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.
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