早期乳腺癌的四箭三雕术前治疗
对于人表皮生长因子受体2（HER2）阳性和雌激素受体（ER）阳性的早期乳腺癌患者，根据美国的TBCRC006研究，HER2双阻断（HER2细胞外结合表皮生长因子阻断剂曲妥珠单抗＋HER2细胞内信号传导阻断剂拉帕替尼）＋芳香酶（雌激素生物合成限速酶，可将雄激素转换为雌激素）抑制剂（来曲唑）术前三药双靶新辅助治疗，可使21%的患者获得病理完全缓解。由于HER2和ER的信号均传导至抑癌基因RB1，而RB1被细胞周期蛋白依赖型激酶4/6（CDK4/6）磷酸化后，即失去对癌细胞周期的抑制作用，故针对这些靶点（HER2、ER、CDK4/6和RB1）进行联合药物干预可能产生协同作用。
2018年1月8日，英国《柳叶刀》肿瘤学分册在线发表意大利圣拉斐尔大学医院、雷焦艾米利亚医院、米兰欧洲肿瘤学研究所、热那亚大学圣马蒂诺医院、圣厄休拉马尔比基综合医院、乌迪内大学综合医院、费拉拉大学医院、米开朗基罗基金会的研究报告，联合CDK4/6和RB1阻断剂（帕泊昔布）＋ER阻断剂（氟维司群）＋HER2细胞外结合EGF阻断剂（曲妥珠单抗）＋HER2细胞外二聚化阻断剂（帕妥珠单抗）对HER2阳性和ER阳性的早期乳腺癌患者进行了术前四药三靶新辅助治疗。
该非盲二期探索研究（NA-PHER2）于2015年5月20日～2016年2月8日在意大利的7个地点进行，首先入组年龄≥18岁、既往未经治疗、组织学证实、单侧、浸润性、未转移、HER2阳性、ER阳性、早期乳腺癌（cT1c～cT4a-d）并且适合术前新辅助治疗的患者36例。研究治疗方案：
曲妥珠单抗：静注，每3周1次，首次8mg/kg、随后6mg/kg，共6个治疗周期
帕妥珠单抗：静注，每3周1次，首次840mg、随后420mg，共6个治疗周期
帕泊昔布：口服，每4周前21天每天1次、每次125mg，共5个治疗周期
氟维司群：肌注，每4周1次、每次500mg，共5个治疗周期
其中，1例筛查时发现转移而未接受研究治疗方案，其余35例接受至少1个治疗周期后复查时发现HER2阴性5例，故实际共有6例不符合入组标准，
对完全符合入组标准的30例患者进行主要和次要终点的有效性评定，对所有接受至少1个治疗周期的35例患者进行安全性评定。
主要终点为基线至治疗2周时和治疗16周后手术时的细胞增值指数Ki67表达变化、基线至手术时的细胞凋亡变化。次要终点为根据实体肿瘤缓解评价标准（RECIST）修订版评价的临床客观缓解、根据手术时乳房和腋窝淋巴结评价的病理完全缓解。
该研究已在美国临床研究数据库在线注册登记，编号：NCT02530424，目前仍在进行，并将继续入组两个队列（帕泊昔布＋曲妥珠单抗＋帕妥珠单抗三药双靶新辅助治疗HER2阳性患者，曲妥珠单抗＋帕妥珠单抗＋帕泊昔布＋氟维司群四药三靶新辅助治疗HER2免疫组化弱阳性患者）。该研究得到辉瑞和罗氏的资助。
有效性评定
主要终点
细胞增殖指数的几何平均值
基线时：31.9±15.7
两周时： 4.3±15.0（25例，P<0.0001）
手术时：12.1±20.0（22例，P=0.013）
细胞凋亡指数的几何平均值
基线时：1.2±0.3
手术时：0.4±0.4（P=0.019）
次要终点
临床客观缓解：29例（97%，95%：83～100）
病理完全缓解：8例（27%，95%：12～46）
安全性评定
最常见的3级不良事件
中性白细胞减少10例（29%）
腹泻5例（14%）
口腔炎：1例（3%）
丙氨酸转氨酶升高：1例（3%）
过敏反应：1例（3%）
无4级或严重不良事件、无死亡
因此，帕泊昔布＋氟维司群＋曲妥珠单抗＋帕妥珠单抗，对于术前新辅助治疗两周时和手术时的Ki67表达显著有效。ER、HER2、RB1三靶对于HER2阳性和ER阳性乳腺癌可能是有效的非化疗治疗策略。有必要开展进一步的临床检验和分子机制研究，不仅对于激素受体阳性肿瘤，而且对于HER2未扩增（免疫组化弱阳性）肿瘤。
对此，法国斯特拉斯堡的保罗·施特劳斯癌症中心和法国里昂癌症研究中心发表同期评论：HER2阳性乳腺癌发展新时代。
Lancet Oncol. 2018 Jan 8. [Epub ahead of print]
Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study.
Luca Gianni, Giancarlo Bisagni, Marco Colleoni, Lucia Del Mastro, Claudio Zamagni, Mauro Mansutti, Milvia Zambetti, Antonio Frassoldati, Raffaella De Fato, Pinuccia Valagussa, Giuseppe Viale.
San Raffaele Scientific Institute, Milan, Italy; IRCCS Arcispedale S Maria Nuova Azienda Ospedaliera di Reggio Emilia, Reggio Emilia, Italy; European Institute of Oncology, Milan, Italy; IRCCS Azienda Ospedaliera Universitaria San Martino—IST, Genoa, Italy; Policlinico Sant'Orsola Malpighi, Bologna, Italy; Azienda Sanitaria Universitaria Integrata, Udine, Italy; Azienda Ospedaliero Universitaria di Ferrara—Arcispedale Sant'Anna, Ferrara, Italy; Fondazione Michelangelo, Milan, Italy.
BACKGROUND: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21% of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer.
METHODS: NA-PHER2 is a multicohort, open-label, exploratory, phase 2 study done at seven sites in Italy. Patients were eligible for the first cohort if they had previously untreated, histologically confirmed, unilateral, invasive, HER2-positive, ER-positive breast cancer and were suitable for neoadjuvant therapy. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) for six cycles plus oral palbociclib (125 mg once a day for 21 days in a 4-week cycle) and intramuscular fulvestrant (500 mg) every 4 weeks for five cycles. The coprimary endpoints were change from baseline in Ki67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment) and changes in apoptosis from baseline to surgery. Secondary endpoints were clinical objective response (according to modified Response Evaluation Criteria in Solid Tumors) and pathological complete response. All patients who met eligibility criteria were assessed for the primary and secondary endpoints. All patients who received at least one cycle of therapy were assessed for safety. This trial is registered with ClinicalTrials.gov, number NCT02530424. The trial is ongoing and two further cohorts are being enrolled.
FINDINGS: Between May 20, 2015, and Feb 8, 2016, we enrolled 36 patients, of whom one was deemed ineligible for the study and five were found to be HER2-negative on retrospective analysis. Thus, 35 patients were included in safety analyses and 30 were assessed for the primary and secondary endpoints. At baseline, geometric mean Ki67 expression was 31.9 (SD 15.7), versus 4.3 (15.0) at week 2 (n=25; p<0.0001) and 12.1 (20.0) at time of surgery (n=22; p=0.013). The geometric mean for apoptosis was 1.2 (SD 0.3) at baseline versus 0.4 (0.4; p=0.019) at surgery. A clinical objective response immediately before surgery was achieved by 29 (97%; 95% CI 83-100) of 30 patients. At surgery, eight (27%; 95% CI 12-46) patients had a pathological complete response in breast and axillary nodes. The most frequent grade 3 adverse events were neutropenia (ten [29%]), diarrhoea (five [14%]), and stomatitis, increased alanine aminotransferase, and hypersensitivity reactions (one [3%] of each event). No grade 4 or serious adverse events were recorded in the study and there were no deaths.
INTERPRETATION: The combination of palbociclib, fulvestrant, trastuzumab, and pertuzumab had a significant effect on the expression of Ki67 at 2 weeks and at surgery. Triple targeting of ER, HER2, and RB1 in HER2-positive and ER-positive breast cancer could be an effective chemotherapy-free treatment strategy. Further clinical testing and additional molecular characterisation is necessary, not only in hormone receptor-positive tumours but also in tumours without HER2 amplification.
FUNDING: Pfizer and Roche.
DOI: 10.1016/S1470-2045(18)30001-9
Lancet Oncol. 2018 Jan 8. [Epub ahead of print]
A new era for treatment development in HER2-positive breast cancer.
Xavier Pivot, David G Cox.
Paul Strauss Cancer Center, Strasbourg, France; INSERM U1052, Lyon, France.
DOI: 10.1016/S1470-2045(18)30002-0