Chemotherapy is an important adjuvant therapy for patients with EC, but chemotherapy resistance is one of the reasons for the failure of clinical EC therapy.[1,37–39] At present, there are many mechanisms of drug resistance, including gene heterogeneity, cell growth heterogeneity, and cell growth repair.[40,41] Previous results showed that there were significant differences in gene expression and phenotypic characteristics between the multiple passages of tumor cell lines and primary tumor cells.[10,42,43] Tumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection, revealing that tumor heterogeneity might affect the response to treatment. During the course of cancer chemotherapy, drug resistance and side effects were the main limitations.
Our results showed that there were DEG profiles between primary EC and the paired metastases or the relapsed samples. Therefore, genetic heterogeneity and cell growth heterogeneity should be considered in clinical chemotherapy.
Paclitaxel combined with carboplatin (Platinum) is the first-line chemotherapy regimen for patients with EC. However, due to the intra-tumor heterogeneity of EC cells, there was a significant difference in the reactivity and efficacy of chemotherapy. Whether according to the EC tissue and cell heterogeneity, different types of patients with EC and the same tissue type of patients with EC, different chemotherapeutic regimens and chemotherapeutic methods may be used to improve the curative effect, which becomes the focus of attention of clinicians. Sequential chemotherapy is the sequential application of non-cross-resistant regimens in accordance with the Norton-Simon hypothesis,[44,45] in which the specific way of therapeutic regimen is to apply several cycles of the optimum dose of regimens A first, and then give several cycles of the optimal dose of regimens B. The most suitable regimens may be treated with a single drug or drug combination regimens, which aims to improve the efficacy of chemotherapy and reduce side effects.[44,45] Sequential chemotherapy has been used as the first-line chemotherapy regimen for gestational trophoblastic neoplasia for many years with excellent therapeutic results, has been applied to other human tumors, such as breast cancer, lung cancer, and ovarian cancer[47,48] and to a certain extent, showed better curative effect than conventional combined chemotherapy. A phase II study conducted by Mäenpää et al also showed that sequential gemcitabine-carboplatin followed by paclitaxel-carboplatin was feasible in the first-line treatment of advanced ovarian cancer. Recent studies of sequential chemotherapy also showed that the efficacy of sequential chemotherapy was better than traditional chemotherapy treatment, and the side effects could be acceptable.[49,50] In view of intra-tumor heterogeneity of EC, sequential chemotherapy may have certain advantages in the treatment of EC, and whether it could become the clinical application chemotherapy regimen for EC needs further verification.
This work was supported by grants from the National Key R&D Program of China (Nos. 2016YFC1303100, 2016YFC1303103), the National Natural Science Foundation of China (Nos. 81502237, 81874108, 81672571, and 81802607), National Key Technology Research and Development Program of the Ministry of Science and Technology of China (No. 2015BAI13B06), and Basic Research Project of Peking University (No. BMU2018JC005).
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