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恩美曲妥珠单抗（T-DM1）由1个大分子抗体曲妥珠单抗（分子量达145531.86）与平均3.5个小分子药物恩坦辛（分子量仅738.29）通过不可分解的共价键缀合（俗称偶联）而成，可在HER2阳性癌细胞内靶向释放高浓度恩坦辛而发挥抗癌作用，能够显著改善晚期HER2阳性乳腺癌患者生存。不过，T-DM1与曲妥珠单抗单药相比，具有独特的副作用，包括血小板减少和转氨酶升高等全身毒性反应，并可能与治疗效果、患者无病生存结局存在相关性。 2021年5月6日，国际抗癌联盟《国际癌症杂志》清样发表美国密西西比大学癌症中心、奥古斯塔大学乔治亚癌症中心、加拿大艾伯塔大学癌症中心的研究报告，探讨了T-DM1全身毒性对HER2阳性晚期乳腺癌治疗效果和患者无病生存结局的预测作用。 该多中心回顾观察研究对2013年T-DM1上市以来美国和加拿大三个癌症中心接受至少一次T-DM1治疗的73例HER2阳性晚期乳腺癌患者进行回顾分析，根据毒性分级汇总结果，创建相应毒性总评分并分析其与临床结局的相关性。 结果发现，毒性总评分每增加1分，进展或死亡风险低34%（风险比：0.66，95%置信区间：0.47～0.92，P=0.014）。 对治疗前血小板计数、谷草转氨酶、谷丙转氨酶进行校正后，毒性总评分每增加1分，进展或死亡风险仍然低33%（校正后风险比：0.67，95%置信区间：0.47～0.93，P=0.020）。 因此，该小样本回顾研究首次对T-DM1全身毒性与临床结局的相关性进行分析，结果表明T-DM1的全身毒性与临床疗效显著相关，可以作为预测抗体缀合药物疗效的生物学指标，尤其对于由不可分解的共价键缀合而成时。如果该研究结果能够被大样本前瞻研究证实，那么具有重要临床意义，因为除了是否存在抗体靶点之外，大多数抗体缀合药物都缺乏可预测临床结局的生物学指标。 Int J Cancer. 2021 May 6. Online ahead of print. Systemic toxicities of trastuzumab-emtansine predict tumor response in HER2+ metastatic breast cancer. Tang SC, Capra CL, Ajebo GH, Meza-Junco J, Mairs S, Craft BS, Zhu X, Maihle N, Hillegass WB. University of Mississippi Medical Center, Jackson, Mississippi, USA; Alabama Oncology, Birmingham, Alabama, USA; Augusta University, Augusta, Georgia, USA; University of Alberta, Edmonton, Alberta, Canada. What's new? Linkage of trastuzumab to emtansine (T-DM1), a tumor-antigen specific antibody, is associated with improved survival in patients with metastatic HER2+ breast cancer. Relative to trastuzumab alone, however, trastuzumab-emtansine (T-DM1) has unique side effects, including throbocytopenia and transaminitis. In this investigation of systemic toxicities, tumor response, and patient outcome, higher toxicity sum score for T-DM1 was significantly associated with improved tumor response and increased progression-free survival in metastatic HER2+ breast cancer patients. The findings suggest that emtansine freed from lysed HER2+ breast cancer cells potentially influences T-DM1 toxicity and that systemic toxicities of antibody-drug conjugates function as predictive biomarkers. The mechanism by which trastuzumab-emtansine (T-DM1) causes systemic toxicities apart from trastuzumab alone is currently unknown. We hypothesized that the systemic toxicities from T-DM1 may have been caused by the free and active maytansine released from the lysed HER2+ tumor cells, and if so, they may correlate with the response to treatment and eventually disease-free survival or patient outcome. In a retrospective, observational study, we evaluated 73 patients from three centers in the United States and Canada with advanced HER2+ breast cancer that received at least one dose of T-DM1. Toxicity grades were summed to create a corresponding toxicity sum score (TSS), and its association with clinical outcomes was analyzed. A higher TSS was significantly associated with longer progression-free survival with an HR = 0.66 [95% confidence interval [CI]: 0.47-0.92], P = .014, for each 1-point increase in the TSS score. Adjusted for baseline platelet count, aspartate transaminase and alanine transaminase, higher TSS remains significantly associated with longer progression-free survival with adjusted HR = 0.67 [95% CI: 0.47-0.93], P = .020. The analysis suggests that the systemic toxicities of T-DM1 were significantly correlated with its clinical efficacy. This is the first report to correlate the systemic toxicities of T-DM1 with clinical outcome. Further, this suggests that systemic toxicities of antibody-drug conjugates (ADCs) may serve as a predictive biomarker, particularly if noncleavable linkers are used. If confirmed in larger prospective studies, the present finding is significant because most ADCs do not have a biomarker predictive of clinical outcome other than the presence or absence of the antibody target. KEYWORDS: antibody-drug conjugate; clinical outcomes; correlative study; systemic toxicities; trastuzumab-emtansine PMID: 33844843 DOI: 10.1002/ijc.33597 |
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