埃及艳后：晚期乳腺癌腹泻皮疹结局
CLEOPATRA研究已证实帕妥珠单抗可显著改善曲妥珠单抗＋多西他赛一线治疗HER2阳性晚期乳腺癌患者无进展生存和总生存结局。不过，腹泻和皮疹是帕妥珠单抗的常见副作用。其他抗HER2药物研究表明，副作用可能是患者生存结局预后指标和药物获益预测标志。不过，帕妥珠单抗相关腹泻和皮疹对患者生存结局的预后作用和帕妥珠单抗获益的预测作用尚不明确。
2021年2月1日，欧洲癌症治疗研究组织《欧洲癌症杂志》将正式发表比利时布鲁塞尔自由大学朱尔博代研究院、葡萄牙里斯本大学、尚帕利莫基金会临床中心、弗朗西斯科任蒂尔肿瘤研究所、意大利热那亚大学、圣马蒂诺综合医院、德国科隆大学、加拿大蒙泰雷吉中心、查尔斯莱莫因医院、巴西圣保罗卡玛戈癌症中心的CLEOPATRA研究回顾分析报告，探讨了帕妥珠单抗相关腹泻或皮疹对HER2阳性晚期乳腺癌患者生存结局的预后作用和帕妥珠单抗获益的预测作用。
CLEOPATRA (NCT00567190): A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer
为了减少生存时间偏倚或恒定时间偏倚，该多中心双盲安慰剂随机对照三期临床研究的回顾分析定义了2个分析队列：队列1包括开始治疗的全部患者，队列2包括多西他赛停药后的患者。研究终点为无进展生存和总生存，并且利用多因素比例风险回归模型，对年龄、美国东部肿瘤学协作组ECOG体力状态评分、激素受体状态、内脏转移、早期术前或术后抗HER2治疗等其他影响因素进行校正。
结果，患者共计808例，队列1和队列2分别包括777例和518例患者。队列1患者分别发生皮疹271例（34.9%）和腹泻470例（60.5%）。
有、无皮疹相比，帕妥珠单抗组2个队列患者的无进展生存和总生存都显著较好：
队列1多因素分析
无进展生存（校正后风险比：0.71，95%置信区间：0.56～0.91，P=0.006）
总生存（校正后风险比：0.66，95%置信区间：0.48～0.91，P=0.010）
队列2多因素分析
无进展生存（校正后风险比：0.55，95%置信区间：0.38～0.81，P=0.002）
总生存（校正后风险比：0.52，95%置信区间：0.30～0.89，P=0.018）
有、无腹泻相比，帕妥珠单抗组仅队列2患者的无进展生存显著较好：
队列1多因素分析
无进展生存（校正后风险比：0.79，95%置信区间：0.61～1.01，P=0.062）
总生存（校正后风险比：0.76，95%置信区间：0.55～1.06，P=0.101）
队列2多因素分析
无进展生存（校正后风险比：0.65，95%置信区间：0.46～0.91，P=0.011）
总生存（校正后风险比：0.66，95%置信区间：0.41～1.06，P=0.087）
帕妥珠单抗组有皮疹、帕妥珠单抗组无皮疹、安慰剂组有皮疹、安慰剂组无皮疹相比，2个队列患者的无进展生存和总生存都相似。
帕妥珠单抗组有腹泻、帕妥珠单抗组无腹泻、安慰剂组有腹泻、安慰剂组无腹泻相比，2个队列患者的无进展生存和总生存都相似。
因此，该研究结果表明，对于帕妥珠单抗＋曲妥珠单抗＋多西他赛一线治疗HER2阳性晚期乳腺癌患者，整个治疗期间只要出现皮疹都具有无进展生存和总生存结局预后作用，与多西他赛无关，而仅出现于多西他赛停药后的腹泻具有无进展生存结局预后作用。不过，皮疹和腹泻对于帕妥珠单抗的生存获益都无预测作用。
相关链接
Eur J Cancer. 2021 Feb 1;144:351-359.
Association between pertuzumab-associated diarrhoea and rash and survival outcomes in patients with HER2-positive metastatic breast cancer: Exploratory analysis from the CLEOPATRA trial.
R Ferreira A, Ferreira S, Lambertini M, Maurer C, Martel S, Costa L, Ponde N, de Azambuja E.
Institut Jules Bordet, L'Université Libre de Bruxelles, Belgium; Universidade de Lisboa, Portugal; Champalimaud Clinical Center, Champalimaud Foundation, Portugal; Instituto Português de Oncologia de Lisboa Francisco Gentil, Portugal; IRCCS Ospedale Policlinico San Martino, Genova, Italy; University of Genova, Genova, Italy; University of Cologne, Germany; CISSS Montérégie-centre/Hopital Charles-Lemoyne, Canada; AC Carmargo Cancer Center, Sao Paulo, Brazil.
HIGHLIGHTS
First-line pertuzumab improves survival in metastatic HER2-positive breast cancer.
Rash and diarrhoea are common side-effects of pertuzumab.
Rash is prognostic independently of docetaxel use.
Diarrhoea is prognostic for PFS only after docetaxel use.
Both rash and diarrhoea are not predictive of PFS and/or OS.
BACKGROUND: Skin rash and diarrhoea are known side-effects of pertuzumab. Studies with other anti-HER2 agents suggested that adverse events correlate with patient outcomes. In this exploratory cohort of patients with metastatic HER2-positive breast cancer included in the CLEOPATRA trial we evaluated the value of rash and diarrhoea as prognostic markers and as predictors of pertuzumab benefit.
METHODS: This is a retrospective analysis of the multicenter, prospective, randomised CLEOPATRA trial. We defined two analytic cohorts: cohort 1 (C1) included patients from treatment initiation, and cohort 2 (C2) included patients after discontinuation of docetaxel. A landmark analysis was introduced to deal with immortal-time bias. Study endpoints were progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazards models were used.
RESULTS: Of the 808 patients and after application of the landmark analysis, C1 and C2 included 777 and 518 patients, respectively. In C1, rash occurred in 271 patients (34.9%) and diarrhoea in 470 (60.5%). Rash was prognostic for PFS and OS (C1: adjusted hazard ratio [aHR] = 0.66 [95% CI = 0.48-0.91], p = 0.010]; C2: aHR 0.52 [95% CI = 0.30-0.89], p = 0.018) in both cohorts, while diarrhoea was only prognostic for PFS in cohort 2 (aHR = 0.65 [95% CI = 0.46-0.91], p = 0.011). Rash and diarrhoea were not predictive of pertuzumab benefit (in terms of PFS/OS) in the two cohorts.
CONCLUSIONS: In patients treated with pertuzumab, trastuzumab, and docetaxel, rash is prognostic whenever it occurs during treatment, while diarrhoea only has prognostic value when occurring after docetaxel discontinuation. However, neither rash nor diarrhoea predict pertuzumab benefit.
KEYWORDS: Advanced breast cancer; Diarrhea; Dual blockade; HER2; Pertuzumab; Predictive markers; Prognostic markers; Rash; Trastuzumab
PMID: 33388492
DOI: 10.1016/j.ejca.2020.11.023