Efficacy and Safety of Neoadjuvant Therapy With Sintilimab and Apatinib Combined Chemotherapy in Triple-negative Breast Cancer

Brief Summary

Detailed Description

In the past decades, the incidence of breast cancer in humans has continued to rise, posing a huge threat to the lives and health of patients worldwide. According to statistics released by the American Cancer Society,In 2019, there were more than 271,000 new cases of breast cancer and about 42260 deaths in the United States. As a highly heterogeneous disease, breast cancer can be based on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) and antigen Ki-67 is divided into several subtypes. TNBC is one of the subtypes of breast cancer, which is characterized by the lack of protein expression of ER, PR and HER-2. Clinically, TNBC is a very aggressive subtype of breast cancer, accounting for about 12% to 17% of all breast cancers. Due to its aggressiveness and lack of drug targets, compared with other subtypes of breast cancer, TNBC patients have a shorter overall survival (OS) and the median OS of metastatic TNBC is only 8-15 months. Chemotherapy is still the main systemic treatment for TNBC, but drug resistance develops rapidly and is poorly tolerated. Therefore, there is an urgent need to develop new treatment strategies for these patients. The clinical and molecular heterogeneity of TNBC is now well understood. Gene expression analysis showed that immune markers, androgen receptors, mesenchymal phenotypes, stem cell markers and basic markers are all related to TNBC subtypes .With reference to previous studies, according to the results of transcriptomics research, and based on transcriptome data, China's "Fudan Classification" divides TNBC into 4 subtypes: (1) luminal androgen receptor (LAR), (2) Immunomodulatory (IM), (3) basal-like and immune-suppressed (BLIS) and (4) mesenchymal-like (MES). Possible therapeutic targets or biomarkers have been identified for each subtype. To date, neoadjuvant chemotherapy has played an important role in the treatment of locally advanced TNBC patients. Through neoadjuvant chemotherapy, tumor shrinkage and stage reduction can improve the surgical radical cure rate and breast conserving rate. Postoperative pCR rate is of great significance in predicting the prognosis of patients, and those who achieve pCR tend to have better prognosis. A meta-analysis of 52 studies showed that the availability of pCR for neoadjuvant therapy in TNBC patients was significantly associated with event-free survival (EFS), with a 5-year EFS of 90% in the pCR group and only 57% in tumor survivors (HR=0.18). The prognosis of non-pCR or drug-resistant patients is relatively poor, and in order to reduce the recurrence and metastasis rate and improve the prognosis, intensive chemotherapy is often needed. Currently, there is no standard treatment regimen for TNBC. Previous studies have shown that the pCR rate of traditional anthracyclines followed by sequenzine therapy for TNBC can reach 25%-40%, but there are still nearly 20% patients with recent recurrence. Therefore, the optimization of TNBC treatment regimen is still a hot spot and difficulty in current clinical studies. In recent years, platinum drugs have attracted more and more attention in the neoadjuvant therapy of TNBC due to their ability to significantly improve pCR rate. Carboplatin can kill cancer cells by destroying their DNA. Currently, it has become an important neoadjuvant chemotherapy drug in the treatment of TNBC. Studies have shown that adding the DNA damage agent carboplatin to the neoadjuvant regimen can improve the pCR rate of TNBC. In 2020, the latest studies showed that carboplatin combined with nab-paclitaxel showed good anti-tumor activity and a high PCR rate of 48%. In addition, antiangiogenic therapy has been considered as a potential therapeutic strategy for patients with TNBC. In 2008, bevacizumab was approved by the US Food and Drug Administration (FDA) for significantly increasing patients' PFS in combination with chemotherapy. Mesylate path is for our country to develop a new type of oral small molecule anti angiogenesis inhibitors, mainly through highly selective inhibition of vascular endothelial growth factor receptor 2 (VEGFR - 2) the activity of tyrosine kinase, blocking vascular endothelial growth factor (VEGF) and its receptor signal transduction pathways, thus potent inhibition of tumor angiogenesis, play a role of anti-tumor. In addition, preclinical studies have shown that anti-angiogenic therapy can improve the sensitivity of anti-PD-1 /PD-L1 therapy by increasing PD-L1 expression and CD8+ T cell infiltration in the tumor microenvironment. Therefore, anti-angiogenic therapy may enhance the response to PD-1/PD-L1 blockade and improve survival. Currently, blocking of programmed death protein 1(PD-1) and programmed death ligand 1(PD-L1) is an attractive treatment option for TNBC, since stromal infiltrating lymphocytes (TILS) and PD-L1 are associated with favorable outcomes for TNBC. Impassion130 showed that first-line treatment with albumin paclitaxel combined with atzumab (anti-PD-L1 antibody) increased PFS by 2.2 months in patients with PD-L1 positive advanced TNBC, and increased OS by 7 months compared with placebo plus albumin paclitaxel. Therefore, the combination of chemotherapy and immunotherapy was proved to be effective. Meanwhile, in 2020, Impassion031 and Keynote-522 published the results of two classic studies: the pCR rate after immunotherapy combined with chemotherapy neoadjuvant therapy reached 58% and 64.8%, respectively, further confirming the high efficacy of immunotherapy combined with chemotherapy. TNBC as one of a kind of high heterogeneity of breast cancer subtypes, its aggressive is strong, postoperative recurrence occurred more transfer, lack of effective treatment of molecular therapeutic targets, endocrine therapy and its ehrs resistance - 2 treatment often invalid, therefore, compared with other subtypes of breast cancer, TNBC after neoadjuvant chemotherapy to pCR has more significant prognostic value. Currently, there is no standard treatment for TNBC except traditional anthracycline and taxane chemotherapy regimens. Therefore, it is critical to optimize the neoadjuvant chemotherapy regimens for TNBC to increase the pCR rate and improve the long-term prognosis of patients. So far, 6 clinical trials of apatinib combined with neoadjuvant chemotherapy for TNBC have been registered in China. However, there are no relevant reports on immunotherapy and antiangiogenesis therapy combined with chemotherapy in the neoadjuvant treatment of TNBC at home and abroad. Based on the results of previous classic studies and preclinical studies, the researchers initiated this clinical study to clarify the efficacy and safety of sintilimab and apatinib combined with chemotherapy in the neoadjuvant treatment of TNBC, in order to provide treatment for TNBC patients Strategy.

Primary Outcomes

Secondary Outcomes

• DFS(2 years)
• DCR(4 months)
• Rate of breast conserving surgery(4 months)
• Difference in pCR rate due to the state of PD-L1 expression(4 months)
• The difference of pCR rates among different subtypes in TNBC(4 months)
• Side effects of neoadjuvant therapy(CTCAE.V5.0)(4 months)
• The correlation between TMB and pCR(4 months)
• Pathological response assessed by the Miller&Payne scoring system combined with residual disease in lymph nodes(4 months)
• The correlation between genomic analyses and pCR(4 months)
• The correlation between TILs and pCR(4 months)