Tang Shou-Ching, Capra Carter L, Ajebo Germame H, Meza-Junco Judith, Mairs Simon, Craft Barbara S, Zhu Xiaofu, Maihle Nita, Hillegass William B
Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Alabama Oncology, Birmingham, Alabama, USA.
Int J Cancer. 2021 Apr 12;149(4):909-16. doi: 10.1002/ijc.33597.
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.
除曲妥珠单抗外，曲妥珠单抗-恩美曲妥珠单抗（T-DM1）导致全身毒性的机制目前尚不清楚。我们推测，T-DM1的全身毒性可能是由裂解的HER2+肿瘤细胞释放的游离且具有活性的美登素引起的，如果是这样，它们可能与治疗反应相关，并最终与无病生存期或患者预后相关。在一项回顾性观察研究中，我们评估了来自美国和加拿大三个中心的73例晚期HER2+乳腺癌患者，这些患者接受了至少一剂T-DM1。将毒性等级相加得出相应的毒性总分（TSS），并分析其与临床结果的关联。TSS每增加1分，更高的TSS与更长的无进展生存期显著相关，风险比（HR）=0.66[95%置信区间（CI）：0.47-0.92]，P=0.014。在对基线血小板计数、天冬氨酸转氨酶和丙氨酸转氨酶进行校正后，更高的TSS仍然与更长的无进展生存期显著相关，校正后的HR=0.67[95%CI：0.47-0.93]，P=0.020。该分析表明，T-DM1的全身毒性与其临床疗效显著相关。这是首篇将T-DM1的全身毒性与临床结果相关联的报告。此外，这表明抗体药物偶联物（ADC）的全身毒性可能作为一种预测性生物标志物，特别是在使用不可裂解连接子时。如果在更大规模的前瞻性研究中得到证实，目前的发现具有重要意义，因为除了抗体靶点的存在与否外，大多数ADC没有预测临床结果的生物标志物。
