An epidermal growth factor receptor-mutated lung adenocarcinoma patient with brain lesions resisted to osimertinib monotherapy but achieved more than 4 years of survival in osimertinib plus bevacizumab metronomic treatment.

Background: Epidermal growth factor receptor (EGFR) mutations have been identified as promising therapeutic targets for non-small cell lung cancer. Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor-targeting drug, has good anti-tumor ability and excellent intracranial effects. However, management of osimertinib resistance is a clinical challenge. The clinical benefit of osimertinib combined with the antiangiogenic drug, bevacizumab, remains to be determined. Case presentation: A 40-year-old female with right lung adenocarcinoma (cT2aN3M1c, IVb) was confirmed positive for EGFR exon 19 deletion mutation (c.2235_2249del, 1.3%). After receiving 5 months of osimertinib (80 mg, qd) therapy, the patient's disease progressed and she subsequently accepted treatment with osimertinib (80 mg, qd) plus bevacizumab (15 mg/kg, q21d) and achieved notable clinical remission for 23 months until renal impairment occurred, after which bevacizumab was discontinued. The patient had 6 months of remission before progression, after which bevacizumab was added again. To date, the disease has been under control. The brain lesion showed partial response again, and the side effects of bevacizumab were tolerable. The overall survival time exceeded 4 years. Conclusion: This case report describes a treatment strategy for osimertinib-resistant patients with EGFR exon 19 deletion mutations. Metronomic treatment with osimertinib plus bevacizumab was achieved for more than 4 years.

Comprehension of rectosigmoid junction cancer molecular features by comparison to the rectum or sigmoid colon cancer.

Background: Colorectal cancer (CRC) is a heterogeneous cancer. Its treatment depends on its anatomical site and molecular features. Carcinomas of the rectosigmoid junction are frequent; however, specific data on these tumors are sparse, as they are frequently assigned to either the colon or rectum. This study sought to identify the molecular features of rectosigmoid junction cancer to determine whether there should be any difference between the therapeutic management of rectosigmoid junction cancer and that of sigmoid colon or rectum cancer. Methods: The data of 96 CRC patients with carcinomas in the sigmoid colon, rectosigmoid junction, and rectum were retrospectively summarized. The next-generation sequencing (NGS) data of the patients were analyzed to study the molecular characteristics of the carcinomas in different locations of the bowel. Results: In total, there was no difference in the clinicopathologic characteristics of the three groups. TP53, APC, and KRAS genes were the top 3 alteration genes in sigmoid colon, rectosigmoid junction, and rectum cancer. The rates of the KRAS, NRAS, and PIK3CA increased as the location moved distally, while the rates of APC and BRAF decreased. Almost no significant molecular differences were found among the three groups. The prevalence of the FLT3, fms-related tyrosine kinase 1 (FLT1), and phosphoenolpyruvate carboxykinase 1 (PCK1) mutation was lower in the rectosigmoid junction group than the sigmoid colon and rectum groups (P>0.05). The proportion of the transforming growth factor beta pathway was higher in the rectosigmoid junction and rectum groups than the sigmoid colon group (39.3% vs. 34.3% vs. 18.2%, respectively, P=0.121, P=0.067, P=0.682); a higher proportion of MYC pathway was also observed in the rectosigmoid junction than that in rectum and sigmoid colon (28.6% vs. 15.2% vs. 17.1%, P=0.278, P=0.202, P=0.171). Regardless of the clustering method employed, the patients were divided into two clusters, and the composition of clusters revealed no significant differences in terms of the different locations. Conclusions: Rectosigmoid junction cancer has a distinctive molecular profile compared to the molecular profiles of the adjacent bowel segment cancers.

RNF43 is associated with genomic features and clinical outcome in BRAF mutant colorectal cancer.

Background: Colorectal cancer (CRC) patients with BRAF mutation have very poor prognosis. It is urgent to search for prognostic factors of BRAF mutant CRC. RNF43 is a ENF ubiquitin ligase of Wnt signaling. Mutation of RNF43 has been observed frequently in various types of human cancers. However, few studies have evaluated the role of RNF43 in CRC. The present study aimed to explore the impact of RNF43 mutations on molecular characteristics and prognosis in BRAF mutant CRC. Methods: Samples of 261 CRC patients with BRAF mutation were retrospectively analyzed. Tumor tissue and matched peripheral blood samples were collected and subjected to targeted sequencing with a panel of 1021 cancer-related genes. The association of molecular characteristics and survival in patients were then analyzed. 358 CRC patients with BRAF mutation from the cBioPortal dataset were used for further confirmation. Results: This study was inspired by a CRC patient with BRAF V600E and RNF43 co-mutation, who achieved a best remission of 70% and a progression free survival (PFS) of 13 months. Genomic analysis indicated that RNF43 mutation affected the genomic characteristics of patients with BRAF mutation, including microsatellite instability (MSI), tumor mutation burden (TMB) and the proportion of common gene mutations. Survival analysis showed that RNF43 mutation was a predictive biomarker for better PFS and OS in BRAF mutant CRC. Conclusion: Collectively, we identified that RNF43 mutations were correlated with favorable genomic features, resulting in a better clinical outcome for BRAF mutant CRC patients.

Genomic characterisation of de novo EGFR copy number gain and its impact on the efficacy of first-line EGFR-tyrosine kinase inhibitors for EGFR mutated non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation generally respond well to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, genomic characterisation of de novo EGFR copy number gain (CNG) and its impact on the efficacy of first-line EGFR-TKIs remains unclear. METHODS: This multicenter, retrospective and real-world study included two cohorts that enroled EGFR mutant NSCLC patients. EGFR CNG was tested by next-generation sequencing of untreated tissue specimens. Cohort 1 detected the impact of EGFR CNG on first-line EGFR-TKIs treatment, and cohort 2 explored the genomic characterisation. RESULTS: Cohort 1 enroled 355 patients from four cancer centres between January 2013 and March 2022. The patients were divided into three groups, included the EGFR non-CNG, EGFR CNG, and EGFR uncertain-CNG. No significant difference in progression-free survival (PFS) was found between the three groups (10.0 months vs. 10.8 months vs. 9.9 months, respectively, p = 0.384). Furthermore, the overall response rate was not statistically significant in the EGFR CNG group compared to the EGFR non-CNG or uncertain arm (70.3% vs. 63.2% vs. 54.5%, respectively, p = 0.154). Cohort 2 included 7876 NSCLC patients with 16.4% showing EGFR CNG. Gene mutations such as TP53, IKZF1, RAC1, MYC, MET, CDKN2A/B and alterations of the metabolic-related and ERK signalling pathway were significantly associated with patients with EGFR CNG compared to those without. CONCLUSIONS: De novo EGFR CNG had no effect on the efficacy of first-line EGFR-TKI treatment in EGFR mutant NSCLC patients, and tumours with EGFR CNG had more complex genomic profiles than those without.

A lung adenocarcinoma patient with ROS1 fusion and NBN germline mutation achieves long progression-free survival from sintilimab combined with niraparib after failure of ROS1 inhibitors: a case report.

Background: Lung cancer is a malignant tumor with high morbidity and mortality worldwide. At present, the main treatment methods for patients with advanced non-small cell lung cancer (NSCLC) include molecular targeted therapy and immunotherapy. The efficacy rate of immune checkpoint inhibitor (ICI) monotherapy is relatively low. Studies have confirmed that some combination therapies have better anti-tumor efficacy and higher response rates, such as PD-1/PD-L1 inhibitors combined with chemotherapy or targeted therapy. Poly (ADP-ribose) polymerase (PARP) inhibitors have become a new line of cancer therapy in ovarian and breast cancer, but it's not approved in lung cancer. Some reports show that homologous recombination repair (HRR) gene variants may be potential biomarkers for immunotherapy. However, whether lung cancer with HRR gene variants can be benefit from ICIs combined with PARP inhibitors is unknown. Case Description: We present a case of a 30-year-old man who was admitted to hospital with several months of cough and the chest computed tomography (CT) scan showed a mass about 2.6 cm × 2.1 cm in the left lung. Then he was diagnosed with lung adenocarcinoma (LUAD). Next generation sequencing (NGS) revealed that he harbors ROS1 fusion and NBN germline mutation. So, he received platinum-based chemotherapy and ROS1 inhibitors, but the disease continued to progress. Ultimately, the patient was switched to sintilimab combined with niraparib and the efficacy was evaluated as stable disease (SD), with a progression-free survival (PFS) of more than 12 months, and the overall survival (OS) is 23 months up to now. During the treatment, the major adverse events (AEs) observed were lymphopenia, nausea, vomiting, and edema. The AEs were tolerable. Conclusions: This case shows that the combination of small-molecule inhibitors and immunotherapy may improve survival in NSCLC patients with driver genes, and sintilimab combined with niraparib provides a successful clinical case for the treatment of refractory tumors HRR gene mutation, which can be used as a reference for personalized treatment. Of course, more clinical trials are needed to confirm this combination treatment strategy.

A lung adenocarcinoma patient with co-mutations of MET and EGFR exon20 insertion responded to crizotinib.

BACKGROUND: Targeted therapy has revolutionized the treatment of patients with malignancies harboring mutations in driver genes and has brought a favorable survival benefit to the population with actionable oncogenic mutations. In recent years, the MET exon14 skipping mutation has been recognized as a potentially promising therapeutic target in non-small cell lung cancer (NSCLC). These changes are mutually exclusive with molecular drivers such as EGFR, KRAS, HER-2, BRAF, ALK and ROS1. The prevalence rate of coexisting MET exon 14 mutations and EGFR sensitive mutations (L858R, exon 19 deletions) in Chinese population was reported to be 0.2% (3/1590). However, the coexistence of MET exon 14 mutations with EGFR exon 20 insertion mutations has never been reported and the management of this subtype is not identified. CASE PRESENTATION: A 69-year-old male with a right lung adenocarcinoma (T4N2M0, IIIB) was confirmed to be positive for MET exon 14 skipping (c.3028_3028+1delGGinsTT, 44.4%), MET amplification (copy number 4.4), and EGFR exon 20 insertion (p. N771_H773dup, 22.1%) mutations. After the progression of one cycle of chemotherapy (Pemetrexed 0.8 g d1), the patient was subsequently accepted treatment with Crizotinib (250 mg twice a day) and achieved an important clinical remission for six months until the development of brain metastases. Then, he was submitted to a cycle of anti-programmed cell death-1 (PD-1) therapy after failure of Crizotinib and eventually acquired resistance despite of the high expression of programmed death ligand-1 (PD-L1) and tumor mutational burden (TMB) status. CONCLUSION: This case report provides treatment strategies for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-untreated lung adenocarcinoma patients simultaneously carrying MET alterations and EGFR exon 20 insertion mutations. In addition, the signatures of PD-L1 or TMB expression were not the candidate for predicting the efficacy of immunotherapy in this context.

The ctDNA-based postoperative molecular residual disease status in different subtypes of early-stage breast cancer.

Background: Breast cancer is a highly heterogeneous disease. Early-stage, non-metastatic breast cancer is considered curable after definitive treatment. Early detection of tumor recurrence and metastasis through sensitive biomarkers is helpful for guiding clinical decision-making and early intervention in second-line treatment, which could improve patient prognosis and survival. Methods: In this real-world study, we retrospectively analyzed 82 patients with stages I to III breast cancer who had been analyzed by molecular residual disease (MRD) assay. A total of 82 tumor tissues and 224 peripheral blood samples were collected and detected by next-generation sequencing (NGS) based on a 1,021-gene panel in this study. Results: MRD positivity was detected in 18 of 82 patients (22.0%). The hormone receptor-/human epidermal growth factor receptor 2+ (HR-/HER2+) subgroup had the highest postoperative MRD detection rate at 30.8% (4/13). The BRCA2 and SLX4 genes were significantly enriched in all patients in the MRD positive group and FGFR1 amplification was significantly enriched in the MRD negative group with HR+/HER2-. The number of single nucleotide variants (SNVs) in tissue samples of MRD-positive patients was higher than that of MRD-negative patients (11.94 vs. 8.50 SNVs/sample). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that there was a similar biological function of the tumor-mutated genes in the 2 MRD status groups. Conclusions: This real-world study confirmed that patient samples of primary tumor tissue with different MRD status and molecular subtypes had differential genetic features, which may be used to predict patients at high risk for recurrence.

Targeted DNA profiling and the prevalence of NTRK aberrations in Chinese patients with head and neck cancer.

OBJECTIVES: Head and neck cancers are aggressive epithelial tumours that are recognised as being particularly challenging to treat. Here, we report the targeted DNA profiling and the prevalence of neurotrophic-tropomyosin receptor tyrosine kinase gene (NTRK) aberrations in Chinese patients with head and neck cancers. METHODS: Samples of 127 patients with head and neck cancer were retrospectively analysed. Profiling was performed by next-generation sequencing of the 1021-gene panel with tumour tissue and matched peripheral blood control samples. RESULTS: This study was inspired by the outcome benefit of a parotid cancer patient harbouring ETV6-NTRK3 fusion, who received crizotinib treatment and achieved a 2-year progression-free survival. Genomic profiling of 127 patients with head and neck cancers indicated that TP53 is the most frequently mutated gene both in our cohort and in The Cancer Genome Atlas (TCGA) database. A higher prevalence of NTRK genetic aberrations (7.9%, 10/127), including NTRK fusion (3.1%) and mutation, was observed in our population than in TCGA. The most common fusion was the ETV6-NTRK3. Compared to the NTRK-wt group, the NTRK aberration group had more APC and PTPRD aberrations (p < 0.05). NTRK fusion was also associated with lower tumour mutation burden (TMB) (p < 0.05). TP53 and LRP1B mutations were significantly associated with higher TMB (both p < 0.01), which may be potential markers of immunotherapy. CONCLUSIONS: This is the first study to report targeted DNA profiling of Chinese patients with head and neck cancers. As NTRK genetic aberrations are more common in this Chinese population, the efficacy of NTRK inhibitors should be studied further.