柳叶刀:曲妥珠单抗治疗早期乳腺癌

  人类表皮生长因子受体HER2过度表达于大约10%~20%的早期乳腺癌,可显著增加复发和死亡风险。曲妥珠单抗可靶向结合HER2的细胞外结构区,抑制促癌信号传导。对于早期HER2阳性乳腺癌患者,将曲妥珠单抗加入化疗,可显著减少复发和死亡风险,不过也可能增加心脏毒性。

  2021年7月31日,英国《柳叶刀》肿瘤学分册在线发表早期乳腺癌试验者协作组(EBCTCG)研究报告,对7项随机对照试验1万3864例早期HER2阳性乳腺癌女性接受曲妥珠单抗辅助治疗的长期获益和风险进行了荟萃分析。

  该研究首先对美国国家医学图书馆、荷兰医学文摘、考科蓝图书馆和会议摘要进行文献检索,筛选出2020年3月31日前发表的化疗±曲妥珠单抗治疗淋巴结阴性或淋巴结阳性可手术乳腺癌女性随机对照试验。随后收集关于基线特征、首次远处乳腺癌复发和任何既往局部区域复发或第二原发癌的日期和部位、死亡日期和可能原因的患者个体水平数据进行荟萃分析。主要结局指标为乳腺癌复发、乳腺癌死亡、无复发死亡、全因死亡。按年龄、淋巴结状态、雌激素受体状态、试验首次事件比值比进行分层,根据标准意向治疗进行对数秩分析。

  结果,7项随机对照试验符合入选标准,包括2000年2月~2005年12月入组的1万3864例患者:

  • FinHER:2000~2003年入组231例

  • NSABP B-31:2000~2005年入组2119例

  • NCCTG N9831:2000~2005年入组3505例

  • HERA:2001~2005年入组5099例

  • PACS 04:2001~2004年入组528例

  • BCIRG 006:2001~2004年入组2147例

  • NOAH:2002~2005年入组235例

  平均计划疗程14.4个月,中位随访10.7年(四分位:9.5~11.9)。

  曲妥珠单抗+化疗与单用化疗相比:

  • 乳腺癌复发率低34%(比值比:0.66,95%置信区间:0.62~0.71,P<0.0001)

  • 乳腺癌所致死亡率低33%(比值比:0.67,95%置信区间:0.61~0.73,P<0.0001)

  • 十年复发率绝对值低9.0%(95%置信区间:7.4~10.7,P<0.0001)

  • 十年乳腺癌死亡率低6.4%(95%置信区间:4.9~7.8,P<0.0001)

  • 任何原因致死亡率低6.5%(95%置信区间:5.0~8.0,P<0.0001)

  • 非复发所致死亡率相似(比值比:0.90,95%置信区间:0.72~1.12,P=0.35)

  • 心血管所致死亡率相似(比值比:1.23,95%置信区间:0.73~2.06,P=0.44)

  • 其他癌所致死亡率相似(比值比:0.79,95%置信区间:0.54~1.17,P=0.24)

  曲妥珠单抗+化疗与单用化疗相比,随机分组后的乳腺癌复发率逐渐接近:

  • 0~1年:低47%(比值比:0.53,99%置信区间:0.46~0.61)

  • 2~4年:低27%(比值比:0.73,99%置信区间:0.62~0.85)

  • 5~9年:低20%(比值比:0.80,99%置信区间:0.64~1.01)

  • ≥10年:随访数据极少

  无论记录在案的患者特征和雌激素受体状态等肿瘤特征如何,曲妥珠单抗+化疗与单用化疗相比,乳腺癌复发率都显著较低。

  曲妥珠单抗+化疗与单用化疗相比,淋巴结分期越高,5年复发率越低:

  • N0期:低5.7%(95%置信区间:3.1~8.3)

  • N1~3期:低6.8%(95%置信区间:4.7~9.0)

  • ≥N4期:低10.7%(95%置信区间:7.7~13.6)

  不过,曲妥珠单抗+化疗与单用化疗相比:

  • 第1年非乳腺癌所致死亡率高115%(0.37%比0.16%,比值比:2.15,95%置信区间:1.11~4.14,P=0.023)

  • 化疗、曲妥珠单抗同时给药的第1年非乳腺癌所致死亡率:0.34%比0.22%

  • 化疗、曲妥珠单抗先后给药的第1年非乳腺癌所致死亡率:0.43%比0.13%

  因此,该研究结果表明,对于早期HER2阳性乳腺癌,曲妥珠单抗+化疗与单用化疗相比,乳腺癌复发率和乳腺癌死亡率可减少三分之一,无论记录在案的患者特征和肿瘤特征如何。虽然曲妥珠单抗+化疗的心脏毒性发生率较高,但是非复发所致死亡率、心血管所致死亡率相似。

  此外,该研究正文仅12页,附录达39页,而且还对上述7项以外的随机对照试验进行了其他结局指标分析,信息量庞大,值得细读。点击本文左下角阅读原文链接,可免费下载全文。

Lancet Oncol. 2021 Aug 1;22(8):1139-1150.

Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13864 women in seven randomised trials.

Early Breast Cancer Trialists' Collaborative group (EBCTCG).

BACKGROUND: Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality.

METHODS: We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs).

FINDINGS: Seven randomised trials met the inclusion criteria, and included 13864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14.4 months and median follow-up was 10.7 years (IQR 9.5 to 11.9). The risks of breast cancer recurrence (RR 0.66, 95% CI 0.62 to 0.71; P<0.0001) and death from breast cancer (0.67, 0.61 to 0.73; P<0.0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Absolute 10-year recurrence risk was reduced by 9.0% (95% CI 7.4 to 10.7; P<0.0001) and 10-year breast cancer mortality was reduced by 6.4% (4.9 to 7.8; P<0.0001), with a 6.5% reduction (5.0 to 8.0; P<0.0001) in all-cause mortality, and no increase in death without recurrence (0.4%, -0.3 to 1.1; P=0.35). The proportional reduction in recurrence was largest in years 0-1 after randomisation (0.53, 99% CI 0.46 to 0.61), with benefits persisting through years 2-4 (0.73, 0.62 to 0.85) and 5-9 (0.80, 0.64 to 1.01), and little follow-up beyond year 10. Proportional recurrence reductions were similar irrespective of recorded patient and tumour characteristics, including ER status. The more high risk the tumour, the larger the absolute reductions in 5-year recurrence (eg, 5.7% [95% CI 3.1 to 8.3], 6.8% [4.7 to 9.0], and 10.7% [7.7 to 13.6] in N0, N1-3, and N4+ disease).

INTERPRETATION: Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics.

FUNDING: Cancer Research UK, UK Medical Research Council.

DOI: 10.1016/S1470-2045(21)00288-6

(0)

相关推荐