Special issue "The advance of solid tumor research in China": FGFR4 alterations predict efficacy of immune checkpoint inhibitors in nonsmall cell lung cancer.

Immune checkpoint inhibitors (ICIs), which represent the new standard of care for advanced nonsmall cell lung cancer (NCSLC), are not effective in many patients. Biomarkers are needed to guide treatment. Sequencing data of an ICI-treated cohort were analyzed to identify genomic signatures predicting ICI efficacy, followed by validation using multiple independent cohorts. Their predictive mechanism was explored by evaluating the tumor immune microenvironment and tumor mutational burden (TMB). In the discovery cohort, patients carrying FGFR4 alterations (FGFR4altered ) had a better objective response rate (ORR) (50.0% vs 19.4%; P = .057) and improved median progression-free survival (mPFS) (13.17 vs 3.17 months; HR 0.37; 95% CI 0.14-1; P = .04) than wild-type patients (FGFR4wt ). In the publicly available validation cohorts, FGFR4 alterations correlated with higher ORR (100% vs 31%; P = .028), longer median overall survival (mOS) (not reached [NR] vs 11 months; HR 0.28, 95% CI 0.09-0.89, P = .02), and mPFS (NR vs 6.07 months; HR 0.05, 95% CI 0-3.94, P = .039). FGFR4 alterations were confirmed as an independent predictor of superior PFS (P = .014) and OS (P = .005). FGFR4altered patients also exhibited a significantly improved disease control rate (100% vs 60%, P = .045) and prolonged mPFS (9.70 vs 3.16 months; P = .095) compared to FGFR4wt patients in our Shanghai Pulmonary Hospital cohort. FGFR4 alterations associated with a higher TMB levels, more CD8+ T cells in the tumor stroma, and a higher M1/M2 ratio for tumor-associated macrophages in the tumor center and stroma. Thus, FGFR4 alterations may serve as a potential independent predictor of ICI efficacy in NSCLC.

Circulating tumor DNA predicts neoadjuvant immunotherapy efficacy and recurrence-free survival in surgical non-small cell lung cancer patients.

Background: There is currently a lack of effective biomarkers to evaluate efficacy of neoadjuvant therapy (NAT) for resectable non-small cell lung cancer (NSCLC) patients. Circulating tumor DNA (ctDNA) has been investigated as a non-invasive tool for the assessment of tumor burden and minimal residual disease (MRD). The utility of ctDNA profiling in reflecting NAT efficacy, however, has not been confirmed. This study explored the association of ctDNA change with treatment response to NAT and recurrence-free survival (RFS) after surgery. Methods: Eligible patients with stage IB-IIIA NSCLC were retrospectively included if they had received neoadjuvant immunotherapy combined with chemotherapy (IO+Chemo), dual immunotherapy (IO+IO), or chemotherapy alone (Chemo). We conducted ctDNA profiling before and after NAT, after surgery, and during follow-ups using an ultra-deep lung cancer-specific MRD (LC-MRD) sequencing panel. Results: A total of 22 patients who received NAT followed by surgery between August 2018 and July 2019 were included in this study. The major pathological response (MPR) rates were 58.33% (7/12) in the IO+Chemo group, 25.00% (1/4) in the IO+IO group, and 16.67% (1/6) in the Chemo group. The ctDNA dynamics during NAT were highly concordant with pathologic response, demonstrating 100% sensitivity and 83.33% specificity, for an overall accuracy of 91.67%. Pre-surgery detectable ctDNA (after NAT) trended to correlate with inferior RFS [hazard ratio (HR), 7.41; 95% confidence interval (CI): 0.91-60.22, log-rank P=0.03]. At 3-8 days after surgery, ctDNA was detectable in 31.8% of patients and was an independent risk factor for recurrence (HR, 5.37; 95% CI: 1.27-22.67; log-rank P=0.01). The presence of ctDNA at 3 months after surgery showed 83% sensitivity and 90% specificity for predicting relapse (C-index, 0.79; 95% CI: 0.62-0.95). During disease monitoring after surgery, molecular recurrence by means of ctDNA preceded radiographic relapse, with a median time of 6.83 months. Conclusions: This study investigated the potential of ctDNA in evaluating NAT efficacy in NSCLC, implying the high concordance between ctDNA and pathological response. We also set out the prognostic value of perioperative ctDNA in predicting recurrence.

Redefine Hyperprogressive Disease During Treatment With Immune-Checkpoint Inhibitors in Patients With Gastrointestinal Cancer.

OBJECTIVE: Emerging evidence showed that immune checkpoint inhibitors (ICIs) lead to hyperprogressive disease (HPD) in a small proportion of patients. There is no well-recognized standard for the evaluation of HPD. Comprehensive exploration of HPD definition system in gastrointestinal cancer treated with ICI is lacking to date. METHODS: A total of 126 patients with advanced or metastatic gastrointestinal cancer treated with ICI monotherapy were analyzed. Seven definitions of HPD were defined with tumor growth kinetics (TGK) or tumor growth rate (TGR) by including new lesions or not, and with different cutoffs. Incidence and performance of different criteria were compared. Clinicopathologic characteristics and baseline genomic variations associated with HPD were also explored. RESULTS: Tumor growth kinetics ratio of more than two fold that incorporated new lesions into calculation of HPD outperformed other definitions by successfully stratifying 14 patients (11.1%) with both accelerated disease progression (median PFS, 1.62 versus 1.93 months; hazard ratio, 1.85; 95% CI, 0.98 to 3.48; P = 0.059) and worse overall survival (median OS, 3.97 versus 10.23 months; hazard ratio, 2.30; 95% CI, 1.11 to 4.78; P = 0.021). Baseline genomic alterations in circulating tumor DNA, including SMARCA2, MSH6, APC signaling pathway, and Wnt signaling pathway, might be associated with the risk of HPD. CONCLUSION: Incorporating new lesions emerging during the treatment was shown to be reliable for the assessment of TGK. TGK serves as a more convenient way to reflect tumor growth acceleration compared with TGR. Genomic alterations were suggested to be associated with the occurrence of HPD.

Landscape of IDH1/2 mutations in Chinese patients with solid tumors: A pan-cancer analysis.

BACKGROUND: Isocitrate dehydrogenase (IDH) is an enzyme family involved in cell aerobic metabolism of tricarboxylic acid cycle. However, the landscape of IDH mutations in pan-cancer has not been fully characterized. METHODS: Tissue or blood samples were subjected to next-generation sequencing (NGS) for detection the IDH mutation. RESULTS: A total of 28.868 patients from more than 20 solid tumor species were analyzed. A total of 374 cases (1.30%) with IDH mutations were identified. Among all the IDH mutations cases, 80 (21.4%) were biliary tract cancer (BTC), 80 (21.4%) were lung cancer, 57 (15.2%) were liver cancer, and 42 (11.2%) were colorectal cancer. The most common IDH variant were IDH1 and IDH2 which were discovered in 0.81% cases and 0.47% cases, respectively. However, there were significant differences in IDH1 and IDH2 mutation frequency among different tumor species (p = 0.0003). Of the patients with IDH1 mutations, about 53.0% of these mutations occur in codons 132. Codons 172 (25.4%) was high-frequency mutation subtypes in IDH2 mutation. TP53, PBRM1, and BAP1 were the most significantly mutated genes in BTC which were different from others cancer. Moreover, TMB were significantly higher in lung cancer, colorectal cancer, and gastric cancer than BTC (p = 0.0164, p < 0.0001, p = 0.0067, respectively) and BTC patients with IDH mutation had lower TMB compared with wild-type IDH. CONCLUSION: Somatic IDH mutation was found in multiple solid tumors and IDH would be a driver gene in BTC.

Efficacy and safety of PD-1/PD-L1 inhibitors plus nab-paclitaxel for patients with non-small cell lung cancer who have progressed after platinum-based chemotherapy.

BACKGROUND: Immunotherapy combined with platinum-based chemotherapy is now the standard first-line treatment for non-small cell lung cancer (NSCLC) patients. However, limited evidence exists to show the efficacy of immunotherapy plus taxanes for patients who have progressed after platinum-based chemotherapy. METHODS: The immunotherapy naïve patients with metastatic NSCLC who received anti-PD-1/PD-L1 monotherapy or combined with nab-paclitaxel after prior platinum-based chemotherapy from 2015 to 2018 in PLA General Hospital were identified. The progression-free survival, overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety were assessed. RESULTS: Of 57 patients, 40 were treated with anti-PD-1/PD-L1 monotherapy and 17 were treated with anti-PD-1/PD-L1 plus nab-paclitaxel. With a median OS follow-up of 16.3 months, the nab-paclitaxel group showed significantly longer OS compared with the immune monotherapy group (median, 28.6 months versus 15.9 months, log-rank p = 0.020). When adjusted by covariates in COX proportional regression model, both the treatment group [p = 0.009, hazard ratio (HR) 0.361; 95% confidence interval (CI) 0.168-0.773] and performance status (p = 0.003, HR 0.372; 95% CI 0.192-0.721) demonstrated independent association with the longer OS from combination therapy. In addition, ORR was 23.5% (4/17) in the immune checkpoints inhibitors (ICIs) plus nab-paclitaxel group versus 13.5% (5/37) in immune monotherapy group (p = 0.439), with a DCR of 88.2% (15/17) and 59.5% (22/37) (p = 0.034), respectively. The incidence of grade 3/4 adverse events was 23.5% (4/17) in the combination group and 2.5% (1/40) in the immune monotherapy group. CONCLUSION: PD-1/PD-L1 inhibitor plus nab-paclitaxel resulted in significantly longer OS and higher response versus ICI single agent in metastatic NSCLC patients who have progressed after platinum-based chemotherapy. These findings need to be further explored by prospective studies.

Pathogenic Germline Mutations in Chinese Patients with Gastric Cancer Identified by Next-Generation Sequencing.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer death in China, while the nature of genetic factors related to GC has not been well-studied. OBJECTIVES: To assess the inherited genetic factors regarding pathogenic germline mutations in Chinese GC population. METHODS: Genomic profiling of DNA was performed through next-generation sequencing with 381 cancer-related genes on tissue from patients with GC between January 1, 2017, and May 7, 2019. RESULTS: 470 GC patients were included for analysis. A total of 28 (6.0%) patients were identified to harbor 25 different pathogenic or very likely pathogenic germline mutations in 15 genes. The variants fell most frequently in BRCA2 (n = 6, 1.28%), CHEK2 (n = 5, 1.06%), MUTYH (n = 3, 0.64%), CDH1 (n = 2, 0.43%), and ATM (n = 2, 0.43%). Of all the germline-mutated genes, 66.7% (n = 10) lay in the DNA damage repair pathways. Seven patients were identified to have a high TMB status, among whom two were also identified as MSI-H. Overall, 20 out of the 28 patients (71.4%) carried clinically actionable mutations. CONCLUSIONS: Our study has depicted the spectrum of pathogenic germline mutations in Chinese GC patients, which may provide valuable clues for the assessment of the genetic susceptibility and clinical management in GC.

Use of Immunotherapy With Programmed Cell Death 1 vs Programmed Cell Death Ligand 1 Inhibitors in Patients With Cancer: A Systematic Review and Meta-analysis.

Importance: Immune checkpoint inhibitors of programmed cell death 1 (PD-1) and its ligand (PD-L1) have led to a paradigm shift in cancer treatment. Understanding the clinical efficacy and safety profile of these drugs is necessary for treatment strategy in clinical practice. Objective: To assess the differences between anti-PD-1 and anti-PD-L1 regarding efficacy and safety shown in randomized clinical trials across various tumor types. Data Sources: Systematic searches of PubMed, Cochrane CENTRAL, and Embase were conducted from January 1, 2000, to March 1, 2019. In addition, abstracts and presentations from all major conference proceedings were reviewed. Study Selection: All randomized clinical trials that compared anti-PD-1 and anti-PD-L1 with standard treatment in patients with cancer were selected as candidates. Retrospective studies, single-arm phase 1/2 studies, and trials comparing anti-PD-1 and anti-PD-L1 with other immunotherapies were excluded. Studies of anti-PD-1 and anti-PD-L1 therapy were screened and paired by the matching of clinical characteristics as mirror groups. Data Extraction and Synthesis: Three investigators independently extracted data from each study following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. Trial names, first author, year of publication, study design, National Clinical Trial identifier number, blinding status, study phase, pathologic characteristics, number of patients, patients' age and sex distribution, Eastern Cooperative Oncology Group Performance Status, lines of treatment, study drugs, biomarker status, follow-up time, incidence of adverse events, and hazard ratios (HRs) with 95% CIs for overall survival and progression-free survival were extracted. A random-effects model was applied for data analysis. Main Outcomes and Measures: Differences in OS between anti-PD-1 and anti-PD-L1 across different cancer types were assessed. An effect size was derived from each mirror group and then pooled across all groups using a random-effects model. Results: Nineteen randomized clinical trials involving 11 379 patients were included in the meta-analysis. Overall, anti-PD-1 exhibited superior overall survival (HR, 0.75; 95% CI, 0.65-0.86; P < .001) and progression-free survival (HR, 0.73; 95% CI, 0.56-0.96; P = .02) compared with anti-PD-L1. No significant difference was observed in their safety profiles. Sensitivity analysis presented consistency in the overall estimates across these analyses. Consistent results were observed through frequentist and bayesian approaches with the same studies. Conclusions and Relevance: Comprehensive analysis suggests that anti-PD-1 exhibited favorable survival outcomes and a safety profile comparable to that of anti-PD-L1, which may provide a useful guide for clinicians.

PLEKHM2-ALK: A novel fusion in small-cell lung cancer and durable response to ALK inhibitors.

OBJECTIVES: In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement identifies a subgroup of patients who are sensitive to ALK tyrosine kinase inhibitors (TKIs). ALK fusion is extremely rare in small-cell lung cancer (SCLC). To the best of our knowledge, only two cases of SCLC harboring ALK fusion mutation has been reported previously, both of whom carrying EML4-ALK fusion. There are no standard treatment options for SCLC patients with ALK fusion mutations. Herein, we described a rare case of ALK-rearranged SCLC responding to ALK inhibitors. MATERIALS AND METHODS: Immunohistochemistry (IHC) assay and next-generation sequencing (NGS) were performed on the biopsied tumor tissue. RESULTS: NGS detected a novel pleckstrin homology and RUN domain containing M2 (PLEKHM2)-ALK fusion, while the IHC analysis revealed an ALK-positive tumor. For extensive SCLC patients, median OS was about 8-13 months. The patient in this case had durable clinical benefit upon the treatment with ALK inhibitors, achieving an overall survival (OS) of more than 27 months. CONCLUSION: This case provides a meaningful reference for the treatment of SCLC patients with ALK fusion mutations. This case also provides valuable information on the response to ALK inhibitors of patients with PLEKHM2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS may be used as a routine test to explore more treatment opportunities for tumor SCLC patients.

DCA1 Acts as a Transcriptional Co-activator of DST and Contributes to Drought and Salt Tolerance in Rice.

Natural disasters, including drought and salt stress, seriously threaten food security. In previous work we cloned a key zinc finger transcription factor gene, Drought and Salt Tolerance (DST), a negative regulator of drought and salt tolerance that controls stomatal aperture in rice. However, the exact mechanism by which DST regulates the expression of target genes remains unknown. In the present study, we demonstrated that DST Co-activator 1 (DCA1), a previously unknown CHY zinc finger protein, acts as an interacting co-activator of DST. DST was found to physically interact with itself and to form a heterologous tetramer with DCA1. This transcriptional complex appears to regulate the expression of peroxidase 24 precursor (Prx 24), a gene encoding an H2O2 scavenger that is more highly expressed in guard cells. Downregulation of DCA1 significantly enhanced drought and salt tolerance in rice, and overexpression of DCA1 increased sensitivity to stress treatment. These phenotypes were mainly influenced by DCA1 and negatively regulated stomatal closure through the direct modulation of genes associated with H2O2 homeostasis. Our findings establish a framework for plant drought and salt stress tolerance through the DCA1-DST-Prx24 pathway. Moreover, due to the evolutionary and functional conservation of DCA1 and DST in plants, engineering of this pathway has the potential to improve tolerance to abiotic stress in other important crop species.

Natural alleles of a proteasome α2 subunit gene contribute to thermotolerance and adaptation of African rice.

Global warming threatens many aspects of human life, for example, by reducing crop yields. Breeding heat-tolerant crops using genes conferring thermotolerance is a fundamental way to help deal with this challenge. Here we identify a major quantitative trait locus (QTL) for thermotolerance in African rice (Oryza glaberrima), Thermo-tolerance 1 (TT1), which encodes an α2 subunit of the 26S proteasome involved in the degradation of ubiquitinated proteins. Ubiquitylome analysis indicated that OgTT1 protects cells from heat stress through more efficient elimination of cytotoxic denatured proteins and more effective maintenance of heat-response processes than achieved with OsTT1. Variation in TT1 has been selected for on the basis of climatic temperature and has had an important role in local adaptation during rice evolution. In addition, we found that overexpression of OgTT1 was associated with markedly enhanced thermotolerance in rice, Arabidopsis and Festuca elata. This discovery may lead to an increase in crop security in the face of the ongoing threat of global warming.

The miR156-SPL9-DFR pathway coordinates the relationship between development and abiotic stress tolerance in plants.

Young organisms have relatively strong resistance to diseases and adverse conditions. When confronted with adversity, the process of development is delayed in plants. This phenomenon is thought to result from the rebalancing of energy, which helps plants to coordinate the relationship between development and stress tolerance; however, the molecular mechanism underlying this phenomenon remains mysterious. In this study, we found that miR156 integrates environmental signals to ensure timely flowering, thus enabling the completion of breeding. Under stress conditions, miR156 is induced to maintain the plant in the juvenile state for a relatively long period of time, whereas under favorable conditions, miR156 is suppressed to accelerate the developmental transition. Blocking the miR156 signaling pathway in Arabidopsis thaliana with 35S::MIM156 (via target mimicry) increased the sensitivity of the plant to stress treatment, whereas overexpression of miR156 increased stress tolerance. In fact, this mechanism is also conserved in Oryza sativa (rice). We also identified downstream genes of miR156, i.e. SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 9 (SPL9) and DIHYDROFLAVONOL-4-REDUCTASE (DFR), which take part in this process by influencing the metabolism of anthocyanin. Our results uncover a molecular mechanism for plant adaptation to the environment through the miR156-SPLs-DFR pathway, which coordinates development and abiotic stress tolerance.