Peking University Cancer Hospital Research Articles

Peripheral Blood Biomarkers Predictive of Efficacy Outcome and Immune-Related Adverse Events in Advanced Gastrointestinal Cancers Treated with Checkpoint Inhibitors.

Simple SummaryAlthough immune checkpoint inhibitors improve the survival of patients with advanced gastrointestinal cancers, they also cause a series of immune-related adverse events, which could sometimes be lethal and may hamper the effectiveness of anticancer therapies. The purpose of this study was to explore clinically accessible biomarkers to predict survival and adverse events in patients with advanced gastrointestinal cancers treated with checkpoint inhibitors. In a retrospective cohort containing 243 patients, we found that early treatment lines, the presence of immune-related adverse events, and a lower posttreatment neutrophil-to-lymphocyte ratio were independent factors predicting superior prognosis. Good physical strength and a low posttreatment neutrophil-to-lymphocyte ratio were independent risk factors for immune-related adverse events. These findings may assist in identifying patients who are more likely to respond to immunotherapy and suffer from fewer toxicities, which is of great value in guiding clinical decisions.Background: Gastrointestinal cancers constitute a major burden of global cancer mortalities. In recent years, the advent of immune checkpoint inhibitors has greatly improved the survival of patients with advanced gastrointestinal cancers, while predictive biomarkers of treatment efficacy and toxicities are still unmet demands. Methods: In our retrospective study, patients with advanced gastrointestinal cancers who received single or double immune checkpoint inhibitors in the Department of Gastrointestinal Oncology in Peking University Cancer Hospital between July 2016 and February 2022 were enrolled. Records of clinicopathological information, survival parameters, safety data, and baseline and posttreatment peripheral blood constituents were retrieved. Cox regression analysis and logistic regression analysis were performed to identify the predictive factors of treatment outcomes and immune-related adverse events. Results: We demonstrated that early treatment lines, the presence of immune-related adverse events, and a lower C2 neutrophil-to-lymphocyte ratio were independent factors predicting a superior objective response rate and progression-free survival in patients treated with immunotherapy. Lower ECOG PS, higher baseline albumin, and lower C2 neutrophil-to-lymphocyte ratios were independent risk factors for the onset of immune-related adverse events. Patients who succumbed to immune-related adverse events during immunotherapy presented better survival. Conclusion: Our results indicate that peripheral blood markers have potential for predicting treatment outcomes and immune-related adverse events in patients with advanced gastrointestinal cancer. Prospective validations are warranted.

O005 Evaluation of occludin, a tight junction transmembrane protein in human lung cancer and its potential role in metastatic disease

Abstract Introduction Tight junctions (TJs) maintain cell adhesion. Modulation can promote cell dissociation/motility/ metastasis. Occludin is a transmembrane protein within TJs and may play a role in TJ modulation. The aim of this research was to identify the expression of Occludin in human lung cancer and its effect in cell motility/dissociation. Methods qPCR was used to quantify Occludin transcripts in a human lung cancer cohort (n=80) (Peking University Cancer Hospital Research Ethics Committee). In vitro experiments on A549/COR-L23 lung cancer cell lines included immunofluorescence staining, cell attachment/migration using ECIS Z-Theta. Cells were treated with Hepatocyte Growth Factor (HGF, 50ng/μl) and/or cell migration inhibitors N-WASPi (Wiskostatin) and ROCKi (Y-27632). Results qPCR analysis revealed reduced expression of Occludin in patients with metastasis (no bone mets 21.7+/- 12 v bone mets 3.23+/- 3 (p=0.42) v boneActv 0.263+/-0.096 (p=0.077). A549 cells showed a similar cell migration pattern with HGF, ROCKi/HGF+ROCKi. In COR-L23, HGF increased cell migration; ROCKi/HGF+ROCKi showed suppression. N-WASPi/HGF+N-WASPi prevented all cell migration. Immunofluorescence demonstrated that HGF caused loss of Occludin from cell-to-cell membranes with single cells and increased pseudopodia in COR-L23 and A549. Conclusion This preliminary study suggests an association between Occludin and bone metastasis in lung cancer. HGF promoted Occludin loss from cell membranes, cell dissociation and increased pseudopodia/increased cell motility. This suggests that loss of Occludin from cell membranes is linked to reduced TJ function leading to cell dissociation/increased motility. NWASPi may provide pharmacological value in future lung carcinoma treatment.

Analysis of the Effcacy and Safety of Amivantamab in Non-small Cell Lung Cancer Patients with EGFR/MET Gene Abnormalities: A Single Center's Experience

背景与目的表皮生长因子受体（epidermal growth factor receptor, EGFR）和细胞间质上皮转换因子（cellular-mesenchymal to epithelial transition factor, c-Met）是非小细胞肺癌（non-small cell lung cancer, NSCLC）中常见的变异基因，都是受体酪氨酸激酶，在下游信号转导方面具有协同作用。针对EGFR和c-Met通路的靶向药物联合应用后，能够阻断PI3K/AKT/mTOR途径和Ras/Raf/Mek途径，限制补偿通路激活，发挥抗肿瘤作用。以Amivantamab为代表的EGFR和c-Met双特异性抗体新型药物能同时阻断两条信号通路，在肺癌临床研究中展现出良好前景。然而目前国内应用较少，相关经验缺乏。本研究将介绍我中心Amivantamab疗效数据和不良反应处理经验，探讨此类药物对我国EGFR/MET基因异常NSCLC的应用价值。方法收集2020年8月-2021年12月于我院接受Amivantamab治疗的晚期NSCLC病例的临床数据，分析其治疗反应率、生存和不良反应。结果本研究共纳入15例患者，其中Amivantamab单药治疗6例，Amivantamab联合Lazertinib治疗9例。治疗后7例（46.7%）达部分缓解（partial response, PR），7例（46.7%）达疾病稳定（stable disease, SD），1例（6.7%）达疾病进展（progressive disease, PD），总体客观缓解率（objective response rate, ORR）为46.7%，总体疾病控制率（disease control rate, DCR）为93.3%。7例EGFR外显子20插入突变患者中，2例（28.6%）达PR，5例（71.4%）达SD，DCR为100.0%，中位缓解持续时间（duration of response, DOR）未成熟，2例PR者仍持续缓解。5例奥希替尼耐药的患者中，2例（40.0%）达PR，3例（60.0%）达SD，DCR为100.0%，中位DOR未成熟，1例PR者仍持续缓解。中位随访时间为8.7个月（0.9个月-18.6个月），截至最后一次随访，共有6例患者发生疾病进展，3例患者死亡，中位无进展生存期和中位总生存期未成熟。常见的不良事件为皮疹（86.7%），甲沟炎（80.0%）和输液反应（60.0%），多为1级-2级。3级及以上不良反应包括皮疹（33.3%），转氨酶升高（13.3%）、水肿（6.7%）、血栓栓塞（6.7%）、间质性肺炎（6.7%）和血小板减低（6.7%）。结论Amivantamab对EGFR外显子20插入突变和奥希替尼耐药的中国晚期NSCLC治疗有效，与国外疗效数据相仿。整体安全性可耐受，需重点关注皮疹、甲沟炎、输液反应等不良反应。

Contrast-enhanced MRI for T Restaging of Locally Advanced Rectal Cancer Following Neoadjuvant Chemotherapy and Radiation Therapy.

Background Accurate restaging of rectal cancer is crucial in the selection of candidates for local excision after neoadjuvant chemotherapy and radiation therapy (NCRT). The conventional approach of combined T2-weighted imaging and diffusion-weighted imaging (DWI) at MRI has been found to have limitations in restaging. Purpose To determine the diagnostic performance of contrast-enhanced MRI in distinguishing between pathologic stage ypT0-1 and ypT2-4 rectal cancer after NCRT compared with T2-weighted imaging and DWI by using surgical pathologic specimens as the reference standard. Materials and Methods This retrospective study evaluated MRI scans in all consecutive patients with locally advanced rectal cancer who underwent total mesorectal excision after NCRT in Peking University Cancer Hospital (Beijing, China) from January 2014 to October 2018. All MRI features obtained before and after NCRT were evaluated by two experienced radiologists, independently and blinded to personal, clinical, and histopathologic information. The post-NCRT yT stage was assigned based on high b value (b = 1000 sec/mm2) DWI with T2-weighted imaging (protocol 1) in the first round and on contrast-enhanced MRI scans (protocol 2) in a second round. The diagnostic accuracies for the differentiation of pathologic stage ypT0-1 from ypT2-4 tumors with the two protocols were compared. Multivariable regression analysis was used to explore the independent predictors of pathologic stage ypT0-1 tumors. Results A total of 328 patients (mean age, 57 years ± 10 [SD]; 227 men; 69%) were enrolled. The area under the receiver operating characteristic curve of the contrast-enhanced MRI protocol in predicting pathologic stage ypT0-1 tumors was 0.81 (95% CI: 0.77, 0.85), which was better than that of the T2-weighted DWI protocol (0.66; 95% CI: 0.60, 0.71; P < .001). Multivariable logistic regression analysis showed that yT stage after NCRT on contrast-enhanced MRI scans was the only independent predictor of pathologic stage ypT0-1 tumors (P < .001). Conclusion Contrast-enhanced MRI provides accurate differentiation of ypT0-1 from ypT2-4 tumors after neoadjuvant chemotherapy and radiation therapy. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Zins and Santiago in this issue.

Alterations in DNA damage response and repair genes as potential biomarkers for immune checkpoint blockade in gastrointestinal cancer.

Objective:Immune checkpoint inhibitors (ICIs) have achieved remarkable results in cancer treatments. However, there is no effective predictive biomarker for gastrointestinal (GI) cancer.Methods:We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the Memorial Sloan Kettering Cancer Center cohort (MSK-GI, n = 227), the Janjigian cohort (n = 40), and the Peking University Cancer Hospital & Institute cohort (PUCH, n = 80) to determine the possible associations between DNA damage response and repair (DDR) gene mutations and clinical outcomes. Data from The Cancer Genome Atlas database were analyzed to determine the possible correlations between DDR gene mutations and the tumor microenvironment.Results:In the MSK cohort, the presence of ≥ 2 DDR gene mutations was correlated with prolonged overall survival (OS). The Janjigian and PUCH cohorts further confirmed that subgroups with ≥ 2 DDR gene mutations displayed a prolonged OS and a higher durable clinical benefit. Furthermore, the DDR gene mutation load could be considered as an independent prognostic factor, and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs. Mechanistically, we showed that the presence of ≥ 2 DDR gene mutations was correlated with higher levels of tumor mutation burden, neoantigen, and T cell infiltration.Conclusions:The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs, which could serve as a potential biomarker to guide patient selection for immunotherapy.

Risk of ipsilateral breast tumor recurrence and contralateral breast cancer in patients with and without TP53 variant in a large series of breast cancer patients

BackgroundThe association between breast cancer patients with a TP53 pathogenic variant and risk of local recurrence and contralateral breast cancer remains largely unknown. MethodsThe study population of 11093 patients was derived from two cohorts at the Breast Center of Peking University Cancer Hospital in China from November 2003, to March 2018. TP53 germline variants were determined for all patients. ResultsIn the study, forty-one (0.37%) carried a TP53 germline pathogenic variant, and 11052 were non-carriers (99.63%). Nineteen TP53 carriers (46.3%) and 4173 non-carriers (37.8%) were treated with breast-conserving therapy (BCT), while the remaining were treated with mastectomy. After a median follow-up of 6.7 years, the rate of ipsilateral breast tumor recurrence (IBTR) in TP53 carriers was significantly higher than that in non-carriers when treated with BCT (21.1% vs 3.8%, P = 0.006). No difference in the rate of IBTR was found between TP53 carriers and non-carriers when treated with mastectomy (0.0% vs 2.6%, P = 1.0). Furthermore, the rate of IBTR in TP53 carriers treated with BCT was significantly higher than that in those treated with mastectomy (21.1% vs 0.0%, P = 0.038). The 10-year cumulative risk of contralateral breast cancer in TP53 carriers was significantly higher than that in non-carriers (17.9% vs 3.6%, hazard ratio (HR) = 7.0, 95% CI: 3.3–14.9, P < 0.001). ConclusionsPatients with TP53 variants have a high risk of IBTR when treated with BCT, and exhibit a very high risk of contralateral breast cancer. TP53 carriers may not be suitable for BCT and prophylactic contralateral mastectomy might be considered.

Longitudinal and time-to-event modeling for prognostic implications of radical surgery in retroperitoneal sarcoma.

Retroperitoneal sarcoma (RPS) is a rare malignancy which can be difficult to manage due to the variety of clinical behaviors. In this study, we aimed to develop a parametric modeling framework to quantify the relationship between postoperative dynamics of several biomarkers and overall/progression‐free survival of RPS. One hundred seventy‐four patients with RPS who received surgical resection with curative intent at the Peking University Cancer Hospital Sarcoma Center were retrospectively included. Potential prognostic factors were preliminarily identified. Longitudinal analyses of body mass index (BMI), serum total protein (TP), and white blood cells (WBCs) were performed using nonlinear mixed effects models. The impacts of time‐varying and time‐invariant predictors on survival were investigated by parametric time‐to‐event (TTE) models. The majority of patients experienced decline in BMI, recovery of TP, as well as transient elevation in WBC counts after surgery, which significantly correlated with survival. An indirect‐response model incorporating surgery effect described the fluctuation in percentage BMI. The recovery of TP was captured by a modified Gompertz model, and a semimechanistic model was selected for WBCs. TTE models estimated that the daily cumulative average of predicted BMI and WBC, the seventh‐day TP, as well as certain baseline variables, were significant predictors of survival. Model‐based simulations were performed to examine the clinical significance of prognostic factors. The current work quantified the individual trajectories of prognostic biomarkers in response to surgery and predicted clinical outcomes, which would constitute an additional strategy for disease monitoring and intervention in postoperative RPS.

The overall survival benefit in Chinese ALK+ NSCLC patients received targeted therapies.

BackgroundAnaplastic lymphoma kinase (ALK) gene rearrangement is a series of mutations of non-small cell lung cancer (NSCLC) patients. Since 2011, multiple ALK inhibitors (ALKis) have been developed and launched for targeted therapy. In this study, we sought to investigate different strategies of sequential applying the ALKis and their clinical benefits to the overall survival (OS).MethodsA total of 176 patients with advanced NSCLC (stage IIIB–IV) harboring the ALK rearrangement were included in this cohort study. They were diagnosed between February 1, 2012 and November 19, 2019 at Peking University Cancer Hospital. Clinical characters were reviewed from patients’ records. Strategies of drugs, progression-free survival (PFS) and OS were collected during the follow-ups. The Kaplan-Meier method and multivariate Cox proportional-hazard analysis were used to conduct the analyses survival and to examine the relationship between the variables and OS.ResultsA significantly longer OS was observed either in patients treated with crizotinib [N=106, median OS (mOS): 32.9 months] or in patients treated with a next-generation ALKi [N=34, mOS: not reached (NR)] as the initial ALKi, compared with patients treated with conventional chemotherapy but no ALKi (N=36, mOS: 10.3 months, P<0.001). After disease progression with initial crizotinib, patients who received no ALKi had shorter OS than those who received only crizotinib beyond progressive disease (CBPD) (mOS: 9.7 vs. 20.3 months; P=0.015), only subsequent next-generation ALKis (mOS: 9.7 vs. 41.1 months; P<0.001), and CBPD followed with subsequent next-generation ALKis (mOS: 9.7 months vs. NR; P<0.001). Patients treated with 2 types of ALKi had better survival than those treated with 1 ALKi (mOS: 45.8 vs. 21.3 months, P=0.003), but no such survival benefit was observed in patients treated with ≥3 ALKis (P=0.366).ConclusionsALKis have been shown to be clinically effective in treating NSCLC patients with ALK rearrangements. In the case of disease progression with crizotinib, either of CBPD or sequential other ALKis can extend patients’ OS. The sequential application of multiple ALKis was found to be better than it of single ALKi in prolonging OS. However, the question of which inhibitor to select as the initial inhibitor needs to be examined further in future studies.

P-235 Elevated protein tyrosine phosphatase kappa expression is associated with disease progression and poor prognosis of pancreatic cancer

Protein tyrosine phosphatase kappa (PTPRK) is a phosphatase which is recognised as a tumour suppressor. PTPRK can promote the internalization of ZNRF3 by dephosphorylating CD133. It is a negative regulator of the invasion and adhesion of breast cancer cells, what is more, it is also enhance the activation of STAT3 in lung cancer. Pancreatic exocrine cancer is an extremely aggressive tumour with a mortality being nearly equal to its incidence. The aim of present study is to assess the involvement of PTPRK in the disease progression of pancreatic cancer. PTPRK transcripts were determined in pancreatic cancers (n=201) and adjacent non-tumour pancreatic tissues (n=201) using real time PCR. The pancreatic tissue samples were collected immediately after surgery at Peking University Cancer Hospital. All procedures used are approved by the Peking University Cancer Hospital Research Ethics Committee. The implication of PTPRK in disease progression and prognosis was analysed which was also further supported by analyses of RNAseq data of pancreatic cancer (The Cancer Genome Atlas, TCGA_PAAD) and a gene array data (GSE15471 and GSE71729). Further bioinformatic analysis has been done to determine which pathway is regulated by PTPRK. Both the public dataset GSE15471 and the Beijing clinical cohort shows increased PTPRK expression in the tumours compared with adjacent normal tissue. PTPRK expression in tumours of the earliest stage (T1) is lower than more invasive tumours (T2, T3 and T4). However, PTPRK tends to be lower in primary tumours that presented lymph node metastases. There is no significant change of PTPRK expression in the primary tumours that developed distant metastases. Moreover, PTPRK is down regulated in distant metastatic tumours from pancreatic cancer (GSE71729). Compared with lesions in the tail of pancreas, the PTPRK has also been found has a higher expression level in pancreatic head and body. Pancreatic cancer patients with a higher PTPRK level had poor overall and relapse free survival compared with patients with tumours of low PTPRK expression. In the TCGA PAAD cohort, PTPRK is positively correlated with some RTKs family gene, including EGFR, KDR, FGF and PDGF. However, neither protein level of EGFR nor phosphorylation of EGFR (Y1068 and Y1173) presented obvious difference according to PTPRK transcripts in the corresponding tumours. The PTPRK is involved in pancreatic cancer progression, it is associated with a poor prognosis. Exact role played by PTPRK in pancreatic cancer and its predictive and therapeutic potential are yet to be fully investigated using both in vitro and in vivo models.

Identification of mutation patterns and circulating tumour DNA-derived prognostic markers in advanced breast cancer patients

BackgroundThe correlations between circulating tumour DNA (ctDNA)-derived genomic markers and treatment response and survival outcome in Chinese patients with advanced breast cancer (ABC) have not been extensively characterized.MethodsBlood samples from 141 ABC patients who underwent first-line standard treatment in Peking University Cancer Hospital were collected. A next-generation sequencing based liquid biopsy assay (PredicineCARE) was used to detect somatic mutations and copy number variations (CNVs) in ctDNA. A subset of matched blood samples and tumour tissue biopsies were compared to evaluate the concordance.ResultsOverall, TP53 (44.0%) and PIK3CA (28.4%) were the top two altered genes. Frequent CNVs included amplifications of ERBB2 (24.8%) and FGFR1 (8.5%) and deletions of CDKN2A (3.5%). PIK3CA/TP53 and FGFR1/2/3 variants were associated with drug resistance in hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-positive (HER2 +) patients. The comparison of genomic variants across matched tumour tissue and ctDNA samples revealed a moderate to high concordance that was gene dependent. Triple-negative breast cancer (TNBC) patients harbouring TP53 or PIK3CA alterations had a shorter overall survival than those without corresponding mutations (P = 0.03 and 0.008). A high ctDNA fraction was correlated with a shorter progression-free survival (PFS) (P = 0.005) in TNBC patients. High blood-based tumor mutation burden (bTMB) was associated with a shorter PFS for HER2 + and TNBC patients (P = 0.009 and 0.05). Moreover, disease monitoring revealed several acquired genomic variants such as ESR1 mutations, CDKN2A deletions, and FGFR1 amplifications.ConclusionsThis study revealed the molecular profiles of Chinese patients with ABC and the clinical validity of ctDNA-derived markers, including the ctDNA fraction and bTMB, for predicting treatment response, prognosis, and disease progression.Trial registration: ClinicalTrials.gov ID: NCT03792529. Registered January 3rd 2019, https://clinicaltrials.gov/ct2/show/NCT03792529.

Long disease-free interval diminishes the prognostic value of primary tumor stage for patients with colorectal cancer liver metastases.

It is assumed that the impact of primary tumor stage (PTS) on prognosis gradually weakens with increasing disease-free interval (DFI) from colorectal cancer resection to liver metastases. Data from 733 patients undergoing hepatectomy in the Hepato-pancreato-biliary Surgery Department I of Peking University Cancer Hospital were retrospectively analyzed. Early and late metastases were defined as DFI ≤ and >12 months, respectively. In early metastases group, patients with T4 stage had a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with T1-3 stage (P=0.002 and P<0.001, respectively). Patients with N1-2 stage disease also demonstrated a worse RFS and OS than those with N0 stage (P=0.006 and P=0.007, respectively). In late metastases group, patients with T4 and T1-3 stages as well as patients with N1-2 and N0 stages, had comparable RFS (P=0.395 and P=0.996, respectively) and OS (P=0.387 and P=0.684, respectively). T and N stages were independent prognostic predictors only in patients with early metastases. The impact of PTS on prognosis is diminished with increasing DFI and limited only to patients with early metastases.

A retrospective study of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing neutropenia during definitive concurrent chemoradiotherapy in patients with esophageal squamous carcinoma

ObjectiveTo compare the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for preventive or delayed treatment in neutropenia, completion rate of concurrent chemoradiotherapy and hospitalization rate in patients with esophageal squamous carcinoma during definitive concurrent chemoradiotherapy. MethodsA total of 70 patients with esophageal squamous carcinoma in Peking University Cancer Hospital from January 2019 to December 2020, who received PEG-rhG-CSF during concurrent chemoradiotherapy, were enrolled in this retrospective analysis. There were 32 patients in the preventive group, and 38 patients in the delayed group. The incidence of neutropenia, completion rate of concurrent chemoradiotherapy and neutropenia-related hospitalization rate were compared between PEG-rhG-CSF preventive group and delayed group. ResultsThe incidence of severe neutropenia (Grades 3–4) in all patients was 31.4%. Comparison between preventive group and delayed group showed that the incidence of severe neutropenia was 6.3% and 39.4% (χ2 ​= ​10.428, P ​= ​0.001), respectively. In preventive group, the incidence of severe neutropenia was 3.7% and 20.0%, respectively, for primary prevention and secondary prevention of PEG-rhG-CSF (χ2 ​= ​12.321, P ​= ​0.001). The completion rate of concurrent chemoradiotherapy was 93.8% in the preventive group and 63.2% in the delayed group (χ2 ​= ​9.220, P ​= ​0.002). The incidence of treatment interruption was 25.7% in the whole group, 12.5% in the preventive group and 36.8% in the delayed group (χ2 ​= ​5.389, P ​= ​0.020). Seven patients (7/70, 10.0%) were hospitalized and treated with intravenous antibiotics for neutropenia, including 1 in the preventive group and 6 in the delayed group (P ​= ​0.078). ConclusionsProphylactic use of PEG-rhG-CSF during concurrent chemoradiotherapy for patients with esophageal squamous carcinoma can effectively reduce the incidence of neutropenia, ensure the safety of treatment, and improve the completion rate of concurrent chemoradiotherapy.

Multicenter real world study on the efficacy and safety of eribulin for the treatment of advanced breast cancer

Objective: To explore the efficacy and safety of real-world eribulin in the treatment of metastatic breast cancer. Methods: From December 2019 to December 2020, patients with advanced breast cancer were selected from Beijing Chaoyang District Sanhuan Cancer Hospital, Shandong Cancer Hospital, Peking University Cancer Hospital, Baotou Cancer Hospital, Shengjing Hospital Affiliated to China Medical University, and Cancer Hospital of Chinese Academy of Medical Sciences. Kaplan-Meier method and Log rank test were used for survival analysis, and Cox regression model was used for multivariate analysis. Results: The median progression-free survival (PFS) of 77 patients was 5 months, the objective response rate (ORR) was 33.8%, and the disease control rate (DCR) was 71.4%. The ORR of patients with triple-negative breast cancer was 23.1%, and the DCR was 57.7%; the ORR of patients with Luminal breast cancer was 40.0%, and the DCR was 77.8%; the ORR of patients with HER-2 overexpression breast cancer was 33.3%, and the DCR was 83.3%. ORR of 50.0% and DCR of 66.7% for patients treated with eribulin as first to second line treatment, ORR of 29.4% and DCR of 76.5% for patients treated with third to fourth line and ORR of 28.6% and DCR of 71.4% for patients treated with five to eleven line. The ORR of patients in the eribulin monotherapy group was 40.0% and the DCR was 66.0%; the ORR of patients in the combination chemotherapy or targeted therapy group was 22.2% and the DCR was 81.5%. Patients with a history of treatment with paclitaxel, docetaxel, or albumin paclitaxel during the adjuvant phase or after recurrent metastasis had an ORR of 32.9% and a DCR of 69.9% when treated with eribulin. The treatment efficacy is an independent prognostic factor affecting patient survival (P<0.001). The main adverse reactions in the whole group of patients were Grade Ⅲ-Ⅳ neutrophil decline [29.9% (23/77)], and other adverse reactions were Grade Ⅲ-Ⅳ fatigue [5.2% (4/77)], Grade Ⅲ-Ⅳ peripheral nerve abnormality [2.6% (2/77)] and Grade Ⅲ-Ⅳ alopecia [2.6% (2/77)]. Conclusions: Eribulin still has good antitumor activity against various molecular subtypes of breast cancer and advanced breast cancer that has failed multiple lines of chemotherapy, and the adverse effects can be controlled, so it has a good clinical application value.

The prevalence and real-world therapeutic analysis of Chinese patients with KRAS-Mutant Non-Small Cell lung cancer.

ObjectiveKirsten rat sarcoma viral oncogene homolog (KRAS) is an important driver gene of non‐small cell lung cancer (NSCLC). Despite a rapid progress achieved in the targeted therapy, chemotherapy remains the standard treatment option for patients with KRAS‐mutant NSCLC. This study aimed to assess real‐world data of Chinese patients with KRAS‐mutant NSCLC undergoing chemotherapy and/or immunotherapy.MethodsKRAS mutational status was analyzed using next‐generation sequencing of 150,327 NSCLC patients from the Lung Cancer Big Data Precise Treatment Collaboration Group (LANDSCAPE) project (Cohort I). Treatment data were collected and analyzed retrospectively from 4348 NSCLC patients who were admitted to the Peking University Cancer Hospital and Institute between January 2009 and October 2020 (Cohort II).ResultsIn Cohort I, 18,224 patients were detected with KRAS mutations (12.1%) of whom G12C (29.6%) was the most frequent subtype, followed by G12D (18.1%) and G12V (17.5%). In case of concomitant mutations, TP53 had the highest incidence of 33.6%, followed by EGFR (11.6%), STK11 (10.4%), KEAP1(6.2%), and CDKN2A (6.0%). Cohort II included 497 patients (11.4%) with KRAS mutations. In the first‐line chemotherapeutic analysis of Cohort II, patients benefited more from the pemetrexed/platinum (PP) regimen than the gemcitabine/platinum (GP) or taxanes/platinum (TP) regimen (median progression‐free survival [PFS], 6.4 vs. 4.9 vs. 5.6 months, hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.48–0.88, p = 0.033 and HR = 0.69, 95% CI 0.47–1.00, p = 0.05, respectively), with no significant difference when combined with bevacizumab. Regarding patients who received immune checkpoint inhibitors (ICIs), the objective response rate was 26% for a median PFS of 9.6 months (95% CI 6.16–13.03). Patients who received ICIs combined with chemotherapy had a significantly longer survival than monotherapy (median PFS, 13.9 vs. 5.2 months, HR = 0.59, 95% CI 0.35–0.99, p = 0.049).ConclusionKRAS is an important driver gene in NSCLC, compromising 12.1% in this study, and G12C was noted as the most common subtype. Patients with KRAS‐mutant NSCLC could benefit from pemetrexed‐based chemotherapy and ICIs.

Cost-Effectiveness of Genetic Testing for All Women Diagnosed with Breast Cancer in China

Simple SummaryUnselected multigene testing at breast cancer (BC) diagnosis has been reported to be cost-effective compared with family history (FH)/clinical-criteria-based testing in high-income countries such as the US and UK. Chinese patients are younger than Caucasian women at diagnosis, tending to have a higher gene mutation prevalence, and the family size and number of female relatives are smaller due to the one-child policy (which has been changed) in China. Therefore, offering genetic testing for BC patients could potentially prevent more cancer cases and deaths in China. However, the health economic evidence for multigene testing at BC diagnosis in China is lacking. The aim of the current study was to evaluate the cost-effectiveness of three genetic testing strategies among BC patients using a microsimulation model at the individual level in China. We found that offering unselected multigene testing to all BC patients in China is highly cost-effective compared with FH/clinical-criteria-based testing or no testing from both the societal and payer perspectives.Unselected multigene testing for all women with breast cancer (BC) identifies more cancer susceptibility gene (CSG) carriers who can benefit from precision prevention compared with family history (FH)/clinical-criteria-based guidelines. Very little CSG testing is undertaken in middle-income countries such as China, and its cost-effectiveness remains unaddressed. We aimed to estimate cost-effectiveness and population impact of multigene testing for all Chinese BC patients. Data from 8085 unselected BC patients recruited to a Peking University Cancer Hospital study were used for microsimulation modeling, comparing three strategies in the Chinese setting: all BC women undergo BRCA1/BRCA2/PALB2 genetic testing, only BC women fulfilling FH/clinical criteria undergo BRCA testing, and no genetic testing. Prophylactic mastectomy and salpingo-oophorectomy would be adopted where appropriate. Societal and payer perspectives with a lifetime horizon along with sensitivity analyses were presented. Incremental cost-effectiveness ratio (ICER): incremental cost per quality-adjusted life-year (QALY) gained is compared to the USD 10,260/QALY (one-times GDP per capita) willingness-to-pay threshold. BC incidence, ovarian cancer (OC) incidence, and related deaths were also estimated. FH/clinical-criteria-based BRCA testing was ruled out on the principle of extensive dominance. Compared with no genetic testing, multigene testing for all BC patients had an ICER = USD 4506/QALY (societal perspective) and USD 7266/QALY (payer perspective), well below our threshold. Probabilistic sensitivity analysis showed unselected multigene testing remained cost-effective for 94.2%/86.6% of simulations from the societal and payer perspectives. One year’s unselected multigene testing could prevent 7868 BC/OC cases and 5164 BC/OC deaths in China. Therefore, unselected multigene testing is extremely cost-effective and should be offered to all Chinese women with BC.

Clinicopathological features of HER2 positive metastatic colorectal cancer and survival analysis of anti-HER2 treatment

BackgroundWe aimed to investigate response and prognostic factors in patients with human epidermal growth factor receptor 2 (HER2) positive metastatic colorectal cancer (mCRC) and compare the curative effect on patients who received different therapy regimens (including chemotherapy and chemotherapy combined with targeted drugs).MethodsWe retrospectively analyzed all HER2 positive mCRC patients treated at Peking University Cancer Hospital between September 2011 and February 2021. We divided 63 HER2 positive mCRC into group A and group B according to the use of trastuzumab or not. Besides, we assigned four subgroups according to the first-line therapies of KRAS/NRAS/BRAF WT patients. The Kaplan–Meier estimator was used to calculate PFS and OS. Univariable analysis and Cox proportional hazards models were used to analyze the association between clinicopathological features and survival outcomes.ResultsAmong 63 patients, 54 (85.7%) were KRAS/NRAS/BRAF wild-type (WT). Univariate analysis showed that the male sex, primary lesions in the right colon, simultaneous metastasis, and unresectable primary lesions were significant risk factors for poor survival of HER2 positive mCRC (P < 0.05). Using Cox proportional hazards models, we found that the two factors of gender and resection of primary lesions were independent prognostic factors (P < 0.05). The median PFS and median OS of HER2-positive patients with mCRC who received first-line treatment were 8.4 months [95% confidence interval (CI): 5.0–11.7] and 48.2 months (95% CI: 23.5–72.8), respectively. The log-rank test revealed a significant difference in median OS survival between group A and group B (χ2 = 5.852, P = 0.016), and the two groups were divided according to the use or absence of trastuzumab treatment. In KRAS/NRAS/BRAF WT patients, there was a significant difference in median PFS and median OS between the fourth group patients (chemotherapy plus trastuzumab) and each of the other three groups (P < 0.05).ConclusionsThe two factors of gender and resection for primary lesion may be independent prognostic factors of advanced HER2 positive colorectal cancer patients. For patients with HER2-positive mCRC, patients in the chemotherapy combined with trastuzumab group have better efficacy than those without trastuzumab.

Characteristics and Prognosis of Acquired Resistance to Immune Checkpoint Inhibitors in Gastrointestinal Cancer

With the expanding use of immune checkpoint inhibitors (ICIs) in gastrointestinal (GI) cancer, the occurrence of acquired resistance (AR) has gradually emerged. However, the progression patterns and survival of patients with AR to ICIs are still unknown. To explore the characteristics and prognosis of AR after ICI therapy in patients with advanced GI cancer. This cohort study screened patients with advanced GI cancer treated with ICIs between January 14, 2016, and December 31, 2020, at Peking University Cancer Hospital. Initial response was defined as complete response, partial response, or stable disease longer than 6 months as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Progression was also based on Response Evaluation Criteria in Solid Tumors version 1.1. Progression or death after the initial response was defined as AR. Oligoprogression of AR was defined as 2 or more disease sites progression. The current status of AR in GI cancer and the patterns of AR and its prognosis were evaluated. The site of AR and subsequent management were also assessed. Data were analyzed from June to August 2021. Patients in the cohort were treated with mono-ICI or combination therapy. Kaplan-Meier analyses and log-rank tests were conducted for overall survival analyses. Univariate and multivariate Cox analyses were conducted to determine the prognostic implications of each variable. Of the 1124 patients who received ICIs, 373 (33.2%) patients (282 men [75.6%]; median [IQR] age, 62 [54-68] years) achieved an initial response, and 173 (46.4%) patients (137 men [79.2%]; median [IQR] age, 61 [54-67] years) developed AR. Almost all patients (167 patients [96.5%]) developed AR within 24.0 months. Progression patterns of AR were most commonly oligoprogression (122 patients [70.5%]) rather than polymetastatic progression (38 patients [22.0%]) and were associated with a good prognosis (38.5 vs 14.0 months; hazard ratio, 0.37; 95% CI, 0.18-0.74; P < .001). Lymph nodes (101 patients [58.4%]) appeared to be the most common site of AR. Management after AR was mainly systemic therapy (96 patients [55.5%]). Oligoprogression was the most common pattern of AR progression, and lymph nodes were the most susceptible site for AR. Further study will be needed to determine the most favorable management for AR.

Multicenter real-world study on safety and efficacy of neoadjuvant therapy in combination with immunotherapy for colorectal cancer

Objective: To provide reference and evidence for clinical application of neoadjuvant immunotherapy in patients with colorectal cancer through multicenter large-scale analysis based on real-world data in China. Methods: This was a retrospective multicenter case series study. From January 2017 to October 2021, data of 94 patients with colorectal cancer who received neoadjuvant immunotherapy in Peking University Cancer Hospital (55 cases), Union Hospital of Tongji Medical College of Huazhong University of Science and Technology (19 cases), Sun Yat-sen University Cancer Center (13 cases) and Changhai Hospital of Navy Medical University (7 cases) were retrospectively collected, including 48 males and 46 females. The median age was 58 years. Eighty-one cases were rectal cancer and 13 cases were colon cancer (2 cases of double primary colon cancer). Twelve cases were TNM staging II and 82 cases were stage III. Forty-six cases were well differentiated, 37 cases were moderately differentiated and 11 cases were poorly differentiated. Twenty-six patients (27.7%) with mismatch repair defects (dMMR) and microsatellite instability (MSI-H) were treated with immunotherapy alone, mainly programmed cell death protein-1 (PD-1); sixty-eight cases (72.3%) with mismatch repair proficient (pMMR) and microsatellite stability (MSS) were treated with immune combined with neoadjuvant therapy, mainly CapeOx (capecitabine+oxaliplatin) combined with PD-1 antibody plus long- or short-course radiotherapy, or PD-1 antibody combined with cytotoxic T lymphocyte associated antigen 4 (CTLA-4) antibody. Analysis and evaluation of adverse events during neoadjuvant immunotherapy were performed according to the National Cancer Institute Common Toxicity Standard version 3.0; the surgical complications were evaluated according to the Clavien-Dindo grading standard; the efficacy evaluation of neoadjuvant immunotherapy included the following indicators: major pathological remission (MPR) was defined as tumor regression induced by neoadjuvant therapy in pathology residual tumor ≤10%; pathological complete response (pCR) was defined as tumor regression induced by neoadjuvant therapy without residual tumor in pathology; the tumor response rate was disease control rate (DCR), namely the proportion of complete response (CR), partial response (PR) and stable disease (SD) in the whole group; the objective response rate (ORR) was CR+PR. Results: The median cycle of neoadjuvant immunotherapy was 4 (1-10) in whole group, and the incidence of immune-related adverse reactions was 37.2% (35/94), including 35 cases (37.2%) of skin-related adverse reactions, 21 cases (22.3%) of thyroid dysfunction and 8 cases (8.5%) of immune enteritis, of which grade III or above accounted for 1.1%. The median interval between completion of neoadjuvant therapy and surgery was 30 (21-55) days. There were 81 cases of radical resection of rectal cancer, 11 cases of radical resection of colon cancer, and 2 cases of colon cancer combined with other organ resection. The primary tumor resection of all the patients reached R0. The incidence of surgical-related complications was 22.3% (21/94), mainly anastomotic leakage (4 cases), pelvic infection (4 cases), abdominal effusion (3 cases), anastomotic stenosis (3 cases ) and abdominal and pelvic hemorrhage (2 cases). Grade I-II complications developed in 13 cases (13.8%), grade III and above complications developed in 8 cases (8.5%), no grade IV or above complications were found. During a median follow-up of 32 (1-46 ) months, DCR was 98.9% (93/94), ORR was 88.3 % (83/94), pCR was 41.5% (39/94), MPR was 60.6% (57/94). The pCR rate of 26 patients with dMMR and MSI-H undergoing simple immunotherapy was 57.7% (15/26), and MPR rate was 65.4% (17/26). The pCR rate of 68 pMMR and MSS patients undergoing combined immunotherapy was 35.3%(24/68), and MPR rate was 58.8% (40/68). Conclusions: Neoadjuvant immunotherapy has favorable tumor control rate and pathological remission rate for patients with initial resectable colorectal cancer. The incidences of perioperative adverse reactions and surgical complications are acceptable.

An Immune-Related Gene Pair Index Predicts Clinical Response and Survival Outcome of Immune Checkpoint Inhibitors in Melanoma.

The durable responses and favorable long-term outcomes are limited to a proportion of advanced melanoma patients treated with immune checkpoint inhibitors (ICI). Considering the critical role of antitumor immunity status in the regulation of ICI therapy responsiveness, we focused on the immune-related gene profiles and aimed to develop an individualized immune signature for predicting the benefit of ICI therapy. During the discovery phase, we integrated three published datasets of metastatic melanoma treated with anti-PD-1 (n = 120) and established an immune-related gene pair index (IRGPI) for patient classification. The IRGPI was constructed based on 31 immune-related gene pairs (IRGPs) consisting of 51 immune-related genes (IRGs). The ROC curve analysis was performed to evaluate the predictive accuracy of IRGPI with AUC = 0.854. Then, we retrospectively collected one anti-PD-1 therapy dataset of metastatic melanoma (n = 55) from Peking University Cancer Hospital (PUCH) and performed the whole-transcriptome RNA sequencing. Combined with another published dataset of metastatic melanoma received anti-CTLA-4 (VanAllen15; n = 42), we further validated the prediction accuracy of IRGPI for ICI therapy in two datasets (PUCH and VanAllen15) with AUCs of 0.737 and 0.767, respectively. Notably, the survival analyses revealed that higher IRGPI conferred poor survival outcomes in both the discovery and validation datasets. Moreover, correlation analyses of IRGPI with the immune cell infiltration and biological functions indicated that IRGPI may be an indicator of the immune status of the tumor microenvironment (TME). These findings demonstrated that IRGPI might serve as a novel marker for treating of melanoma with ICI, which needs to be validated in prospective clinical trials.

Systemic therapy in patients with metastatic Xp11.2 translocation renal cell carcinoma.

341 Background: Xp11.2 translocation renal cell carcinoma (RCC) is a unique RCC subtype with high malignant potential and poor prognosis, its natural course and response to systemic therapy are not fully understood. We analyzed the clinic features of this distinct entity and the benefit of systemic therapy in these patients. Methods: Between May 2006 and December 2019, 1113 consecutive patients diagnosed with RCC from Peking university cancer hospital (Beijing, China) were reviewed, data of the clinical characteristics and outcome of patients with metastatic Xp11.2 RCC were retrospectively collected. Tumor response to systemic therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Results: Metastatic Xp11.2 tRCC was found in 45 patients. The median PFS and median OS was 7.4 months (4.5 - 8.8) and 17.9 months (12.4 - 24.4), respectively. First-line treatment mainly included sunitinib (n = 14), sorafenib (n = 15), axitinib (n = 6), and pazopanib (n = 5), and the median PFS of these regimens were 7.4 months, 5.4 months, 9.4 months, 8.9 months, respectively. Two patients who received Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) plus immune checkpoint inhibitor (ICI) as first line therapy had a PFS of more than 16.6 months and more than 25.6 months, respectively. Twenty-four patients received subsequent therapies, which included VEGFR-TKI/ICI, axitinib and mTOR inhibitor, the median PFS for these regimens was 8.5, 7.2 and 2.0 months, respectively. Patients with serous cavity effusion or IMDC poor risk groups had significantly shorter median PFS and median OS. Conclusions: Metastatic Xp11.2 tRCC is an aggressive disease. VEGFR-TKI agents appeared to demonstrate some efficacy, VEGFR-TKI/ICI combination might be a useful tool for the treatment of metastatic Xp11.2 tRCC.