pathway of HER2 plays an important role in the resistance to endocrine therapy for breast cancer. Although our study was small in scope and retrospective in design, our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.     

Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.     

Human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive breast cancer: new insights into molecular interactions and clinical implications

Recent data show a significant benefit from combining an anti-HER-2 agent with endocrine therapy in HER2-positive and hormone receptor (HR)-positive metastatic breast cancer. However, as the clinical outcomes achieved by these combinations do not favourably match those with chemotherapy, clinicians still perceive HER2-positive breast cancer as an homogeneous group and consider chemotherapy with anti-HER2 agents as the preferred treatment option, regardless of the HR status. Indeed, in HR-positive HER2-positive tumours, chemotherapy with anti-HER2 agents is the backbone of treatment, while endocrine therapy is commonly used in sequence when HR and HER2 are co-expressed rather than as a real alternative. Emerging biological and clinical data challenge this paradigm, suggesting that HER2-positive tumours are rather heterogeneous that HRs co-expression may account for part of this heterogeneity and, finally, that chemotherapy may represent an overtreatment in selected cases. The present review aims to summarise the biological features of HER2-positive breast cancer according to HR status, the role of the bi-directional cross-talk between HER2 and HR pathways on resistance development to anti-HER2 and endocrine therapy, and finally, the novel therapeutic strategies, including but not limited to chemotherapy, targeting these two pathways.     

Prognostic factors for survival in metastatic breast cancer by hormone receptor status

Hormone receptor (HR) status is an important prognostic factor for patients with metastatic breast cancer (MBC) and is also correlated with other prognostic factors, such as initial lymph node status, HER2-Neu status and age. The prognostic value of these other factors, however, is unknown when stratified by HR positive versus HR negative patients. The aim of this study was to evaluate prognostic factors for MBC survival in relation to HR status. Dutch women diagnosed with breast cancer in 2003–2006 treated with curative intent who developed MBC within 5 years of follow-up were selected from the Netherlands cancer registry (N = 2,001). Independent prognostic factors for survival after metastatic occurrence were determined by multivariable Cox survival analyses stratified by HR status. Interactions between HR status and prognostic factors were determined. Median survival for MBC patients with HR negative (HR?) tumours was 8 months, compared to 19 months for HR positive (HR+) patients. The prognostic value of lymph node status, HER2-Neu status, adjuvant endocrine treatment and first-line palliative chemotherapy was dependent on HR status. Initial lymph node status was independently associated with survival in HR? patients, but not in HR+ patients. HER2-Neu positive status was associated with better survival in both HR+ and HR? patients, although the association was stronger in HR? patients. Similarly, patients treated with first-line palliative chemotherapy fared better, especially HR? patients. HR+ patients had worse survival if they had received adjuvant endocrine treatment. This study shows that the prognostic value of various factors depends on HR status in MBC. This information may help physicians to determine individual prognostic profiles and therapeutic strategies for MBC patients.     

Novel Agents for the Management of Endocrine Resistant Breast Cancer

Purpose of Review

Most women with hormone receptor (HR)-positive, HER2-negative (HR+/HER2?) breast cancer will ultimately develop endocrine-resistant disease, either primary or acquired. This review will discuss the proposed mechanisms underlying endocrine resistance and key advances in the treatment of endocrine-resistant breast cancer.

Recent Findings

Estrogen receptor 1 mutations (ESR1) occur in the majority of patients with HR+/HER2? metastatic breast cancer after prolonged exposure to aromatase inhibitors. Data from the SoFEA trial showed that patients had improved progression-free survival (PFS) after taking fulvestrant compared with exemestane. Fulvestrant is currently the only selective estrogen receptor degrader (SERD) available and development of oral novel SERDs with higher bioavailability and potency are currently being investigated.

Summary

Despite significant advances in the treatment of HR+/HER2? breast cancer over the past four decades, a significant proportion of patients do still develop endocrine resistance following optimal endocrine therapy. In this review, we aim to provide an overview of the different classes of novel agents currently being investigated to overcome endocrine resistance.