Many clinical studies have shown that patients with non-small cell lung carcinoma (NSCLC) can benefit from immune checkpoint inhibitor (ICI) therapy; however, PD-L1 and tumor mutation burden (TMB), which are recommended by the NCCN guidelines, are still insufficient in predicting the response to and prognosis of immunotherapy. Given the widespread use of ICIs, it is important to find biomarkers that can predict immunotherapy outcomes in NSCLC patients, and the exploration of additional effective biomarkers for ICI therapy is urgently needed.A total of 33 stage II-IV NSCLC patients were included in this study. We analyzed immune markers in biopsy and surgical tissue resected from these patients before treatment with ICIs. We examined the infiltration of immune cells and expression of PD-L1 in immune cells using fluorescent multiplex immunohistochemistry (mIHC) stained with CD8/CD68/CD163/PD-L1 antibodies.In this cohort, we observed that the levels of CD8+ T cells, CD8+PD-L1+ T cells, and CD68+CD163+ M2 macrophages in the total region were independent prognostic factors for progression-free survival (PFS) in NSCLC patients treated with ICIs (HR=0.04, P=0.013; HR=17.70, P=0.026; and HR=17.88, P=0.011, respectively). High infiltration of CD8+ T cells and low infiltration of CD8+PD-L1+ T cells throughout the region were correlated with prolonged PFS (P=0.016 and P=0.02, respectively). No statistically significant difference was observed for CD68+CD163+ M2 macrophages. The joint parameters CD8+ high/CD8+PD-L1+ low, CD8+ high/CD68+CD163+ low and CD8+PD-L1+ low/CD68+CD163+ low predicted better PFS than other joint parameters (P<0.01, P<0.01, and P<0.001, respectively), and they also demonstrated stronger stratification than single biomarkers. The response rate of patients with high infiltration of CD8+ T cells was significantly higher than that of those with low infiltration (P<0.01), and the joint parameters CD8+/CD8+PD-L1+ and CD8+/CD68+CD163+ also demonstrated stronger stratification than single biomarkers.This retrospective study identified the predictive value of CD8+PD-L1+ T cells, CD8+ T cells, and CD68+CD163+ M2 macrophages in NSCLC patients who received ICIs. Interestingly, our results indicate that the evaluation of joint parameters has certain significance in guiding ICI treatment in NSCLC patients.
Abstract Background: The present study has evaluated the prognostic value of pretherapy serum ferritin (SF) levels in advanced cancer patients receiving apatinib therapy after multiline treatment for drug resistance. Methods: This retrospective cohort reviewed the clinicopathological characteristics and pretreatment levels of SF of 124 patients with advanced cancer treated with apatinib. The Kaplan-Meier method was used to calculate the overall survival rate (OS) and progression-free survival (PFS), and the log-rank test was used to assess the statistical significance. Univariate and multivariate analyses of Cox proportional hazard regression were used to assess the prognostic impact of advanced cancer. Results: Participants in this study were previously treated with at least two treatment regimens. 52.4% of the patients had the Eastern Cooperative Oncology Group Performance Status (ECOG-PS)≥2. Median PFS was 8.57 weeks, and the median overall survival was 9.43 weeks. The OS and PFS of patients with elevated SF were significantly shorter than those with low SF (p <0.001 and p <0.001, respectively). Conclusions: SF can be used as an important prognostic indicator for advanced cancer patients with the treatment of apatinib after multiline treatment for drug resistance.
The most notable side-effect of apatinib, a novel antiangiogenic agent for the treatment of cancer, is hypertension, but there are few published studies regarding the use of apatinib to treat patients with cancer and severe hypotension. Here, the cases of three patients with tumours and severe hypotension are described: case 1, a 73-year-old male patient with lung squamous cell carcinoma who initially received radiotherapy and chemotherapy, and developed pneumonia and severe hypotension after 6 months; case 2, a 56-year-old male patient with nasopharyngeal carcinoma who was treated with chemotherapy and presented with fever and persistent hypotension; and case 3, a 77-year-old male patient with oesophageal cancer who was admitted with deglutition difficulty and severe hypotension. Apatinib was added to the treatment regimen of all three patients for antitumor therapy. Pneumonia, tumour progression, and severe hypotension improved noticeably in all patients within 1 month after receiving apatinib. Apatinib was associated with a positive effect on blood pressure stability, in synergy with other means of therapy, and the patients achieved satisfactory short-term clinical results. The role of apatinib in treating patients with cancer and hypotension merits further investigation.
e24061 Background: EGFR T790M mutation is the most common acquired EGFR-TKI resistant mutation in NSCLC patients, and is sensitive to the third-generation EGFR-TKI osimertinib. But osimertinib acquired resistance mechanism is still under study. We report the molecular and clinical characteristics of osimertinib resistance patients. Methods: In total 39 advanced NSCLC patients (pts) who had received but become resistant to osimertinib treatment were enrolled in this study. Baseline genetic variants of those patients were documented. Genomic alterations (GAs) were assayed by a next generation sequencing (NGS) based liquid biopsy assay targeting common driver genes in NSCLC. Results: The median age of the 39 pts, including 17 males and 22 females, was 55 years (range: 35-77). As baseline genetic alterations, 20 pts harbored EGFR sensitive mutations, 14 pts harbored EGFR T790M, and 7 harbored both, for a total of 27 pts with EGFR mutations (the EGFR status of 12 pts remained unknown). The median response time to osimertinib was 7 months, ranging from 1 to 32 months. After resistance to osimertinib, EGFR T790M was detected in only 21.4% (3/14) of the pts who were T790M positive at baseline. 11.1% (3/27) of the pts harboring EGFR mutations at baseline were positive for EGFR C797S, one of the known mechanisms of acquired resistance to osimertinib. Besides secondary mutation of EGFR, other most common related mutated TKI-resistant genes was PI3KCA (12.8%, 5/39). Also BRAF, KRAS, PTEN, and RB1 mutations were found each on two out of 39 pts. One ERBB2 amplification and one MET amplification were detected as well. Further analysis of GAs and the response time revealed that there was no significant difference between the median PFS of EGFR T790M negative and positive group (7 months vs. 9.5 months, p = 0.53). Conclusions: In this study we investigated the circulating tumor specific molecular characteristics of advanced NSCLC pts who were resistant to the third generation EGFR-TKI osimertinib. No significant difference of median PFS was found between plasma EGFR T790M positive and negative groups. Further analyses of the genomic alterations of acquired resistance to ostimertinib by plasma ctDNA testing are still needed.
The development of acquired resistance to the first-line epidermal growth factor-tyrosine kinase inhibitor (EGFR-TKI) treatment in non-small-cell lung cancer (NSCLC) is inevitable, and most of these patients needed second-line chemotherapy. Furthermore, the optimum chemotherapeutic regimen is unclear. The aim of this meta-analysis was to evaluate the chemotherapeutic regimens "with-pemetrexed" versus "non-pemetrexed" in advanced NSCLC patients who had progressed after first-line EGFR-TKIs.We searched PubMed, Embase, Cochrane Library, and the Web of science for relevant clinical trials. Outcomes analyzed were response rate (RR), disease control rate (DCR), 1-year survival rate (1-year SR), progression-free survival (PFS), and overall survival (OS).One randomized controlled trial (RCT) and three retrospective studies were included in this meta-analysis, covering a total of 354 patients. The results showed that there was no significant difference between with-pemetrexed arm and non-pemetrexed arm in RR (OR 1.43, 95% CI 0.85-2.41, P=0.18), DCR (OR 1.5, 95% CI 0.94-2.39, P=0.09), and 1-year SR (OR 1.47, 95% CI 0.79-2.74, P=0.22). But the with-pemetrexed chemotherapeutic regimens significantly improved the PFS (HR 0.61, 95% CI 0.46-0.81, P=0.0005) and OS (HR 0.62, 95% CI 0.42-0.90, P=0.01).The second-line with-pemetrexed chemotherapeutic regimens provided significantly longer PFS and OS than non-pemetrexed chemotherapeutic regimens. These findings indicate that the with-pemetrexed chemotherapeutic regimen may be an optimal second-line chemotherapeutic regimen for patients with advanced NSCLC following EGFR-TKI failure.
e15032 Background: EGFR is a major oncogene in non-small cell lung cancer (NSCLC) patients. Although EGFR tyrosine kinase inhibitors (TKIs) have effectively improved the survival of NSCLC patients, acquired drug resistance is a critical clinical challenge. Minimal residual disease (MRD) is the direct cause of tumor recurrence, and the abundance of circulating tumor DNA (ctDNA) can be used to reflect the status of MRD. We sought to identify the evaluation of effect of ctDNA on tumor therapeutic efficacy. Methods: Blood samples from 32 advanced NSCLC patients were dynamically collected at different timepoints (0, 4, 8, 12, months) with 1 sampling in 6 patients, 2 samplings in 15 patients, 3 samplings in 7 patients, 4 samplings in 3 patients, and 5 samplings in 1 patient. Targeted sequencing of 450 cancer-related genes were performed for genomic alteration identification at OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory in Shanghai, China. The average variant allele frequency of each sample was used to represent ctDNA abundance. Results: A total of 32 advanced NSCLC patients harboring EGFR sensitive mutations were enrolled in the study. Patients consisted of 12 (37.5%) males and 20 (62.5%) females, with a median age of 60 years old, ranged from 38 to 82 years old. These patients were randomly divided into TKI monotherapy group (N = 11) or TKI treatment combined with pemetrexed group (N = 21). The percentage of stable disease (SD) was more pronounced in patients receiving TKI combined with chemotherapy when compared to patients treated with TKI monotherapy (47.6% [10/21] vs. 36.4% [4/11], respectively). Less patients experienced the progression of disease (PD) when they were treated with TKI combined with chemotherapy than those receiving TKI monotherapy (52.4% [11/21] vs. 63.6% [7/11], respectively). For patients with PD, ctDNA abundance was progressively increased in 55.6% (10/18) during dynamic monitoring; whereas ctDNA abundance kept stable in 44.4% (8/18) patients, while 6/8 patients did not continue to perform ctDNA detection for more than half a year. In patients experienced SD, ctDNA abundance was declined in 78.6% (11/14) during dynamic monitoring, while 21.4% (3/14) patients displayed elevated ctDNA abundance. These 3 patients did not continue to perform ctDNA detection for more than 10 months. In majority of NSCLC patients (65.6% [21/32]), variation of ctDNA abundance was correlated to the treatment-induced clinical response. Conclusions: In conclusion, our results suggested that the variation of ctDNA abundance could promptly reflect the clinical response of treatment. The dynamic variation of ctDNA/MRD can possibly be considered as a biomarker of clinical efficacy following treatment in NSCLC patients.
DNA damage response and repair (DDR) genes are crucial for maintaining the integrity of the genome. This study aims to explore the correlation of DDR gene mutations with TMB, clinical characteristics, and outcomes to platinum-based chemotherapy and platinum-based chemotherapy/immunotherapy in non-small cell lung cancer (NSCLC) without EGFR and ALK alterations.
To evaluate the clinical significance of pretreatment levels of plasma Epstein–Barr virus DNA (pEBV DNA) on prognoses in pediatric nasopharyngeal carcinoma (NPC) patients. Eighty-nine patients aged 21 years old or younger with nonmetastatic NPC were evaluated to determine the effect of pEBV DNA levels on progression-free survival (PFS), distant metastasis-free survival (DMFS), and overall survival (OS). Survival probabilities in patient groups that were segregated by clinical stage or pEBV DNA load (low or high) were compared. The median pretreatment concentrations of pEBV DNA were 3440 copies/mL in 35 patients with stage III disease and 14,900 copies/mL in 50 patients with stage IV disease (P = 0.059). The median concentration of pEBV DNA was 34,500 copies/mL in 17 patients with relapse, which was higher than the concentration in 72 patients without relapse, who had a median level of 4985 copies/mL (P = 0.057). Further study showed that pretreatment pEBV DNA load was an independent prognostic indicator in pediatric NPC patients. High pEBV DNA was associated with adverse clinical outcomes, including PFS [3-year PFS rate = 80.5% versus 95.8%, hazard ratio (HR) = 5.00, 95% confidence interval (CI) = 1.00–25.00; P = 0.050], DMFS (3-year DMFS rate = 80.5% versus 95.8%, HR = 5.20, 95% CI = 1.04–26.00; P = 0.045), and OS (3-year OS rate = 82.9% versus 95.8%, HR = 5.41, 95% CI = 1.08–27.22; P = 0.040). Pretreatment pEBV DNA load was an independent prognostic indicator for PFS, DMFS, and OS in pediatric patients with NPC. Prospective studies, however, are needed to validate these results.
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