Huabing Yang

Non-genetic risk factors and predicting efficacy for docetaxel–drug-induced liver injury among metastatic breast cancer patients

Background and Aim:  Docetaxel has been chosen as one of the most popular anticancer drugs in the treatment of breast cancer for more than a decade. There is increasingly awareness for the occurrence of docetaxel and/or docetaxel–drug‐induced liver injury (DILI), although the underlying mechanism of occurrence and its risk factors remain unclear.

Breast Cancer Challenges and Screening in China: Lessons From Current Registry Data and Population Screening Studies

BACKGROUND As one of its responses to the increasing global burden of breast cancer (BC), China has deployed a national registration and BC screening campaign. The present report describes these programs and the initial results of these national BC control strategies, highlighting the challenges to be considered. MATERIALS AND METHODS The primary BC incidence and prevalence data were obtained from the Chinese National Central Cancer Registry. MapInfo software was used to map the geographic distribution and variation. The time trends were estimated by the annual percentage of change from 2003 to 2009. The description of the screening plans and preliminary results were provided by the Ministry of Health. RESULTS Chinese cancer registries were primarily developed and activated in the East and Coastal regions of China, with only 12.5% of the registries located in West China. Geographic variation was noted, with the incidence of BC higher in North China than in South China and in urban areas compared with rural areas. Of great interest, these registries reported that the overall BC incidence has been increasing in China, with an earlier age of onset compared with Western countries and a peak incidence rate at age 50. In response to this increasing incidence and early age of onset, BC screening programs assessed 1.46 million women aged 35-59 years, using clinical breast examinations and ultrasound as primary screening tools between 2009 and 2011. The diagnostic rate for this screening program was only 48.0/10(5) with 440 cases of early stage BC. Early stage BC was detected in nearly 70% of screened patients. Subsequently, a second-generation screening program was conducted that included older women aged 35-64 years and an additional 6 million women were screened. CONCLUSION The cancer registration system in China has been uneven, with a greater focus on East rather than West China. The data from these registries demonstrate regional variation, an increasing BC incidence, and an early age of onset. The 2009 to 2011 BC screening program targeting women aged 35-59 years had a low detection rate that resulted in a second-generation screening program that extended the cohort size and ages screened to 35-64 years. IMPLICATIONS FOR PRACTICE Cancer registration has been active in China for decades; however, a national survey of registries has not been routinely reported. This study used MapInfo to describe the reported data and found asymmetric registration activities, geographic variations in breast cancer (BC) burdens, and an increasing incidence with a peak at age 50. The initial Chinese BC screening programs focused on a relatively young population of women aged 35-59 years and had a low detection rate, but 69.7% of patients had early stage BC. Older women were included in the second-generation screening programs, and an additional 6 million women were screened. Consideration of regional variations and age is necessary to optimize the efficiency and utility of BC screening in China, with the ultimate goal to reduce BC mortality.

Continuous DC-CIK Infusions Restore CD8 + Cellular Immunity, Physical Activity and Improve Clinical Efficacy in Advanced Cancer Patients Unresponsive to Conventional Treatments

BACKGROUND There are few choices for treatment of advanced cancer patients who do not respond to or tolerate conventional anti-cancer treatments. Therefore this study aimed to deploy the benefits and clinical efficacy of continuous dendritic cell-cytokine induced killer cell infusions in such patients. MATERIALS AND METHODS A total of 381 infusions (from 67 advanced cases recruited) were included in this study. All patients underwent peripheral blood mononuclear cell apheresis for the following cellular therapy and dendritic cells-cytokine induced killer cells were expanded in vitro. Peripheral blood T lymphocyte subsets were quantified through flow cytometry to address the cellular immunity status. Clinical efficacy and physical activities were evaluated by RECIST criteria and Eastern Cooperative Oncology Group scores respectively. Logistic regression model was used to estimate the association between cellular infusions and clinical benefits. RESULTS An average of 5.7±2.94x10(9) induced cells were infused each time and patients were exposed to 6 infusions. Cellular immunity was improved in that cytotoxic CD8+CD28+T lymphocytes were increased by 74% and suppressive CD8+CD28-T lymphocytes were elevated by 16% (p<0.05). Continuous infusion of dendritic cells-cytokine induced killer cells was associated with improvement of both patient status and cellular immunity. A median of six infusions were capable of reducing risk of progression by 70% (95%CI 0.10-0.91). Every elevation of one ECOG score corresponded to a 3.90-fold higher progression risk (p<0.05) and 1% increase of CD8+CD28- T cell proportion reflecting a 5% higher risk of progression (p<0.05). CONCLUSIONS In advanced cancer patients, continuous dendritic cell-cytokine induced killer cell infusions are capable of recovering cellular immunity, improving patient status and quality of life in those who are unresponsive to conventional cancer treatment.

The prognostic value of peripheral CD4+CD25+ T lymphocytes among early stage and triple negative breast cancer patients receiving dendritic cells-cytokine induced killer cells infusion.

Objective This study aimed to assess the prognostic value of CD4+CD25+ T lymphocyte in peripheral blood among breast cancer patients treated with adoptive T lymphocytes immunotherapy. Methods 217 patients participated in the follow-up study. CD4+CD25+ proportion was measured by flow cytometry in peripheral T cells. The median survival was estimated by Kaplan-Meier curve, Log-rank test and Cox hazard proportion regression model, between groups of CD4+CD25+ proportion more than 5% and less than or equal to 5% in peripheral T cells. Results Peripheral CD4+CD25+ T lymphocytes had not a relationship with progression-free survival. It was featured that above 5% peripheral CD4+CD25+ proportion of T cells was related with the median overall survival by a shorten of 51 months (p < 0.05) with the HR 1.65 (95%CI 1.04, 2.62). Above 5% CD4+CD25+proportion of T cells produced the HR to be 1.76 (95%CI 1.07, 2.87) In stage 0-II patients, and 3.59 (95%CI 1.05, 12.29) in triple negative breast cancer patients. Conclusion Cellular immunity restoration recovered by adoptive T cell infusions which resulted in less proportion of peripheral CD4+CD25+T lymphocytes could be a potential prognostic indicator among early stage and triple negative patients.

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

BACKGROUND The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. METHODS 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. RESULTS GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. CONCLUSIONS These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

The prognostic values of CYP2B6 genetic polymorphisms and metastatic sites for advanced breast cancer patients treated with docetaxel and thiotepa.

This study investigated interactive effects of CYP2B6 genotypes and liver metastasis on the prognosis of metastatic breast cancer patients who received combined chemotherapy of docetaxel and thiotepa. Totally 153 patients were retrospectively genotyped rs8192719 (c.1294 + 53C > T) and rs2279343 (c.785A > G). Kaplan-Meier method and Cox Proportional Hazard Regression model were used to estimate the survival. Patients with liver metastasis had worsen prognosis, conferring a 2.26-fold high risk of progression and 1.93-fold high risk of death (p < 0.05). Both CT/TT genotype of rs8192719 (c.1294 + 53C > T) and AG genotype of rs2279343 (c.785A > G) prolonged survival (p < 0.05). Furthermore, among liver metastatic patients, AG genotype of rs2279343 (c.785A > G) was associated with a 47% reduced risk of death and a 6-month-longer overall survival (p < 0.05). Among non-liver metastatic patients, hazard ratios of CT/TT genotype of rs8192719 (c.1294 + 53C > T) were 0.45 for progression and 0.40 for death; and the corresponding survival was improved by 6 months and 16 months, respectively (p < 0.05). Genotypes of CYP2B6 had an interaction with clinical efficacy of docetaxel and thiotepa on metastatic breast cancer patients; and metastatic sites also affected clinical responses. Further therapies should take into account of chemotherapy regimen, genotypes of metabolizing enzymes and metastatic sites for the particular subpopulation.

Abstract 5298: Two distinctive single nucleotide polymorphisms determine liver metastases responses to docetaxel plus thiotepa for metastatic breast cancer patients.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The successful predictively treatment of metastatic breast cancer (MBC) remains a major challenge. Until now there is no definite marker to distinguish responder from non-responder and more and more important, metastasis occurred within different organs lead to serious variations of overall survival. In this study, paclitaxel and anthracyclines pretreated153 patients with MBC received 606 cycles of docetaxel plus thiotepa. 65 of 153 patients were concurrently diagnosed as MBC involved liver metastasis (LM). Among 153 patients, the response were 1 complete response (CR) (0.7%), 25 partial responses (PR) (16.3%), 73 stable diseases (SD) (47.7%), 46 progressive diseases (PD) (30.1%) and 8 unevaluable(5.2%). For LM patients, the localized liver response were 2 CR (3.1%), 20 PR (30.8%), 16 SD (24.6%), 22 PD (33.8%),5 unevaluable (7.7%). Median PFS and OS for both entire and LM subgroup were 6.5 (95% CI, 5.6 to 7.4) versus 4.2 (95%CI, 2.3-6.1), and 20.0 (95% CI, 15.6 to 24.4) versus 14.2 (95%CI, 9.5-18.9) months respectively. 79 SNPs in CYP450, whose minor allele frequency were ≥ 10% were genotyped. There was no significant difference of SNPs in therapeutic responses, PFS or OS. Of importance, there were two distinctive SNPs, rs2277119 and rs4646487 \*2/\*3 alleles, which tended to have the better liver metastases response than *1 when choosing a false discovery rate as 12%. It seemed that docetaxel plus thiotepa might be regarded as an active specific regimen for MBC with liver metastasis. The generation of conceptually specific chemotherapy targeting the organ with cancer metastasis should be considered in the future. Citation Format: Jing Yu, Ningning Dong, Ying Yan, Bin Shao, Lijun Di, Guohong Song, Li Che, Jun Jia, Hanfang Jiang, Xu Liang, Yulin Zhu, Chaoying Wang, Jie Zahng, Budong Zhu, Xinna Zhou, Xiaoli Wang, Huabing Yang, Jun Ren, Herbert Kim Lyerly. Two distinctive single nucleotide polymorphisms determine liver metastases responses to docetaxel plus thiotepa for metastatic breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5298. doi:10.1158/1538-7445.AM2013-5298 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.