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Mutation Analysis of Radioresistant Early-Stage Cervical Cancer.

ABSTRACT: Radiotherapy is a definitive treatment for early-stage cervical cancer; however, a subset of this disease recurs locally, necessitating establishment of predictive biomarkers and treatment strategies. To address this issue, we performed gene panel-based sequencing of 18 stage IB cervical cancers treated with definitive radiotherapy, including two cases of local recurrence, followed by in vitro and in silico analyses. Simultaneous mutations in KRAS and SMAD4 (KRAS^mt/SMAD4^mt) were detected only in a local recurrence case, indicating potential association of this mutation signature with radioresistance. In isogenic cell-based experiments, a combination of activating KRAS mutation and SMAD4 deficiency led to X-ray resistance, whereas either of these factors alone did not. Analysis of genomic data from 55,308 cancers showed a significant trend toward co-occurrence of mutations in KRAS and SMAD4. Gene Set Enrichment Analysis of the Cancer Cell Line Encyclopedia dataset suggested upregulation of the pathways involved in epithelial mesenchymal transition and inflammatory responses in KRAS^mt/SMAD4^mt cancer cells. Notably, irradiation with therapeutic carbon ions led to robust killing of X-ray-resistant KRAS^mt/SMAD4^mt cancer cells. These data indicate that the KRAS^mt/SMAD4^mt signature is a potential predictor of radioresistance, and that carbon ion radiotherapy is a potential option to treat early-stage cervical cancers with the KRAS^mt/SMAD4^mt signature.

SUBMITTER: Oike T

PROVIDER: S-EPMC8744703 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Minimally invasive surgery was adopted as an alternative to laparotomy (open surgery) for radical hysterectomy in patients with early-stage cervical cancer before high-quality evidence regarding its effect on survival was available. We sought to determine the effect of minimally invasive surgery on all-cause mortality among women undergoing radical hysterectomy for cervical cancer. METHODS:We performed a cohort study involving women who underwent radical hysterectomy for stage IA2 or IB1 cervical cancer during the 2010-2013 period at Commission on Cancer-accredited hospitals in the United States. The study used inverse probability of treatment propensity-score weighting. We also conducted an interrupted time-series analysis involving women who underwent radical hysterectomy for cervical cancer during the 2000-2010 period, using the Surveillance, Epidemiology, and End Results program database. RESULTS:In the primary analysis, 1225 of 2461 women (49.8%) underwent minimally invasive surgery. Women treated with minimally invasive surgery were more often white, privately insured, and from ZIP Codes with higher socioeconomic status, had smaller, lower-grade tumors, and were more likely to have received a diagnosis later in the study period than women who underwent open surgery. Over a median follow-up of 45 months, the 4-year mortality was 9.1% among women who underwent minimally invasive surgery and 5.3% among those who underwent open surgery (hazard ratio, 1.65; 95% confidence interval [CI], 1.22 to 2.22; P=0.002 by the log-rank test). Before the adoption of minimally invasive radical hysterectomy (i.e., in the 2000-2006 period), the 4-year relative survival rate among women who underwent radical hysterectomy for cervical cancer remained stable (annual percentage change, 0.3%; 95% CI, -0.1 to 0.6). The adoption of minimally invasive surgery coincided with a decline in the 4-year relative survival rate of 0.8% (95% CI, 0.3 to 1.4) per year after 2006 (P=0.01 for change of trend). CONCLUSIONS:In an epidemiologic study, minimally invasive radical hysterectomy was associated with shorter overall survival than open surgery among women with stage IA2 or IB1 cervical carcinoma. (Funded by the National Cancer Institute and others.).

Project description:Objective: To provide updated evidence on comparative efficacy for clinical outcomes of radical trachelectomy and radical hysterectomy in patients with early-stage cervical cancer. Methods: A systematic search was conducted in the PubMed, Scopus, Cochrane Database of Systematic Reviews, and Google scholar databases. Studies were done in patients with early-stage cervical cancer that compared the outcomes between radical trachelectomy (RT) and hysterectomy (RH) were considered for inclusion in the review. The outcomes of interest were operative time, the volume of blood loss, need for blood transfusion, any complications, length of hospital stay, risk of recurrence, and survival. The strength of association was presented in the form of pooled relative risk (RR), hazards risk (HR), and weighted mean difference (WMD). Statistical analysis was done using STATA version 16.0. Results: A total of 12 articles were included in the meta-analysis. The majority were retrospective cohort-based studies. Compared to RH, the operative time (in min) was comparatively higher in RT (WMD 23.43, 95% CI: 5.63, 41.24). Patients undergoing RT had blood loss (in ml) similar to those undergoing RT (WMD -81.34, 95% CI: -170.36, 7.68). There were no significant differences in the risk of intra-operative (RR 1.61, 95% CI: 0.49, 5.28) and post-operative complications (RR 1.13, 95% CI: 0.54, 2.40) between the two groups. Patients in the RT group had lesser duration of post-operative hospital stay (in days) (WMD -1.65, 95% CI: -3.22, -0.09). There was no statistically significant difference in the risk of recurrence (HR 1.21, 95% CI: 0.68, 2.18), 5-year overall survival (HR 1.00, 95% CI: 0.99, 1.02), and recurrence-free survival (HR 0.99, 95% CI: 0.96, 1.01) between the two groups. Conclusion: Among the patients with early-stage cervical cancer, RT is similar to RH in safety and clinical outcomes. Future studies with a randomized design and larger sample sizes are needed to further substantiate these findings.

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Mutation Analysis of Radioresistant Early-Stage Cervical Cancer.

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