Background and Purpose Gut microbes play an important role in the occurrence of lung cancer, immunotherapy, and chemotherapy. In this study, we analyzed the characteristics of gut microbes in patients with lung cancer and investigated the effect of gut microbes on anti‐PD‐1 therapy combined with chemotherapy. Methods Fecal samples from 21 non‐small cell lung cancer (NSCLC) patients and 22 healthy volunteers who were treated in the Fourth Hospital of Hebei Medical University from 2019 to 2021 were collected. DNA was extracted from all samples, and the V3‐V4 region of the bacterial 16S rRNA gene was PCR‐amplified using the Illumina sequencing platform, and R language was used for data analysis. Results There were significant differences in the Beta diversity and metabolic pathways of gut microbes between NSCLC patients and healthy individuals (p < 0.05). Bifidobacterium, Escherichia, and Sarterella were significantly enriched in patients with clinical benefit response (p < 0.05), and these three bacteria had certain predictive value for clinical benefit. Patients with Bifidobacterium breve had significantly longer median progression‐free survival (mPFS) compared with patients with no detectable Bifidobacterium breve feces at baseline (106 days vs. NR, p < 0.001). Multivariate COX analysis showed that the presence of B.breve was an independent good prognostic factor affecting the PFS of patients receiving combination therapy (p < 0.05). Conclusion The clinical efficacy of anti‐PD‐1 therapy combined with chemotherapy in Chinese advanced NSCLC patients is closely related to the gut microbiota, and Bifidobacterium breve may be a potential biomarker to predict the efficacy of immune‐combined chemotherapy.
e21005 Background: The gut microbiome has been demonstrated to be closely related to not only the occurrence of lung cancer but also its anti-PD-1 based immunotherapy and chemotherapy. There is little characteristic analysis of gut microbiota in Chinese lung cancer patients, and the impact of gut microbiota on combined anti-PD-1 treatment and chemotherapy remains unclear. Methods: Fecal samples from 22 healthy volunteers and advanced-NSCLC 21 patients who were treated in the Fourth Hospital of Hebei Medical University from 2019 to 2021 before and after anti-PD-1 treatment combined with chemotherapy were collected. DNA was extracted from all samples, and the V3-V4 region of the bacterial 16S rRNA gene was PCR-amplified using the Illumina sequencing platform. The study results were analyzed using bioinformatic data. Results: The composition of gut microbes in NSCLC patients and healthy people at the phylum level was roughly similar, with Firmicutes as the main phylum. However, there were significant differences in Beta diversity (P<0.05). The bray_curtis principal coordinate analysis revealed a significant difference in the microbiota between patients before and after combined treatment (P<0.05). According to the RECIST 1.1 criteria, the efficacy of the combination therapy was evaluated. The patients with complete remission, partial remission, or stable efficacy after 6 cycles were the clinical benefit response group (CBR, n=10), and the patients with disease progression in the efficacy evaluation were the non-clinical benefit group (NCB, n=8). The results suggested that the CBR group was enriched in Bifidobacterium_longum, Bifidobacterium_adolescentis, Bifidobacterium_bifidum, and Bifidobacterium_breve at the species level (P<0.05) compared with the NCB group. Compared with the median progression-free survival (mPFS) of patients without Bifidobacterium_breve at baseline, the mPFS of patients with the kind of gut bacteria was significantly prolonged (P<0.001).Specifically, mPFS without Bifidobacterium_breve group was 106 days (95% CI: 37-175), mPFS of the Bifidobacterium_breve group was Not Reached (95% CI: NC-NC). Conclusions: The clinical response of combined anti-PD-1 treatment and chemotherapy in advanced NSCLC patients was closely associated with the gut microbiome,and Bifidobacterium_breve may be effective biomarkers to predict the survival benefit of NSCLC combined therapy, which provided new therapeutic targets for modulating the response to cancer therapy.
e21075 Background: Advanced-stage anaplastic lymphoma kinase fusion-positive (ALK[+]) NSCLC has significantly benefited from ALK-TKI. It is still uncertain which second-generation(2G) ALK-TKI will benefit patients more after crizotinib resistance. Methods: We retrospectively analyzed the treatment history of 104 patients with ALK[+] NSCLC. Grouping was determined according to the type of 2G TKI patients selected after failure of crizotinib, including systemic and intracranial. Results: Overall, the median follow-up time was 24.2 (95%CI: 21.3-27.1) months, and 45(43.2%) eligible patients were alive at the end of follow-up. After Crizotinib treatment failure, 91(87.5%) patients received subsequent therapy (including targeted therapy and chemotherapy), and 90.1% (82/91) of patients received sequential 2G TKI treatment, with overall ORR of 68.3%, mPFS of 13.4 (95%CI:10.0-16.7) months, and mOS of 26.3 (95%CI:11.6-41.1) months. The mOS for Alectinib, Ceritinib, and Brigatinib were 34.5 (95%CI: 14.8-54.3), 19.4 (95%CI: 11.8-27.0) and 43.8 (95%CI: 10.0-77.6) months, respectively. The mPFS of Alectinib, Ceritinib, Brigatinib and Ensartinib were 17.3 (95%CI: 12.9-21.8) months, 13.4 (95%CI: 9.5-17.8) months, 10.7 (95%CI: 6.6-14.9) months and 8.4 (95%CI: 1.3-14.8) months, ORR were 68.6%, 70.8%, 69.2% and 60.0%, respectively (Table.1). For crizotinib resistant patient, 2G TKI showed no significant difference in prolonging PFS (P = 0.599) and OS (P = 0.681). Brain metastases were found in 67.1% (55/82) of crizotinib resistant patients, and mPFS of Alectinib, Ceritinib, Brigatinib and Ensartinib were 22.1 (95%CI:9.6-30.6) months, 12.6 (95%CI:8.3-16.9) months, 21.0 (95%CI:0.5-45.7) months and 14.7 (95%CI:3.8-25.5) months; ORR were 72.4%, 50.0%, 66.7% and 40.0%, respectively (Table.1). In particular, the ORR of Alectinib and Brigatinib was significantly higher than that of Ceritinib and Ensartinib (P < 0.000), while the mPFS of Alectinib was significantly better than Ensartinib (P = 0.029). Conclusions: After crizotinib resistance, nearly 90% of patients choose sequential 2G TKI. There was no significant difference in mPFS and mOS among patients treated with different 2G ALK-TKI. For patients with CNS metastases, treatment with Alectinib and Brigatinib results in higher ORR and PFS.[Table: see text]
e15533 Background: Our previous study have found that TRIM29 expressed higher in right colon cancer than left colon cancer and rectal cancer.But the main functions of TRIM29 was not fully clarified.Bioinformatics can be used for exploring the biological function of a gene.So we further explored the molecular mechanism by using bioinformatics analysis.The results showed that TRIM29 correlated to immune dysfunction.Mismatch repair deficient(dMMR) is closely related to the efficacy of immunotherapy in colorectal cancer.We also used GEO data to explore the relationship between TRIM29 and dMMR.At last, clinical pathological data were used to explore the relationship between TRIM29 and tumor lymphocyte infiltration. Methods: At first, bioinformatics analysis was used to further explore the molecular mechanism of TRIM29.Hub genes correlated with TRIM29 and Reactome/KEGG Pathway of the hub genes were identified and performed using String database(http://string.embl.de/).TISIDB(http://cis.hku.hk/TISIDB/) was utilized to analyse the correlations between TRIM29 expression and tumor infiltrating lymphocytes, immunomodulator and chemokine.Then GEO public data including 583 sample size was download and used to confirm the correlation ship between TRIM29 expressed and pMMR/dMMR status.At last, HE sections of the 227 CRC patients were collected to explore the connection between TRIM29 and tumor infiltrating lymphocytes. Results: Functional annotations and immune activity analysis showed TRIM29 is related to tumor infiltrating lymphocytes and due to immune dysfunction in colorectal patients.For tumor infiltrating lymphocytes analyzing, elevated TRIM29 was significantly associated with Act_DC, iDC,monocyte, NK,NKT, pDC, Tcm_CD4, Tcm_CD8, Tem_CD8 and Th1 cell infltration in colorectal ( P< 0.05), leading to a general increase in immune infiltration.For chemokines analyzing,elevated TRIM29 was significantly associated with high expression of CXCR1,CXCR2 and CXCR4( P< 0.05).For immunostimulators analyzing,TRIM29 over-expression was significantly associated with C10orf54, CD70, CD276, HHLA2 and ICOSLG, causing immune imbalance( P< 0.05).For immunoinhibitors analyzing, elevated TRIM29 expression was significantly associated with PD-L1, LGALS9, PD-1, PVRL2,TGFBR1,TIGIT and VTCN1( P< 0.05).The HE results revealed that high TRIM29 protein expression was correlated with high tumor-infiltrating lymphocytes ( P= 0.0053).GSE39582 data analyzing results showed that dMMR patients expressed higher TRIM29 level than dMMR patients( P= 0.0014). Conclusions: High TRIM29 expression is related to tumor infiltrating lymphocytes and due to immune dysfunction in colorectal patients.Elevated TRIM29 expression up regulating immune checkpoint molecules after immune stimulation to avoid immune damage.TRIM29 may serve as a new biomarker for immunotherapy.
e21046 Background: To explore the prognostic value of TP53 co-mutation with EGFR or KRAS in advanced non-small cell lung cancer. Methods: 314 patients with advanced non-small cell lung cancer (NSCLC) admitted to the Department of Oncology of the Fourth Hospital of Hebei Medical University from January 2016 to January 2021 were retrospectively analyzed, all with complete genetic information.According to the analysis results, EGFR and KRAS were identified as co-mutated genes.TP53 mutation was used as the experimental group and TP53 wild as the control group.Patients in TP53 mutation group were further classified and discussed according to different exon 4, 5, 6, 7, 8, other mutations and mutations could not be classified.Co-mutation group was studied according to TP53/KRAS mutation status, and according to KRASG12 mutation, Patients were divided into TP53/KRASG12C (wt/wt), TP53/KRASG12C (wt/mut), TP53/KRASG12C (mut/mut) and TP53/KRASG12C (mut/mut) for further grouping.In the study of TP53/EGFR co-mutation, TP53/EGFR mutation status was divided into groups, and subgroup analysis was conducted according to different TP53 exon mutations.SPSS 26.0 software was used to analyze the data, and P < 0.05 indicated statistical difference. Results: The frequency of single gene mutation in 314 patients was analyzed. The most common mutation was TP53 (64.3%), followed by EGFR (49.4%).TP53wt group compared with TP53mut group OS (34.3m vs 28.9m; HR = 1.263, 95% ci: 0.933 1.709;P = 0.131).The OS of Exon4 group was 23 months, Exon8 group was 44.5 months, and TP53wt group was 34.3 months, no statistical significance was observed (P = 0.159).In the TP53/KRAS co-mutation group, the median OS of KRAS/TP53 (mut/mut) group and KRAS/TP53 (wt/wt) group was 29.4m vs 34.3m; HR = 2.482, 95%Cl:1.378-4.471, P = 0.002).In subgroup analysis, the median OS of KRASG12Cmut/TP53mut group and KRASG12Cmut/TP53wt group were (8.9m vs 34.9m; HR = 38.268, 95%CL: 8.359-175.183, P = 0.199), (3.1m vs 34.3m; HR = 2.572, 95%Cl:1.344-4.922,P = 0.004).In the TP53/EGFR co-mutation group, the median OS of EGFRmut/TP53mut, EGFRwt/TP53mut, EGFRmut/TP53wt and EGFRwt/TP53wt were 32.9, 17.9, 42.7 and 31.2 months, respectively (P = 0.004).In subgroup analysis, the median OS of EGFRmut/ TP53Exon4-mut versus EGFRwt/TP53wt group was (25.8m vs 31.1m; HR = 2.909, 95%Cl: 1.438-5.886, P = 0.003). Conclusions: TP53 is a factor of poor prognosis in NSCLC patients, patients with TP53/KRAS co-mutation have poor survival, and kRASG12C-mut /TP53mut subgroup have worse prognosis.Patients with TP53/EGFR co-mutation had a better prognosis, and the EGFRmut/ TP53Exon4-mut subgroup had the worst prognosis.
e24132 Background: Patients with cancer experience different degrees of loss of dignity. Exploring the characteristics of dignity loss for patients with cancer is rare in China, but it is of great significance for patients and their families in the whole anti-cancer trajectory. Methods: Inpatients and outpatients with cancer from the Fourth Hospital of Hebei Medical University were enrolled in this study. The Patient Dignity Inventory(PDI) and EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) was used for measuring patients’ dignity loss and quality of life. Spearman’s correlation analysis was conducted to analyze the correlation factors of dignity loss, and the correlation among dignity loss, quality of life and its dimensions. Results: A total of 403 patients with cancers were included in this study. In terms of loss of dignity, 20 patients (4.96%) didn’t report loss of dignity, 295 patients (73.20%) had mild loss of dignity, 78 (19.35%) had moderate and 10(2.48%) had severe loss of dignity. The three most prevalent PDI problems of patients were “experiencing physically distressing symptoms”(146, 36.23%), “Feeling that I am a burden to others” (126,31.27%) and “worrying about future” (114, 28.29%) . Companionship(r = 0.167, P = 0.001), PS(r = 0.392, P < 0.001), diagnosis to investigation time (r = 0.107, P = 0.031), stage of disease (r = 0.279, P < 0.001), stage of treatment (r = 0.333, P < 0.001), surgery and recurrence (r = 0.158, P = 0.001), anxiety (r = 0.612, P < 0.001), depression (r = 0.603, P < 0.001), psychological distress (r = 0.453, P < 0.001), symptom burden (r = 0.421, P < 0.001) and impact on life (r = 0.450, P < 0.001) were positive correlated with loss of dignity. Age (r = -0.134, P = 0.007), occupation (r = -0.124, P = 0.013) were negative correlated with loss of dignity. Loss of dignity and quality of life are significant correlated with each other. Dignity existential distress showed moderate negative correlation with emotional function (r = -0.513, P < 0.001). Dignity symptom distress showed moderate negative correlation with emotional function (r = -0.675, P < 0.001) and social function (r = -0.515,P < 0.001). Dignity symptom distress showed moderate positive correlation with fatigue symptoms (r = 0.541, P < 0.001). Conclusions: Most cancer patients’ dignity were impaired slightly or moderately in North China. Dignity of cancer patients showed significant association with quality of life. Anxiety and depression were more consistent with dignity than other factors. Improving the quality of life and dignity of patients is vital.
e21008 Background: Anaplastic lymphoma kinase (ALK) is one of the major oncogenic driver genes in lung cancer, and fusion as the main mutation type, of which EML4 is the most common fusion ligand. With the development of next-generation sequencing (NGS), some other rare fusion ligands and complex fusions have been discovered. The prognosis of patients with EML4-ALK fusion, non EML4-ALK fusion and multiple ALK fusion was different. Methods: We retrospectively analyzed NGS (including tissue, blood, or other body fluid samples) in 61 patients with ALK[+] lung cancer, including 59 patients with NSCLC and 2 patients with SCLC. Grouping was determined according to whether it was EML4-ALK fusion and multiple fusion. Results: In our data, the partner fused to the ALK gene are diverse, including EML4, KIF5B, TSN and others. Among them, EML4 was the most common ligand in ALK[+] NSCLC, accounting for 93.2% (55/59). Among the different fusion sites of EML4-ALK, V1 (E13:A20) and V3 (E6:A20) mutations were the most common, accounting for 45.5% (25/55) and 41.8% (23/55), respectively. Several novel ALK fusion partners were discovered in this study, including MCFD2, LINC01251, MVP17, CREG2, LINCO1498 and so on. In addition, the incidence of intergenic sequence-ALK fusions was 16.4% (10/61), such as ANXA4-ALK(A[intergenic]:A20), CREG2-ALK (C[intergenic]:A20), HCN1-ALK(H[intergenic]:A20), TSN-ALK(T[intergenic]:A20), RSAD2-ALK(R [intergenic]:A20) and so on. 19.0% (12/61) of the patient had multiple fusion, of which only one patient had multiple fusion of EML4-ALK (V2+V5'+V3a/b), and the remaining patients had co-fusion of EML4-ALK and non EML4-ALK (Table). V3 were more likely to coexist with non EML4-ALK fusions than V1 or other variants (P = 0.047). Multiple fusions were more likely to occur with non EML4-ALK fusions (P < 0.000). Compared with EML4-ALK fusion, mPFS treated with crizotinib in non EML4-ALK fusion were significantly shorter (18.2 vs. 8.5 months, P = 0.035). In the context of crizotinib treatment, multiple fusions were associated with worse mPFS compared with single fusions (13.8 vs. 8.4 months, P = 0.008). In addition, For SCLC patients with ALK fusion (n = 2), the PFS of crizotinib treatment were 8.0 and 30.6 months, respectively. Conclusions: Due to the heterogeneity of tumor development resulting in the diversity of ALK fusions, non EML4-ALK fusions and multiple fusions imply a poorer response to crizotinib. ALK gene status prior to ALK-TKI therapy helps predict drug efficacy and patient prognosis.[Table: see text]
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