马飞教授:2020年乳腺癌治疗新进展

2021-01-19 翟婧彤 吕丹 马飞 博鳌肿瘤创新研究院

马 飞 教授

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马 飞 教授

  • 主任医师、教授、博士生导师

  • 国家癌症中心/中国医学科学院肿瘤医院内科治疗中心主任

  • 兼任国家肿瘤质控中心乳腺癌专委会副主委、中国药师协会肿瘤专科药师分会副主委、中国抗癌协会整合肿瘤心脏病分会副主委、中国抗癌协会多原发和不明原发肿瘤专委会副主委、中国抗癌协会肿瘤药物临床研究专委会秘书长、全国女性卵巢保护与抗衰促进工程专委会副主委、中国老年学和老年医学学会老年肿瘤分会总干事长、中国医促会乳腺癌青委会主任委员、北京市肿瘤治疗质量控制和改进中心肿瘤化疗质控专委会主委、北京乳腺病防治学会健康管理专委会主委、中国抗癌协会乳腺癌青委会副主委、Cardio-Oncology等中英文杂志编委等职。

  • 承担国家自然科学基金、863等多项国家级重大科研专项,在JCO等国内外著名杂志发表学术论著60余篇,编译肿瘤学专著13部,获得国家科技进步二等奖、中国抗癌协会科技一等奖等省部级以上科研奖励9项,获得国家专利授权4项,获得“首都十大杰出青年医生”、“中国肿瘤青年科学家奖”等荣誉称号。

2020年度乳腺癌治疗新进展

翟婧彤,吕丹,马飞

国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院肿瘤内科  

乳腺癌的诊疗水平逐年提高,5年生存率已高达90%[1],远超其他癌种。乳腺癌的全身治疗已初步形成包括化疗、靶向治疗、内分泌治疗和免疫治疗在内的成熟体系。近年来“精准治疗”逐渐受到重视,要进一步改善乳腺癌患者的预后和提高患者生活质量,需要制定更加个体化的治疗策略。本文将总结乳腺癌化疗、靶向治疗、内分泌治疗和免疫治疗在过去一年的重大进展,并对乳腺癌未来治疗的研究方向进行展望,以便更好地指导乳腺癌个体化精准治疗。

1、化疗

化疗作为乳腺癌治疗中重要的组成部分,是改善患者生存和预后的主要手段之一,但化疗容易发生耐药,不良反应较重,这是目前亟待解决的问题。

卡培他滨用于新辅助化疗后仍有肿瘤残存的三阴性乳腺癌(triple negative breast cancer,TNBC)患者的术后强化治疗已被国内外所接受,而在单纯术后辅助治疗阶段使用卡培他滨强化治疗尚无定论。SYSUCC-001研究探索了TNBC术后标准辅助治疗后卡培他滨节拍化疗强化辅助治疗1年的获益情况,结果显示,中位随访5年后,术后接受卡培他滨治疗的患者5年无病生存(disease free survival,DFS)率显著高于观察组(82.8%∶73.0%),患者相对复发风险降低36.0%,尤其是肺转移发生率降低50%[2]。研究结果充分说明了早期TNBC患者在标准治疗以后,进行节拍化疗强化辅助治疗可带来显著的临床获益,为改善TNBC不良预后提供有价值的证据。

艾立布林是一种新型的微管抑制剂。Study-301研究针对经蒽环类和紫杉类药物治疗后的晚期乳腺癌患者,在TNBC亚组中,与卡培他滨组比较,艾立布林组患者总生存(overall survival,OS)时间延长5个月,死亡风险降低29.8%[3],为原本缺乏有效治疗手段的转移性TNBC提供了新的治疗选择。2020年美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)会议公布了RU011201I研究的结果,艾立布林与紫杉醇一线或二线治疗人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)阴性晚期乳腺癌的临床疗效相当,艾立布林血液学毒性重于紫杉醇,两组患者外周神经病变的性质和严重程度相似,但艾立布林在发病时间、持续时间和对日常生活的干扰方面的数据更具优势,安全性更好[4]。在中国进行的304研究的亚组分析显示,与长春瑞滨组相比,艾立布林组患者神经毒性出现更晚,自主神经病变发生比例更低[5]。更多以艾立布林为基础的联合方案研究正在进行中,为转移性乳腺癌患者提供更多优效选择。详细见:艾立布林是晚期乳腺癌蒽环紫杉类治疗后化疗的重要治疗选择

GeparOcto的Ⅲ期临床研究入组TNBC或HER2阳性或高危的激素受体(hormone receptor,HR)阳性、HER2阴性的患者,分别接受剂量密集表柔比星、紫杉醇和环磷酰胺(iddEPC)方案或周疗紫杉醇联合多柔比星脂质体(PM)方案[TNBC需再联合卡铂(Cb)]新辅助治疗,2020年欧洲肿瘤内科学会(European Society for Medical Oncology,ESMO)会议公布了该研究47个月的随访结果,新辅助化疗iddEPC组和PM(Cb)组不论在整体队列还是在HER2阳性和TNBC亚组中的无浸润性疾病生存(invasive disease free survival,IDFS)和OS均无显著差异,但HR阳性、HER2阴性的患者应用iddEPC方案有更好的IDFS和OS获益[6],这一结果也支持Luminal型中HER2阴性乳腺癌可以从新辅助化疗中获益。

优替德隆(utidelone,UTD1)是一种基因工程埃博霉素类似物,也是一类新型的非紫杉类抗微管蛋白聚合类抗肿瘤药物。BG01-1323L研究旨在评估优替德隆联合卡培他滨对比单药卡培他滨对于蒽环类/紫杉类药物治疗失败的晚期乳腺癌患者的有效性和安全性[7],在意向性治疗(intention to treatment,ITT)人群中,优替德隆+卡培他滨组患者中位无进展生存(progression free survival,PFS)时间(8.4个月∶4.1个月)、中位OS时间(19.8个月∶16.0个月)和客观缓解率(objective response rate,ORR)(45.6%∶23.7%)均优于卡培他滨组,为晚期乳腺癌患者提供了更有效的治疗选择。

2、靶向治疗

随着对乳腺癌发病机制研究的不断深入和精准医学的不断发展,乳腺癌分子靶向治疗不断取得新的进展。靶向治疗能够高效、有选择性地杀伤肿瘤细胞,且不良反应比化疗更低。

2.1  HER2阳性乳腺癌靶向治疗

2.1.1  新辅助治疗  对于早期乳腺癌,如何在争取治愈的前提下采用低毒的治疗方案提高生活质量是一个值得探索的方向。BCIRG-006研究结果证实,辅助治疗多西他赛+卡铂+曲妥珠单抗(TCH)方案和多柔比星+环磷酰胺序贯多西他赛+曲妥珠单抗(AC-TH)方案的10年DFS和OS相似,但是在新辅助治疗阶段,哪种方案可使患者获得更大的病理完全缓解(pathologic complete response,pCR)率尚无定论[8]。2020年ASCO会议公布的NeoCARH研究首次对比了新辅助化疗TCH方案与表柔比星+环磷酰胺序贯多西他赛+曲妥珠单抗(EC-TH)方案,研究结果显示TCH组患者的pCR率显著高于EC-TH组(56.1%∶38.5%),在安全性方面,二者不良反应发生率相似,说明TCH方案可能更适用于HER2阳性乳腺癌的新辅助治疗[9]。

TRAIN-2研究是第一项评估无蒽环类药物化疗联合曲妥珠单抗、帕妥珠单抗用于HER2阳性早期乳腺癌患者新辅助治疗的Ⅲ期临床研究。既往研究结果提示,双靶治疗是否联合蒽环类药物对患者pCR率并无影响,2020年ASCO会议更新了其3年的随访数据,结果显示在双靶基础上联合蒽环类药物并未使患者受益,无论是早期研究终点pCR,还是长期研究终点无事件生存期和OS,无蒽环类药物的方案均显示出良好的疗效及更好的安全性[10]。WSG-TP-II研究是首个评价在HR阳性、HER2阳性早期乳腺癌患者中进行曲妥珠单抗+帕妥珠单抗联合新辅助化疗对比联合内分泌治疗的前瞻性研究,结果显示联合化疗组患者的pCR率明显提高(56.8%∶23.9%),反映了双靶联合化疗的优势[11]。

2.1.2  术后辅助治疗  化疗联合HER2靶向治疗后继续HER2靶向治疗是HER2阳性早期乳腺癌的标准治疗,曲妥珠单抗-美坦新偶联物(T-DM1)是新辅助治疗后残存浸润性病灶患者的标准辅助治疗方案,然而对于高危人群,肿瘤复发及全身化疗相关毒性带来的困扰尚未解决。KAITLIN研究旨在探索通过T-DM1替代紫杉类药物和曲妥珠单抗是否能够提高辅助治疗的疗效并降低毒性[12],研究纳入术后HER2阳性早期乳腺癌患者,将其分为T-DM1组(蒽环类药物序贯T-DM1+帕妥珠单抗)和曲妥珠单抗组(蒽环类药物序贯紫杉类药物+曲妥珠单抗+帕妥珠单抗),目前该研究尚未达到主要终点IDFS,初步发现淋巴结阳性的患者接受蒽环类药物辅助化疗后,使用T-DM1替代紫杉醇+曲妥珠单抗未能显著改善疗效,在安全性方面,T-DM1组比曲妥珠单抗组有更多的不良事件导致的停药。

2.1.3  晚期解救治疗  对于HER2阳性晚期乳腺癌患者,最基本的治疗原则是系统治疗联合抗HER2治疗,对于抗HER2治疗失败的患者,持续抑制HER2通路可以给患者带来生存获益。吡咯替尼是中国研发的小分子泛ErbB受体酪氨酸激酶抑制剂,在2020年ASCO会议上公布的Ⅲ期PHOEBE研究结果显示,与拉帕替尼联合卡培他滨相比,吡咯替尼联合卡培他滨可显著延长患者PFS时间(12.5个月∶6.8个月),吡咯替尼组患者的ORR和临床获益率均显著高于拉帕替尼组,虽然目前OS结果尚未成熟,但是吡咯替尼组获益趋势明显,1年OS率达91.3%[13]。考虑到药物的安全性、有效性、可及性及患者经济状况等因素,吡咯替尼联合卡培他滨在中国被批准作为HER2阳性转移性乳腺癌患者二线治疗的可选方案。

PRECIOUS研究是帕妥珠单抗作为三线或四线再治疗用于既往接受过帕妥珠单抗(P)、曲妥珠单抗(T)和化疗(C)的HER2阳性乳腺癌患者的Ⅲ期临床研究,2020年圣安东尼奥乳腺癌研讨会(San Antonio Breast Cancer Symposium,SABCS)公布了其研究结果,PTC组的中位PFS时间明显优于TC组(5.3个月∶4.2个月)[14],使帕妥珠单抗跨线治疗成为可能。

HER2阳性乳腺癌患者易发生脑转移,但目前对于此类患者的治疗选择较少。tucatinib是一种具有高度选择性的口服酪氨酸激酶抑制剂,对HER2具有较高的靶向选择性。2020年ASCO会议更新了HER2CLIMB研究的数据,在曲妥珠单抗和卡培他滨的基础上增加tucatinib用于经曲妥珠单抗、帕妥珠单抗、T-DM1治疗后存在脑转移的HER2阳性转移性乳腺癌患者,可使颅内缓解率提升至47.3%,中枢神经系统PFS时间延长5.7个月(9.9个月∶4.2个月),颅内进展或死亡风险降低2/3[15,16]。该研究提示tucatinib联合曲妥珠单抗和卡培他滨可能成为经曲妥珠单抗、帕妥珠单抗、T-DM1治疗后伴或不伴脑转移的HER2阳性转移性乳腺癌患者新的治疗方案。

trastuzumab deruxtecan(DS-8201)是由靶向HER2的人源化单克隆抗体、可切割的四肽连接物和有效的拓扑异构酶Ⅰ抑制剂组成的新型抗体药物偶联物(antibody drug conjugate,ADC)。2019年SABCS会上报道的DESTINY-Breast01研究结果显示,经过多线治疗和T-DM1治疗的HER2阳性转移性乳腺癌患者接受DS-8201治疗,ORR可达60.9%,中位PFS时间达16.4个月[17],其亚组分析结果显示,各亚组ORR和中位PFS时间与既往总体结果相似[18]。2020年SABCS会议更新了其最新数据,随着中位随访时间增加至20.5个月,ORR进一步提高至61.4%,中位PFS时间为19.4个月,疾病控制率达97.3%,再次证实了DS-8201的疗效[19]。

2.2  TNBC靶向治疗  

多腺苷二磷酸核糖聚合酶(poly ADP ribose polymerase,PARP)抑制剂的问世填补了TNBC靶向治疗的空白。TBCRC048研究是一项针对转移性乳腺癌患者的Ⅱ期临床研究,探索了PARP抑制剂奥拉帕利单药治疗同源重组通路基因胚系或体系突变的转移性乳腺癌的疗效,结果显示,存在BRCA1/2体系突变的患者,ORR为50.0%,存在PALB2胚系突变的患者,ORR高达82.0%,但ATM或CHEK2基因突变的患者从奥拉帕利单药治疗中获益不明显[20]。该研究进一步拓展了PARP抑制剂的应用人群,使更多患者获益,然而其样本量较小,仍需大样本的临床研究来进一步验证。

在BRCA野生型TNBC患者中,有近1/2人群表现出同源重组缺陷,导致BRCA样表型可能使其对PARP抑制剂敏感。目前还没有研究评价PARP抑制剂联合铂类治疗BRCA野生型TNBC的疗效。2020年ASCO会议报道的SWOGS1416研究针对顺铂联合PARP抑制剂veliparib在BRCA基因相关晚期乳腺癌中的应用进行了探索,入组患者分为BRCA胚系突变、BRCA样表型和非BRCA样表型三类,结果显示顺铂联合veliparib可显著改善BRCA样表型晚期乳腺癌患者的PFS时间,并有延长OS时间的趋势,顺铂联合veliparib或可成为此类患者新的治疗选择[21]。

sacituzumab govitecan(SG)是新型、首创的ADC药物,由靶向TROP-2抗原的人源化IgG1抗体与化疗药物伊立替康的代谢活性产物SN-38偶联而成,TROP-2是一种在90%以上的TNBC中表达的细胞表面糖蛋白。IMMU-132-01研究显示[22],SG在转移性TNBC患者的ORR为33.3%,中位PFS时间为5.5个月,该研究结果使SG获得美国食品药品管理局加速批准,用于治疗既往已接受至少2种疗法的转移性TNBC。随后展开的ASCENT研究也进一步证实,与医生选择的单药标准化疗方案相比,SG显著改善患者中位PFS时间(1.7个月∶5.6个月)、OS时间(6.7个月∶12.1个月)及ORR(5.0%∶35.0%)[23],提示SG或可考虑作为经治转移性TNBC患者新的治疗选择。

3、内分泌治疗

乳腺癌患者中约80%为HR阳性[24],内分泌治疗已成为激素敏感型乳腺癌患者的主要且有效的治疗方式,在HR阳性、HER2阴性的早期乳腺癌患者中,接受新辅助化疗较难达到pCR,因此,越来越多的临床研究开始探索新辅助内分泌治疗在此类患者中的疗效。在晚期乳腺癌患者中,内分泌治疗耐药依然是临床研究关注的焦点,其与细胞周期蛋白依赖性激酶4/6(cyclin-dependent kinase 4 and 6,CDK4/6)、磷脂酰肌醇3激酶(phosphatidylinositol 3-kinase,PI3K)/蛋白激酶B(protein kinase B,PKB/AKT)信号通路等多种作用机制相关[25],对于相关靶向药物的研究也取得了重大进展。

3.1  早期乳腺癌

3.1.1  新辅助内分泌治疗  对于HR阳性乳腺癌,新辅助内分泌治疗可以有效评估内分泌治疗的敏感性,但是达到pCR的情况相对少见[26]。术前内分泌治疗预后指数(preoperative endocrine therapy prognosis index,PEPI)包括新辅助内分泌治疗后的肿块大小、淋巴结状态、Ki67水平和雌激素受体(estrogen receptor,ER)状态,PEPI=0被认为复发风险低,不需要辅助化疗[26],改良PEPI(modified PEPI,mPEPI)则不考虑PEPI中的ER因素。

ALTERNATE研究发现,在绝经后ER阳性、HER2阴性的临床Ⅱ期或Ⅲ期乳腺癌患者中,使用氟维司群或氟维司群+阿那曲唑与单用阿那曲唑进行新辅助内分泌治疗,均未显著提升其内分泌治疗的敏感率,即6个月的新辅助内分泌治疗后,达到pCR或mPEPI=0的患者比例并未显著提高,其后期的生存数据仍需继续观察[27]。FELINE研究发现,在绝经后ER阳性、HER2阴性的临床Ⅱ期或Ⅲ期乳腺癌患者中,单用来曲唑和来曲唑联合ribociclib作为新辅助治疗并没有增加PEPI为0分患者的比例[28],提高新辅助内分泌治疗疗效的用药方案还有待探索。

3.1.2  辅助内分泌治疗  约20%的HR阳性、HER2阴性早期乳腺癌患者接受标准治疗后,在前10年内会出现复发和远处转移[29],具有临床或病理高危因素的患者复发风险更高,尤其是辅助内分泌治疗中的前几年[30],临床中亟需新的辅助内分泌治疗方案来预防早期复发和远处转移。

monarchE研究发现,在HR阳性、HER2阴性的高危早期乳腺癌患者中,与单用内分泌治疗相比,abemaciclib联合内分泌治疗显著改善了IDFS。2020年SABCS会议报道了monarchE研究结果,2年IDFS率绝对获益为3.0%(92.3%∶89.3%),与对照组相比,abemaciclib组患者的无远距离复发生存率更优,分别为93.8%和90.8%,复发风险降低31.3%[31]。PALLAS研究初步分析发现,在HR阳性、HER2阴性早期乳腺癌患者中,与单纯内分泌治疗相比,在辅助内分泌治疗中加入哌柏西利并没有延长IDFS[32]。PENELOPE-B研究纳入了新辅助化疗和肿瘤切除术后未能达到pCR且具有高复发风险的HR阳性、HER2阴性乳腺癌患者,患者按1∶1随机分组接受哌柏西利联合内分泌治疗或安慰剂联合内分泌治疗,结果显示哌柏西利联合内分泌治疗并没有延长IDFS[33]。与哌柏西利在晚期乳腺癌中获益趋势不同,其用于早期乳腺癌辅助治疗并未显著获益,其中有多重潜在因素需要进一步探索。

3.2  晚期乳腺癌

3.2.1  联合CDK4/6抑制剂  哌柏西利联合来曲唑已成为HR阳性、HER2阴性晚期乳腺癌患者的一线标准治疗[34],对于初始内分泌治疗后进展或耐药的患者,哌柏西利联合氟维司群是标准治疗[35]。PARSIFAL研究旨在探索内分泌治疗敏感的ER阳性、HER2阴性晚期乳腺癌患者中,联合哌柏西利的最佳内分泌药物。2020年ASCO会议报道了其研究结果,氟维司群+哌柏西利与来曲唑+哌柏西利相比,PFS未达到统计学优效性,两组间OS亦无显著差异[36],因此,最终的治疗决策须平衡患者和临床医生的选择以及后续的治疗策略。FLIPPER研究证实氟维司群+哌柏西利相较于氟维司群+安慰剂,可使内分泌治疗敏感的HR阳性、HER2阴性晚期乳腺癌患者有更好的疗效获益,可显著提高患者1年PFS率(83.5%∶71.9%),同时改善患者中位PFS时间(31.8个月∶22.0个月)和ORR(68.3%∶42.2%)[37]。

在MONALEESA-3和MONALEESA-7研究中,对于HR阳性、HER2阴性晚期乳腺癌患者,ribociclib+内分泌治疗较安慰剂+内分泌治疗显示出显著的OS获益[38,39]。内脏转移通常提示患者预后不良,生存率低,但在2020年ASCO会议报道的两项研究中,接受ribociclib+内分泌治疗的内脏转移亚组患者OS和PFS获益与总体人群一致[40]。MONARCH 2研究发现,在内分泌治疗耐药的HR阳性、HER2阴性晚期乳腺癌患者中,与安慰剂+氟维司群相比,abemaciclib+氟维司群可显著改善患者PFS和OS[41],2020年ASCO会议报道,接受abemaciclib+氟维司群治疗的内脏转移亚组患者中,PFS和OS获益与MONARCH 2研究的ITT人群一致[42]。

nextMONARCH研究探索了abemaciclib单药或与他莫昔芬联合对既往多线治疗过的HR阳性、HER2阴性晚期乳腺癌患者的效果,研究初步分析中,PFS和ORR结果显示出abemaciclib稳健的单药活性,而联用他莫昔芬后PFS无显著改善。2020年ESMO会议报道了最终24个月的OS结果,与abemaciclib单药治疗相比,abemaciclib联合他莫昔芬可显著改善患者OS时间(24.2个月∶17.0个月),PFS结果与初步分析结果一致[43],进一步明确了abemaciclib单药的疗效。

3.2.2  联合PI3Kα抑制剂  PIK3CA是乳腺癌中最常见的突变基因之一,约40%的HR阳性、HER2阴性晚期乳腺癌患者存在PIK3CA突变[44],其引起的PI3K通路高活化可促进内分泌耐药,与预后不良相关[45]。

alpelisib是α选择性PI3K抑制剂,在SOLAR-1研究中,对芳香化酶抑制剂(aromatase inhibitor,AI)治疗中或治疗后进展的HR阳性、HER2阴性、PIK3CA突变的晚期乳腺癌患者,alpelisib联合氟维司群展现了临床有效性,显著改善患者PFS[46]。2020年ESMO会议报道了本研究的最终结果,alpelisib+氟维司群与安慰剂+氟维司群相比,中位OS时间延长了7.9个月,但并未无统计学意义,亚组分析结果提示,在肝和/或肺转移以及循环肿瘤DNA中存在PIK3CA突变的患者中,alpelisib联合氟维司群可改善患者OS,OS数据显示出alpelisib联合氟维司群的治疗优势,进一步支持了前期该方案显著延长患者PFS的结果[47]。

BYLieve研究是第一个评估alpelisib联合内分泌治疗用于CDK4/6抑制剂联合内分泌治疗进展的ER阳性、HER2阴性、PIK3CA突变患者疗效的前瞻性试验,2020年ASCO会议报道了队列A(既往接受CDK4/6抑制剂+AI治疗的患者,接受alpelisib+氟维司群治疗)的结果,其6个月PFS率为50.4%,中位PFS时间为7.3个月[48],2020年SABCS会议报道了队列B(既往接受CDK4/6抑制剂+氟维司群治疗的患者,接受alpelisib+来曲唑治疗)的结果,其6个月PFS率为46.1%,中位PFS时间为5.7个月[49]。BYLieve研究的随访仍在进行,alpelisib有望成为PIK3CA突变患者在CDK4/6抑制剂耐药或复发转移后的优选方案。

3.2.3  联合AKT抑制剂  为原发或继发CDK4/6抑制剂耐药患者寻找治疗策略是至关重要且未被满足的需求,从患者活检和临床前分析得出的结论表明,AKT1激活可导致CDK4/6抑制剂耐药。

TAKTIC研究评估了AKT1抑制剂ipatasertib+内分泌治疗±CDK4/6抑制剂哌柏西利治疗HR阳性、HER2阴性晚期乳腺癌患者的抗肿瘤活性、安全性和耐受性,三种药物组合分别为A组(ipatasertib+AI)、B组(ipatasertib+氟维司群)、C组(ipatasertib+氟维司群+哌柏西利)。2020年ASCO会议报道了C组的中期分析,结果表明对既往CDK4/6抑制剂治疗失败的患者,AKT抑制剂+CDK4/6抑制剂+内分泌治疗在一部分患者中获得较好的临床疗效,且耐受性良好[50]。AKT抑制剂可能成为CDK4/6抑制剂耐药后的选择,TAKTIC研究的后续研究结果尚待观察。

4、免疫治疗

乳腺癌被认为是弱或中等免疫原性的肿瘤[51],而TNBC作为临床上比较难治的一种亚型,具有免疫治疗的潜在靶点。目前乳腺癌免疫治疗主要集中在TNBC,其中研究最多的是靶向程序性死亡蛋白-1(programmed death-1,PD-1)和程序性死亡蛋白配体1(programmed death ligand-1,PD-L1)的抗体,随着各种PD-1/PD-L1抗体的获批,对乳腺癌免疫治疗的研究也取得了较大进展。

4.1  新辅助治疗  

Ⅰ~Ⅲ期TNBC在新诊断的早期乳腺癌中占10%~20%[52],IMpassion130研究显示,阿替利珠单抗联合白蛋白结合型紫杉醇可为PD-L1阳性转移性TNBC患者带来PFS及OS获益[53]。IMpassion031研究旨在评估阿替利珠单抗联合化疗在早期TNBC新辅助治疗中的疗效和安全性,结果显示,阿替利珠单抗+化疗与安慰剂+化疗相比,ITT人群pCR率增加16.5%(57.6%∶41.1%),且不论PD-L1状态如何,均可观察到临床获益[54],阿替利珠单抗联合新辅助化疗治疗早期TNBC患者,取得了具有临床意义的pCR获益,安全性可耐受,这种新的组合疗法有望为早期TNBC患者提供一种更合适的治疗选择。

4.2  一线治疗  

IMpassion130研究是第一个证实免疫治疗在晚期TNBC一线治疗有效的Ⅲ期临床研究,研究发现,对初治不可手术的局部晚期或转移性TNBC患者,PD-L1阳性人群存在PFS和OS获益[53],2020年ESMO会议报道了最终的OS分析,在PD-L1阳性人群中,阿替利珠单抗+白蛋白结合型紫杉醇组患者的中位OS时间长达25.4个月,较安慰剂+白蛋白结合型紫杉醇组患者中位OS时间延长7.5个月[55],进一步支持了阿替利珠单抗+白蛋白结合型紫杉醇作为PD-L1阳性转移性TNBC患者一线治疗的有效性。IMpassion131研究评估了阿替利珠单抗联合紫杉醇一线治疗不可切除局部晚期或转移性TNBC的疗效,但IMpassion131研究没有达到首要研究终点,与安慰剂+紫杉醇相比,阿替利珠单抗+紫杉醇并未显著延长PD-L1阳性转移性TNBC患者的PFS和OS[56],与获益的IMpassion130研究相比,IMpassion131研究失败的潜在原因需要进一步探索。

KEYNOTE-355研究探索了帕博利珠单抗联合化疗对比安慰剂联合化疗用于初治的局部复发且不可手术或转移性TNBC的临床疗效,在PD-L1阳性(联合阳性评分≥10)转移性TNBC的一线治疗中,帕博利珠单抗+化疗与安慰剂+化疗相比,显著提高了患者PFS时间,绝对获益达到4.1个月(9.7个月∶5.6个月),降低了35.0%的复发风险[57]。2020年SABCS会议公布了其他疗效终点数据,不同化疗方案患者的PFS结果显示,帕博利珠单抗联合白蛋白紫杉醇(9.9个月∶5.5 个月)、紫杉醇(9.6个月∶3.6个月)、吉西他滨和卡铂(8.0个月∶7.2个月)均可获益[58]。KEYNOTE-355研究提示在转移性TNBC的一线治疗中,标准化疗基础上增加帕博利珠单抗可带来显著获益,期待后续OS的随访结果。

4.3  多线治疗  

KEYNOTE-119研究发现帕博利珠单抗对比化疗用于经治的转移性TNBC,并未显著改善患者OS。2020年ASCO会议报道了该研究中接受帕博利珠单抗治疗患者肿瘤突变负荷(tumor mutation burden,TMB)和临床结局的相关性。在转移性TNBC患者中,TMB与帕博利珠单抗治疗临床获益呈正相关,而与化疗无关。ORR和OS结果显示,与化疗相比,帕博利珠单抗治疗TMB≥10 mut/Mb的患者有获益趋势[59]。

ENHANCE 1研究评估了艾立布林联合帕博利珠单抗治疗转移性TNBC的Ⅰb/Ⅱ期研究,根据既往系统抗肿瘤治疗线数进行分层,艾立布林+帕博利珠单抗在接受过0~2线系统抗肿瘤治疗的患者中具有抗肿瘤活性,整体ORR为23.4%,中位PFS时间为4.1个月,中位OS时间为16.1个月,初治患者中,与PD-L1阴性患者相比,PD-L1阳性患者的疗效更好[60]。研究结果表明,艾立布林联合帕博利珠单抗有望成为转移性TNBC患者的一种潜在治疗选择。

5、挑战与展望

中国乳腺癌患者5年生存率高达83.2%,在过去10年间提高了7.3%[1],近年来个体化治疗策略对乳腺癌患者越发重要,针对不同患者,选择不同的治疗药物和治疗方式,为患者带来最大的获益和最佳的预后,需要医药和临床工作者的共同努力。

在化疗方面,蒽环类、紫杉类药物问世20余年,研究人员仍致力于探索新作用机制的化疗药物,以期在有效延长OS时间的同时减少药物毒性,提高生活质量,如艾立布林、优替德隆等。而传统的标准化疗药也在探索新的治疗方式,节拍化疗便是新的治疗理念在临床实践应用中的真实体现,卡培他滨、长春瑞滨、环磷酰胺等口服化疗制剂节拍化疗的疗效和安全性均已得到验证。

此外,越来越多的药物从用于晚期解救治疗,到早期辅助治疗,再到新辅助治疗,随着各类临床试验和新的治疗理念不断涌现,其治疗模式也从单一的新辅助化疗,转变为当前基于不同分子亚型的新辅助化疗、新辅助抗HER2靶向治疗联合化疗、新辅助内分泌治疗等。其优势在于可评估病理缓解程度,进行危险度分层,在辅助治疗中实现个体化治疗[61,62]。新辅助治疗是值得探索和研究的方向,同时也需要更多的研究去寻找评价治疗疗效的指标和最佳的药物组合。

在靶向治疗方面,ADC是抗肿瘤治疗的新兴药物,具有独特的作用机制,是极具潜力的治疗方式,T-DM1已经在乳腺癌治疗中显示出良好疗效,新开发的ADC药物DS-8201和SG都展现出这种抗体偶联新模式的可行性和有效性。

在内分泌治疗中,耐药问题仍是治疗的困境和亟待解决的主要难点之一,CDK4/6抑制剂是内分泌治疗的最佳搭档,然而为原发或继发CDK4/6抑制剂耐药患者寻找新的治疗策略是至关重要的且未被满足的需求,PI3Kα抑制剂及AKT抑制剂或许可成为此类患者的选择。免疫治疗药物阿替利珠单抗和帕博利珠单抗的阳性结果为TNBC患者的治疗带来了曙光,但优势人群的选择标准尚未成熟,缺乏能够精准预测疗效及预后的免疫生物标志物,最佳的药物配伍方案仍待探索。

乳腺癌治疗药物在不断开发,越来越多的临床试验在陆续开展,期待有更多的阳性结果为乳腺癌患者带来获益,以精准医学为基础,指导后续治疗,为乳腺癌患者带来疗效及生活质量的双重改善!

附:马飞:2019年乳腺癌治疗新进展

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[16]MURTHY RK, LOI S, OKINES A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer[J]. N Engl J Med, 2020, 382(7):597-609. 

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[31]O'SHAUGHNESSY J A , JOHNSTON S, HARBECK N, et al. GS1-01 Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer[OL]. (2020-12-09)[2020-12-15]. https://www.abstractsonline.com/pp8/#!/9223/presentation/664.

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[33]LOIBL S, MARMÉ F, MARTIN M, et al. GS1-02 Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B[OL]. (2020-12-09)[2020-12-15]. https://www.abstractsonline.com/pp8/#!/9223/presentation/666. 

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[37]ALBANELL J, MARTINEZ M T M, RAMOS M, et al. LBA19 GEICAM/2014-12 (FLIPPER) study: First analysis from a randomized phase II trial of fulvestrant (F)/palbociclib (P) versus (vs) F/placebo (PL) as first-line therapy in postmenopausal women with HR (hormone receptor)+/HER2– endocrine sensitive advanced breast cancer (ABC)[J]. Ann Oncol, 2020, 31:S1151.

[38]SLAMON D J, NEVEN P, CHIA S, et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3[J]. J Clin Oncol, 2018, 36(24):2465-2472. 

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[43]HAMILTON E P, CORTÉS J, OZYILKAN O, et al. 273O nextMONARCH: Final overall survival analysis of abemaciclib monotherapy or in combination with tamoxifen in patients with HR+, HER2- metastatic breast cancer[J]. Ann of Oncol, 2020, 31:S348.

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[47]ANDRÉ F, CIRUELOS E M, JURIC D, et al. LBA18 Overall survival (os) results from SOLAR-1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC)[J]. Ann Oncol, 2020, 31:S1150-S1151.

[48]RUGO HS, LEREBOURS F, CIRUELOS E, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results[J]. J Clin Oncol, 2020, 38(15_suppl):1006-1006.

[49]RUGO H S, LEREBOURS F, JURIC D, et al. PD2-07 Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results[OL]. (2020-12-09)[2020-12-15]. https://www.abstractsonline.com/pp8/#!/9223/presentation/787.

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[55]EMENS L A, ADAMS S, BARRIOS C H, et al. LBA16 IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer[J]. Ann Oncol, 2020, 31:S1148.

[56]MILES D W, GLIGOROV J, ANDRÉ F, et al. LBA15 Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC)[J]. Ann Oncol, 2020, 31:S1147-S1148.

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  1. [GetPortalCommentsPageByObjectIdResponse(id=958319, encodeId=8ffe958319bb, content=太好了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4bde5480711, createdName=ms7000001119266541, createdTime=Mon Apr 19 12:22:41 CST 2021, time=2021-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=949215, encodeId=e87694921548, content=总结的非常好,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201209/54baa477bcfc4ce48fae57028fa9dc77/14c9d8e5c41d40818d0c578258130859.jpg, createdBy=b2ce2306721, createdName=@医路相伴, createdTime=Thu Mar 18 11:50:37 CST 2021, time=2021-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=920482, encodeId=ac3592048277, content=真的是很全面, beContent=null, objectType=article, channel=null, level=null, likeNumber=91, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210413/8061a962539d452bbfb306396ed79deb/e0ea950e3e474920b8d8d1b11a5ffced.jpg, createdBy=be095402886, createdName=ms5000000000121449, createdTime=Thu Jan 28 00:03:51 CST 2021, time=2021-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918260, encodeId=a7c191826098, content=感谢review,很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f90e5454304, createdName=ms7000001130823801, createdTime=Wed Jan 20 08:03:26 CST 2021, time=2021-01-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918202, encodeId=9d4d918202b7, content=了解, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Tue Jan 19 21:36:33 CST 2021, time=2021-01-19, status=1, ipAttribution=)]
    2021-04-19 ms7000001119266541

    太好了

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=958319, encodeId=8ffe958319bb, content=太好了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4bde5480711, createdName=ms7000001119266541, createdTime=Mon Apr 19 12:22:41 CST 2021, time=2021-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=949215, encodeId=e87694921548, content=总结的非常好,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201209/54baa477bcfc4ce48fae57028fa9dc77/14c9d8e5c41d40818d0c578258130859.jpg, createdBy=b2ce2306721, createdName=@医路相伴, createdTime=Thu Mar 18 11:50:37 CST 2021, time=2021-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=920482, encodeId=ac3592048277, content=真的是很全面, beContent=null, objectType=article, channel=null, level=null, likeNumber=91, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210413/8061a962539d452bbfb306396ed79deb/e0ea950e3e474920b8d8d1b11a5ffced.jpg, createdBy=be095402886, createdName=ms5000000000121449, createdTime=Thu Jan 28 00:03:51 CST 2021, time=2021-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918260, encodeId=a7c191826098, content=感谢review,很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f90e5454304, createdName=ms7000001130823801, createdTime=Wed Jan 20 08:03:26 CST 2021, time=2021-01-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918202, encodeId=9d4d918202b7, content=了解, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Tue Jan 19 21:36:33 CST 2021, time=2021-01-19, status=1, ipAttribution=)]
    2021-03-18 @医路相伴

    总结的非常好,学习了

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=958319, encodeId=8ffe958319bb, content=太好了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4bde5480711, createdName=ms7000001119266541, createdTime=Mon Apr 19 12:22:41 CST 2021, time=2021-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=949215, encodeId=e87694921548, content=总结的非常好,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201209/54baa477bcfc4ce48fae57028fa9dc77/14c9d8e5c41d40818d0c578258130859.jpg, createdBy=b2ce2306721, createdName=@医路相伴, createdTime=Thu Mar 18 11:50:37 CST 2021, time=2021-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=920482, encodeId=ac3592048277, content=真的是很全面, beContent=null, objectType=article, channel=null, level=null, likeNumber=91, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210413/8061a962539d452bbfb306396ed79deb/e0ea950e3e474920b8d8d1b11a5ffced.jpg, createdBy=be095402886, createdName=ms5000000000121449, createdTime=Thu Jan 28 00:03:51 CST 2021, time=2021-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918260, encodeId=a7c191826098, content=感谢review,很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f90e5454304, createdName=ms7000001130823801, createdTime=Wed Jan 20 08:03:26 CST 2021, time=2021-01-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918202, encodeId=9d4d918202b7, content=了解, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Tue Jan 19 21:36:33 CST 2021, time=2021-01-19, status=1, ipAttribution=)]
    2021-01-28 ms5000000000121449

    真的是很全面

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=958319, encodeId=8ffe958319bb, content=太好了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4bde5480711, createdName=ms7000001119266541, createdTime=Mon Apr 19 12:22:41 CST 2021, time=2021-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=949215, encodeId=e87694921548, content=总结的非常好,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201209/54baa477bcfc4ce48fae57028fa9dc77/14c9d8e5c41d40818d0c578258130859.jpg, createdBy=b2ce2306721, createdName=@医路相伴, createdTime=Thu Mar 18 11:50:37 CST 2021, time=2021-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=920482, encodeId=ac3592048277, content=真的是很全面, beContent=null, objectType=article, channel=null, level=null, likeNumber=91, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210413/8061a962539d452bbfb306396ed79deb/e0ea950e3e474920b8d8d1b11a5ffced.jpg, createdBy=be095402886, createdName=ms5000000000121449, createdTime=Thu Jan 28 00:03:51 CST 2021, time=2021-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918260, encodeId=a7c191826098, content=感谢review,很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f90e5454304, createdName=ms7000001130823801, createdTime=Wed Jan 20 08:03:26 CST 2021, time=2021-01-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918202, encodeId=9d4d918202b7, content=了解, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Tue Jan 19 21:36:33 CST 2021, time=2021-01-19, status=1, ipAttribution=)]
    2021-01-20 ms7000001130823801

    感谢review,很有用

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=958319, encodeId=8ffe958319bb, content=太好了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4bde5480711, createdName=ms7000001119266541, createdTime=Mon Apr 19 12:22:41 CST 2021, time=2021-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=949215, encodeId=e87694921548, content=总结的非常好,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201209/54baa477bcfc4ce48fae57028fa9dc77/14c9d8e5c41d40818d0c578258130859.jpg, createdBy=b2ce2306721, createdName=@医路相伴, createdTime=Thu Mar 18 11:50:37 CST 2021, time=2021-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=920482, encodeId=ac3592048277, content=真的是很全面, beContent=null, objectType=article, channel=null, level=null, likeNumber=91, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210413/8061a962539d452bbfb306396ed79deb/e0ea950e3e474920b8d8d1b11a5ffced.jpg, createdBy=be095402886, createdName=ms5000000000121449, createdTime=Thu Jan 28 00:03:51 CST 2021, time=2021-01-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918260, encodeId=a7c191826098, content=感谢review,很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f90e5454304, createdName=ms7000001130823801, createdTime=Wed Jan 20 08:03:26 CST 2021, time=2021-01-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918202, encodeId=9d4d918202b7, content=了解, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Tue Jan 19 21:36:33 CST 2021, time=2021-01-19, status=1, ipAttribution=)]
    2021-01-19 wxl882001

    了解

    0

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