Chemotherapy re-use versus anti-angiogenic monotherapy as the third-line treatment of patients with metastatic colorectal cancer: a real-world cohort study.

BACKGROUND: There are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy. METHODS: Using electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher's exact test. ROC curve and surv_cutpoint function of 'survminer' package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors. RESULTS: A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy. CONCLUSIONS: Third-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.

Role of a Rare Variant in APC Gene Promoter 1B Region in Classic Familial Adenomatous Polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) is most commonly caused by germline variants in the adenomatous polyposis coli (APC) gene. Although definite pathogenic variants could be detected in the majority of individuals with FAP, there are still numerous variant-negative FAP patients. METHOD: We utilized a 139-gene next-generation sequencing (NGS) panel and multiplex ligation-dependent probe amplification (MLPA) to detect pathogenic variants in FAP patients and found a variant-negative pedigree. Through whole-exome sequencing (WES), we identified a point variant in the noncoding region in the APC gene. Finally, we used Sanger sequencing to analyze its pedigree cosegregation and a dual-luciferase reporter (DLR) assay to assess its function. RESULTS: With the exception of 2 variants of undetermined significance (VUS), WES showed no pathogenic or likely pathogenic variants. After performing MLPA, the pedigree was still variant-negative. Interestingly, through WES, a point variant c.-190G>A located in the promoter 1B region of the APC gene was identified in 3 affected individuals. Moreover, a variant carrier was found during screening of the family with Sanger sequencing. Through the DLR assay, we further confirmed that the variant c.-190G>A caused significant suppression of downstream transcription of APC. CONCLUSIONS: The variant (c.-190G>A) in the APC promoter 1B region is able to cause FAP with a classic phenotype, but this kind of variant in the noncoding region could be missed by conventional genetic testing. Thus, utilizing sequencing technologies covering a larger area can help us to further explore the pathogenesis in variant-negative FAP cases.

APC Promoter Methylation in Gastrointestinal Cancer.

The adenomatous polyposis coli (APC) gene, known as tumor suppressor gene, has the two promoters 1A and 1B. Researches on APC have usually focused on its loss-of-function variants causing familial adenomatous polyposis. Hypermethylation, however, which is one of the key epigenetic alterations of the APC CpG sequence, is also associated with carcinogenesis in various cancers. Accumulating studies have successively explored the role of APC hypermethylation in gastrointestinal (GI) tumors, such as in esophageal, colorectal, gastric, pancreatic, and hepatic cancer. In sporadic colorectal cancer, the hypermethylation of CpG island in APC is even considered as one of the primary causative factors. In this review, we systematically summarized the distribution of APC gene methylation in various GI tumors, and attempted to provide an improved general understanding of DNA methylation in GI tumors. In addition, we included a robust overview of demethylating agents available for both basic and clinical researches. Finally, we elaborated our findings and perspectives on the overall situation of APC gene methylation in GI tumors, aiming to explore the potential research directions and clinical values.