HER2阳性乳腺癌治疗的研究进展

[摘要] 人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）阳性乳腺癌侵袭性高,预后差。随着抗HER2药物的不断出现及广泛应用,HER2 阳性乳腺癌患者的预后出现了非常显著的改善。10 年随访结果证实1 年曲妥珠单抗辅助治疗可以显著降低疾病复发风险;对于术后的高危人群,曲妥珠单抗联合帕妥珠单抗或者曲妥珠单抗序贯来那替尼可以进一步减少复发。5 年随访结果表明帕妥珠单抗+曲妥珠单抗为基础的新辅助治疗可使病理完全缓解（pathological complete response,pCR）转化为长期生存获益;白蛋白紫杉醇代替普通紫杉醇与抗HER2 药物联用可以进一步提高pCR率;而抗HER2 药物联合内分泌治疗尚不能达到与联合化疗在新辅助治疗中疗效,即使联合CDK4/6 抑制剂,对于pCR的提高依然有限。曲妥珠单抗+帕妥珠单抗联合紫杉类药物是晚期HER2 阳性乳腺癌的标准一线方案;对于老年、体弱的患者,节拍环磷酰胺可以作为紫杉类药物的替代品;拉帕替尼+曲妥珠单抗联合内分泌治疗可以作为HER2 阳性伴激素受体阳性的选择,疗效优于曲妥珠单抗联合内分泌治疗;T-DM1 无论是作为二线治疗还是三线及以后的治疗均提高了患者生存获益,是治疗晚期、耐药HER2阳性乳腺癌的首选。     

HER2阳性乳腺癌治疗的研究进展

人表皮生长因子受体2(HER2)阳性乳腺癌因其侵袭性高、预后差而一直备受关注。随着曲妥珠单抗的应用,早期HER2阳性乳腺癌患者的预后已得到显著改善,由于其仍存在耐药性和不良反应,在标准治疗中加入新的抗HER2药物又成为新的研究重点,这些药物包括帕妥珠单抗、抗体药物偶联物曲妥珠单抗-美坦新(T-DM1)和各种小分子抑制剂(拉帕替尼、来那替尼、吡咯替尼)。同时PD1及PD-L1抑制剂如帕博利珠单抗在HER2阳性乳腺癌中的研究也在进行中,并有部分基础研究和病例报道已经证实了其疗效和安全性。本文旨在对目前HER2阳性乳腺癌的治疗方案和支持HER2阳性乳腺癌治疗的最新证据进行综述。     

乳腺癌新辅助治疗前后HER-2低表达及其变化和临床意义

目的:探讨乳腺癌新辅助治疗(neoadjuvant therapy, NAT)前后人表皮生长因子受体-2(human epidermal growth factor receptor-2,HER-2)低表达及其变化和临床意义。方法:收集458例接受NAT的乳腺癌患者资料,对比分析不同HER-2状态临床病理特征及病理完全缓解(pathological complete response, pCR)率的差异,并对NAT前后HER-2状态进行一致性检验。结果:HER-2低表达组与阴性组在年龄、组织学分级、淋巴结转移、激素受体状态、Ki-67表达水平、Miller-Payne分级等方面的差异有统计学意义(均P<0.05)。458例患者pCR率为40.83%,其中HER-2低表达组的pCR率(17.50%)低于阳性组(59.36%)和阴性组(36.71%),差异有统计学意义(均P<0.05)。Luminal型患者中,HER-2低表达组的pCR率低于阴性组(11.40%33.33%,P=0.005);三阴性患者中,HER-2低表达组pCR率与阴性组患者的差异无统计学意义(32.61%v...     

新辅助化疗联合双靶治疗HER-2阳性乳腺癌的有效性比较

  目的  比较多西他赛+卡铂+曲妥珠单抗+帕妥珠单抗（TCbHP）、多西他赛+曲妥珠单抗+帕妥珠单抗（THP）与蒽环类+环磷酰胺序贯紫杉类+曲妥珠单抗+帕妥珠单抗（AC-THP）作为新辅助治疗方案对HER-2阳性激素受体（hormone receptor,HR）阳性和HER-2阳性HR阴性乳腺癌患者的有效性。  方法  回顾性分析2019年6月至2022年12月于天津医科大学肿瘤医院就诊的408例HER-2阳性且行标准新辅助治疗的乳腺癌患者的临床病理资料,根据HR状态分为HER-2阳性HR阳性组 211例、HER-2阳性HR阴性组197例。根据不同新辅助治疗方案进一步分为TCbHP、THP和AC-THP组,分别比较各组患者行各治疗方案的病理学完全缓解（pathological complete response,pCR）率 。  结果  HER-2阳性HR阳性乳腺癌患者中,TCbHP、THP和AC-THP组的pCR率分别为43.1%（69/160）、36.0%（9/25）和 38.5%（10/26）,各组间比较差异无统计学意义（χ²=0.580,P=0.748）;HER-2阳性HR阴性患者中,TCbHP、THP和AC-THP组的pCR率分别为85.5%（94/110）、57.3%（43/75） 和 66.7%（8/12）,TCbHP组与THP组比较差异具有统计学意义（χ²=19.967,P<0.001）。  结论  TCbHP、THP和AC-THP新辅助治疗方案对HER-2阳性HR阳性乳腺癌患者的疗效相似,TCbHP作为新辅助治疗对HER-2阳性HR阴性乳腺癌疗效更优。     

HER-2阳性乳腺癌新辅助治疗腋窝病理完全缓解的预测因素分析

目的:研究人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)阳性乳腺癌新辅助治疗腋窝病理完全缓解(axillary pathological complete response,apCR)的预测因素.方法:回顾性分析2017年1月至2019年12月四川...     

HER2阳性乳腺癌治疗模式的进展和优化

随着抗人表皮生长因子受体2（human epidermalgrowth factor receptor 2 ,HER2）抗肿瘤药物的不断出现及广泛应用,HER2 阳性乳腺癌患者的治疗以及预后得到了显著的改善。PEONY 研究结果的发布再次奠定了帕妥珠单抗+曲妥珠单抗的双靶治疗模式在新辅助治疗领域中的地位;结合TRYPHAENA 和TRAIN-2 两项研究,紫杉类+铂类应该是抗HER2 双靶治疗的首选化疗方案,疗程宜6 个周期。结合中国乳腺癌新辅助治疗专家共识和辅助APT 研究的最新随访结果,新辅助治疗适用人群为肿瘤直径超过3 cm 和/或淋巴结阳性的患者,新辅助治疗后如果没有获得pCR,T-DM1 应该是辅助治疗的首选模式,帕妥珠单抗+曲妥珠单抗的双靶辅助模式期待PEONY 研究的后续生存随访;对于没有淋巴结转移的小肿瘤（≤3 cm）低危患者可以考虑免除新辅助治疗,采取直接手术+术后给予曲妥珠单抗联合单药紫杉醇的辅助治疗模式。曲妥珠单抗+帕妥珠单抗联合紫杉类药物依然是晚期HER2 阳性患者的标准一线治疗;对于中国患者而言,吡咯替尼联合卡培他滨可以作为二线的优选;T-DM1 可以作为三线及后线选择;曲妥珠单抗、帕妥珠单抗、T-DM1 治疗失败的情况下,DS-8201 成为新的选择模式;伴有脑转移的HER2 阳性晚期乳腺癌患者则可以考虑图卡替尼与曲妥珠单抗和卡培他滨的联合治疗模式。     

曲妥珠单抗在HER-2阳性乳腺癌患者新辅助治疗中的应用研究进展

曲妥珠单抗是人表皮生长因子受体-2（human epidermal growth factor receptor-2,HER-2）的特异性抑制剂,在HER-2阳性乳腺癌患者新辅助治疗中的应用日益广泛。大规模的随机、对照临床试验证实,新辅助化疗联合曲妥珠单抗与单纯化疗比较能显著提高病理完全缓解（pathologic complete response,pCR）率。在曲妥珠单抗联合化疗的基础上加用拉帕替尼较单用曲妥珠单抗可大大提高pCR率。蒽环与非蒽环类化疗药物均可作为曲妥珠单抗的联合用药,内分泌治疗也可作为雌激素受体阳性患者的联合用药。pCR是曲妥珠单抗新辅助治疗后生存获益的独立预后因素,HER-2转阴而未达到pCR的患者为不良预后因素。本文将对曲妥珠单抗在HER-2阳性乳腺癌患者新辅助治疗中的研究进展进行综述。      

HER2阳性和三阴性乳腺癌新辅助化疗后选择性避免腋窝手术分期的研究

背景与目的：新辅助化疗（neoadjuvant chemotherapy,NAC）目前已成为局部晚期乳腺癌患者的标准治疗模式。探讨人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）阳性和三阴性乳腺癌（triple-negative breast cancer,TNBC）患者NAC后选择性避免腋窝手术分期的可行性及可能获益人群。方法：回顾性分析2010年1月—2018年8月山东省肿瘤防治研究院（山东省肿瘤医院）收治的865例行NAC患者的临床病理学资料,其中184例（21.3%）为HER2阳性和TNBC患者,分析其临床病理学特征与NAC后腋窝淋巴结病理学阴性（ypN ₀ ）的相关性。结果：NAC前肿瘤分期、淋巴结分期及Ki-67,NAC后腋窝淋巴结临床阴性（ycN ₀ ）、乳房影像学完全缓解（breast radiologic complete response,brCR）及乳房病理学完全缓解（breast pathologic complete response,bpCR）均与NAC后ypN ₀ 显著相关（P<0.05）,其中NAC前临床淋巴结分期（OR=0.363,P<0.001）、bpCR（OR=11.285,P<0.001）及ycN ₀（OR=4.995,P<0.001）是NAC后ypN ₀ 的独立预测因素。cN ₀ →ycN ₀ 组37例,NAC后bpCR、未达bpCR患者ypN ₀ 率分别为100.0%（17/17）、90.0%（18/20）（P=0.178）。cN ₁ →ycN ₀ 组42例,NAC后bpCR、未达bpCR患者ypN ₀ 率分别为95.8%（23/24）、55.6%（10/18）（P<0.001）。NAC后未达bpCR的cN 1 患者腋窝淋巴结残留转移的相对风险是bpCR患者的10.56倍（95% CI：2.720~41.003;P<0.001）。结论：在HER2阳性和TNBC患者中,NAC后bpCR与腋窝淋巴结状态具有高度相关性。NAC后bpCR的cN ₀ 及部分cN ₁ 患者（NAC后降期为ycN ₀ ）腋窝淋巴结残留转移的风险<5%,使其选择性避免腋窝手术分期成为可能。     

Faslodex治疗ER阳性原发性乳腺癌中HER—2扩增状态在抗增殖反应中的影响

大约 1 0 %的乳腺癌雌激素受体 (ER)及人类表皮生长因子受体 2 (HER 2 )同时阳性。大量临床证据证实此类乳腺癌对三苯氧胺治疗效果差。三苯氧胺耐药部分原因是由于HER 2与ER信号传导通路的交叉 ,导致对三苯氧胺激动效应增强。Faslodex(Fulves trant)是新型ER拮抗剂 ,可下调ER水平 ,无激动效应 ,在ER(+)、HER 2阳性患者中可能比三苯氧胺更有效。将绝经后术前组织学证实的原发性乳腺癌患者随机分 3组 :①Faslodex(5 0mg、1 2 5mg、2 5 0mg)肌注 ;②三苯氧胺 2 0mg d ,连续 1 4～ 2 1天 ;③安慰剂每日 1次口服 ,连续 1 4～ 2 1天。治…     

Escalating and de-escalating treatment in HER2-positive early breast cancer

The current standard adjuvant systemic treatment of early HER2-positive breast cancer consists of chemotherapy plus 12 months of trastuzumab, with or without endocrine therapy. Several trials have investigated modifications of the standard treatment that are shorter and less resource-demanding (de-escalation) or regimens that aim at dual HER2 inhibition or include longer than 12 months of HER2-targeted treatment (escalation). Seven randomized trials investigate shorter than 12 months of trastuzumab treatment duration. The shorter durations were not statistically inferior to the 1-year duration in the 3 trials with survival results available, but 2 of the trials were small and 1 had a relatively short follow-up time of the patients at the time of reporting. The pathological complete response (pCR) rates were numerically higher in all 9 randomized trials that compared chemotherapy plus dual HER2 inhibition consisting of trastuzumab plus either lapatinib, neratinib, or pertuzumab with chemotherapy plus trastuzumab as neoadjuvant treatments, but the superiority of chemotherapy plus dual HER2-inhibition over chemotherapy plus trastuzumab remains to be demonstrated in the adjuvant setting. One year of adjuvant trastuzumab was as effective as 2 years of trastuzumab in the HERA trial, and was associated with fewer side-effects. Extending 1-year adjuvant trastuzumab treatment with 1 year of neratinib improved disease-free survival in the ExteNET trial, but the patient follow-up times are still short, and no overall survival benefit was reported. Several important trials are expected to report results in the near future and may modify the current standard.     

Discordances in ER, PR and HER2 receptors after neoadjuvant chemotherapy in breast cancer

Neoadjuvant chemotherapy (NAC) for breast cancer is evolving and subsequent adjuvant systemic treatment is mainly based on the presence of the Estrogen (ER) receptor, Progesterone (PR) receptor and Human Epidermal growth factor Receptor 2 (HER2) status on the core needle biopsy prior to treatment. It is not well known whether these biomarkers change after NAC, requiring a change in further adjuvant systemic treatment. A review of the literature (PubMed search) revealed 32 relevant studies that investigated the concordance of the hormone receptors (ER and/or PR) and HER2 after NAC with or without trastuzumab. Discordance of the hormone receptor status was reported in four out of eight studies in 8-33% of the patients. About half of the studies that tested the ER and PR receptor status separately reported discordances of 2.5-17% and 5.9-51.7% respectively. Studies that concluded that ER and/or PR receptor remained stable after NAC were performed with evidently lower number of patients compared to studies that reported a change. Good concordance of the HER2 amplification tested with FISH was reported, although the HER2 expression measured with immunohistochemistry was more discordant. A switch to a negative HER2 receptor in up to 43% of the patients was reported when NAC was combined with trastuzumab.Until more comparable studies are being published, retesting the receptor status of the residual tumor after NAC should be considered in order to improve future tailored adjuvant therapies.     

雌激素受体β和人类表皮生长因子受体2在乳腺癌中的表达及其临床意义

我们应用免疫组化两步法,对133例乳腺癌和29例乳腺良性病变的标本进行雌激素受体(estrogen receptor,ER)β、ERα和人类表皮生长因子受体(human epidermal growth factor receptor,HER)2表达的测定,比较了ERβ在临床病理指标各组中的阳性表达差异,并探讨ERβ与HER 2和ERα的关系。     

新辅助化疗联合保乳术治疗乳腺癌的疗效观察

目的 探讨新辅助化疗联合保乳术治疗乳腺癌患者的临床疗效及患者雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体-2(HER-2)水平变化情况.方法 选取2018年1月至2020年1月间武警河南总队医院收治的56例乳腺癌患者纳入研究对象,采用随机数表法将患者分为观察组和对照组,每组28例.观察组采用新辅助化疗联合...     

Age interacts with the expression of steroid and HER-2 receptors in operable invasive breast cancer

BACKGROUND: The negative association between the oestrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER-2) in breast cancer travels in both directions. ER+ tumours are less likely HER-2+ and HER-2+ tumours are less likely ER+. METHODS: We studied the age-related immunohistochemical (IHC) expression of ER, progesterone receptor (PR) and HER-2 in 2,227 tumours using age as a continuous variable. Steroid receptors were considered positive for any nuclear staining of invasive cancer cells and for HER-2, either for strong expression by IHC (score 3+) or gene amplification by fluorescence in situ hybridisation (FISH). Based on nonparametric regression, the age-related association between steroid receptors and HER-2 was presented as likelihood curves. RESULTS: The association between ER or PR and HER-2 is age-related. The age-related expression of ER and PR is HER-2 dependent. In HER-2(-) cases, the odds ratio (OR) for being ER+ was 2.594 (95% CI = 1.874-3.591) up to age 50 and age-independent thereafter; for PR-expression the OR was 2.687 (95% CI = 1.780-4.057) up to age 45 and 0.847 (95% CI = 0.761-0.942) thereafter. In HER-2+ cases, the OR was 0.806 (95% CI = 0.656-0.991) to be ER+ and 0.722 (95% CI = 0.589-0.886) to be PR+. The age-related OR for breast cancers to be HER-2+ is steroid receptor dependent. Taking together, ER+PR+HER-2+ breast cancers appear on average 5.4 years earlier than breast cancers of any other ER/PR/HER-2 phenotype (95% CI = 3.3-7.5; P < 0.0001). CONCLUSION: There is a qualitative interaction between age and expression of steroid and HER-2 receptors. Our findings suggest a strong age-related selective growth advantage for breast tumour cells belonging to the ER+PR+HER-2+ subgroup.     

Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients

Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25–0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06–3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13–2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29–6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43–0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48–7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25–7.58; p = 0.015). In conclusion: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways – AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.