Genomic Correlates of Unfavorable Outcome in Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemoradiation.

PURPOSE: Neoadjuvant therapy modality can increase the operability rate and mitigate pathological risks in locally advanced cervical cancer, but treatment response varies widely. It remains unclear whether genetic alterations correlate with the response to neoadjuvant therapy and disease-free survival (DFS) in locally advanced cervical cancer. MATERIALS AND METHODS: A total of 62 locally advanced cervical cancer (stage IB-IIA) patients who received neoadjuvant chemoradiation plus radical hysterectomy were retrospectively analyzed. Patients' tumor biopsy samples were comprehensively profiled using targeted next generation sequencing. Pathologic response to neoadjuvant treatment and DFS were evaluated against the association with genomic traits. RESULTS: Genetic alterations of PIK3CA were most frequent (37%), comparable to that of Caucasian populations from The Cancer Genome Atlas. The mutation frequency of genes including TERT, POLD1, NOS2, and FGFR3 was significantly higher in Chinese patients whereas RPTOR, EGFR, and TP53 were underrepresented in comparison to Caucasians. Germline mutations were identified in 21% (13/62) of the cohort and more than half (57%) had mutations in DNA damage repair genes, including BRCA1/2, TP53 and PALB2. Importantly, high tumor mutation burden, TP53 polymorphism (rs1042522), and KEAP1 mutations were found to be associated with poor pathologic response to neoadjuvant chemoradiation treatment. KEAP1 mutations, PIK3CA-SOX2 co-amplification, TERC copy number gain, and TYMS polymorphism correlated with an increased risk of disease relapse. CONCLUSION: We report the genomic profile of locally advanced cervical cancer patients and the distinction between Asian and Caucasian cohorts. Our findings highlight genomic traits associated with unfavorable neoadjuvant chemoradiation response and a higher risk of early disease recurrence.

miRNA-Based Signature Associated With Tumor Mutational Burden in Colon Adenocarcinoma.

Colon adenocarcinoma (COAD) is one of the most common malignant tumors. Tumor mutation burden (TMB) has become an independent biomarker for predicting the response to immune checkpoint inhibitors (ICIs). miRNAs play an important role in cancer-related immune regulation. However, the relationship between miRNA expression and TMB in COAD remains unclear. Therefore, the transcriptome profiling data, clinical data, mutation annotation data, and miRNA expression profiles for cases of COAD were downloaded from the TCGA database. Subsequently, 323 COAD cases were randomly divided into training and test sets. The differential expression of miRNAs in the high and low TMB groups in the training set was obtained as a signature using the least absolute shrinkage and selection operator (LASSO) logistic regression and verified in the test set. Based on the LASSO method, principal component analysis (PCA), and ROC, we found that the signature was credible because it can discriminate between high and low TMB levels. In addition, the correlation between the 18-miRNA-based signature and immune checkpoints was performed, followed by qRT-PCR, to measure the relative expression of 18 miRNAs in COAD patients. The miRNA-based model had a strong positive correlation with TMB and a weak positive correlation with CTLA4 and CD274 (PD-L1). However, no correlation was observed between the model and SNCA (PD-1). Finally, enrichment analysis of the 18 miRNAs was performed to explore their biological functions. The results demonstrated that 18 miRNAs were involved in the process of immunity and cancer pathways. In conclusion, the 18-miRNA-based signature can effectively predict and discriminate between the different TMB levels of COAD and provide a guide for its treatment with ICIs.

Association of Twice-Daily Radiotherapy With Subsequent Brain Metastases in Adults With Small Cell Lung Cancer.

Importance: Although thoracic twice-daily radiotherapy (TDRT) is one of the standards of care for small cell lung cancer, its association with brain metastases remains unknown. Objective: To investigate the association of TDRT vs once-daily radiotherapy (ODRT) with brain metastases after prophylactic cranial irradiation in patients with small cell lung cancer. Design, Setting, and Participants: In this multicenter cohort study, data on 778 consecutive patients with small cell lung cancer who had undergone thoracic radiotherapy (609 received ODRT and 169 received TDRT), chemotherapy, and prophylactic cranial irradiation were retrieved from the databases of 8 hospitals in China between July 1, 2003, and June 30, 2016. A 1:1 propensity score matching approach was used to control for confounding between the ODRT and TDRT groups. Confounding covariates included 8 demographic variables and 8 treatment-related covariates. Data analysis was conducted from November 1, 2017, to May 31, 2018, and reanalyzed for revision. Exposures: The ODRT group received 50 to 66 Gy given in 25 to 33 fractions. The TDRT group received 45 Gy given in 30 fractions. Main Outcomes and Measures: The primary end point was brain metastases. Secondary end points included progression-free survival and overall survival. Results: Of the 778 patients (median age, 55 years [interquartile range, 48-61 years]), 204 were women and 574 were men. At a median follow-up of 23.6 months (interquartile range, 14.2-38.2 months), 131 patients (16.8%) experienced brain metastases. The rate of brain metastasis at 3 years in the TDRT group was significantly higher than in the ODRT group (26.0% vs 16.9%; hazard ratio, 1.55; 95% CI, 1.06-2.26; P = .03). Of the 338 matched patients (169 in the ODRT group vs 169 in the TDRT group), 60 (17.8%) experienced brain metastases, with a rate at 3 years of 14.9% in the ODRT group vs 26.0% in the TDRT group (hazard ratio, 1.71; 95% CI, 1.02-2.88; P = .04). Progression-free survival was similar in both the whole cohort and the matched cohort. Median overall survival in the ODRT group tended to be significantly longer than in the TDRT group after matching (47.2 vs 32.8 months; hazard ratio, 1.41; 95% CI, 0.99-2.01; P = .06). Conclusions and Relevance: In this study, patients with small cell lung cancer who received thoracic TDRT appeared to have a higher risk of brain metastases than those who received ODRT, which supports the need for further prospective randomized clinical trials, especially in China and other parts of Asia.