Sun Yat-sen University Cancer Center Research Articles

Are more courses of immunochemotherapy beneficial for the short-term outcome of locally advanced esophageal squamous cell carcinoma?

Immune checkpoint inhibitor (ICI) monotherapy and neoadjuvant immunochemotherapy have shown promising results in esophageal carcinoma. However, it is still unclear whether more courses of immunochemotherapy are therapeutically better. We aimed to investigate the safety and efficacy of three courses of neoadjuvant treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Patients with locally advanced ESCC received three courses of camrelizumab plus nab-paclitaxel and capecitabine before undergoing surgery. Additionally, patients received safety, computed tomography (CT), and endoscopy (with endoscopic ultrasonography and mucosal biopsy) assessments before and in the second and third courses of treatment. We used the CT and endoscopic assessment results from the second and third courses for comparison. From May 2020 to December 2021, 47 patients were enrolled at Sun Yat-sen University Cancer Center. In our study, 43 patients completed three courses of preoperative chemotherapy combined with anti-Programmed cell death-1 (PD-1) therapy and radical surgical resection. The toxicity of the third course of immunochemotherapy was mild and well tolerated without increased treatment-related adverse events (TRAEs) and mortality compared with that of the second course of treatment. In terms of efficacy, an additional course of treatment after the second course of treatment was effective, with increased CT and endoscopy T (clinical T stage) downstaging rates by 16.3% and 25.9%, N (clincial N stage) downstaging rates by 7.0% and 11.1%, and objective response rates (ORRs) by 13.6% and 22.0%, respectively. Regardless of downstaging or ORR, three courses of immunochemotherapy appear to be superior to two courses of treatment without increasing TRAEs.

Dissected subgroups predict the risk of recurrence of stage II colorectal cancer and select rational treatment.

Stage II colorectal cancer(CRC) patients after surgery alone have a five-year survival rate of ~60-80%; the incremental benefit of adjuvant chemotherapy is <5%. Predicting risk of recurrence and selecting effective personalized adjuvant drugs for stage II CRC using formalin-fixed, paraffin-embedded(FFPE) samples is a major challenge. 1319 stage II CRC patients who enrolled in 2011-2019 at Sun Yat-sen University Cancer Center were screened. RNAseq data of FFPE tumor samples of 222 stage II microsatellite stable(MSS) CRC patients(recurrence (n=47), norecurrence (n=175), median follow-up=41 months) were used to develop a method TFunctionalProg for dissecting heterogeneous subgroups of recurrence and predicting risk of recurrence. TFunctionalProg showed significant predictive values in 222 stage II MSS CRCs. The TFunctionalProg low-risk group had significantly better recurrence free survival (validation set: HR=4.78, p-value=1e-4, low-risk group three-year recurrence free survival=92.6%, high-risk group three-year recurrence free survival=59.7%). TFunctionalProg dissected two subgroups of transition states of stage II MSS CRCs at a high risk of recurrence; each state displays distinct levels of hybrid epithelial-mesenchymal traits, CD8+ T cell suppression mechanisms and FOLFOX resistance. Based on mechanisms in two subgroups, TFunctionalProg proposed personalized rational adjuvant drug combinations of immunotherapy, chemotherapy and repurposed CNS drugs. TFunctionalProg provides different utilities from ctDNA-based prognostic biomarkers. TFunctionalProg was validated using FFPE samples to predict the risk of recurrence and propose rational adjuvant drug combinations for stage II CRC.

Intravesical instillation of bacillus Calmette-Guerin for non-muscle invasive bladder cancer: outcomes of 421 patients in a single center

To assess the therapeutic effect and adverse effect of intravesical instillation of bacillus Calmette-Guerin (BCG) for treatment of non-muscle invasive bladder cancer (NMIBC) and analyze the independent predictors of patient survival. We retrospectively collected the clinical data from 421 patients (mean age 61.79±11.51 years) with NMIBC, who received intravesical instillation of BCG after surgery in Sun Yat-sen University Cancer Center from September, 2015 to September, 2021. Recurrence-free survival (RFS), progression-free survival (PFS), and disease specific survival (DSS) of the patients were analyzed, and the adverse effects were assessed using Common Terminology Criteria for Adverse Events 5.0. Kaplan-Meier analysis, univariate and multivariate COX regression analyses were used to identify the independent predictors of the patients' survival outcomes. The median follow-up of the patients was 17 months, during which 88 (20.9%) patients experienced recurrence (median time to recurrence of 10 months, range 3-58 months); 40 (9.5%) patients showed tumor progression (median time to progression of 18 months, range 3-50 months); and 14 (3.3%) patients died (median survival time of 30 months, range 8-52 months). Adverse events of grade 1, 2, and 3 occurred in 69, 110, and 23 of the patients, respectively. Survival analysis indicated that an age below 67.5 years (P=0.013), first tumor onset (P < 0.001), solitary tumor (P= 0.010), time to recurrence over one year (P=0.042), low levels of neutrophils (P=0.005), monocytes (P=0.005) and neutrophil/lymphocyte ratio (NLR; P=0.014), and cytokeratin 19 fragment 21-1 (CyFra21-1; P=0.002) were all associated with a higher PFS rate. Multivariate COX analysis suggested that the time of tumor recurrence (P=0.007, HR=2.669, 95% CI: 1.316-5.414), monocyte counts (P=0.015, HR=0.376, 95% CI: 0.171-0.829), and serum CyFra21-1 level (P=0.002, HR=0.312, 95% CI: 0.151-0.647) were independent predictors of RFS; primary tumor or tumor relapse (P=0.003, HR=0.301, 95% CI: 0.138-0.660), neutrophil counts (P=0.028, HR=0.302, 95% CI: 0.103-0.882), and CyFra21-1 level (P=0.029, HR=0.358, 95% CI: 0.142-0.903) were independent predictors of PFS following BCG instillation. Intravesical instillation of BCG is effective for treatment of intermediate or high-risk NMIBC, and the adverse effects are tolerable in most cases. The time of tumor recurrence, monocyte counts, and serum CyFra21-1 level are independent predictors of RFS, and primary tumor or tumor relapse, neutrophil counts, and CyFra21-1 level are independent predictors of PFS.

The Prognostic Significance of FOXD1 Expression in Head and Neck Squamous Cell Carcinoma

It has been reported that forkhead box D1 (FOXD1) plays an established role in human early embryonic development and is broadly involved in various malignancies. However, there is limited information regarding FOXD1 expression in head and neck squamous cell carcinoma (HNSCC). This present study aimed to explore the clinical significance of FOXD1 in patients with HNSCC. Tissue microarrays of 334 primary HNSCC patients who underwent surgery between 2008 and 2010 at Sun Yat-sen University Cancer Center were investigated by immunohistochemistry regarding FOXD1 expression. χ2 test was used to estimate the relationship of FOXD1 expression with clinicopathologic characteristics. Univariate and multivariate analyses were performed to identify FOXD1 expression as an independent prognostic indicator of overall survival (OS) and disease-free survival (DFS). FOXD1 expression is closely associated with postoperative recurrence. HNSCC patients with high FOXD1 expression have poorer prognoses than the low-expression group (p < 0.05). According to multivariate analysis, FOXD1 was an independent prognostic factor for OS and DFS. The results revealed that FOXD1 could be a prognostic factor for HNSCC and might serve as a potential target for novel therapies.

Serum Amyloid a Predicts Prognosis and Chemotherapy Efficacy in Patients with Advanced Pancreatic Cancer.

There is an urgent need to discover a predictive biomarker to help patients with advanced pancreatic cancer (APC) choose appropriate chemotherapy regimens. This study aimed to determine whether baseline serum amyloid A (SAA) levels were associated with overall survival (OS), progression-free survival (PFS), and treatment response in patients with APC received chemotherapy. This retrospective study included 268 patients with APC who received first-line chemotherapy at the Sun Yat-Sen University Cancer Center between January 2017 and December 2021. We examined the effect of baseline SAA on OS, PFS and chemotherapy response. The X-Tile program was used to determine the critical value for optimizing the significance of segmentation between Kaplan-Meier survival curves. The Kaplan-Meier curves and Cox regression analyses were used to analyze OS and PFS. The best cut-off value of baseline SAA levels for OS stratification was 8.2 mg/L. Multivariate analyses showed that SAA was an independent predictor of OS (Hazard Ratio (HR) = 1.694, 95% Confidence Interval (CI) = 1.247-2.301, p = 0.001) and PFS (HR = 1.555, 95% CI = 1.152-2.098, p = 0.004). Low SAA was associated with longer OS (median, 15.7 months vs 10.0 months, p < 0.001) and PFS (median, 7.6 months vs 4.8 months, p < 0.001). The patients with a low SAA who received mFOLFIRINOX had longer OS (median, 28.5 months vs 15.1 months, p = 0.019) and PFS (median, 12.0 months vs 7.4 months, p = 0.035) than those who received nab-paclitaxel plus gemcitabine (AG) or SOXIRI, whereas there was no significant difference among the three chemotherapy regimens in patients with a high SAA. Owing to the rapid and simple analysis of peripheral blood, baseline SAA might be a useful clinical biomarker, not only as a prognostic biomarker for patients with APC, but also as a guide for the selection of chemotherapy regimens.

Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient, locally advanced rectal cancer: an open-label, single-centre phase 2 study

The current standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by radical surgery, but this approach can lead to multiple complications. We aimed to investigate the clinical activity and safety of neoadjuvant therapy with sintilimab, a single-agent PD-1 antibody, in patients with mismatch-repair deficient locally advanced rectal cancer. This open-label, single-arm, phase 2 study was done at the Sun Yat-sen University Cancer Center, Guangzhou, China. Patients aged 18-75 years with mismatch-repair deficient or microsatellite instability-high locally advanced rectal cancer were enrolled and received neoadjuvant sintilimab monotherapy (200 mg by intravenous infusion) every 21 days. After an initial four cycles of treatment, patients and clinicians could choose one of the following options: total mesorectal excision surgery, followed by four cycles of adjuvant sintilimab with or without CapeOX chemotherapy (capecitabine 1000 mg/m2, orally administered twice daily on days 1-14; oxaliplatin 130 mg/m2, intravenously administered on day 1 every 3 weeks), determined by clinicians; or another four cycles of sintilimab followed by radical surgery or observation (only for patients with a clinical complete response; also known as the watch and wait strategy). The primary endpoint was the complete response rate, which included both a pathological complete response after surgery and a clinical complete response after completion of sintilimab treatment. Clinical response was evaluated by digital rectal examination, MRI, and endoscopy. Response was assessed in all patients who received treatment at least until the first tumour response assessment, after the first two cycles of sintilimab. Safety was analysed in all patients who received at least one dose of treatment. This trial is closed to enrolment and is registered with ClinicalTrials.gov (NCT04304209). Between Oct 19, 2019, and June 18, 2022, 17 patients were enrolled and received at least one dose of sintilimab. The median age was 50 years (IQR 35-59) and 11 (65%) of 17 patients were male. One patient was excluded from efficacy analyses because they were lost to follow-up after the first sintilimab cycle. Of the remaining 16 patients, six underwent surgery, of whom three had a pathological complete response. Nine other patients had a clinical complete response and chose the watch and wait strategy. One patient had a serious adverse event and discontinued treatment; this patient did not have a complete clinical response and refused to undergo surgery. A complete response was thus noted for 12 (75%; 95% CI 47-92) of 16 patients. One of the three patients who underwent surgery but did not have a pathological complete response showed an increase in tumour volume after the initial four cycles of sintilimab (at which point they underwent surgery); this patient was deemed to have primary resistance to immune checkpoint inhibitors. After a median follow-up of 17·2 (IQR 8·2-28·5) months, all patients were alive and none had disease recurrence. Only one (6%) patient had a grade 3-4 adverse event, which was deemed a serious adverse event (grade 3 encephalitis). The preliminary results of this study suggest that anti-PD-1 monotherapy is effective and tolerable for patients with mismatch-repair deficient locally advanced rectal cancer and could potentially spare some patients from radical surgery. Longer treatment courses might be needed to achieve maximum effects in some patients. Longer follow-up is also needed to observe the duration of response. The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, Science and Technology Program of Guangzhou, and Innovent Biologics.

Adjuvant icotinib versus observation in patients with completely resected EGFR-mutated stage IB NSCLC (GASTO1003, CORIN): a randomised, open-label, phase 2 trial

This phase 2 trial aimed to compare adjuvant icotinib with observation in patients with epidermal growth factor receptor (EGFR) mutation-positive resected stage IB non-small cell lung cancer (NSCLC). We performed a randomised, open-label, phase 2 trial from May 1, 2015 to December 29, 2020at Sun Yat-sen University Cancer Center in China. Patients with completely resected, EGFR-mutant, stage IB (the 7th edition of TNM staging) NSCLC without adjuvant chemotherapy were randomised (1:1) to receive adjuvant therapy with icotinib (125mg, three times daily) for 12 months or to undergo observation until disease progression or intolerable toxicity occurred. The primary endpoint was 3-year disease-free survival (DFS). CORIN (GASTO1003) was registered with Clinicaltrials.gov, with the number NCT02264210. A total of 128 patients were randomised, with 63 patients in the icotinib group and 65 patients in the observation group. The median duration of follow-up was 39.9 months. The three-year DFS was significantly higher in the icotinib group (96.1%, 95% confidence interval [CI], 91.3-99.9) than in the observation group (84.0%, 95% CI, 75.1-92.9; P=0.041). The DFS was significantly longer in the icotinib group than in the observation group, with a hazard ratio (HR) of 0.23 (95% CI, 0.07-0.81; P=0.013). The OS data were immature, with three deaths in the observation arm. In the icotinib group, adverse events (AEs) of any grade were reported in 49 patients (77.8%), and grade 3 or greater AEs occurred in four patients (6.3%). No treatment-related deaths occurred. Our findings suggested that adjuvant icotinib improved the 3-year DFS in patients with completely resected EGFR-mutated stage IB NSCLC with a manageable safety profile. This study was sponsored by Betta Pharmaceutical Co., Ltd.

Abstract P5-02-35: Radiomic biomarkers to predict the efficacy of anti-PD-1 immunotherapy-based combinational treatment in advanced breast cancer: a multi-center study

Abstract Introduction: Immunotherapy, especially immune checkpoint inhibitors, is regarded as one of the major breakthroughs in breast cancer treatment. However, it is an important challenge to accurately locate the patients who benefit from immunotherapy, because there is still a lack of universal and robust predictors of the efficacy of immunotherapy. Radiomics can extract quantitative imaging features in a highthroughput manner and assess tumor microenvironment and heterogeneity. This study investigated the correlation between deep learning radiomic biomarkers, including its predictive value for immunotherapy response in advanced breast cancer (ABC) patients. Methods: 240 patients with metastatic breast cancer treated with anti-PD-1 immunotherapy in three institutions from February 2018 to January 2022 were studied retrospectively, among which, the data of 61 patients were collected through prospective clinical trials. For these data, 189 ABC patients from prospective clinical trials and Sun Yat-sen University Cancer Center were evaluated as a training set to establish a radiomic model to predict value of immunotherapy, then this model was independently validated with 51 ABC patients from Sun Yat-sen Memorial Hospital. The CE-CT (contrast enhanced computed tomography) images of patients within one month before immunotherapy were were delineated with regions of interest (ROI) and radiomics features extraction. Data dimension reduction, feature selection and radiomic model construction were carried out with multilayer perceptron (MLP) deep learning. Combined with the radiomics signatures, independent clinical characteristics and pathological risk factors, the predictive model was established by multivariable logistic regression analysis. ROC curve (receiver operator area under receiver operator area, AUC) and Delong test were used to evaluate and compare the prediction performance of the model. Finally, decision curve analysis (DCA) is used to determine the net benefits predicted by the model. Results: The radiomic biomarker performed well in predicting response to immunotherapy, reflflected by the AUCs in the training set(AUC=0.885, 95% CI: 0.829-0.941) and validation set (AUC=0.871, 95% CI: 0.752-0.991), respectively. The accuracy of this radiomics model was better than those of clinical indicators, including PD-L1 expression. Conclusions: By combining deep learning technology and CT images and PD-L1 expression, we developed an independent predictive model that could identify MBC patients most likely to benefifit from immunotherapy, and may effectively improve more precise and individualized decision support. Citation Format: Jieqiong Liu, Jianli Zhao, Zhixian Sun, Yunfang Yu, Zhongyu Yuan, Herui Yao, Ying Wang. Radiomic biomarkers to predict the efficacy of anti-PD-1 immunotherapy-based combinational treatment in advanced breast cancer: a multi-center study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-35.

Abstract P5-02-40: Anthracycline improves the outcome of neoadjuvant trastuzumab-treated breast cancer patients with FcγRIIIA F/F genotype by decreasing the ratios of CD8+PD1+ and CD68+PDL1+ cells

Abstract Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the most important mechanisms of trastuzumab. Fragment C Gamma receptor (FcγR) IIA and IIIA polymorphisms influence the affinity of immunoglobin G (IgG). Recently, FcγRIIA and FcγRIIIA polymorphisms have identified with the efficacy of trastuzumab. However, whether FcγR polymorphisms are associated with the efficacy of trastuzumab in the neoadjuvant setting was unclear. Patients and methods: We retrospectively enrolled 101 patients with HER2-positive breast cancer receiving chemotherapy plus trastuzumab at least four cycles as neoadjuvant therapy and mastectomy in Sun Yat-sen university cancer center from May 2015 to March 2021. Among them, twenty patients were excluded because lacking of blood samples. Polymorphisms of FcγRIIA(rs1801274) and FcγRIIIA(rs396991) were examined by nested polymerase chain reaction (PCR) and sanger sequencing. Lastly, we performed multiple immunohistochemistry (mIHC) to examine the expressions of CD8, CD68, CD57, PD1 and PDL1. Results: Blood samples (n=81) were successfully detected. No significant differences between FcγRIIA/FcγRIIIA genotypes and clinical characteristics, including age, clinical stages, menstrual status, molecular subtyping, treatment and pathological complete response (pCR) rate. In paclitaxel-based treatment subgroup (n=34), FcγRIIIA polymorphism was significantly correlated with pCR rate (P&amp;lt; 0.05,Table1), moreover, the disease-free survivals (DFS) in FcγRIIIA-158V carriers subgroup (high affinity) were significantly longer than that in FcγRIIIA-158 F/F genotype group (low affinity) (P=0.036), while that was not significant difference in patients with anthracycline-based treatment (n=47, P=0.248), indicating that anthracycline enhanced the efficacy of neoadjuvant therapy in patients with FcγRIIIA F/F genotype(low affinity). So far, there is no recurrence events in paclitaxel-based treatment group with FcγRIIIA-158V carriers genotype. The mIHC showed that the ratios of stroma CD8+PD1+ and CD68+PDL1+ cells were significantly higher in anthracycline-based treatment group (Table 2), respectively, indicating that anthracycline improved the efficacy of neoadjuvant targeted therapy by decreasing the ratios of exhausted immune cells. Conclusions: FcγRIIIA-158V genotype is associated with better outcome in HER2-positive breast cancer patients who received paclitaxel combined with trastuzumab as neoadjuvant therapy. Anthracycline improves the outcome of neoadjuvant trastuzumab-treated breast cancer patients with FcγRIIIA F/F genotype by decreasing the ratios of CD8+PD1+ and CD68+PDL1+ cells. Correlation between FcγRIIIA and pCR Correlation between FcγRIIIA and pCR in total population and paclitaxel-based treatment population. Ratios of immune cells Ratios of immune cells in anthracycline-based and paclitaxel-based treatment group. Citation Format: Kaping Lee, Rongzhen Luo, Qianyi Lu, Shusen Wang, Fei Xu. Anthracycline improves the outcome of neoadjuvant trastuzumab-treated breast cancer patients with FcγRIIIA F/F genotype by decreasing the ratios of CD8+PD1+ and CD68+PDL1+ cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-40.

A proposed grading scheme for predicting recurrence in medullary thyroid cancer based on the Ki67 index and metastatic lymph node ratio.

The Ki67 index and lymph node ratio (LNR) have been proposed as components of alternative pathological classification schemes, but the most appropriate classification for patients with medullary thyroid cancer (MTC) remains unknown. The aim of the present study was to examine the usefulness of a new grading system combining the Ki67 index and LNR as a predictor of prognostic and disease-free survival (DFS) in MTC. We conducted a retrospective study of patients with MTC who were registered at Sun Yat-sen University Cancer Center, Guangzhou, P. R. China from June 2003 to October 2021. The DFS rates were assessed using risk-adjusted Cox proportional hazard regression modeling to explore the relationship among pathological features, nutritional status and DFS. The Ki67 index (cutoff value: 5% and 10%) and LNR (cutoff value: 0.2 and 0.3) were combined to create a new grading system. In total, 101 matched patients were assessed. The integrated grading system showed better separation of Kaplan Meier (KM) curves for DFS. As the grading stage progressed, there was a significant stepwise decrease in DFS, which was better than Ki67, LNR and N staging alone. According to the grading system, the high-risk group had a worse prognosis. The proposed grading scheme demonstrated a better prognostic performance in MTC patients than the Ki67, LNR and N staging alone. However, larger scale studies are needed to further verify our findings.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial

Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

M5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization

The significance of 5-methylcytosine (m5C) methylation in human malignancies has become an increasing focus of investigation. Here, we show that m5C regulators including writers, readers and erasers, are predominantly upregulated in urothelial carcinoma of the bladder (UCB) derived from Sun Yat-sen University Cancer Center and The Cancer Genome Atlas cohort. In addition, NOP2/Sun RNA methyltransferase family member 2 (NSUN2) as a methyltransferase and Aly/REF export factor (ALYREF) as a nuclear m5C reader, are frequently coexpressed in UCB. By applying patient-derived organoids model and orthotopic xenograft mice model, we demonstrate that ALYREF enhances proliferation and invasion of UCB cells in an m5C-dependent manner. Integration of tanscriptome-wide RNA bisulphite sequencing (BisSeq), RNA-sequencing (RNA-seq) and RNA Immunoprecipitation (RIP)-seq analysis revealed that ALYREF specifically binds to hypermethylated m5C site in RAB, member RAS oncogene family like 6 (RABL6) and thymidine kinase 1 (TK1) mRNA via its K171 domain. ALYREF controls UCB malignancies through promoting hypermethylated RABL6 and TK1 mRNA for splicing and stabilization. Moreover, ALYREF recognizes hypermethylated m5C site of NSUN2, resulting in NSUN2 upregulation in UCB. Clinically, the patients with high coexpression of ALYREF/RABL6/TK1 axis had the poorest overall survival. Our study unveils an m5C dependent cross-regulation between nuclear reader ALYREF and m5C writer NSUN2 in activation of hypermethylated m5C oncogenic RNA through promoting splicing and maintaining stabilization, consequently leading to tumor progression, which provides profound insights into therapeutic strategy for UCB.

Clinical efficacy and safety of individualized pembrolizumab administration based on pharmacokinetic in advanced non-small cell lung cancer: A prospective exploratory clinical trial

IntroductionPembrolizumab is recommended with a fixed dose of 200 mg 3-weekly. We performed this study to explore the clinical efficacy and safety of pharmacokinetic (PK)-guided pembrolizumab administration in advanced non-small cell lung cancer (NSCLC). MethodsIn this prospective exploratory study, we enrolled advanced NSCLC patients in Sun Yat-Sen University Cancer Center. Eligible patients received pembrolizumab 200 mg 3-weekly with or without chemotherapy for four cycles, then for patients without progressive disease (PD), pembrolizumab was administrated in new dose-intervals according to steady state plasma-concentration (Css) of pembrolizumab until PD. We set the effective concentration (Ce) at 15 μg/ml and new dose-intervals (T) was calculated according to Css of pembrolizumab using following equation: Css × 21D = Ce (15 μg/ml) × T. Primary endpoint was the progression-free survival (PFS), secondary endpoints were objective response rate (ORR) and safety. Besides, advanced NSCLC patients received pembrolizumab 200 mg 3-weekly and more than four cycles in our center were defined as the history-controlled cohort. Patients with Css of pembrolizumab underwent genetic polymorphism analysis of variable number of tandem repeats (VNTR) region in neonatal Fc receptor (FcRn). The study was registered at ClinicalTrials.gov, NCT05226728. ResultsA total 33 patients received pembrolizumab in new adjusted dose-intervals. The Css of pembrolizumab ranged from 11.01 to 61.21 μg/ml, 30 patients need prolonged intervals (22-80d) and 3 shortened intervals (15–20 d). In PK-guided cohort, the median PFS was 15.1 months and ORR 57.6 %, whereas in history-controlled cohort was 7.7 months and ORR 48.2 %. The immune-related adverse events were 15.2 % and 17.9 % between two cohort. The VNTR3/VNTR3 genotype of FcRn had significantly higher Css of pembrolizumab than VNTR2/VNTR3 (p = 0.005). ConclusionsPK-guided pembrolizumab administration showed promising clinical efficacy and manageable toxicity. Meanwhile less frequent dosing of pembrolizumab by PK-guided could reduce financial toxicity potentially. This provided an alternative rational therapeutic strategy of pembrolizumab in advanced NSCLC.

Synergistic Association of Hepatitis B Surface Antigen and Plasma Epstein-Barr Virus DNA Load on Distant Metastasis in Patients With Nasopharyngeal Carcinoma

Hepatitis B surface antigen (HBsAg) reportedly increases the risk of distant metastasis among patients with nasopharyngeal carcinoma (NPC). However, the associated potential interaction and changes in hazard ratios (HRs) between HBsAg and different plasma Epstein-Barr (EBV) DNA levels are unknown. Moreover, the potential HBsAg-positive-associated NPC metastatic mechanism remains unclear. To investigate the prognostic value and biological associations of HBsAg and plasma EBV DNA levels on distant metastasis in patients with NPC. Retrospective cohort study performed at Sun Yat-sen University Cancer Center between January 2010 and January 2013. A total of 792 patients with nonmetastatic NPC were enrolled. The median (range) follow-up time was 62.1 (1.4-83.4) months. Of these patients, 17.8% presented with HBsAg positivity. Cytological experiments were performed to evaluate the role of HBsAg in the invasion and migration of EBV-positive NPC cells. Data analysis was performed from July 2020 to April 2021. The primary end point was distant metastasis-free survival. Association rules were used to identify new rules related to distant metastasis. Interaction plots, univariate and multivariate Cox regression analyses, stratification analysis, and quantification using HRs were conducted. Additionally, cell migration and invasion assays, as well as Western blotting, were performed in the cytological validation. Among the 792 patients, 576 (72.7%) were male, with a median (IQR) age of 45 (38-53) years. The HBsAg-positive group exhibited a significant interaction and increased risk of distant metastasis when plasma EBV DNA cutoff levels were 1.5 × 1000 copies/mL or greater. The HR was 9.16 (95% CI, 2.46-34.14) when the plasma EBV DNA load reached 6 × 1000 copies/mL, which was higher than that in patients with stage IV disease (HR, 2.01; 95% CI, 1.13-3.56; P = .02). In cytological experiments, HBsAg promoted epithelial-mesenchymal transition by upregulating vimentin and fibronectin in EBV-positive NPC cells in vitro, thereby promoting invasion and migration of EBV-positive NPC cells. In this cohort study, the observed synergistic association between HBsAg and plasma EBV DNA load represented a novel potential mechanism underlying the increased risk of distant metastasis in patients with NPC. Hence, attention should be paid to patients with NPC with HBsAg positivity, especially when the plasma EBV DNA level is 6 × 1000 copies/mL or greater. Consideration of this synergistic association will contribute to more accurate individualized management.

Medial retropharyngeal nodal region sparing radiotherapy versus standard radiotherapy in patients with nasopharyngeal carcinoma: open label, non-inferiority, multicentre, randomised, phase 3 trial

ObjectivesTo address whether sparing the medial retropharyngeal lymph node (MRLN) region from elective irradiation volume provides non-inferior local relapse-free survival versus standard radiotherapy in patients with nasopharyngeal carcinoma.DesignOpen-label, non-inferiority, multicentre,...

Comparison of anti–PD-L1 with anti–PD-1 antibodies in the combination of HAIC and lenvatinib for the treatment of unresectable hepatocellular carcinoma.

509 Background: Previous study showed the combination of hepatic artery infusion chemotherapy (HAIC), Lenvatinib and immune checkpoint inhibitors (ICIs) makes better overall response rate (ORR) as well as survival benefit than pure systematic treatment for unresectable hepatocellular carcinoma (uHCC). But how to choose different ICIs remains unclear. This study aimed to compare the efficacy and safety of anti-PD-1/PD-L1 antibodies combined with HAIC and Lenvatinib. Methods: This study retrospectively included 184 patients with uHCC treated with HAIC+ Lenvatinib +PD-1/PD-L1 antibody from June 2019 to January 2022 in the liver surgery department of Sun Yat-sen University Cancer Center. We used propensity score match (PSM) to screen and match 60 patients of HAIC+durvalumab+ Lenvatinib (HIL) versus 60 HAIC+PD-1+ Lenvatinib (HPL) to compare the efficacy and safety profile of these two groups. Results: The baseline is basically equilibrium between HIL and HPL group after matching. The median OS and PFS are not evaluable on the data cut-off date Sep 10, 2022. The ORR was higher in the HIL group than in the HPL group according to modified RECIST (mRECIST) (74.1% vs. 53.6%, p = 0.022) and RECIST 1.1 (60.3% vs. 41.1%, p = 0.040) respectively. In addition, 10 (17.2%) patients in the HIL group achieved complete response (CR) while 3 (5.4%) in the HPL group according to mRECIST. The results of subgroup analyses suggested that HIL approach could bring more survival benefits than HPL approach for patients with tumor smaller than 10cm and bilateral liver involvement. The incidence of grades 3 or 4 adverse events (AEs) was 10.0% and 18.3% with HIL and HPL group, respectively. Conclusions: Anti-PD-L1 antibody seems to be a better companion in the combination therapy of HAIC+ICIs+Lenvatinib than anti-PD-1 antibody for higher ORR and lower incidence of severe AEs. Further prospective study including larger population of patients is required.[Table: see text]

Lipid profile as a novel prognostic predictor for patients with acute myeloid leukemia.

This study investigated the relationship between serum lipid levels and clinical outcomes in acute myeloid leukemia (AML) by establishing a predictive risk classification model. A total of 214 AML patients who were pathologically diagnosed and treated with standard induction chemotherapy at Sun Yat-Sen University Cancer Center were included. The patients were randomly divided into the training (n = 107) and validation (n=107) cohorts. Univariate and multivariate Cox analyses were used to assess the value of triglyceride (TG), Apolipoprotein B (Apo B), Apo Apolipoprotein A-I (Apo A-I), cholesterol (CHO), and high-density lipoprotein (HDL) as prognostic factors for AML. After a series of data analyses, a five-factor model was established to divide the patients into high- and low-risk groups. Kaplan-Meier survival analysis showed that the high-risk group had a poor prognosis (P<0.05). The area under the curve of the novel model for five-year OS was 0.737.A nomogram was constructed to integrate the model with age and the 2017 ELN cytogenetic classification, with the merged model showing improved accuracy with an area under the curve of 0.987 for five-year OS. A novel model was constructed using a combination of the serum lipid profile and clinical characteristics of AML patients to enhance the predictive accuracy of clinical outcomes. The nomogram used the lipid profile which is routinely tested in clinical blood biochemistry and showed both specific prognostic and therapeutic potential.

Single-center study of different treatment for advanced or unresectable angiosarcoma patients

Objective: To evaluate the efficacy and safety of different medical treatment in advanced or unresectable angiosarcoma. Methods: This study was a single-center retrospective clinical study. Fifty-five advanced or unresectable angiosarcoma patients treated in Sun-Yat Sen University Cancer Center from January 2005 to August 2020 were enrolled. There were 34 patients who received first-line doxorubicin-based chemotherapy (doxorubicin group), 12 patients received first-line doxorubicin or liposome doxorubicin plus paclitaxel or albumin bound paclitaxel chemotherapy (combination therapy group), and 4 patients received first-line paclitaxel-based treatment (paclitaxel group). There were 6 patients who received anti-angiogenesis targeted therapy, another 2 patients received anti-PD-1 antibody plus anti-angiogenesis targeted therapy. Targeted therapy and immunotherapy plus targeted therapy included 5 cases of first-line therapy and 3 cases of second-line therapy. The therapeutic effect was evaluated by RECIST 1.1 standard. The adverse reactions were evaluated by CTCAE4.0 standard. Kaplan-Meier survival analysis was evaluated with Log rank test. Cox proportional hazard model was used to analyze the influencing factors. Results: There were 18 patients achieved partial response (PR) in 34 patients in the doxorubicin group, median progression-free survival (mPFS) was 4.5 months, and median overall survival (mOS) was 15 months. Four patients achieved PR in 12 patients in the combination therapy group, mPFS and mOS were 4 months and 19 months. Two patients achieved PR in 4 patients in the paclitaxel group, mPFS and mOS were 3 months and 9 months. However, only 1 in 6 patients achieved PR for anti-angiogenesis targeted therapy, mPFS and mOS were 3 months and 16 months. Two patients who received anti-PD-1 immunotherapy combined with anti-angiogenesis targeted therapy acquired PR for 17 months and more than 16 months. Median PFS (7.5 months) were longer in those with primary liver, lung and spleen angiosarcoma than in those with other primary site (3.0 months, P=0.028). The mOS (20 months) was longer in females than that in males (12 months, P=0.045). Primary tumor site, sex, age and treatment were not independent prognostic factors for angiosarcoma patients (P>0.05). Grade 3-4 cardiac toxicity was found in 2 patients in the combination therapy group. Conclusions: Doxorubicin-based and paclitaxel-based chemotherapy are the most important treatment for advanced angiosarcoma. Potential efficacy for targeted therapy combined with anti-PD-1 immunotherapy are showed in some patients with long duration of response and moderate adverse event.

Establishment of a risk stratification model based on the combination of post-treatment serum squamous cell carcinoma antigen levels and FIGO stage of cervical cancer for treatment and surveillance decision-making

ObjectiveTo develop a risk stratification model based on the International Federation of Gynecology and Obstetrics (FIGO) staging combined with squamous cell carcinoma antigen (SCC-Ag) for the classification of patients with cervical squamous cell carcinoma (CSCC) into different risk groups.MethodsWe retrospectively reviewed the data of 664 women with stage IIA–IVB CSCC according to the 2018 FIGO staging system who received definitive radiotherapy from March 2013 to December 2017 at the department of radiation oncology of Sun Yat-sen University Cancer Center. Cutoff values for continuous variables were estimated using receiver operating characteristic curve analysis. Using recursive partitioning analysis (RPA) modeling, overall survival was predicted based on the prognostic factors determined via Cox regression analysis. The predictive performance of the RPA model was assessed using the consistency index (C-index). Intergroup survival differences were determined and compared using Kaplan–Meier analysis and the log-rank test.ResultsMultivariate Cox regression analysis identified post-treatment SCC-Ag (< 1.35 ng/mL and > 1.35 ng/mL; hazard ratio (HR), 4.000; 95% confidence interval (CI), 2.911–5.496; P < 0.0001) and FIGO stage (II, III, and IV; HR, 2.582, 95% CI, 1.947–3.426; P < 0.0001) as the independent outcome predictors for overall survival. The RPA model based on the above prognostic factors divided the patients into high-, intermediate-, and low-risk groups. Significant differences in overall survival were observed among the three groups (5-year overall survival: low vs. intermediate vs. high, 91.3% vs. 76.7% vs. 29.5%, P < 0.0001). The predictive performance of the RPA model (C-index, 0.732; 95% CI, 0.701–0.763) was prominently superior to that of post-treatment SCC-Ag (C-index, 0.668; 95% CI, 0.635–0.702; P < 0.0001) and FIGO stage (C-index, 0.663; 95% CI, 0.631–0.695; P < 0.0001).ConclusionsThe RPA model based on FIGO staging and post-treatment SCC-Ag can predict the overall survival of patients with CSCC, thereby providing a guide for the formulation of risk-adaptive treatment and individualized follow-up strategies.

Prognostic and predictive value of Immunoscore and its correlation with ctDNA in stage II colorectal cancer

ABSTRACT This study aimed to validate the prognostic value of Immunoscore (IS) in stage II colorectal cancer (CRC), and explore the roles of IS and circulating tumor DNA (ctDNA) in the adjuvant treatment for early-stage CRC. Resected tumor samples from stage II CRC patients were collected from the Sun Yat-sen University Cancer Center. The densities of CD3+ and CD8+ lymphocytes were quantified and converted to IS and classified into Low, Intermediate (Int), and High groups according to predefined cutoffs. A total of 113 patients were included in the study. Patients with IS-High, Int, and Low were 43 (38%), 62 (55%), and 8 (7%), respectively. Patients with IS-High had an excellent clinical outcome, with none recurring during a median follow-up of 3 years, including 15 (35%) clinical high-risk patients. The 3-year disease-free survival (DFS) was 100% for IS-High, 76% for IS-Int, and 47% for IS-Low (P < .001). In the multivariate Cox analysis, IS was the only significant parameter associated with DFS. IS-Int and IS-Low patients with adjuvant chemotherapy had improved DFS compared to those who did not receive adjuvant chemotherapy (HR = 0.3; 95% CI 0.1–0.92; P = .026). Among the 49 patients with postoperative ctDNA data, IS-High patients had the lowest ctDNA positivity rate, suggesting that they were most eligible for chemotherapy-free treatment. IS had a strong prognostic value in Chinese patients with stage II CRC and demonstrates its clinical utility. IS and ctDNA will jointly optimize the adjuvant treatment strategies for early-stage CRC.