A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity.

Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. We evaluated the efficacy and safety of 24-week treatment of mazdutide up to 6 mg in Chinese overweight adults or adults with obesity, as an interim analysis of a randomised, two-part (low doses up to 6 mg and high dose of 9 mg), double-blind, placebo-controlled phase 2 trial (ClinicalTrials.gov, NCT04904913). Overweight adults (body-mass index [BMI] ≥24 kg/m2) accompanied by hyperphagia and/or at least one obesity-related comorbidity or adults with obesity (BMI ≥ 28 kg/m2) were randomly assigned (3:1:3:1:3:1) to once-weekly mazdutide 3 mg, 4.5 mg, 6 mg or matching placebo at 20 hospitals in China. The primary endpoint was the percentage change from baseline to week 24 in body weight. A total of 248 participants were randomised to mazdutide 3 mg (n = 62), 4.5 mg (n = 63), 6 mg (n = 61) or placebo (n = 62). The mean percentage changes from baseline to week 24 in body weight were -6.7% (SE 0.7) with mazdutide 3 mg, -10.4% (0.7) with 4.5 mg, -11.3% (0.7) with 6 mg and 1.0% (0.7) with placebo, with treatment difference versus placebo ranging from -7.7% to -12.3% (all p < 0.0001). All mazdutide doses were well tolerated and the most common adverse events included diarrhoea, nausea and upper respiratory tract infection. In summary, in Chinese overweight adults or adults with obesity, 24-week treatment with mazdutide up to 6 mg was safe and led to robust and clinically meaningful body weight reduction.

A phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes.

The success of glucagon-like peptide-1 (GLP-1) receptor agonists to treat type 2 diabetes (T2D) and obesity has sparked considerable efforts to develop next-generation co-agonists that are more effective. We conducted a randomised, placebo-controlled phase 1b study (ClinicalTrials.gov: NCT04466904) to evaluate the safety and efficacy of IBI362 (LY3305677), a GLP-1 and glucagon receptor dual agonist, in Chinese patients with T2D. A total of 43 patients with T2D were enrolled in three cohorts in nine study centres in China and randomised in each cohort to receive once-weekly IBI362 (3.0 mg, 4.5 mg or 6.0 mg), placebo or open-label dulaglutide (1.5 mg) subcutaneously for 12 weeks. Forty-two patients received the study treatment and were included in the analysis, with eight receiving IBI362, four receiving placebo and two receiving dulaglutide in each cohort. The patients, investigators and study site personnel involved in treating and assessing patients in each cohort were masked to IBI362 and placebo allocation. Primary outcomes were safety and tolerability of IBI362. Secondary outcomes included the change in glycated haemoglobin A1c (HbA1c), fasting plasma glucose (FPG) and post-mixed-meal tolerance test (post-MTT) glucose levels. IBI362 was well tolerated. Most commonly-reported treatment-emergent adverse events were diarrhoea (29.2% for IBI362, 33.3% for dulaglutide, 0% for placebo), decreased appetite (25.0% for IBI362, 16.7% for dulaglutide, 0% for placebo) and nausea (16.7% for IBI362, 16.7% for dulaglutide and 8.3% for placebo). HbA1c, FPG and post-MTT glucose levels were reduced from baseline to week 12 in patients receiving IBI362 in all three cohorts. IBI362 showed a favourable safety profile and clinically meaningful reductions in blood glucose in Chinese patients with T2D.

EGFR Thr790Leu as a Potential Resistance Mechanism to First-Generation EGFR Tyrosine Kinase Inhibitor May Respond to Osimertinib in Patients With Lung Adenocarcinoma.

INTRODUCTION: It has been well established that EGFR Thr790Met is one of the major resistance mechanisms to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). Nevertheless, whether EGFR Thr790Leu (T790L), which shares the mutation site of Thr790 with EGFR Thr790Met, mediates resistance to EGFR TKIs remains elusive. The treatment options for patients harboring this rare mutation have not been reported. METHODS: Capture-based targeted ultradeep sequencing was performed on tumor and plasma samples collected at various treatment milestones from three patients with advanced lung adenocarcinoma undergoing targeted therapy. RESULTS: Needle biopsy of lymph node metastasis from patient 1 revealed EGFR T790L at disease progression on first-line treatment of gefitinib. Patient 2 had EGFR T790L identified from needle biopsy of lung tissue at disease progression on icotinib treatment. This patient was subsequently treated with osimertinib and achieved stable disease with a progression-free survival of 9 months. For patient 3, at disease recurrence after surgery, resected lung tumor tissue was retrieved for molecular profiling and revealed EGFR exon 19 deletion and EGFR T790L. The patient subsequently received osimertinib treatment and continued to benefit for 16 months and counting. She has maintained stable disease at the time of submission of this manuscript. CONCLUSIONS: We revealed for the first time that EGFR T790L may serve as a potential resistance mechanism to first-generation EGFR TKIs. We also report the first clinical evidence of efficacy generated by osimertinib in patients with lung adenocarcinoma harboring primary or acquired EGFR T790L, shedding light on treatment options for this subset of patients.

IBI362 (LY3305677), a weekly-dose GLP-1 and glucagon receptor dual agonist, in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple ascending dose phase 1b study.

BACKGROUND: IBI362 (LY3305677) is a novel weekly-dose glucagon-like peptide-1 and glucagon receptor dual agonist being developed for the treatment of obesity and type 2 diabetes. The aim of this randomised, placebo-controlled, multiple ascending dose phase 1b study was to evaluate the safety, tolerability, pharmacokinetics and efficacy of IBI362 in Chinese adults with overweight or obesity. METHODS: This study enrolled adults with overweight (body mass index [BMI]≥24 kg/m2) accompanied by hyperphagia and/or at least one comorbidity or obesity (BMI≥28 kg/m2) from six study centres in China. Eligible participants were randomised 2:1 to receive once-weekly subcutaneous injection of IBI362 or placebo in each of the three ascending dose cohorts for 12 weeks with additional 8 weeks of safety follow-up. The dose-escalation regimens were: 3.0 mg cohort (1.0 mg weeks 1-4; 2.0 mg weeks 5-8; 3.0 mg weeks 9-12); 4.5 mg cohort (1.5 mg weeks 1-4; 3.0 mg weeks 5-8; 4.5 mg weeks 9-12); 6.0 mg cohort (2.0 mg weeks 1-4; 4.0 mg weeks 5-8; 6.0 mg weeks 9-12). The participants, investigators and study site personnel involved in treating and assessing participants within each cohort were masked to treatment allocation. The primary endpoints were safety and tolerability of IBI362. This study is registered with ClinicalTrials.gov, number NCT04440345. FINDINGS: Between June 15th, 2020 and January 15th, 2021, 12 participants were enrolled and randomised in each cohort. Throughout the study, no participant discontinued the treatment due to safety reason and no serious adverse event was reported. Gastrointestinal adverse events and decreased appetite were the most common adverse events and mostly mild in severity. Three participants receiving IBI362 reported mild and asymptomatic cardiac disorders revealed by electrocardiogram. Estimated percent changes in mean body weight from baseline to week 12 were -4.81% (95%CI -6.61 to -3.02), -6.40% (-8.23 to -4.58) and -6.05% (-7.91 to -4.18) for participants receiving IBI362 in the 3.0 mg, 4.5 mg and 6.0 mg cohort, respectively, compared with 0.60% (-0.86 to 2.07) for those receiving placebo. INTERPRETATION: IBI362 was well tolerated and showed a body weight-lowering effect in Chinese adults with overweight or obesity. FUNDING: Innovent Biologics.

Ultrasensitive detection of circulating tumour DNA via deep methylation sequencing aided by machine learning.

The low abundance of circulating tumour DNA (ctDNA) in plasma samples makes the analysis of ctDNA biomarkers for the detection or monitoring of early-stage cancers challenging. Here we show that deep methylation sequencing aided by a machine-learning classifier of methylation patterns enables the detection of tumour-derived signals at dilution factors as low as 1 in 10,000. For a total of 308 patients with surgery-resectable lung cancer and 261 age- and sex-matched non-cancer control individuals recruited from two hospitals, the assay detected 52-81% of the patients at disease stages IA to III with a specificity of 96% (95% confidence interval (CI) 93-98%). In a subgroup of 115 individuals, the assay identified, at 100% specificity (95% CI 91-100%), nearly twice as many patients with cancer as those identified by ultradeep mutation sequencing analysis. The low amounts of ctDNA permitted by machine-learning-aided deep methylation sequencing could provide advantages in cancer screening and the assessment of treatment efficacy.

Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics.

Background: Comprehensive analysis of PI3K-AKT-mTOR pathway gene alterations in breast cancer may be helpful for targeted therapy. Methods: We performed targeted sequencing using a panel of 520 cancer-related genes to investigate gene alterations in the PI3K-AKT-mTOR pathway from 589 consecutive Chinese women diagnosed with stage I-III breast cancer. Analyses of overall survival (OS) were performed using the publicly available clinical and genomic data from METABRIC. Results: PI3K-AKT-mTOR pathway gene alterations were detected in 62.6% (369/589) of our cohort. The most commonly altered genes were PIK3CA (45%), PTEN (7.5%), AKT1 (5.9 %), PIK3R1 (2.7%), and PIK3CG (2%). Four PIK3CA mutations (E545K, H1047R, E542K, and H1047L) were detected in all the breast cancer molecular subtypes. Seven PIK3CA mutations (E545G, E418_L422delinsV, E726K, E110del, G1049R, G118D, and D350G) were only detected in HR+ subtypes. Two PIK3CA mutations (C420R and N345K) were only detected in non-triple-negative subtypes. Most cases with PTEN mutation were HR+/HER2- subtype (77.3%), followed by triple-negative subtype (18.2%). In the METABRIC breast cancer dataset, no significant OS difference was observed between the PIK3CA-mutant and wild-type groups. However, patients with multiple PIK3CA mutations (mOS: 131 vs. 159 months, P= 0.029), or PIK3CA mutations located in the C2 domain had significantly shorter OS (mOS, 130 vs. 154 months, P=0.020) than those without the mutations. Conclusions: Our study reveals the heterogeneity in PI3K-AKT-mTOR pathway among the breast cancer molecular subtypes in our cohort. Moreover, the number and specific sites of PIK3CA mutations have distinct prognostic impact.

Liquid biopsy in extranodal NK/T-cell lymphoma: a prospective analysis of cell-free DNA genotyping and monitoring.

Satisfactory tumor material is often hard to obtain for molecular analysis in extranodal natural killer (NK)/T-cell lymphoma (NKTCL) at present. However, the accuracy and utility of circulating cell-free DNA (cfDNA) genotyping have not been adequately assessed in NKTCL. We therefore performed targeted next-generation sequencing on tumor tissues and a series of longitudinal plasma samples prospectively collected from a cohort of high-risk NKTCL patients. Concordance of genotyping results of paired baseline tumor and cfDNA and the predictive value of dynamic cfDNA monitoring were evaluated. At baseline, 59 somatic variants in 31 genes were identified in tumor and/or plasma cfDNA among 19 out of 24 high-risk NKTCL patients (79.2%). Plasma cfDNA had a sensitivity of 72.4% for detection of somatic variants identified in tumor biopsies before treatment. Plasma cfDNA also allowed the identification of mutations that were undetectable in tumor biopsies. These results were also verified in a validation cohort of an additional 23 high-risk NKTCL patients. Furthermore, longitudinal analysis showed that patients with rapid clearance of NKTCL-related mutations from plasma had higher complete remission rates (80.0% vs 0%; P = .004) and more favorable survival (1-year progression-free survival [PFS] rate, 79.0% vs 20.0%; P = .002) compared with those with persisting or emerging mutations in plasma. In addition, low cfDNA concentration before treatment was associated with favorable survival outcome for patients with NKTCL (1-year PFS, 90.0% vs 36.4%; P = .012). In conclusion, cfDNA mirrors tumor biopsy for detection of genetic alterations in NKTCL and noninvasive dynamic plasma cfDNA monitoring might be a promising approach for tracking response and survival outcome for patients with NKTCL.

Characterization of Frequently Mutated Cancer Genes and Tumor Mutation Burden in Chinese Breast Cancer.

OBJECTIVES: Various genomic alterations and genomic signatures, including ERBB2 amplification, mutations in PIK3CA, AKT1, and ESR1, and tumor mutational burden (TMB), have become important biomarkers for treatment selection in breast cancer (BC). This study aimed to investigate the mutational features of Chinese early-stage BC patients. METHODS: Tumors and matched blood samples collected from 589 Chinese patients with early-stage BC were sequenced using a commercial gene panel consisting of 520 cancer-related genes to analyze all types of genomic alterations and estimate the TMB status. RESULTS: A total of 18 genes were found to be more frequently mutated (P<0.05) or amplified (P<0.05) in stage T3-4 tumors as compared with T1-2 tumors. A total of 18 genes were found to be differentially mutated (P<0.05) or amplified (P<0.05) in patients with lymph node metastasis than those without lymph node metastasis. Younger patients (≤35 years) were more frequently identified with mutations or gene amplifications in eleven genes (P<0.05). TMB >10mutations/Mb were found in 5.7% of our cohort. Although the TMB was similar for various molecular subtypes between our cohort and the BC cohort of The Cancer Genome Atlas (TCGA) study, the TMB were statistically different for HR+/HER-, HR+/HER2+, and triple-negative subtypes between our cohort and African Americans in the TCGA study. As compared to the TCGA BC cohort, our cohort had a much earlier median age of diagnosis (48 vs. 58 years, P<0.001), and had significantly lower frequency of triple-negative subtype (11.5% vs. 18.4%, P<0.001) and invasive lobular BC (2.4% vs. 19.0%, P<0.001). Further subgroup analyses revealed that mutation rates in various genes including TP53, ERBB2, and PIK3CA were distinct for patients who were younger (≤35 years), had triple-negative or invasive lobular BC in our cohort than in the TCGA cohort. CONCLUSIONS: This study revealed distinct mutational features of various molecular subtypes of early-stage BC among Chinese patients. Moreover, we provide new insights into the differences in early-stage BC between the East and West.

Targeted Sequencing Analysis of Predominant Histological Subtypes in Resected Stage I Invasive Lung Adenocarcinoma.

Objective: Lung adenocarcinoma (LADC) is classified into five main histological subtypes with distinct clinicopathologic characteristics: lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary-predominant adenocarcinoma (MPA) and solid-predominant adenocarcinoma (SPA). However, the mutational profiles of predominant histological subtypes have not been well defined. In this study, we aimed to reveal the genomic landscape of 5 main histological subtypes. Patients and Methods: We performed next-generation sequencing (NGS) in a cohort of 86 stage I invasive adenocarcinoma (IAC) patients, using a customized panel including 168 cancer-associated genes. Results: Our analysis identified a total of 302 genomic alterations. Five subtypes showed different mutation profiles with LPA, APA, PPA, MPA and SPA had an average mutation rate of 1.95 (range: 0-5), 2.56 (range: 1-6), 3.5 (range: 1-7), 3.75 (range: 1-8) and 6.05 (range: 2-12), respectively (p=4.17e-06). Driver mutations occurred in 96.55% (83/86) of all patients. EGFR (73.3%), KRAS (9.3%), ALK (4.7%) and MET (4.7%) are the most commonly mutated lung cancer driver genes, TP53 is the top mutated tumor suppressor gene. SPA patients harbored more driver mutations and higher frequency of TP53 than LPA patients. Interestingly, LRP1B mutations, which has been reported to be associated with high tumor mutation burden and better response to immunotherapy, were only detected from 5 SPA patients (p=0.001). No patients from other four cohorts harbored LRP1B mutations. Conclusions: We revealed distinctive mutation landscape of the 5 major histological subtypes of LADC, evident by distinctive average mutation rate with SPA and LPA having the highest and lowest average mutation rate, respectively. SPA patients showed higher mutation rate of LRP1B and higher rates for PD-L1 positivity, indicating that SPA patients may have better response to immunotherapy.

HER2 transmembrane domain mutation: comprehensive characteristics and real-world evidence of treatment response in Chinese lung adenocarcinoma.

BACKGROUND: HER2 transmembrane domain (TMD) mutation has been reported as a rare driver mutation associated with advanced stage disease and a poor prognosis in patients with lung adenocarcinoma (LUAD). We aimed to comprehensively profile the genetic landscape and treatment response information of HER2 TMD-mutant LUAD. METHODS: An in-house database of 7,812 LUAD patients was screened for mutation prevalence. A multi-center cohort of 16 HER2 V659E-mutant patients and an external cohort of 38 HER2-mutant patients from cBioPortal with overall survival (OS) data were analyzed. Eight patients from the in-house cohort were included in the real-world study of treatment response. Molecular docking simulation and binding affinity prediction were performed. RESULTS: In Chinese LUAD, the prevalence of HER2 TMD mutation was 0.18% (14/7,812), and 0.14% (11/7,812) for the HER2 V659E mutation. The most recurrent co-alteration was TP53 mutation (n=4, 25%) and HER2 amplification (n=2, 12.5%). TMD-mutant patients were diagnosed at more advance stages (P<0.001) and had poorer OS (median OS 10.0 vs. 61.6 months, HR =7.9, 95% CI: 1.0-61.0, P<0.001) than non-TMD mutations. The overall response rate of targeted therapy, chemo-based therapy, and immunotherapy was 57.1%, 22.2%, and 0%, respectively. We postulated to challenge the resistance of tyrosine kinase inhibitor (TKI) with another with stronger binding energy to HER2 and supported the conclusion with a successful case. Additionally, we demonstrated a three-month response to the off-label use of pyrotinib in fifth-line therapy. CONCLUSIONS: Comapred with non-TMD mtuations, HER2 TMD mutation is a rare driver mutation with poorer prognosis in LUAD. Targeted therapy is the dominant choice for patients harboring this targetable mutation and longer OS could possibly be achieved through rechallenge with TKI of stronger binding affinity. Response to fifth-line pyrotinib was observed.

Distinctive genomic characteristics in POLE/POLD1-mutant cancers can potentially predict beneficial clinical outcomes in patients who receive immune checkpoint inhibitor.

BACKGROUND: Mutations in POLE /POLD1 proofreading domain can cause deficiencies in DNA repair, conferring ultramutated cancer phenotypes. Preliminary clinical studies have revealed an association between POLE/POLD1 mutations and beneficial clinical outcomes to immune checkpoint inhibitor (ICI) therapy This study aims to investigate the genomic characteristics of POLE/POLD-mutant tumors and the prognostic value of POLE/POLD mutation for ICI treatment. METHODS: Genomic data of 21,074 patients with 23 cancer types were retrieved from Burning Rock variant database (BR VarDB). The prevalence and spectra of POLE and POLD1 mutations were assessed and compared with that in The Cancer Genome Atlas (TCGA) samples. The correlations of POLE/POLD1 mutation with tumor mutational burden (TMB) and microsatellite instability (MSI) were investigated. The prognostic value of POLE/POLD1 mutations was also explored in 2,487 ICI-treated patients from published studies. RESULTS: BR VarDB samples displayed a similar mutational prevalence of POLE (3.2% vs. 3.2%) and POLD1 (1.4% vs. 1.6%, P=0.248) versusTCGA samples, but a slightly lower frequency of POLE and POLD1 co-mutations (0.21% vs. 0.43%, P<0.001). POLE/POLD1-mutant tumors harbored increased TCT→TAT and TCG→TTG transversions, and genomic signatures associated with DNA mismatch repair (MMR) deficiency and ultra-hypermuation. Furthermore, tumors with POLE/POLD1 proofreading mutation showed a significantly higher TMB than tumors with non-proofreading mutations (P<0.01), although both possessed a higher TMB than POLE/POLD1 wild-type (WT) tumors (P<0.0001 and P<0.0001, respectively). MSI was commonly observed in tumors harboring dominant clone of POLE/POLD1 mutation (10.2%), but occurred rarely in POLE/POLD1 WT tumors (0.5%) and tumors with accumulating sub-cloned POLE/POLD1 mutation (0%). Survival analysis revealed that POLE/POLD1 mutation was not independently correlated with longer survival after adjusting for TMB and other factors (HR =0.86, P=0.372). However, patients harboring POLE/POLD1 mutation demonstrated a higher response rate than patients with POLE/ POLD1 WT tumors (35.2% vs. 19.6%, P=0.0165). CONCLUSIONS: We delineated distinctive genomic characteristics in POLE/POLD1-mutant tumors, suggesting the potential predictive role of POLE/POLD1 mutations, especially those in the proofreading domain, for beneficial outcomes of immunotherapy. Our results also suggest that MSI caused by a loss-of-function mutation in the MMR pathway tends to result from POLE/POLD1 proofreading deficiency in POLE/POLD1-mutant tumors with MSI.

A heavily pre-treated adenocarcinoma patient with EGFR exon 20 insertion mutation responded to pembrolizumab plus nab-paclitaxel/bevacizumab: a case report.

Non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) exon 20 insertions are often associated with poor clinical outcomes due to low response rate to EGFR tyrosine kinase inhibitors. Although recent studies have demonstrated that several novel small molecule compounds could selectively inhibit these mutations, there are still some patients who cannot benefit from them. Another potential therapeutic approach is the use of immune checkpoint inhibitors. Growing evidence suggests that patients harboring EGFR mutations show low efficacy with the use of immunotherapy. However, according to the different immunogenicity of different EGFR mutations, the role of immunotherapy in EGFRex20ins NSCLCs needs further confirmation. Herein we report a case of a 39-year-old woman with NSCLC harboring EGFRex20ins who was diagnosed as postoperative recurrence of lung cancer. She failed with oral poziotinib, then underwent four cycles of systemic chemotherapy with pemetrexed plus carboplatin and bevacizumab. CT scan after chemotherapy showed the metastatic tumors increased in size. The patient then received osimertinib plus cetuximab. CT evaluation performed one month after treatment revealed the enlargement of bilateral lung metastasis. Pembrolizumab plus nab-paclitaxel/bevacizumab was given every three weeks afterwards. Significant shrinkage in multiple metastatic tumors was observed through CT, resulting in a partial response and a progression-free survival of more than 5.0 months. This case highlighted that the use of pembrolizumab in combination with nab-paclitaxel/bevacizumab could help in the management of the uncommon EGFRex20ins in heavily pretreated patients.

Germline Profiling and Molecular Characterization of Early Onset Metastatic Colorectal Cancer.

BACKGROUND: Early onset colorectal cancer (EO CRC) is a heterogeneous colorectal cancer subtype with obvious hereditary tendencies and increasing incidence. We sought to determine the susceptibility genes and molecular characteristics of EO CRC. METHODS: 330 EO metastatic CRC (mCRC) (≤55 years) and 110 average-onset (AO) mCRC patients (>55 years) were enrolled. Capture-based targeted sequencing was performed on tumor tissue and paired white blood cells using a sequencing panel of 520 genes. The association between molecular alterations and overall survival (OS) was analyzed. RESULTS: Of the 330 EO mCRC patients, 31 carried pathogenic or likely pathogenic germline mutations, with 16 of them diagnosed with lynch syndrome. Fifteen patients had germline mutations in non-mismatch repair genes, including four in MUTHY, three in RAD50, one in TP53, and eight in other genes. Twenty-nine genes were recurrently mutated in EO mCRC, including TP53, APC, KRAS, SMAD4, and BRCA2. The majority of genomic alterations were comparable between EO and AO mCRC. EO mCRC patients were more likely to have a high tumor mutation burden (p < 0.05). RNF43, RBM10, TSC, and BRAF V600E mutations were more commonly observed in EO mCRC, while APC, ASXL1, DNMT3B, and MET genes were more commonly altered in AO patients. At the pathway level, the WNT pathway was the only differentially mutated pathway between EO and AO mCRC (p < 0.0001). The wild-type WNT pathway (p = 0.0017) and mutated TGF-ß pathway (p = 0.023) were associated with unfavorable OS in EO mCRC. CONCLUSIONS: Approximately one in 10 EO mCRC was associated with hereditary tumors. The spectrum of somatic alterations was largely comparable between EO and AO mCRC with several notable differences.

A comprehensive pan-cancer study of fibroblast growth factor receptor aberrations in Chinese cancer patients.

BACKGROUND: The prevalence and types of fibroblast growth factor receptor (FGFR) mutations vary significantly among different ethnic groups. The optimal application of FGFR inhibitors depends on these variations being comprehensively understood. However, such an analysis has yet to be conducted in Chinese patients. METHODS: We retrospectively screened the genomic profiling results of 10,582 Chinese cancer patients across 16 cancer types to investigate the frequency and distribution of FGFR aberrations. RESULTS: FGFR aberrations were identified in 745 patients, equating to an overall prevalence of 7.0%. A majority of the aberrations occurred on FGFR1 (56.8%), which was followed by FGFR3 (17.7%), FGFR2 (14.4%), and FGFR4 (2.8%). Further, 8.5% of patients had aberrations of more than 1 FGFR gene. The most common types of aberrations were amplification (53.7%), other mutations (38.8%), and fusions (5.6%). FGFR fusion and amplification occurred concurrently in 1.9% of the patients. FGFR aberrations were detected in 12 of the 16 cancers, with the highest prevalence belonging to colorectal cancer (CRC) (31%). Other FGFR-aberrant cancer types included stomach (16.8%), breast (14.3%), and esophageal (12.7%) cancer. Breast tumors were also more likely than other cancer types to have concurrent FGFR rearrangements and amplifications (P<0.001). In comparison with the public dataset, our cohort had a significantly higher number of FGFR aberrations in colorectal (P<0.001) and breast cancer (P=0.05). CONCLUSIONS: Among the Chinese cancer patients in our study, the overall prevalence of FGFR aberrations was 7.0%. FGFR1 amplification was the most common genetic alteration in CRC, breast cancer, and lung cancer; while FGFR2 amplification was more commonly observed in gastric cancer than in other cancers in our cohort. Our study advances the understanding of the distribution of FGFR aberrations in various cancer types in the Chinese population, which will facilitate the further development of FGFR inhibitors.

Characterization of MET exon 14 alteration and association with clinical outcomes of crizotinib in Chinese lung cancers.

BACKGROUND: Most studies on MET exon 14 (MET-ex14) alteration, defined as an oncogenic driver, have been carried out among Caucasians; similar studies among Chinese people are limited. METHODS: We retrospectively analyzed the genomic profiles of 11,306 Chinese patients with various stages of lung cancer to investigate the prevalence of MET-ex14. Survival outcomes were analyzed in evaluable patients who received front-line crizotinib (n = 44) or chemotherapy (n = 14). RESULTS: MET-ex14 alterations were identified in 125 patients, a frequency of 1.1 %, which is much lower than that in Caucasians (∼2.7 %). We found that MET-ex14 alterations were more likely to be detected in older patients (median age 69.0 years, p <0.001). Among evaluable patients harboring MET-ex14 alterations, longer progression-free survival (PFS) was observed with crizotinib than with chemotherapy (8.5 months versus 4.0 months, p = 0.041), but there was no difference in overall survival (OS, 11.3 months versus 12.0 months, p = 0.66). No significant difference in PFS or OS was found among MET splice-site variants or when there were concurrent TP53 alterations. Concurrent MET amplification results in a shorter PFS (4.2 months versus 8.5 months, p = 0.029) but a comparable OS (7.8 months versus 14.0 months, p = 0.12). Patients with undetectable baseline plasma MET-ex14 had a trend of longer PFS (p = 0.097) but comparable OS (p = 0.18). A novel MET Y1003C mutation was detected and demonstrated a clinical response to crizotinib. CONCLUSIONS: Our study demonstrated a prevalence of 1.1 % for MET-ex14 alterations among the Chinese population. Our study also contributes to a better understanding of molecular factors that are associated with clinical outcomes of patients with MET exon 14 alterations.

Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer.

Previous studies found patients with POLE exonuclease domain mutations (EDMs) in targeted exons were related to significant better outcomes in stage II-III colorectal cancer (CRC). The detailed mutational profile of the entire POLE exonuclease domain, tumor mutation burden (TMB) and immune cell infiltration in POLE EDMs tumors, and the prognostic value of such mutations in stage II CRCs were largely unknown to us. This study was to clarify the characteristics, immune response and prognostic value of somatic POLE EDMs in stage II CRC. A total of 295 patients with stage II CRC were sequenced by next-generation sequencing with a targeted genetic panel. Simultaneous detection of the immune cells was conducted using a five-color immunohistochemical multiplex technique. The detailed molecular characteristics, tumor-infiltrating lymphocyte (TIL) and prognostic effect of POLE EDMs in stage II CRC were analyzed. For stage II CRCs, the POLE EDMs were detected in 3.1% of patients. Patients with POLE EDMs were more prone to be microsatellite instability-high (MSI-H) (33.3% vs 11.2%, p=0.043), younger at diagnosis (median 46 years vs 62 years, p<0.001) and more common at right-sided location (66.7% vs 23.1%; p=0.003). All patients with POLE EMDs were assessed as extremely high TMB, with a mean TMB of 200.8. Compared with other stage II CRCs, POLE EDMs displayed an enhanced intratumoral cytotoxic T cell response, evidenced by increased numbers of CD8+TILs and CD8A expression. Patients with stage II CRCs could be classified into three risk subsets, with significant different 5 years disease-free survival rates of 100% for POLE EDMs, 82.0% for MSI-H and 63.0% for MSS, p=0.013. In conclusion, characterized by a robust intratumoral T cell response, ultramutated POLE EDMs could be detected in a small subset of stage II CRCs with extremely high TMB. Patients with POLE EDMs had excellent outcomes in stage II CRCs, regardless of MSI status. Sequencing of all the exonuclease domain of POLE gene is recommended in clinical practice.

Tumor mutation burden in Chinese cancer patients and the underlying driving pathways of high tumor mutation burden across different cancer types.

BACKGROUND: Tumor mutation burden (TMB) has an important association with immunotherapy responses. TMB in the Chinese population has not been well established. Finding differences between the Chinese and Caucasian populations and elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. METHODS: Chinese cancer patients fresh tissue (n=2,177), formalin-fixed, paraffin-embed (FFPE) specimens (n=3,294), and pleural fluid (n=189) were profiled using a 295- or 520-gene next-generation sequencing (NGS) panel. The association of the TMB status with a series of molecular features and biological pathways was determined using bootstrapping. RESULTS: TMB, measured by 295- or 520-cancer-related gene panels, was correlated with whole-exome sequencing (WES) TMB based on the in silico simulation in The Cancer Genome Atlas cohort. The median TMB of our data was slightly higher than that from the Foundation Medicine Inc. (FMI) dataset. TMB was also slightly different within the same cancer type between the Chinese and Caucasian population. We discovered that the underlying pathways of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 23-gene and a 16-gene signature to predict TMB prediction for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively, indicating a histology-specific mechanism for driving high-TMB in lung cancer. CONCLUSIONS: TMB varies among different ethnic populations. Our findings extend the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types.

The prognostic value of a Methylome-based Malignancy Density Scoring System to predict recurrence risk in early-stage Lung Adenocarcinoma.

Current NCCN guidelines do not recommend the use of adjuvant chemotherapy for stage IA lung adenocarcinoma patients with R0 surgery. However, 25% to 40% of patients with stage IA disease experience recurrence. Stratifying patients according to the recurrence risk may tailor adjuvant therapy and surveillance imaging for those with a higher risk. However, prognostic markers are often identified by comparing high-risk and low-risk cases which might introduce bias due to the widespread interpatient heterogeneity. Here, we developed a scoring system quantifying the degree of field cancerization in adjacent normal tissues and revealed its association with disease-free survival (DFS). Methods: We recruited a cohort of 44 patients with resected stage IA lung adenocarcinoma who did not receive adjuvant therapy. Both tumor and adjacent normal tissues were obtained from each patient and subjected to capture-based targeted genomic and epigenomic profiling. A novel methylome-based scoring system namely malignancy density ratio (MD ratio) was developed based on 39 patients by comparing tumor and corresponding adjacent normal tissues of each patient. A MD score was then obtained by Wald statistics. The correlations of MD ratio, MD score, and genomic features with clinical outcome were investigated. Results: Patients with a high-risk MD ratio showed a significantly shorter postsurgical DFS compared with those with a low-risk MD ratio (HR=4.47, P=0.01). The MD ratio was not associated with T stage (P=1), tumor cell fraction (P=0.748) nor inflammatory status (p=0.548). Patients with a high-risk MD score also demonstrated an inferior DFS (HR=4.69, P=0.039). In addition, multivariate analysis revealed EGFR 19 del (HR=5.39, P=0.012) and MD score (HR= 7.90, P=0.01) were independent prognostic markers. Conclusion: The novel methylome-based scoring system, developed by comparing the signatures between tumor and corresponding adjacent normal tissues of individual patients, largely minimizes the bias of interpatient heterogeneity and reveals a robust prognostic value in patients with resected lung adenocarcinoma.