乳腺癌术前妥妥双靶合璧能否去蒽环
对于HER2阳性乳腺癌，曲妥珠单抗联合蒽环类可能产生严重的心脏毒性，尤其蒽环类还可能产生血液毒性。不过，由于蒽环类具有强大的抗肿瘤活性，故许多临床医师仍然不愿去掉蒽环类。随着帕妥珠单抗的问世，进一步提高了曲妥珠单抗的疗效。那么，帕妥珠单抗＋曲妥珠单抗双靶合璧时，能否去掉蒽环类？2018年，英国《柳叶刀》肿瘤学分册发表的TRAIN-2研究短期（中位19个月）随访结果表明，HER2阳性早期乳腺癌术前曲妥珠单抗＋帕妥珠单抗±蒽环类新辅助化疗方案的术后病理完全缓解率相似，≥3级中性粒细胞减少伴发热发生率显著较高，短期心脏毒性发生率相似，长期毒性和生存结局尚不明确。
TRAIN-2 (NCT01996267): Neoadjuvant Chemotherapy in HER2 Positive Breast Cancer (Optimizing Neoadjuvant Systemic Treatment for HER2 Positive Breast Cancer)
2021年5月20日，《美国医学会杂志》肿瘤学分册在线发表荷兰癌症研究所、阿姆斯特丹大学、雷尼尔格拉夫医院、特温特医院、伊萨拉医院、马克西玛医疗中心、维埃库里医疗中心、卡尼修斯威廉敏娜医院、卡塔琳娜癌症中心的TRAIN-2研究长期随访结果，对HER2阳性早期乳腺癌术前曲妥珠单抗＋帕妥珠单抗±蒽环类新辅助化疗方案的3年无事件生存和总生存进行了比较。
该多中心非盲随机对照三期临床研究于2013年12月9日～2016年1月14日从37家荷兰医院入组早期（II或III期）HER2阳性乳腺癌患者438例，按年龄、肿瘤分期、淋巴结分期、雌激素受体状态进行分层，按1∶1的比例随机分为两组：
有蒽环组219例（中位年龄49岁，四分位43～55岁）：每3周曲妥珠单抗＋帕妥珠单抗＋3轮氟尿嘧啶＋表柔比星90mg/m²＋环磷酰胺→6轮紫杉醇＋卡铂
无蒽环组219例（中位年龄48岁，四分位43～56岁）：每3周曲妥珠单抗＋帕妥珠单抗＋9轮紫杉醇＋卡铂
对意向治疗患者进行无事件生存和总生存分析，对实际治疗患者进行安全性分析。事件定义为疾病进展造成无法手术、复发（除了对侧乳腺导管原位癌）、继发原发恶性肿瘤、任何原因所致死亡。
结果，中位随访48.8个月（四分位44.1～55.2个月）期间，有蒽环组219例与无蒽环组219例意向治疗患者相比：
无事件生存事件：23例比21例（10.5%比9.6%，风险比：0.90，95%置信区间：0.50～1.63）
三年无事生存率：92.7%比93.6%（95%置信区间：89.3%～96.2%、90.4%～96.9%）
三年总体生存率：97.7%比98.2%（95%置信区间：95.7%～99.7%、96.4%～100%）
激素受体和淋巴结状态对上述结果影响不大。
随机分入无蒽环组的1例患者实际接受了蒽环类化疗，故被纳入有蒽环组进行安全性分析，有蒽环组220例与无蒽环组218例实际治疗患者相比：
左心室射血分数下降：17例比7例（7.7%比3.2%，P=0.04）
中性粒细胞减少发热：17例比2例（8%比1%，P<0.0001）
化疗相关急性白血病：2例比0例
因此，该研究长期随访结果表明，对于II或III期HER2阳性乳腺癌患者，术前曲妥珠单抗＋帕妥珠单抗±蒽环类新辅助化疗相比，3年无事件生存和总生存相似，中性粒细胞减少伴发热、心脏毒性反应、继发恶性肿瘤风险较高。
对此，美国洛杉矶加利福尼亚大学（俗称加州大学洛杉矶分校）大卫·格芬医学院琼森综合癌症中心萨拉·赫维茨教授发表同期评论：蒽环类用于HER2阳性乳腺癌亟待重新培训（Re-TRAIN）。
不过，该研究所用化疗方案似乎都不是目前临床实践通用最佳标准方案，表柔比星剂量也偏低，前3轮化疗貌似氟尿嘧啶＋表柔比星＋环磷酰胺与紫杉醇＋卡铂比较，并非严格的有无表柔比星比较，而且3年随访时间对于早期乳腺癌患者而言显然偏短，样本量也偏小，疗效相似的说服力可能不足。
相关链接
JAMA Oncol. 2021 May 20. Online ahead of print.
Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients With ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial.
Anna van der Voort; Mette S. van Ramshorst; Erik D. van Werkhoven; Ingrid A. Mandjes; Inge Kemper; Annelie J. Vulink; Irma M. Oving; Aafke H. Honkoop; Lidwine W. Tick; Agnes J. van de Wouw; Caroline M. Mandigers; Laurence J. van Warmerdam; Jelle Wesseling; Marie-Jeanne T. Vrancken Peeters; Sabine C. Linn; Gabe S. Sonke.
Netherlands Cancer Institute, Amsterdam, the Netherlands; Amsterdam University Medical Centers, Amsterdam, the Netherlands; Reinier de Graaf Gasthuis, Delft, the Netherlands; Ziekenhuisgroep Twente, Almelo, the Netherlands; Isala, Zwolle, the Netherlands; Maxima Medical Center, Eindhoven, the Netherlands; VieCuri Medical Center, Venlo, the Netherlands; Canisius Wilhelmina hospital, Nijmegen, the Netherlands; Catharina Cancer Centre, Eindhoven, the Netherlands.
This randomized clinical trial evaluates 3-year event-free survival and overall survival of an anthracycline-free and anthracycline-containing regimen with dual ERBB2 blockade in patients with stage II and III ERBB2-positive breast cancer.
QUESTION: What are the 3-year efficacy and safety results of a regimen with or without anthracyclines with dual ERBB2 (formerly HER2) blockade for stage II and III ERBB2-positive breast cancer?
FINDINGS: The follow-up results of this randomized multicenter phase 3 trial of 438 patients with stage II and III ERBB2-positive breast cancer showed similar 3-year event-free survival estimates of 93% in patients treated with anthracyclines and 94% in patients treated without anthracyclines. Left ventricular ejection fraction decline was more common in the anthracycline group and 2 patients treated with anthracyclines developed acute leukemia.
MEANING: These results add to the literature on omitting anthracyclines in early-stage ERBB2-positive breast cancer.
IMPORTANCE: Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dual ERBB2 (formerly HER2) blockade.
OBJECTIVE: To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dual ERBB2 blockade in patients with stage II and III ERBB2-positive breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: A total of 438 patients with stage II and III ERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis.
INTERVENTIONS: Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m2 days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks.
MAIN OUTCOMES AND MEASURES: Three-year EFS, OS, and safety.
RESULTS: A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%]; P=0.04). Two patients treated with anthracyclines developed acute leukemia.
CONCLUSIONS AND RELEVANCE: This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and III ERBB2-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01996267
DOI: 10.1001/jamaoncol.2021.1371
JAMA Oncol. 2021 May 20. Online ahead of print.
Anthracycline Use in ERBB2-Positive Breast Cancer: It Is Time to Re-TRAIN.
Sara A. Hurvitz.
Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles.
DOI: 10.1001/jamaoncol.2021.1314