Pan-cancer efficacy and safety of anlotinib plus PD-1 inhibitor in refractory solid tumor: A single-arm, open-label, phase II trial.

The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD-1 inhibitor to treat refractory solid tumor. APICAL-RST is an investigator-initiated, open-label, single-arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD-1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression-free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty-one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention-to-treat cohort, and 24.3% and 81.1% in the efficacy-evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%-77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23-24.4), and the 12- and 36-month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty-one (75.6%) patients experienced at least one treatment-related adverse event. The most common adverse events were hypothyroidism, hand-foot syndrome and malaise. This phase II trial showed that anlotinib plus PD-1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor.

Acquired EML4-ALK fusion and EGFR C797S in cis mutation as resistance mechanisms to osimertinib in a non-small cell lung cancer patient with EGFR L858R/T790M.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) dramatically improve the clinical outcomes of non-small cell lung cancer (NSCLC) patients harboring EGFR -sensitive mutations. Despite the remarkable efficacy of first-and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is a primary contributor to the acquired resistance to first- and second-generation EGFR TKIs. Osimertinib, which is an irreversible third-generation EGFR TKI, was designed for EGFR -activating mutations as well as the EGFR T790M mutation in patients with advanced NSCLC and has demonstrated a convincing efficacy. However, acquired resistance to osimertinib after treatment inevitably occurs. The acquired resistance mechanisms to osimertinib are highly complicated and not fully understood, encompassing EGFR -dependent as well as EGFR -independent mechanisms. Treatment approaches for patients progressing from osimertinib have not been established. We present a case of a stage IV lung adenocarcinoma patient harboring EGFR L858R, acquired T790M after treatment with first-line gefitinib. She then acquired a new EML4-ALK gene fusion after treatment with osimertinib. A combination targeted therapy of osimertinib plus alectinib was initiated, with a progression-free survival of 5 months without any serious adverse reaction. After disease progression, EGFR C797S in cis was detected with a loss of the EML4-ALK fusion by targeted next-generation sequencing. Then therapy was changed to pemetrexed combined with bevacizumab plus camrelizumab, but no obvious effect was observed. The patient had achieved an overall survival of 31 months. As far as we know, this was the first reported case that an EGFR -mutant NSCLC patient-acquired ALK fusion mediating resistance to osimertinib, and sequential EGFR C797S mutation mediating resistance to combined targeted therapy with osimertinib and alectinib. Our case shows that EML4-ALK fusion is a rare but critical resistance mechanism to osimertinib, and C797S mutation in cis may be an underlying mechanism of acquired resistance mutation in double TKIs therapy. Furthermore, molecular detection and rebiopsy play important roles in the selection of therapeutic strategies when the disease progresses.

Membrane-associated RING-CH protein (MARCH8) is a novel glycolysis repressor targeted by miR-32 in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and leading cause of cancer-related deaths worldwide. Aberrant cellular metabolism is a hallmark of cancer cells, and disturbed metabolism showed clinical significance in CRC. The membrane-associated RING-CH 8 (MARCH8) protein, the first MARCH E3 ligase, plays an oncogenic role and serves as a prognostic marker in multiple cancers, however, the role of MARCH8 in CRC is unclear. In the present study, we aimed to investigate the biomarkers and their underlying mechanism for CRC. METHOD: In this study, we first examined the function of MARCH8 in CRC by analysing public database. Besides, we performing gene silencing studies and generating cellular overexpression and xenograft models. Then its protein substrate was identified and validated. In addition, the expression of MARCH8 was investigated in tissue samples from CRC patients, and the molecular basis for decreased expression was analysed. RESULTS: Systematic analysis reveals that MARCH8 is a beneficial prognostic marker in CRC. In CRC, MARCH8 exhibited tumor-suppressive activity both in vivo and in vitro. Furthermore, we found that MARCH8 is negatively correlated with hexokinase 2 (HK2) protein in CRC patients. MARCH8 regulates glycolysis and promotes ubiquitination-mediated proteasome degradation to reduces HK2 protein levels. Then HK2 inhibitor partially rescues the effect of MARCH8 knockdown in CRC. Poised chromatin and elevated miR-32 repressed MARCH8 expression. CONCLUSION: In summary, we propose that in CRC, poised chromatin and miR-32 decrease the expression of MARCH8, further bind and add ubiquitin, induce HK2 degradation, and finally repress glycolysis to promote tumor suppressors in CRC.

Cutting Edge: Inhibition of Glycogen Synthase Kinase 3 Activity Induces the Generation and Enhanced Suppressive Function of Human IL-10+ FOXP3+-Induced Regulatory T Cells.

IL-10 is critical for Foxp3+ regulatory T cell (Tregs)-mediated immune suppression, but how to efficiently upregulate IL-10 production in Tregs remains unclear. In this article, we show that human IL-10+ FOXP3+-induced regulatory T cell (iTreg) generation can be dramatically promoted by inhibiting GSK3 activity. IL-10+ FOXP3+ iTregs induced by GSK3 inhibition exhibit classical features of immune-suppressive T cells. We further demonstrate that IL-10+ iTregs exhibit enhanced suppressive function in both IL-10-dependent and -independent manners. The enhanced suppressive function of IL-10+ Tregs is not due to a single factor such as IL-10, although IL-10 may mediate this enhanced suppressive function to some extent. Mechanistically, the increased transcriptional activity of IL-10 promoter and the enhanced expression of C-Maf and BLIMP1 coordinately facilitate IL-10 expression in human iTregs under GSK3 inhibition. Our study provides a new strategy to generate human immune-suppressive IL-10+ FOXP3+ Tregs for immunotherapies.

HER2 Splice Site Mutation c.1899-1G>A as the Potential Acquired Resistance to Trastuzumab in a Patient with HER2-Positive Gastric Adenocarcinoma.

The addition of trastuzumab to chemotherapy regimen is the standard of care for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer; however, most patients eventually acquire trastuzumab resistance. Although some resistance mechanisms to trastuzumab-based regimens have been proposed, further understanding is required for developing therapeutic strategies to overcome the resistance. In the present work, we attempted to determine the possible resistance mechanism to trastuzumab in a patient with HER2-positive stage IV gastric adenocarcinoma. In this study, we first report the nucleotide change c.1899-1G>A at the intron 15 acceptor splice site promoting exon 16 deletion of HER2 as the potential mechanism of trastuzumab resistance in HER2-positive gastric adenocarcinoma. KEY POINTS: The combination of trastuzumab with chemotherapy is considered to be the standard therapy for HER2-positive advanced gastric cancer (GC), but most of the patients eventually acquire trastuzumab resistance. The mechanisms of resistance to trastuzumab in GC are poorly characterized. To the best of the authors' knowledge, this study is the first to implicate HER2 c.1899-1G>A, which results in exon 16 skpping, as the acquired resistance mechanism to trastuzumab in HER2-positive gastric adenocarcinoma. This work provides insights into the potential molecular mechanism of trastuzumab resistance, which is crucial in developing effective therapeutic strategies for HER2-positive GC patients refractory to trastuzumab.

Metastatic Low-Grade Sarcoma with CARS-ALK Fusion Dramatically Responded to Multiple ALK Tyrosine Kinase Inhibitors: A Case Report with Comprehensive Genomic Analysis.

This article reports a case of advanced metastatic low-grade sarcoma. The patient was diagnosed with an inoperable large (14 × 12 cm) lesion on his neck in September 2015 and underwent two ineffective chemotherapies in the following 4 months. Interestingly, although several pathologists could not agree on the histopathological diagnosis, the precise molecular pathological diagnosis was obtained using next-generation sequencing (NGS) and finally brought excellent therapeutic effects. The patient was detected to have CARS-ALK fusion by NGS and then was successfully treated with crizotinib orally. He received surgical resection of primary and metastatic lesions after tumor shrinkage. The combined treatment brought a durable response for 40 months. Although the tumor recurred in July 2019, the patient has been responding well to the second-line ALK tyrosine kinase inhibitor alectinib to date. We performed whole genome sequencing on the patient's primary, metastatic, and recurrent tumors and did comprehensive genomic analysis. Furthermore, our analysis results revealed that a whole genome duplication event might have happened during tumorigenesis of this case. KEY POINTS: To our best knowledge, this is the first report of a very successful treatment with first- and second-line ALK tyrosine kinase inhibitors for CARS-ALK fusion-positive metastatic low-grade sarcoma. Molecular pathological result can guide precision treatment for sarcoma, even when the exact histopathology cannot be obtained. Multiple samples from this patient were analyzed using whole genome sequencing. Results provided detailed genomic characteristics and showed tumor evolution of this low-grade sarcoma case. A whole genome duplication event might have happened during tumorigenesis of this low-grade sarcoma case.

A meta-analysis of efficacy and safety of S-1 monotherapy or combination therapy as first-line treatment in metastatic colorectal cancer.

PURPOSE: To compare the efficacy and safety profile of S-1-based versus non-S-1-based chemotherapy as first-line treatment in mCRC. METHODS: Relevant randomized controlled trials (RCTs) were obtained from PubMed, Embase, and Ovid databases and the Cochrane library from database set up in May 2018. The RCTs of S-1-based monotherapy or combination therapy as first-line treatment were selected. The impact of S-1-based chemotherapy on progression-free survival (PFS) and overall survival (OS) was assessed by pooling data via RevMan 5.3. RESULTS: Meta-analysis of 10 RCTs showed that S-1-based chemotherapy significantly improved PFS (HR 0.90, 95% CI 0.84-0.97, P = 0.006). In subgroup analysis, there was a statistically significant increase in PFS when S-1-based chemotherapy was compared with 5-FU-based (HR 0.92, 95% CI 0.84-1.00, P = 0.04) or capecitabine-based chemotherapy (HR 0.85, 95% CI 0.73-0.99, P = 0.04). The meta-analysis of OS (HR 0.95, 95% CI 0.86-1.05, P = 0.36), overall response rate (ORR) (HR 0.99, 95% CI 0.84-1.17, P = 0.90), and disease control rate (DCR) (HR 1.61, 95% CI 0.87-3.00, P = 0.13) showed no statistical significance between S-1-based and non-S-1-based chemotherapy. The statistically significant differences in the meta-analysis indicated less incidence of graded 3-4 leucopenia (OR = 0.30, 95% CI 0.13-0.71, P = 0.006) and hand-foot syndrome (HFS) (OR = 0.24, 95% CI 0.10-0.58, P = 0.001) in the S-1-based chemotherapy, and there was no statistically significant difference for other adverse events. CONCLUSIONS: S-1-based chemotherapy in mono or combined therapy was an attractive alternative to standard first-line regimen for patients of mCRC.

Rapid symptomatic relief of HER2-positive gastric cancer leptomeningeal carcinomatosis with lapatinib, trastuzumab and capecitabine: a case report.

BACKGROUND: Gastric cancer patients with widespread metastasis, especially meningeal metastases, have an extremely prognosis and limited therapeutic choices. CASE PRESENTATION: We reported the case of a 39-year-old male patient with HER2-positive gastric cancer with bone and meningeal metastases. He presented with multiple bone metastases and received 3 cycles of docetaxel plus S1. However, he complained with headache and imaging examinations revealed leptomeningeal carcinomatosis. FISH revealed that tumor cells in the cerebrospinal fluid were HER-positive. Herceptin was added to the regimen, but the symptoms were not relieved, the patient suffered from dizziness and nausea. The chemotherapy regimen was switched d to lapatinib (orally at 1250 mg/day, every day), capecitabine (orally at 1000 mg/m2, bid for 2 weeks, followed by a 1-week rest interval, as 1 cycle) and Herceptin (390 mg/3 weeks). After 3 weeks of the new treatment, all the symptoms relieved. The clinical complete response was maintained for 3 months. CONCLUSIONS: Lapatinib/Capecitabine combination therapy is an alternative treatment strategy for leptomeningeal carcinomatosis of HER2-positive gastric cancer in which trastuzumab and/or chemotherapy essentially has no effect.

BAT3 rs1052486 and rs3117582 polymorphisms are associated with lung cancer risk: a meta-analysis.

Several studies have examined the associations of polymorphisms in HLA-B-associated transcript 3 (BAT3) with lung cancer risk. However, the results were conflicting. Thus, a meta-analysis was conducted to determine the relationship between BAT3 polymorphisms and lung cancer risk. Databases including PubMed, EMBASE, and Wanfang were searched. Summary odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were estimated using random effects models or fixed effects models. Nine studies were included in this meta-analysis. BAT3 rs1052486 was associated with a significantly increased lung cancer risk (OR = 1.06, 95 % CI 1.01-1.12, P = 0.03). This polymorphism was also significantly associated with lung cancer risk in Caucasians (OR = 1.07; 95 % CI, 1.01-1.12; P = 0.02). Furthermore, BAT3 rs3117582 increased lung cancer risk (OR = 1.31, 95 % CI, 1.26-1.35, P < 0.00001). This polymorphism was also significantly associated with squamous carcinoma risk (OR = 1.30; 95 % CI, 1.11-1.52; P = 0.001) and lung cancer risk in smokers (OR = 1.23; 95 % CI, 1.10-1.38; P = 0.0005). This meta-analysis suggested that BAT3 polymorphisms contributed the development of lung cancer.

New clinical trial design in precision medicine: discovery, development and direction.

In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.

Targeted therapy for intractable cancer on the basis of molecular profiles: An open-label, phase II basket trial (Long March Pathway).

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated. Materials and methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients. Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%). Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.

Circulating lncRNA EGFR-AS1 as a diagnostic biomarker of colorectal cancer and an indicator of tumor burden.

Background: Colorectal cancer (CRC) is one of the most common malignancies. Although CRC treatment has been significantly improved, patient survival remains low because most patients already have advanced disease at diagnosis. Early screening and diagnosis of tumors is critical; however, the current tissue biopsy and radiological evaluation methods have very limited effectiveness. Therefore, establishing new convenient and non-invasive biomarkers is urgently needed for timely detection, therapeutic assessment, and prognostic prediction. At present, non-coding RNAs (ncRNAs) have attracted research attention owing to their potential oncological applications. Methods: The long ncRNA epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) is overexpressed in multiple malignancies including CRC. The present study examined the circulating EGFR-AS1 level in CRC, and the results showed that EGFR-AS1 could be considered an indicator of tumor burden. Results: Elevated circulating EGFR-AS1 levels were detected in CRC cases (n=128) compared with control cases comprising endoscopy confirmed CRC-free individuals [n=64, median expression normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 1.578 vs. 0.780, P<0.001]. Individuals with larger tumors (≥5 cm) had elevated circulating EGFR-AS1 levels compared to those with smaller tumors (<5 cm, 1.739 vs. 1.290, P<0.001). The expression of serum EGFR-AS1 in stage III/IV CRC was higher than that in stage I/II CRC (1.691 vs. 1.412, P<0.05). Plasma EGFR-AS1 levels were markedly reduced following surgical resection of colorectal lesions in a subset of patients [n=32, 1.192 (pre-surgery) vs. 0.692, P<0.001]. Furthermore, the expression of EGFR-AS1 in resected CRC tissues was significantly higher than that in paracancerous tissues (n=32, 1.336 vs. 0.487, P<0.001). Conclusions: These results highlight the potential of EGFR-AS1 as a diagnostic biomarker in CRC.

Effect of smoking habits on the efficacy of EGFR-TKI plus anti-angiogenic agent in advanced EGFR-mutant NSCLC.

BACKGROUND: The types of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients who could obtain significant clinical benefit from the dual inhibition of EGFR/vascular EGFR (VEGFR) pathways remain unclear. No consensus has been reached on the significance of smoking habits in clinical benefit obtained from EGFR-TKI plus anti-angiogenic agents. METHODS: PubMed, EMBASE, and Cochrane databases for all phase II/III randomized clinical trials (RCTs) investigating the efficacy of EGFR-TKI combined with anti-angiogenic agents stratified by smoking habits (updated October 2021) were searched systematically. The primary outcomes were the pooled HRs for PFS/OS in smokers and non-smokers, and differences in efficacy of EGFR-TKI plus anti-angiogenic treatment between smokers and non-smokers, measured by difference in PFS and OS. RESULTS: Seven phase II/III RCTs involving 1452 patients were identified. The pooled analysis demonstrated that EGFR-TKI plus anti-angiogenic agent could decrease the risk of progression by 40% (HR, 0.60; 95%CI 0.48-0.75) in smokers when compared with EGFR-TKI alone, but not in non-smokers (HR, 0.92; 95%CI 0.68-1.25). The comparison analysis further demonstrated that EGFR-mutated NSCLC patients who smoked obtained greater progression-free survival (PFS) benefit from treatment with EGFR-TKI plus anti-angiogenic agents (HR, 0.68; 95%CI 0.51-0.91). Consistent with the results for PFS, smokers receiving EGFR-TKI plus anti-angiogenic agents appeared to exhibit better overall survival (OS) than non-smokers but not to a statistically significant degree (HR, 0.60; 95%CI 0.23-1.52). Meta-regression analysis revealed no significant effect of the line of treatment (P = 0.52), trial phase (P = 0.52), EGFR-TKI type (P = 0.13), or anti-angiogenic agent type (P = 0.50) on PFS effect sizes under multivariate models. CONCLUSION: Comprehensive analysis suggested that EGFR-TKI plus anti-angiogenic agents led to favorable PFS among smoking EGFR-mutant patients, comparable to nonsmokers, which might provide a useful guide for clinicians.

Durable Clinical Response to ALK Tyrosine Kinase Inhibitors in Epithelioid Inflammatory Myofibroblastic Sarcoma Harboring PRRC2B-ALK Rearrangement: A Case Report.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm and patients with IMT tend to have a favorable outcome after complete surgical resection. However, some tumors of IMT cases have recurred and grown rapidly after successful surgery. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a highly aggressive intra-abdominal IMT variant with epithelioid-to-round cell morphology. Currently, no standard therapy exists for recurrent or invasive IMTs and EIMS, but anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are recommended for those harboring ALK gene rearrangements. We herein report the first case of PRRC2B-ALK fusion associated IMTs with clinical and pathological manifestation matched the diagnosis criteria of EIMS and the durable clinical response of the sequential use of ALK TKIs (crizotinib, alectinib, ceritinib, and lorlatinib). A female patient with EIMS of the greater omentum was suffering from a rapid recurrence after cytoreductive surgery was done. Crizotinib was administered when PRRC2B-ALK fusion was detected, and partial response was achieved. The progression-free survival (PFS) of crizotinib was 5 months. Alectinib was administered based on the results of second next-generation sequencing (NGS) analysis, which identified the secondary mutation ALK R1192P. The best overall response of alectinib treatment was a partial response (PR) and the PFS was 5.5 months. Ceritinib was prescribed as third-line therapy after alectinib resistance with ALK L1196M mutation. PR was achieved and the PFS of ceritinib was 6 months. The patient was taking lorlatinib after ceritinib resistance and achieved a stable disease at 2 months with the PFS more than 5 months. The overall survival was more than two years as of the time of manuscript preparation. We describe an EIMS of greater omentum caused by PRRC2B-ALK fusion gene and showed durable clinical response to the sequential use of ALK TKIs.

Cetuximab and vemurafenib plus FOLFIRI (5-fluorouracil/leucovorin/irinotecan) for BRAF V600E-mutated advanced colorectal cancer (IMPROVEMENT): An open-label, single-arm, phase II trial.

BACKGROUND: Current therapeutic regimens for patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E-mutated colorectal cancer show unsatisfactory efficacy. To improve outcomes in this area, we assessed the safety and efficacy of a new protocol using vemurafenib and cetuximab combined with FOLFIRI (5-fluorouracil/leucovorin/irinotecan) in patients with BRAF V600E-mutated colorectal cancer. METHODS AND MATERIALS: This was an investigator-initiated, open-label, single-arm, phase II trial conducted in patients with BRAF V600E-mutated advanced colorectal cancer. Patients were eligible to receive FOLFIRI combined with vemurafenib and cetuximab. The primary end-point was the objective response rate, and the secondary end-points included disease control rate, progression-free survival, overall survival and safety. This trial is registered with ClinicalTrials.gov, NCT03727763. RESULTS: Between 12th January 2018, and 18th June 2021, we screened 27 patients, 21 of which were enrolled in this study. Efficacy analysis showed that objective response rates were 81.0% (17/21; 95% confidence interval [CI] 57.4-93.7) in the intention-to-treat population and 85.0% (17/20, 95%CI 61.0-96.0) in the per-protocol population; two patients achieved complete response, and 15 patients achieved a partial response. In the entire cohort, the median progression-free survival was 9.7 months (95%CI 6.3-10.9), and the median overall survival for all patients was 15.4 months (95%CI 8.5-15.4). The most common adverse events (grade 3 to 4) were neutropenia (8/21), anaemia (3/21) and skin rash (3/21). CONCLUSION: Vemurafenib and cetuximab can be safely combined with the FOLFIRI regimen, showing promising antitumour activity and tolerable toxicity in patients with BRAF V600E-mutated advanced colorectal cancer. This regimen warrants a further randomised study in phase III clinical trials.

Low-dose anti-VEGFR2 therapy promotes anti-tumor immunity in lung adenocarcinoma by down-regulating the expression of layilin on tumor-infiltrating CD8+T cells.

PURPOSE: Our study intended to explore how low-dose anti-angiogenic drugs affected anti-tumor immunity of tumor-infiltrating exhausted CD8+T cells and achieved better clinical response when combined with immunotherapy. We set out to find potential targets or predictive biomarker on CD8+T cells for immunotherapy. METHODS: We tested different doses of anti-VEGFR2 antibody combined with anti-PD1 antibody to treat LUAD in vivo and analyzed tumor-infiltrating CD8+T cells by flow cytometry. CD8+T cells overexpressing LAYN were co-cultured with LA795 cell lines to identify the function of LAYN in CD8+T cells. We also analyzed clinical samples from advanced LUAD patients treated with anti-angiogenesis therapy combined with immunotherapy. RESULTS: Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody treatment delayed tumor growth and prolonged the survival time of tumor-bearing mice. The number of tumor-infiltrating CD8+T cells was reduced and the expression of LAYN was down-regulated in tumor-infiltrating CD8+T cells in the low-dose anti-VEGFR2 combination group. It was found that LAYN inhibited the killing function of CD8+T cells. In patients with advanced LUAD who received anti-angiogenesis therapy combined with immunotherapy, the LAYN+CD8+T cell subpopulation in good responders was significantly higher than that in poor responders. Furthermore, we demonstrated the expression of LAYN was regulated by upstream transcription factor NR4A1. CONCLUSION: Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody therapy promoted anti-tumor immunity and the downregulation of LAYN in tumor-infiltrating CD8+T cells played an important role in this process. These findings had implications for improving the efficacy of immune checkpoint blockade therapy and further optimized clinical treatment guidelines in advanced LUAD.

Prognostic value of tumor mutation burden in patients with advanced gastric cancer receiving first-line chemotherapy.

Background: Tumor mutation burden (TMB) is a promising biomarker positively associated with the benefit of immunotherapy and that might predict the outcome of chemotherapy. We described the prognostic value of TMB in advanced gastric cancer and explored the underlying mechanism. Methods: We enrolled 155 TMB-evaluated advanced gastric cancer patients and analyzed the relationship between clinicopathological characteristics and both overall survival (OS) and progression-free survival (PFS) among 40 patients treated with first-line chemotherapy. We further verified the distribution of TMB and analyzed the potential mechanism underlying the prognosis based on The Cancer Genome Atlas (TCGA) database. Results: Among the 155 patients, 29 (18.7%) were TMB-high (TMB ≥ 10), roughly the same as the proportion in the TCGA data. Of the 40 patients receiving first-line chemotherapy, the median OS (7.9 vs. 12.1 months; HR 3.18; p = 0.0056) and PFS (4.4 vs. 6.2 months; HR 2.94; p = 0.0099) of the tissue-tested TMB (tTMB)-high patients were inferior to those of the tTMB-low patients. Similarly, unfavorable median OS (9.9 vs. 12.1 months; HR 2.11; p = 0.028) and PFS (5.3 vs. 6.5 months; HR 2.49; p = 0.0054) were shown in the blood-tested TMB (bTMB)-high than in the bTMB-low patients. The Cox analysis demonstrated that both tTMB-high and bTMB-high were significant independent predictors of dreadful OS and PFS. The differentially expressed genes (DEGs) according to TMB status were most significantly enriched in the downregulated metabolic pathway among the TMB-high patients. Conclusions: TMB-high advanced gastric cancer patients accounted for around one-sixth and had a poorer prognosis than TMB-low patients when treated with first-line chemotherapy. The potential mechanism might be the downregulated metabolic activity in TMB-high patients.

Prognostic Biomarkers on a Competitive Endogenous RNA Network Reveals Overall Survival in Triple-Negative Breast Cancer.

The objective of this study was to construct a competitive endogenous RNA (ceRNA) regulatory network using differentially expressed long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in patients with triple-negative breast cancer (TNBC) and to construct a prognostic model for predicting overall survival (OS) in patients with TNBC. Differentially expressed lncRNAs, miRNAs, and mRNAs in TNBC patients from the TCGA and Metabric databases were examined. A prognostic model based on prognostic scores (PSs) was established for predicting OS in TNBC patients, and the performance of the model was assessed by a recipient that operated on a distinctive curve. A total of 874 differentially expressed RNAs (DERs) were screened, among which 6 lncRNAs, 295 miRNAs and 573 mRNAs were utilized to construct targeted and coexpression ceRNA regulatory networks. Eight differentially expressed genes (DEGs) associated with survival prognosis, DBX2, MYH7, TARDBP, POU4F1, ABCB11, LHFPL5, TRHDE and TIMP4, were identified by multivariate Cox regression and then used to establish a prognostic model. Our study shows that the ceRNA network has a critical role in maintaining the aggressiveness of TNBC and provides comprehensive molecular-level insight for predicting individual mortality hazards for TNBC patients. Our data suggest that these prognostic mRNAs from the ceRNA network are promising therapeutic targets for clinical intervention.

Hormone Receptor Status May Impact the Survival Benefit Between Medullary Breast Carcinoma and Atypical Medullary Carcinoma of the Breast: A Population-Based Study.

BACKGROUND: A rare subtype of breast cancer, atypical medullary carcinoma of the breast (AMCB), shows a highly adverse prognosis compared to medullary carcinoma of the breast (MBC). The current study aimed to establish a correlated nomogram for the identification of the prognostic factors of AMCB and MBC. METHODS: Kaplan-Meier and Cox regression analyses were applied to data acquired from the Surveillance, Epidemiology and End Results (SEER) database for 2004 to 2013 to analyse tumour characteristics and overall survival. Propensity score matching (PSM) analysis was performed to determine the overall survival (OS) among those with AMCB and MBC. A predictive nomogram was created, and the concordance index (C-index) was used to predict accuracy and discriminative ability. RESULTS: A total of 2,001 patients from the SEER database were diagnosed with MBC between 2004 and 2013, including 147 patients diagnosed with AMCB. The number of diagnoses gradually increased in both groups. Cox analysis of multivariate and Kaplan-Meier analysis showed that older age (HR = 3.005, 95% CI 1.906-4.739) and later stage were significantly associated with poor prognosis, while cancer-directed surgery was an independent protective factor (HR = 0.252, 95% CI 0.086-0.740). In the HR-negative stratification analysis, older age (HR = 2.476, 95% CI 1.398-4.385), later stage and histological type (HR=0.381, 95% CI 0.198-0.734) were found to be independent prognostic factors for low standard survival. The log-rank analysis demonstrated significantly worse prognostic factors for patients with AMCB than for those with MBC (P = 0.004). A nomogram (C-index for survival = 0.75; 95% CI 0.69-0.81) was established from four independent prognostic factors after complete identification. CONCLUSIONS: MBC is rare, and cancer-directed surgery, older age, and later stage are independently linked with prognosis. In the HR negative population, AMCB patients show a worse survival gain than those with MBC.

Long noncoding RNA DATOC-1 that associate with DICER promotes development in epithelial ovarian cancer by upregulating miR-7 expression.

BACKGROUND: DICER is a key RNase III enzyme that cleaves processes miRNAs into their mature form. It is remarkably down-regulated in most epithelial ovarian cancer (EOC) and the down-regulation is associated with high grade malignancy as well as poor clinical outcomes. In this study, we aimed to discover a lncRNA interacting with DICER to participate in the process of microRNAs maturation and as a result promoting development of EOC. METHODS: We conducted a RIP-seq aimed at DICER and we obtained its chromosomal location by aligning the sequence in PubMed. And the lncRNA was named DATOC-1 (DICER Associated Transcript 1 in Ovarian Cancer). We tested relative expression of DATOC-1 in 53 EOC and 7 adjacent ovarian samples by qRT-PCR. Then the expression in EOC patients derived from The Cancer Genome Atlas (TCGA) were analysed to identify DATOC-1-based signatures for EOC prognosis with survival analysis. Lastly, shRNA Screening and lentiviral transduction was used to determine the function of DATOC-1 in vitro and in vivo. RESULTS: We identified the lncRNA RP5-1120P11.1 as DATOC-1, which highly expressed in EOC tissues than in adjacent. And Kaplan-Meier analysis indicated that the patients with EOC that expressed high levels of DATOC-1 had a worse prognosis and shorter disease OS compared with DATOC-1 low-expressed patients. In addition, DATOC-1 were further identified participating in EOC cell proliferation, cell cycle regulation and cell invasion. And knockdown of DATOC-1 inhibits tumor progression in vivo. Furthermore, knockdown of DATOC-1 increased the expression of miR7. The evidence showed that miR7 functioning as a tumor suppressor gene in EOC. CONCLUSIONS: Our research shows that DATOC-1 can inhibit the development of EOC and is a promising therapeutic target.