Systemic toxicities of trastuzumab-emtansine predict tumor response in HER2+ metastatic breast cancer
| Autor: | Simon Mairs, Nita J. Maihle, Shou-Ching Tang, Barbara S. Craft, William B. Hillegass, Xiaofu Zhu, Judith Meza-Junco, Germame Ajebo, Carter Louis Capra |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty Antibody-drug conjugate Aspartate transaminase correlative study 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Breast cancer Trastuzumab Internal medicine Medicine Cancer Therapy and Prevention biology trastuzumab‐emtansine business.industry systemic toxicities medicine.disease Metastatic breast cancer clinical outcomes Alanine transaminase chemistry Trastuzumab emtansine 030220 oncology & carcinogenesis biology.protein Biomarker (medicine) business medicine.drug antibody‐drug conjugate |
| Zdroj: | International Journal of Cancer |
| ISSN: | 1097-0215 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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