In Situ Nanofiber Formation Blocks AXL and GAS6 Binding to Suppress Ovarian Cancer Development.

Anexelekto (AXL) is an attractive molecular target for ovarian cancer therapy because of its important role in ovarian cancer initiation and progression. To date, several AXL inhibitors have entered clinical trials for the treatment of ovarian cancer. However, the disadvantages of low AXL affinity and severe off-target toxicity of these inhibitors limit their further clinical applications. Herein, by rational design of a nonapeptide derivative Nap-Phe-Phe-Glu-Ile-Arg-Leu-Arg-Phe-Lys (Nap-IR), a strategy of in situ nanofiber formation is proposed to suppress ovarian cancer growth. After administration, Nap-IR specifically targets overexpressed AXL on ovarian cancer cell membranes and undergoes a receptor-instructed nanoparticle-to-nanofiber transition. In vivo and in vitro experiments demonstrate that in situ formed Nap-IR nanofibers efficiently induce apoptosis of ovarian cancer cells by blocking AXL activation and disrupting subsequent downstream signaling events. Remarkably, Nap-IR can synergistically enhance the anticancer effect of cisplatin against HO8910 ovarian tumors. It is anticipated that the Nap-IR can be applied in clinical ovarian cancer therapy in the near future.

Concordance of RT-qPCR with immunohistochemistry and its beneficial role in breast cancer subtyping.

This study was to compare the concordance of transcription-quantitative polymerase chain reaction (RT-qPCR) with immunohistochemistry (IHC) in determining estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and tumor proliferation index (Ki67) status in breast cancer, and to assess the prognosis based on different subtypes. Totally 323 breast cancer patients were selected, including 216 in the training set and 107 in the validation set. Logistic regression models were constructed using 5-fold cross-validation with the mRNA expression of each biomarker as the predictor and the corresponding IHC expression level as the binary response variable. Receiver operating characteristic curve was used to determine the cutoff value. When the thresholds of ER, PR, HER2, and Ki67 were 0.764, 0.709, 0.161, and 0.554, there existed high concordance rates between IHC and RT-qPCR in ER (94.4%), PR (88.0%) and HER2 (89.4%) and a medium concordance rate in Ki67 (67.8%), which were further confirmed in the validation set (ER: 81.3%, PR: 78.3%, HER2: 80.4%, and Ki67: 69.1%). Based on the subtyping stratified by RT-qPCR, the 5-year recurrence-free interval rates of patients with luminal, HER2-enriched, and triple-negative subtypes were 88% (95% CI: 0.84-0.93), 82% (95% CI: 0.73-0.92) and 58% (95% CI: 0.42-0.80), respectively, which were similar to those assessed by IHC (88%, 78% and 47%). RT-qPCR may be a complementary method to IHC, which can not only provide additional useful information in clinic, but also show more advantages over IHC in determining certain subtypes of breast cancer.

An Analysis of Clinical and Pathologic Features, RecurIndex Genomic Profiles, and Survival Outcomes in HER2-Low Breast Cancer.

BACKGROUND: In recent years, breast cancer has become the most common cancer in the world, increasing women's health risks. Approximately 60% of breast cancers are categorized as human epidermal growth factor receptor 2 (HER2)-low tumors. Recently, antibody-drug conjugates have been found to have positive anticancer efficacy in patients with HER2-low breast cancer, but more studies are required to comprehend their clinical and molecular characteristics. METHODS: In this study, we retrospectively analyzed the data of 165 early breast cancer patients with pT1-2N1M0 who had undergone the RecurIndex testing. To better understand HER2-low tumors, we investigated the RecurIndex genomic profiles, clinicopathologic features, and survival outcomes of breast cancers according to HER2 status. RESULTS: First, there were significantly more hormone receptor (HR)-positive tumors, luminal-type tumors, and low Ki67 levels in the HER2-low than in the HER2-zero. Second, RI-LR (P = .0294) and RI-DR (P = .001) scores for HER2-low and HER2-zero were statistically significant. Third, within HER2-negative disease, HR-positive/HER2-low tumors showed highest ESR1, NFATC2IP, PTI1, ERBB2, and OBSL1 expressions. Fourth, results of the survival analysis showed that lower expression of HER2 was associated with improved relapse-free survival for HR-positive tumors, but not for HR-negative tumors. CONCLUSIONS: The present study highlights the unique features of HER2-low tumors in terms of their clinical characteristics as well as their gene expression profiles. HR status may influence the prognosis of patients with HER2-low expression, and patients with HR-positive/HER2-low expression may have a favorable outcome.

Association of smoking, alcohol, and coffee consumption with the risk of ovarian cancer and prognosis: a mendelian randomization study.

OBJECTIVE: Currently, the association between smoking, alcohol, and coffee intake and the risk of ovarian cancer (OC) remains conflicting. In this study, we used a two-sample mendelian randomization (MR) method to evaluate the association of smoking, drinking and coffee consumption with the risk of OC and prognosis. METHODS: Five risk factors related to lifestyles (cigarettes per day, smoking initiation, smoking cessation, alcohol consumption and coffee consumption) were chosen from the Genome-Wide Association Study, and 28, 105, 10, 36 and 36 single-nucleotide polymorphisms (SNPs) were obtained as instrumental variables (IVs). Outcome variables were achieved from the Ovarian Cancer Association Consortium. Inverse-variance-weighted method was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl). RESULTS: The two-sample MR analysis supported the causal association of genetically predicted smoking initiation (OR: 1.15 per SD, 95%CI: 1.02-1.29, P = 0.027) and coffee consumption (OR: 1.40 per 50% increase, 95%CI: 1.02-1.93, P = 0.040) with the risk of OC, but not cigarettes per day, smoking cessation, and alcohol consumption. Subgroup analysis based on histological subtypes revealed a positive genetical predictive association between coffee consumption and endometrioid OC (OR: 3.01, 95%CI: 1.50-6.04, P = 0.002). Several smoking initiation-related SNPs (rs7585579, rs7929518, rs2378662, rs10001365, rs11078713, rs7929518, and rs62098013), and coffee consumption-related SNPs (rs4410790, and rs1057868) were all associated with overall survival and cancer-specific survival in OC. CONCLUSION: Our findings provide the evidence for a favorable causal association of genetically predicted smoking initiation and coffee consumption with OC risk, and coffee consumption is linked to a greater risk of endometrioid OC.

Genomic landscape of Chinese patients with hepatocellular carcinoma using next-generation sequencing and its association with the prognosis.

INTRODUCTION AND OBJECTIVES: The occurrence of hepatocellular carcinoma (HCC) is not entirely clear at present. This study comprehensively described the landscape of genetic aberrations in Chinese HCC patients using next-generation sequencing (NGS) and investigated the association of genetic aberrations with clinicopathological characteristics and prognosis. MATERIALS AND METHODS: The clinicopathological data of 78 HCC patients undergoing surgery were retrospectively analyzed. The genomic DNA extracted from tumor samples was detected using a NGS-based gene panel. RESULTS: Mutations in TP53 (55%), TERT (37%), MUC16 (29%) and CTNNB1 (27%) were most common in HCC. The co-occurrences between frequently mutated genes occurring ≥10% were relatively common in HCC. Forty-eight (61.5%) cases harbored DNA damage repair gene mutations, mainly including PRKDC (11.5%), SLX4 (9.0%), ATM (7.7%), MSH6 (7.7%), and PTEN (6.4%), and 39 (50.0%) patients had at least one actionable mutation. FH amplification (odds ratio: 3.752, 95% confidence interval: 1.170-12.028, p=0.026) and RB1 mutations (odds ratio: 13.185, 95% confidence interval: 1.214-143.198, p=0.034) were identified as the independent risk factors for early postoperative recurrence in HCC. CONCLUSIONS: Our study provides a novel insight into the genomic profiling of Chinese HCC patients. FH amplification and RB1 mutations may be associated with an increased risk of early postoperative recurrence in HCC.

RecurIndex assay as an aid for adjuvant chemotherapy decisions in HR-positive HER2-negative breast cancer patients.

Background: Adjuvant chemotherapy is a major adjuvant treatment modality for hormonal receptor (HR)-positive and HER2-negative early breast cancer, but only 2%-20% of patients derive practical benefits. How to balance its potential benefits and risks becomes a challenging clinical problem. The purpose of this study was to assess whether RecurIndex assay could serve as an aid for adjuvant chemotherapy decisions in Chinese patients with HR-positive HER2-negative early breast cancer. Methods: The tissue samples of pT1-2N0 HR-positive HER2-negative breast cancer from multiple centers were detected using RecurIndex assay, based on which the patients were assigned into low- and high-risk groups. The survival outcomes of low- and high-risk patients including those with and without adjuvant chemotherapy were compared, and the risk factors for recurrence and metastasis were identified. Results: Totally 445 patients were eligible for analysis. By contrast to high-risk patients, low-risk patients represented better 7-year recurrence-free survival (RFS), distant recurrence-free survival (DRFS) and local recurrence-free survival (LRFS) rates. For low-risk patients, no significant differences were shown between those with and without adjuvant chemotherapy in 7-year RFS, DRFS and LRFS rates. These differences were also inapparent between high-risk patients with and without adjuvant chemotherapy. The multivariate model revealed high-risk patients had a significantly elevated risk of recurrence and metastasis than those at low risk. Conclusion: HR-positive HER2-negative early breast cancer patients at low risk stratified by RecurIndex assay might be exempt from adjuvant chemotherapy. Whether adjuvant chemotherapy may derive survival benefits for high-risk patients still needs larger cohorts to verify.

Development of a 4-miRNA prognostic signature for endometrial cancer.

To develop an effective uterine corpus endometrial carcinoma (UCEC) risk assessment tool to monitor treatment outcomes. Limma package was used to analyze differentially expressed microRNAs (miRNAs) between UCEC tissues and normal tissues in the TCGA database. According to univariate Cox risk regression, least absolute shrinkage, and selection operator (LASSO) Cox analysis were performed to screen prognostic miRNAs and construct a risk scoring model. The prognostic performance of signature was evaluated by Kaplan-Meier and receiver operating characteristic. Multivariate Cox regression analysis was used to determine the independent prognostic factors of UCEC. Nomogram was constructed according to age, clinical stage, and risk score. A 4-miRNA signature based on miR-31-5p, miR-34a-5p, miR-26a-1-3p and miR-4772-3p was established. Risk scores of each patient were calculated by the 4-miRNA signature. After z-score, the patients were divided into high- and low-risk groups. The overall survival of high-risk patients was significantly shorter than that of low-risk patients, pointing to the high performance and independence of the 4-miRNA signature in predicting UCEC prognosis. The nomogram showed a high accuracy in predicting overall survival of UCEC patients. We developed a 4-miRNA signature that could effectively predict the prognosis of UCEC.

Case Report: Clinicopathological and Genetic Features of IDH-Mutant Brainstem Glioma in Adults: Report of Five Cases.

Adult brainstem gliomas are rare central nervous system tumors that represent a heterogeneous group of tumors. Somatic IDH mutations are uncommon in adult brainstem gliomas and there are few relevant clinical studies. Here, we reported five patients with IDH1 mutations associated with brainstem gliomas, including four cases of IDH1 R132H mutations and one case of R132G mutation. All patients were treated with focal intensity-modulated radiation therapy (IMRT) with concurrent temozolomide (TMZ). One patient died, one relapsed, and three survived to date. All these cases carried a pathogenic variant of TP53, among whom 1 harbored ATRX mutation and 1 had H3K27M mutation. Moreover, we also found some genes related to a worse prognosis, such as CDK4/6 amplification. These findings demonstrate that the specific characteristics of IDH-mutant brainstem gliomas should be considered in diagnostic workflows to make therapeutic regimens and improve the prognosis.

Genomic Features of Solid Tumor Patients Harboring ALK/ROS1/NTRK Gene Fusions.

The fusions of receptor tyrosine kinase (RTK) involving anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and neurotrophic receptor tyrosine kinase (NTRK) represent the potential targets of therapeutic intervention for various types of solid tumors. Here, the genomic features of 180 Chinese solid tumor patients with ALK, ROS1, and NTRK fusions by next generation sequencing (NGS) were comprehensively characterized, and the data from 121 patients in Memorial Sloan Kettering Cancer Center (MSKCC) database were used to compare. We found that ALK, ROS1, and NTRK fusions were more common in younger female patients (p<0.001) and showed a higher expression of programmed death ligand 1 (PD-L1). The gene-intergenic fusion and the fusion with rare formation directions accounted for a certain proportion in all samples and 62 novel fusions were discovered. Alterations in TP53 and MUC16 were common in patients with RTK fusions. The mutational signatures of patients were mainly distributed in COSMIC signature 1, 2, 3, 15 and 30, while had a higher frequency in copy number variations (CNVs) of individual genes, such as IL-7R. In the MSKCC cohort, patients with fusions and CNVs showed shorter overall survival than those with only fusions. Furthermore, the differentially mutated genes between fusion-positive and -negative patients mainly concentrated on MAPK signaling and FOXO signaling pathways. These results may provide genomic information for the personalized clinical management of solid tumor patients with ALK, ROS1, and NTRK fusions in the era of precision medicine.

Prevalence of SWI/SNF genomic alterations in cancer and association with the response to immune checkpoint inhibitors: A systematic review and meta-analysis.

BACKGROUND: The association between SWI/SNF genomic alterations and responses to immune checkpoint inhibitors (ICIs) remains conflicting. This meta-analysis was performed to systematically assess the impact of SWI/SNF genomic alterations on response to ICIs in cancer. METHODS: Relevant studies were searched in multiple databases updated to April 29, 2021. Outcomes of interest included prevalence of SWI/SNF alterations, overall survival (OS), progression-free survival (PFS) and time to treatment failure (TTF). For survival data, the hazard ratio (HR) was adopted, and the effect size was described as 95% confidence intervals (CI). RESULTS: 15 studies involving 10,849 patients were included, with the overall frequency of 18.5% in SWI/SNF alterations. Across different cancer types, the mutational frequency of PBRM1 (32.0%) was the highest, followed by ARID1A (18.1%), SMARCA4 (15.6%), SMARCA2 (10.3%), ARID2 (8.1%), SMARCC2 (6.4%) and SMARCB1 (5.0%). Overall analysis showed that SWI/SNF alterations were not associated with improved OS (HR: 0.822, 95 %CI: 0.583-1.158, p = 0.262), PFS (HR: 0.608, 95 %CI: 0.434-1.067, p = 0.094) and TTF (HR: 0.923, 95 %CI: 0.757-1.125, p = 0.427) in patients treated with ICIs. In subgroup analysis, PBRM1 mutations were observed to be linked with improved OS (HR: 0.650, 95 %CI: 0.440-0.960, p = 0.030), PFS (HR: 0.539, 95 %CI: 0.314-0.926, p = 0.025) and TTF (HR: 0.490, 95 %CI: 0.271-0.885, p = 0.018) in RCC patients receiving ICIs. CONCLUSIONS: The overall prevalence of SWI/SNF alterations was 18.5% across different cancer types. Except for PBRM1 mutations in RCC, SWI/SNF alterations may be uncorrelated with improved clinical outcomes in cancer.

TET1 mutations as a predictive biomarker for immune checkpoint inhibitors in colon adenocarcinoma.

BACKGROUND: The ten-eleven translocation 1 (TET1), which is essential for active DNA demethylation, plays a multifaceted role in the pathogenesis of colorectal cancer. The study has demonstrated the association of TET1 mutations with a high response to immune checkpoint inhibitors (ICIs) in diverse cancers. However, the relationship between TET1 mutations and the response to ICIs in colon cancer is still lacking. METHODS: The prognosis, predictive markers, immune characteristics, mutation number of DNA damage repair (DDR) pathways, pathway enrichment, and drug sensitivity conditions were all compared between TET1-mutated and wild-type patients with colon adenocarcinoma (COAD). RESULTS: The overall survival of patients with TET1 mutations in the ICI-treated cohort was significantly longer than those without (p = 0.0059). Compared with the wild-type patients, TET1-mutated patients had higher tumor mutational burden and neoantigen load, enhanced abundance of tumor-infiltrating immune cells, increased expression of immune-related genes, and mutation number of DDR pathways. Additionally, the patients with TET1 mutations were found to be more sensitive to lapatinib and 5-fluorouracil. CONCLUSION: These findings suggest that TET1 mutations may serve as a potential biomarker for the response to ICIs in COAD patients.

Case Report: Identification of a Novel GNAS Mutation and 1p/22q Co-Deletion in a Patient With Multiple Recurrent Meningiomas Sensitive to Sunitinib.

BACKGROUND: Although surgical resection can cure the majority of meningiomas, there are still approximately 20% of patients suffering from an aggressive course with recurrence or progression. In this study, we reported a novel GNAS mutation and 1p/22q co-deletion responding to sunitinib in a patient with multiple recurrent meningiomas. CASE PRESENTATION: A 53-year-old woman with meningioma was hospitalized due to postoperative tumor progression for 3 weeks. WHO grade I meningioma was pathologically diagnosed after the first three surgeries, but the second recurrence occurred approximately 3 years following the third surgery. Next-generation sequencing was performed on the first two recurrent samples. GNAS mutations and 1p/22q co-deletion were both identified, and amplification at 17q and chromosome 19 was also found in the second recurrent sample, based on which WHO grade II/III meningioma was diagnosed. The lesion in the left cerebellopontine angle area enlarged after use of radiotherapy combined with temozolomide chemotherapy for 2 months. When sunitinib was added, the residual lesions began to lessen and continuously reduced. CONCLUSION: This typical case suggested that timely molecular diagnosis for refractory meningiomas contributed to guiding the molecular classification and clinicians to make more reasonable individualized therapeutic regimens, consequently benefiting the patients. This case report also highlighted the potential role of sunitinib in the treatment of refractory meningiomas.

Comprehensive identification of FGFR1-4 alterations in 5 557 Chinese patients with solid tumors by next-generation sequencing.

Deregulation of fibroblast growth factor receptor (FGFR) network is common in cancer due to activating mutations, gene amplifications and chromosomal translocations. Currently, various FGFR inhibitors are being developed. In order to optimize their clinical applications, understanding the frequencies and types of FGFR alterations in multiple cancer types appears to be extremely important. This study characterized FGFR1-4 alterations in solid tumors by next-generation sequencing (NGS). Between Jun. 2019 and Aug. 2020, the sequencing data of 5 557 solid tumors of diverse types in the database of Simcere Diagnostics, Inc. (Nanjing, China) were retrospectively analyzed. A panel-based NGS assay was used to detect FGFR1-4 alterations in tumor samples. 9.2% of cancer cases had FGFR1-4 alterations, in which gene amplifications (51.5%) and mutations (40.7%) were frequent, whereas gene rearrangements were less common (10.0%). FGFR1 was involved in 4.6% of 5 557 cases, FGFR2 in 2.1%, FGFR3 in 1.6%, and FGFR4 in 1.4%. Of patients with FGFR1-4 alterations, TP53, MUC16, NSD3, MYC and LRP1B genes were the top 5 mutant genes. FGFR1-4 aberrations occurred in almost every type of solid tumors, with the most common tumor being endometrial carcinoma (22.2%), followed by sarcoma (17.3%), breast cancer (13.2%), gastric cancer (12.2%), and more. 0.6% of cancer cases harbored FGFR1-4 fusions, with the most common fusion partner being TACC3. Two cases of GBM harboring FGFR3-TACC3 fusions were responsive to anlotinib treatment. In conclusion, FGFR1-4 alterations are prevalent in solid tumors of diverse types, with the majority being gene amplifications and mutations. FGFR1-4 fusions only occur in a minority of cancer cases, and those with glioblastoma harboring FGFR3-TACC3 fusions may benefit from anlotinib.

Is it beneficial for patients with pT1-2N1M0 breast cancer to receive postmastectomy radiotherapy? An analysis based on RecurIndex assay.

The benefit of postmastectomy radiotherapy (PMRT) for pT1-2N1M0 breast cancer patients currently remains controversial. This study was conducted to investigate whether pT1-2N1M0 breast cancer patients could benefit from PMRT based on RecurIndex assay. The clinical data of 213 pT1-2N1M0 breast cancer patients were retrospectively analyzed. Through RecurIndex assay, 81 cases were assessed as the low risk, and 132 as the high risk. Compared to low-risk patients, high-risk patients especially those not receiving PMRT had a significantly increased risk of recurrence and metastasis, and worse 7-year local-regional recurrence-free interval (LRFI), distance recurrence-free interval (DRFI) and recurrence-free survival (RFS) rates. PMRT-based subgroup analysis indicated no significant differences between the low-risk patients with and without PMRT in 7-year LRFI, DRFI, RFS and overall survival (OS) rates, but apparent differences were all shown between the high-risk patients with and without PMRT in 7-year LRFI, DRFI, RFS and OS rates. Overall, for pT1-2N1M0 breast cancer patients at low risk of recurrence and metastasis stratified by RecurIndex assay, there may be a phenomenon of no PMRT benefits, while for those at high risk, use of PMRT may produce survival benefits.

The beneficial role of Asian-based RecurIndex test in the prognostic prediction in Chinese male breast cancer patients.

RecurIndex, a multigene profiling assay, can predict the risk of local recurrence and distant metastasis in female breast cancer (FBC), but its role in male breast cancer (MBC) remains unclear. In this study, the clinicopathological data of 43 consecutive MBC patients undergoing surgeries between 2009 and 2018 were retrospectively analysed. Their paraffin-embedded tissue sections were examined by RecurIndex test which comprised 2 models: recurrence index for local recurrence (RI-LR) and recurrence index for distant recurrence (RI-DR). Of 43 patients, there were 26 low-risk and 17 high-risk patients assessed by RI-LR, while 17 low-risk and 26 high-risk patients by RI-DR. For RI-LR, tumor N stage showed statistically significant (P < 0.001) between low- and high-risk patients; for RI-DR, differences were pronounced in tumor grade (P = 0.033), T stage (P = 0.043) and N stage (P = 0.003). In terms of clinical outcomes, the overall survival (OS) of low- and high-risk patients stratified by RI-LR showed no statistically significant differences (P = 0.460), while high-risk patients identified by RI-DR had a significantly worse distant recurrence-free survival (DRFS) (P = 0.035), progression-free survival (PFS) (P = 0.019) and OS (P = 0.044) than low-risk patients. Overall, RI-DR can effectively predict the DRFS, PFS and OS of MBC patients and identify those at low risk of recurrence, which may serve as a potential prognostic tool for MBC.

An extremely rare case of Rosai-Dorfman disease in the spleen.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare, multisystemic histiocytic disorder, and commonly manifesting as lymphadenopathy in the young male. Abdominal manifestations of RDD are extremely rare. CASE PRESENTATION: In August 2018, a 42-year-old man underwent an abdominal ultrasonography examination due to his weight loss of 10 kg in only three months and found a giant solid tumor was found in his spleen. Then, he was admitted to our hospital and diagnosed as a splenic mass via abdominal enhanced CT and MRI. Laparoscopic splenectomy was administrated within six days of admission due to the clear surgical indications. The pathogenesis of RDD remained poorly understood and the disease should be diagnosed based on histopathology and immunohistochemistry (IHC). The mutations in ATM and NFKBIA were observed using next generation sequencing (NGS). CONCLUSION: We reported a case of splenic involvement of RDD with NGS genetic testing, indicating the difficulty of making a diagnosis before surgery. This extremely rare case offers new references for the understanding of abdominal viscera RDD.