乳腺癌辅助靶向治疗NCCN指南2015v3

Adjuvant HER2-Targeted Therapy

辅助HER2靶向治疗

The panel recommends HER2-targeted therapy in patients with HER2- positive tumors (see Principles of HER2 Testing). Trastuzumab is a humanized monoclonal antibody with specificity for the extracellular domain of HER2. Results of several randomized trials testing trastuzumab as adjuvant therapy have been reported.山东省肿瘤医院呼吸肿瘤内科张品良

在HER2阳性的肿瘤患者中专家组推荐HER2靶向治疗(见HER2检测原则)。曲妥珠单抗是一种HER2胞外域的特异性人源化单克隆抗体。已报道研究曲妥珠单抗作为辅助治疗若干随机试验的结果。

NSABP B-31 patients with HER2-positive, node-positive breast cancer were randomly assigned to 4 cycles of AC every 3 weeks followed by paclitaxel for 4 cycles every 3 weeks or the same regimen with 52 weeks of trastuzumab commencing with paclitaxel. In the NCCTG N9831 trial, patients with HER2-positive breast cancer that was node-positive, or node-negative, with primary tumors greater than 1 cm in size if ER- and PR-negative or greater than 2 cm in size if ER- or PR-positive, were similarly randomized except that paclitaxel was given by a low-dose weekly schedule for 12 weeks and a third arm delayed trastuzumab until the completion of paclitaxel.

NSABP B-31 HER2阳性、淋巴结阳性乳腺癌患者被随机分配至每3周1次AC4周期序贯每3周1次紫杉醇4周期或同样的方案联合52周的曲妥珠单抗从紫杉醇开始。在NCCTG N9831试验中，淋巴结阳性或淋巴结阴性ER和PR阴性而原发肿瘤大于1cm或ER或PR阳性而原发肿瘤大于2cm的HER2阳性的乳腺癌患者，除紫杉醇外以同样的随机方法给予低剂量每周方案12周而第3组曲妥珠单抗延迟至紫杉醇结束后。

The B-31 and NCCTG N9831 trials have been jointly analyzed with the merged control arms for both trials compared with the merged arms using trastuzumab begun concurrently with paclitaxel. There were 4045 patients included in the joint analysis performed at 3.9 years median follow-up. A 48% reduction in the risk of recurrence (HR, 0.52; 95% CI, 0.45-0.60; P < .001) and a 39% reduction in the risk of death (HR, 0.61; 95% CI, 0.50-0.75; log-rank P = .001) were documented. Similar significant effects on DFS were observed when results of the NSABP B-31 and NCCTG N9831 trials were analyzed separately. Cardiac toxicity was increased in patients treated with trastuzumab. In the adjuvant trastuzumab trials, the rates of grade III/IV congestive heart failure (CHF) or cardiac-related death in patients receiving treatment regimens containing trastuzumab ranged from 0% (FinHer trial) to 4.1% (NSABP B-31 trial). The frequency of cardiac dysfunction appears to be related to both age and baseline left ventricular ejection fraction. An analysis of data from N9831 showed the 3-year cumulative incidence of CHF or cardiac death to be 0.3%, 2.8%, and 3.3% in the arms of the trial without trastuzumab, with trastuzumab following chemotherapy, and with trastuzumab initially combined with paclitaxel, respectively. The acceptable rate of significant cardiac toxicity observed in the trastuzumab adjuvant trials in part reflects rigorous monitoring for cardiac dysfunction. Furthermore, concerns have been raised regarding the long-term cardiac risks associated with trastuzumab therapy based on results of follow-up evaluations of cardiac function in patients enrolled in some of these trials.

B-31与NCCTG N9831试验已联合研究了两个试验合并的对照组与合并的与紫杉醇同时开始的曲妥珠单抗组相比较。在中位随访3.9年时该联合分析纳入了4045例患者。证明复发风险降低48%(HR，0.52；95% CI，0.45-0.60；P＜.001)、死亡风险降低39%(HR，0.61；95% CI，0.50-0.75；对数秩和检验P=.001)。当NSABP B-31与NCCTG N9831试验独立分析时观察到对DFS具有相似的显著影响。在接受曲妥珠单抗治疗的患者中心脏毒性增加。在曲妥珠单抗辅助治疗试验中，在接受含曲妥珠单抗的治疗方案的患者中Ⅲ/Ⅳ度充血性心力衰竭(CHF)或与心脏有关的死亡率范围从0%(FinHer试验)至4.1%(NSABP B-31试验)。心脏功能障碍的发生率似乎与年龄和基线左室射血分数两者都有关。一项N9831的数据分析显示无曲妥珠单抗试验组、在化疗后用曲妥珠单抗组和曲妥珠单抗最初联合紫杉醇组CHF或心脏死亡的3年累计发生率分别是0.3%、2.8%和3.3%。在妥珠单抗辅助试验中观察到的显著心脏毒性的发生率可接受，在某种程度上反映出严谨的心脏功能障碍监测。此外，基于这些试验中某些入组患者心脏功能的随访评估结果关于与曲妥珠单抗治疗有关的长期心脏风险的担心增加。

A third trial (HERA) (N = 5081) tested trastuzumab for 1 or 2 years compared to none following all local therapy and a variety of standard chemotherapy regimens in patients with node-positive disease or node-negative disease with tumor greater than or equal to 1 cm. At a median follow-up of one year, a 46% reduction in the risk of recurrence was reported in those who received trastuzumab compared with those who did not (HR, 0.54; 95% CI, 0.43-0.67; P < .0001), there was no difference in OS, and acceptable cardiac toxicity was reported. The 2-year data indicate that 1 year of trastuzumab therapy is associated with an OS benefit when compared with observation (HR for risk of death = 0.66; 95% CI, 0.47-0.91; P = .0115). After this initial analysis, patients randomized to chemotherapy alone were allowed to cross over to receive trastuzumab. Intent-to-treat analysis including a crossover patient was reported at 4-year median follow-up. The primary endpoint of DFS continued to be significantly higher in the trastuzumab-treated group (78.6%) versus the observation group (72.2; HR, 0.76; 95% CI, 0.66-0.87; P < .0001). At a median follow-up of 8 years, the study reported no significant difference in DFS, a secondary endpoint, in patients treated with trastuzumab for 2 years compared with 1 year. Therefore, 1 year of adjuvant trastuzumab remains the current standard of treatment.

一项三期试验(HERA)(N＝5081)研究了在淋巴结阳性或淋巴结阴性而肿瘤≥1cm的患者中曲妥珠单抗1或2年与所有的局部治疗和各种各样的标准化疗方案之后没有曲妥珠单抗相比较。在中位随访1年时，与未接受曲妥珠单抗者相比那些接受曲妥珠单抗者复发风险降低46%(HR，0.54；95%CI，0.43-0.67；P＜.0001)，在OS方面没有差异，且具有可接受的心脏毒性。2年数据显示与观察组相比1年的曲妥珠单抗治疗与OS获益相关(死亡风险HR=0.66；95%CI，0.47-0.91；P=.0115)。在这个初步分析以后，随机至单独化疗的患者被允许交叉至接受曲妥珠单抗。在中位随访4年时意向治疗分析包括已报道的交叉患者。主要终点DFS与观察组(72.2%)相比曲妥珠单抗治疗组(78.6%)仍旧显著更高(HR，0.76；95% CI，0.66-0.87；P＜.0001)。在中位随访8年时，该研究报道接受曲妥珠单抗治疗2年与1年的患者相比DFS、次要终点没有显著差异。因此，1年的辅助性曲妥珠单抗仍然是当前的标准治疗。

The BCIRG 006 study randomized 3222 women with HER2-positive, node-positive, or high-risk node-negative breast cancer to AC followed by docetaxel; AC followed by docetaxel plus trastuzumab for one year; or carboplatin, docetaxel, and trastuzumab for one year. At 65-month follow-up, patients receiving AC followed by docetaxel with trastuzumab (AC-TH) had an HR for DFS of 0.64 (P < .001) when compared with the group of patients in the control arm receiving the same chemotherapy regimen without trastuzumab (AC-T). The HR for DFS was 0.75 (P = .04) when patients in the carboplatin/docetaxel/ trastuzumab (TCH)-containing arm were compared to patients in the control arm. No statistically significant difference in the HR for DFS was observed between the two trastuzumab-containing arms. An OS advantage was reported for patients in both trastuzumab-containing arms relative to the control arm (HR for AC-TH vs. AC-T = 0.63; P = .001; HR for TCH vs. AC-T = 0.77; P = .04). Cardiac toxicity was significantly lower in the TCH arm (9.4% patients with >10% relative decline in left ventricular ejection fraction) compared with the AC-TH arm (18.6%; P < .0001). CHF was also more frequent with AC-TH than TCH (2% vs. 0.4%; P < .001). Analysis of this trial by critical clinical event revealed more distant breast cancer recurrences with TCH (144 vs. 124) but fewer cardiac events with TCH compared with AC-TH (4 vs. 21). In the FinHer trial, 1010 women were randomized to 9 weeks of vinorelbine followed by 3 cycles of FEC chemotherapy versus docetaxel for 3 cycles followed by 3 cycles of FEC chemotherapy. Patients (n = 232) with HER2-positive cancers that were either node-positive or node-negative and greater than or equal to 2 cm and PR-negative were further randomized to receive or not receive trastuzumab for 9 weeks during the vinorelbine or docetaxel portions of the chemotherapy only. With a median follow-up of 3 years, the addition of trastuzumab was associated with a reduction in risk of recurrence (HR, 0.42; 95% CI, 0.21-0.83; P = .01). No statistically significant differences in OS (HR, 0.41; 95% CI, 0.16-1.08; P = .07) or cardiac toxicity were observed with the addition of trastuzumab. At 5-year follow-up, a comparison of the two arms (ie, chemotherapy with and without trastuzumab) demonstrated that the HRs for distant DFS (HR, 0.65; 95% CI, 0.38-1.12; P = .12) and OS (HR, 0.55; 95% CI, 0.27-1.11; P = .094) were higher relative to those reported at 3 years.

BCIRG 006研究将3222例淋巴结阳性或高危的淋巴结阴性、HER2阳性乳腺癌女性随机化至AC序贯多西他赛、AC序贯多西他赛加1年的曲妥珠单抗或卡铂、多西他赛和1年的曲妥珠单抗。在随访65个月时，与AC序贯多西他赛无曲妥珠单抗(AC-T)的对照组患者相比接受AC序贯多西他赛联合曲妥珠单抗(AC-TH)的患者DFS HR0.64(p＜.001)。与对照组患者相比含卡铂/多西他赛/曲妥珠单抗(TCH)组患者DFS HR是0.75(P=.04)。在两个含曲妥珠单抗组之间观察到的DFS HR统计上没有显著差异。相对于对照组两个含曲妥珠单抗组患者都具有OS优势(AC-TH对AC-T HR=0.63；P=.001；TCH对AC-T HR=0.77；P=.04)。心脏毒性(患者左室射血分数相对降低>10%)与AC-TH组(18.6%)相比TCH组显著更低(9.4%；P＜.0001)。AC-TH比TCH CHF也更常见(2%对0.4%；P< .001)。此试验关键性临床事件的分析显示TCH乳腺癌远处复发更多(144对124)但是与AC-TH相比TCH心脏事件更少(4对21)。在FinHer试验中，1010例女性被随机分入9周的长春瑞滨序贯3周期的FEC化疗与3周期的多西他赛序贯3周期的FEC化疗。淋巴结阳性或淋巴结阴性而≥2cm且PR阴性、HER2阳性的癌症患者(n＝232)被进一步随机至在只有长春瑞滨或多西他赛化疗期间接受或不接受9周曲妥珠单抗。中位随访3年，曲妥珠单抗的加入与复发风险降低有关(HR，0.42；95%CI，0.21-0.83；P=.01)。曲妥珠单抗的加入OS(HR，0.41；95%CI，0.16-1.08；P=.07)或心脏毒性没有观察到显著的统计学差异。在随访5年时，两组(例如，化疗加和不加曲妥珠单抗)的比较显示相对于在3年时报道的远处DFS(HR，0.65；95% CI，0.38-1.12；P=.12)和OS(HR，0.55；95% CI，0.27-1.11；P=.094)HRs更高。

All of the adjuvant trials of trastuzumab have demonstrated clinically significant improvements in DFS, and the combined analysis from the NSABP B31 and NCCTG N9831 trials, and the HERA trial, showed significant improvement in OS with the use of trastuzumab in patients with high-risk, HER2-positive breast cancer. Therefore, regimens from each of these trials are included as trastuzumab-containing adjuvant regimen choices in the guideline. The benefits of trastuzumab are independent of ER status. In the FNCLCC-PACS-04 trial, 528 women with HER2-positive, node-positive breast cancer were randomly assigned to receive trastuzumab or observation after completion of adjuvant anthracycline-based chemotherapy with or without docetaxel. No statistically significant DFS or OS benefit was observed with the addition of trastuzumab. These results suggest that the sequential administration of trastuzumab following chemotherapy is not as efficacious as a schedule involving concomitant chemotherapy and trastuzumab. The NCCN Guidelines recommend a total of 12 months of adjuvant trastuzumab as the standard of care. Shorter than 12-month duration has not been found to be as effective and longer than 12 months duration does not have any added benefit, it has been found to 360 be as effective as the 12 months of trastuzumab therapy.

所有的曲妥珠单抗辅助试验均已证明临床上显著改善DFS，并且NSABP B31和NCCTG N9831试验以及HERA试验联合分析显示曲妥珠单抗的使用显著改善高危、HER2阳性乳腺癌患者的OS。因此，这些试验中收入的每一个方案均作为此指南中含曲妥珠单抗的辅助方案选择。

曲妥珠单抗的获益与ER状态无关。在FNCLCC-PACS-04试验中，528例HER2阳性、淋巴结阳性乳腺癌女性在辅助性以蒽环类抗生素为基础的化疗±多西他赛结束以后被随机分配至接受曲妥珠单抗或观察。曲妥珠单抗的加入观察到的DFS或OS获益统计上没有显著意义。这些结果提示化疗序贯曲妥珠单抗不是与化疗同步曲妥珠单抗同样有效的一个方案。NCCN指南推荐总共12个月的辅助性曲妥珠单抗作为标准治疗。比12个月更短的持续时间尚未被认为是有效的而比12个月更长的持续时间没有增加任何获益，已发现其与12个月的曲妥珠单抗治疗等效。

Retrospective analyses of low-risk patients with small tumors demonstrate that in T1a-bN0 breast cancers, HER2 overexpression added a 15% to 30% risk for recurrence. These risks rates are substantially higher than seen among similarly sized HER2-negative tumors.

低危小肿瘤患者的回顾性分析表明在T1a-bN0乳腺癌中HER2过表达复发危险增加15%-30%。这些风险率显著高于在同样大小的HER2阴性肿瘤当中见到的。

A recent single-arm, multicenter trial studied the benefit of trastuzumab- based chemotherapy in patients with HER2-positive, node-negative tumors less than or equal to 3 cm. All patients received trastuzumab and weekly paclitaxel for 12 weeks, followed by completion of a year of trastuzumab monotherapy. Fifty percent of patients enrolled had tumors less than or equal to 1.0 cm and 9% of patients had tumors that were between 2 and 3 cm. The endpoint of the study was DFS. The results presented at the 2013 Annual San Antonio Breast Cancer Symposium demonstrated that the 3-year DFS rate in the overall population was 98.7% (95% CI, 97.6-99.8; P < .0001).

最近一项单臂、多中心试验研究了以曲妥珠单抗为基础的化疗在HER2阳性、淋巴结阴性、肿瘤≤3cm患者中的获益。所有患者均接受了曲妥珠单抗和每周1次紫杉醇12周，然后完成1年的曲妥珠单抗单药治疗。入组的患者50%肿瘤≤1.0cm而9%的患者肿瘤在2-3cm之间。研究终点是DFS。2013圣安东尼奥乳腺癌座谈年会介绍的结果显示总体3年DFS率是98.7%(95% CI，97.6-99.8；P＜.0001)。

Dual anti-HER2 blockade associated with trastuzumab plus lapatinib and trastuzumab plus pertuzumab has shown significant improvements in the pCR rate when compared with chemotherapy associated with one anti-HER2 agent in the neoadjuvant setting.

在新辅助治疗方案中曲妥珠单抗加拉帕替尼与曲妥珠单抗加帕妥珠单抗联合双抗HER2阻滞已证明与化疗联合一个抗HER2药物相比显著提高pCR率。

However, in the adjuvant setting, the results of the ALTTO trial failed to demonstrate a significant improvement in DFS with dual anti-HER2 therapy compared with trastuzumab alone. After a median follow-up of 4.5 years, the DFS rates were 86% for patients who received trastuzumab alone; 88% for participants treated with trastuzumab and lapatinib concurrently; and 87% for patients who received trastuzumab followed by lapatinib.

然而，在辅助治疗情况下，ALTTO试验的结果未能证明与单独曲妥珠单抗相比联合双抗HER2治疗显著改善DFS。

在中位随访4.5年后，DFS率仅接受曲妥珠单抗的患者是86%；同时接受曲妥珠单抗和拉帕替尼治疗者是88%；而接受曲妥珠单抗序贯拉帕替尼的患者是87%。

NCCN Recommendation for Adjuvant HER2-Targeted Therapy

NCCN推荐的辅助HER2靶向治疗

Based on these studies, the panel has designated use of trastuzumab with chemotherapy as a category 1 recommendation in patients with HER2-positive tumors greater than 1 cm.

基于这些研究，小组已指定在HER2阳性肿瘤大于1cm的患者中曲妥珠单抗联合化疗的应用为1类推荐。

The NCCN Panel suggests trastuzumab and chemotherapy be used for women with HER2-positive, node-negative tumors measuring 0.6 to 1.0 cm (ie, T1b) and for smaller tumors that have less than or equal to 2 mm axillary node metastases (pN1mi). Some support for this recommendation comes from studies showing a higher risk of recurrence for patients with HER2-positive, node-negative tumors less than or equal to 1 cm compared to those with HER2-negative tumors of the same size. Ten-year breast cancer-specific survival and 10-year recurrence-free survival were 85% and 75%, respectively, in women with tumors characterized as HER2-positive, ER-positive tumors, and 70% and 61%, respectively, in women with HER2-positive, ER-negative tumors. Two more retrospective studies have also investigated recurrence-free survival in this patient population. None of the patients in these two retrospective studies received trastuzumab. In the first study, 5-year recurrence-free survival rates of 77.1% and 93.7% (P < .001) were observed for patients with HER2-positive and HER2-negative T1a-bN0M0 breast tumors, respectively, with no recurrence-free survival differences seen in the HER2-positive group when hormonal receptor status was considered. In the other retrospective study of women with small HER2-positive tumors, the risk of recurrence at 5 years was low (99% [95% CI; 96%-100%] for HER2- negative disease and 92% [95% CI; 86%-99%] for HER2-positive disease). Subgroup analyses from several of the randomized trials have shown consistent benefit of trastuzumab irrespective of tumor size or nodal status.

NCCN小组建议曲妥珠单抗和化疗用于HER2阳性、淋巴结阴性、肿瘤0.6-1.0cm(如，T1b)和肿瘤较小腋淋巴结转移≤2mm(pN1mi)的女性。支持该推荐的一些研究显示与淋巴结阴性、肿瘤≤1cmHER2阴性的患者相比肿瘤同样大小HER2阳性的患者复发风险更高。10年乳腺癌特异性生存和10年无复发生存在肿瘤特征为HER2阳性、ER阳性的女性中分别是85%和75%，而在HER2阳性、ER阴性肿瘤女性中分别是70%和61%。两项回顾性研究还进一步研究了这一患者群的无复发生存。在这两项回顾性研究中没有1例患者接受曲妥珠单抗。在第一项研究中，5年无复发生存率HER2阳性和HER2阴性T1a-bN0M0乳腺癌患者分别是77.1%和93.7%(P＜.001)，在HER2阳性组中当考虑激素受体状态时无复发生存没有见到差异。在另一项HER2阳性小肿瘤女性的回顾性研究中，在5年时复发风险低(HER2阴性疾病99%[95% CI；96%-100%]而HER2阳性疾病92%[95% CI；86%-99%])。若干随机试验的亚组分析已经证明不管肿瘤大小或淋巴结情况如何曲妥珠单抗均一致获益。

NCCN Recommended HER-Targeted Regimens

NCCN推荐的HER靶向方案

The panel recommends AC followed by paclitaxel with trastuzumab for 1 year commencing with the first dose of paclitaxel as a preferred HER2 targeting adjuvant regimen. The TCH regimen is also a preferred regimen, especially for those with risk factors for cardiac toxicity, given the results of the BCIRG 006 study that demonstrated superior DFS in patients receiving TCH or AC followed by docetaxel plus trastuzumab compared with AC followed by docetaxel alone.

专家组推荐AC序贯紫杉醇从第一剂紫杉醇开始联合曲妥珠单抗1年作为一个首选的HER2靶向辅助方案。TCH方案也是一个首选方案，特别是对于那些具有心脏毒性危险因素者，已知BCIRG 006研究结果证明与单纯AC序贯多西他赛相比接受TCH或AC序贯多西他赛加曲妥珠单抗的患者DFS占优势。

Other trastuzumab-containing regimens included in the NCCN Guidelines are: AC followed by docetaxel and trastuzumab, and docetaxel plus trastuzumab followed by FEC (see Neoadjuvant/Adjuvant Chemotherapy in the algorithm for a complete list of regimens).

NCCN指南中收入的其它含曲妥珠单抗方案是：AC序贯多西他赛和曲妥珠单抗，多西他赛加曲妥珠单抗序贯FEC(见新辅助/辅助化疗规则系统方案一览表)。

Considering the unprecedented improvement in OS in the metastatic setting and the significant improvement in pCR seen in the neoadjuvant setting, the NCCN Panel considers it reasonable to incorporate pertuzumab into the above adjuvant regimens, if the patient did not receive pertuzumab as a part of neoadjuvant therapy. An ongoing study is evaluating pertuzumab and trastuzumab with standard chemotherapy regimens in the adjuvant setting.

考虑到在转移组OS空前改善以及此新辅助治疗方案显著提高pCR，NCCN小组认为如果患者未接受帕妥珠单抗作为新辅助治疗的一部分，帕妥珠单抗并入上述辅助方案是合理的。一项正在进行的研究评估帕妥珠单抗和曲妥珠单抗联合标准化疗方案辅助治疗。

The NCCN Panel has included paclitaxel and trastuzumab as an option for patients with low-risk, HER2-positive, stage 1 tumors. This is based on a trial that studied this combination in 406 patients with small, node- negative, HER2-positive tumors. The results showed that the 3-year rate of disease-free survival was 98.7% (95% CI, 97.6-99.8) and the risk of serious toxic effects with this regimen was low (incidence of heart failure reported was 0.5%).

NCCN小组已经收入紫杉醇和曲妥珠单抗作为低危、HER2阳性、1期肿瘤患者的一个选择。这是根据一项研究这一联合治疗406例小肿瘤、淋巴结阴性、HER2阳性患者的试验。结果显示3年无病生存率是98.7%(95% CI，97.6-99.8)而此方案的严重毒性风险低(报道的心衰发生率是0.5%)。