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Prognostic Value of the Serum Apolipoprotein B to Apolipoprotein A-I Ratio in Metastatic Colorectal Cancer Patients

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Prognostic Value of the Serum Apolipoprotein B to Apolipoprotein A-I Ratio in Metastatic Colorectal Cancer Patients Journal of Cancer 2020, Vol. 11 1063 Ivyspring International Publisher Journal of Cancer 2020; 11(5): 1063-1074. doi: 10.7150/jca.35659 Research Paper Prognostic value of the serum apolipoprotein B to apolipoprotein A-I ratio in metastatic colorectal cancer patients Dong-Dong Yang1,*, Zhan-Hong Chen1, 2*, De-Shen Wang1*, Hong-En Yu1, Jia-Huan Lu 1, Rui-Hua Xu1, Zhao-Lei Zeng1 1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong fengdong Road, Guangzhou, 510060, China. 2. Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. *These authors contributed equally to this work. Corresponding author: Zhao-Lei Zeng, Address: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou 510060, China. Tel: +86-20-87342297.Fax: +86-20-87343392.E-mail: [email protected]. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2019.04.11; Accepted: 2019.11.16; Published: 2020.01.01 Abstract Background: The aim of our research was to assess the prognostic value of the apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) ratio (ApoB/ApoA-I) in metastatic colorectal cancer (mCRC) patients. Methods: We randomly assigned 838 patients into the training cohort (n=578) and the validation cohort (n=260). The cut-off value of the ApoB/ApoA-I in the training cohort identified by a receiver operating characteristic (ROC) curve was 0.69 and was further validated in the validation cohort. A propensity score matching (PSM) analysis was carried out to eliminate the imbalance in the baseline characteristics of the high and low ApoB/ApoA-I group. The PSM cohort of 542 mCRC patients was generated. We also validated our main findings and conclusions with an independent cohort (n=150). Univariate and multivariate analyses were conducted to explore the independent prognostic value of the ApoB/ApoA-I in the training cohort (n=578), the validation cohort (n=260), the PSM cohort (n=542) and the independent cohort (n=150). Results: Patients in the high ApoB/ApoA-I group had significantly shorter overall survival compared to those in the low ApoB/ApoA-I group in the training cohort, the validation cohort, the PSM cohort and the independent cohort (P <0.01). Multivariate analysis indicated that the ApoB/ApoA-I was an independent prognostic index for OS in the training cohort [hazard ratio (HR):1.371; 95% confidence interval (CI):1.205-1.870, P=0.045], the validation cohort (HR: 1.924; 95% CI: 1.360-2.723, P<0.001), the PSM cohort (HR: 1.599; 95% CI: 1.287-1.988, P<0.001) and the independent cohort (HR: 1.949; 95% CI: 1.014-3.747, P=0.046). Conclusions: An increased baseline serum ApoB/ApoA-I is an independent prognostic factor for a poor prognosis in mCRC patients. Key words: ApoB to ApoA-I ratio, metastatic colorectal cancer, overall survival, prognostic factor, retrospective study. Introduction Colorectal cancer (CRC) was the fourth most cause of cancer-related deaths worldwide in 2018. common malignant cancer and the second leading More than 20% of CRC patients were diagnosed with http://www.jcancer.org Journal of Cancer 2020, Vol. 11 1064 distant metastasis at initial diagnosis. Although prognostic factor of OS in mCRC patients remains obvious progress was achieved in the fields of unknown. We examined a large cohort of 838 mCRC molecular targeted therapy, immunotherapy and patients to analyze the prognostic value of the multidisciplinary treatment (MDT), the 5-year overall pretreatment serum ApoB/ApoA-I on OS in mCRC survival (OS) rate of metastatic colorectal cancer patients. We also used the propensity score matching (mCRC) is still below 20% [1-3]. Different mCRC method to reduce the imbalance in the baseline patients may have different prognoses, with OS characteristics to better identify the independent varying from several months to several years. Factors prognostic value of the ApoB/ApoA-I. Finally, we such as liver oligometastasis, RAS mutation and validated our main findings and conclusions with an BRAF mutation status have been reported to be independent cohort of 150 mCRC patients. prognostic of OS and can also guide treatment options for mCRC patients. The identification of new Methods independent prognostic factors for mCRC is Patient selection and data collection important and will help us better predict the prognosis of mCRC patients. Lipid disequilibrium has We retrospectively collected the clinical data of been reported to contribute to the occurrence and 1049 patients who were pathologically diagnosed development of CRC. Clinical parameters reflecting with mCRC between Jan 2005 and Dec 2013 at Sun lipid disequilibrium may serve as prognostic factors Yat-sen University Cancer Center (SYSUCC). The for mCRC patients. An increased low-density inclusion criteria of this study were as follows: 1) lipoprotein cholesterol (LDL-C) to high-density Eastern Cooperative Oncology Group performance lipoprotein cholesterol (HDL-C) ratio (LHR) has been status (ECOG PS) score ≤2, 2) received reported to predict a poor prognosis for mCRC multidisciplinary treatment (MDT), and 3) available patients with elevations in LDL-C [4-6]. However, complete lab-based serum indexes before treatment. little is known about the prognostic value of the ApoB Exclusion criteria were as follows: 1) with previous or to ApoA-I ratio (ApoB/ApoA-I) in mCRC patients. coexisting malignant tumors, 2) suffered from acute Apolipoproteins have been reported to be illnesses, including hepatic failure, severe trauma or extensively involved in the processes of cancer stroke, 3) taking lipid-lowering drugs (statins, occurrence, progression and treatment [7-10]. Several fibrates), antidiabetic drugs (oral antidiabetics, studies have suggested that apolipoproteins can insulin) or corticosteroids, and 4) without complete participate in carcinogenesis by promoting follow-up data. We obtained the clinical data of proliferation and invasion, enhanced antitumor participants, including patient demographics, immunity or drug delivery, and an immediate clinicopathological information (tumor grade, oxidative stress reaction[11-16]. Apolipoprotein A-I primary tumor site, etc.) and clinical therapy (surgery, (ApoA-I), mainly synthesized in the liver and the chemotherapy regimen, etc.) at first diagnosis from small intestine, is a major fraction of HDL-C, the patient electronic medical record (EMR) system. accounting for approximately 70% [17, 18]. In CRC Serological biomarkers, including lipid metabolism patients, the serum ApoA-I level has been reported to indexes, carcinoembryonic antigen (CEA), and be an independent prognostic indicator to predict carbohydrate antigen 19-9 (CA19-9), were analyzed chemotherapy efficacy and survival time [19-23]. On by a blood automatic biochemical analyzer. The the other hand, apolipoprotein B (ApoB), an patients were followed up every 3-6 months until important blood apolipoprotein existing mostly in death or dropout, with a median follow-up duration LDL-C and very-low-density lipoprotein cholesterol of 26 months (interquartile range (IQR): 15-45 (VLDL-C), has been paid less attention to in CRC than months). A total of 838 patients (534 males, 304 ApoA-I. Päivi Sirniö et al. analyzed the correlation females) were enrolled in our cohort. Then, we between the serum ApoB/ApoA-I and survival in 144 randomly divided 838 patients into two independent CRC patients. They found that a decreased cohorts, namely, the training cohort (N=578) and the ApoB/ApoA-I was associated with improved validation cohort (N=260). cancer-specific survival and OS. However, the study An independent cohort of 150 mCRC patients sample size was small, and the independent hospitalized in SYSUCC between Jan 2014 and Dec prognostic value of the ApoB/ApoA-I was not 2014 was also included in this study to validate the explored. Furthermore, there were only 19 CRC independent prognostic value of ApoB/ApoA-I on patients with distant metastasis [20]. Whether the OS in mCRC patients. ApoB/ApoA-I can serve as an independent http://www.jcancer.org Journal of Cancer 2020, Vol. 11 1065 Figure 1. The study flow chart. *ECOG PS score: Eastern Cooperative Oncology Group performance status score. generate 542 patients, which were named the PSM Statistical analyses cohort. According to clinical practice, we defined Differences in categorical variables or medians cholesterols >6.47 mmol/L, triglycerides > 1.70 between groups were compared by the chi-square test mmol/L, HDL-C < 0.78 mmol/L, LDL-C >3.40 and the Mann-Whitney test. Kaplan-Meier curves mmol/L, ApoA-I <1.05 ng/L, and ApoB >1.15 ng/L (log-rank test) and Cox proportional hazard as dyslipidemia groups. We defined the best cut-off regression models (backward method) were used to value of LHR at 2.55 and the ApoB/ApoA-I at 0.69 to identify the independent prognostic factors of OS. stratify patients according to receiver operating All statistical analyses were performed by using characteristic (ROC) curve analysis in the training MedCalc (version 15.8; MedCalc Software bvba, cohort. The cut-off values of LHR and the Acacialaan, Belgium), SPSS (version 24.0; IBM Corp., ApoB/ApoA-I were further validated in the Armonk, NY, USA) and SAS (version 9.1.3; SAS validation cohort (N=260), the propensity score Institute, Inc., Cary, NC, USA). All statistical tests matching cohort (PSM) cohort (N=542) and the were two-sided, and P values less than 0.05 were independent cohort (N=150). In this study, we considered statistically significant.
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