Whole-exome sequencing reveals an association of rs112065068 in TGOLN2 gene with distant metastasis of non-small cell lung cancer.

Early prediction and prevention of recurring illness is critical for improving the survival rates of patients with non-small cell lung cancer (NSCLC). Previously, we demonstrated that the presence of premalignant epithelial changes in the small bronchi distant to the primary tumor is associated with NSCLC progression: isolated basal cell hyperplasia (iBCH) indicates a high risk of distant metastasis, BCH combined with squamous metaplasia (BCHSM) - a high risk of locoregional recurrence. Here, we aimed to identify germline single nucleotide variants (SNVs) and insertions and deletions (InDels) associated with distant metastasis and locoregional recurrence in cases with iBCH and BCHSM using whole-exome sequencing of 172 NSCLC patients. The rs112065068 of the TGOLN2 gene was identified only in iBCH patients and was associated with a high risk of distant metastasis (P < .001) and worse metastasis-free survival (HR = 4.19 (95 %CI 1.97-8.93); P < .001). This variant was validated in a group of 109 NSCLC patients using real-time PCR and Sanger sequencing analyses. To our knowledge, this study is the first to identify a germline variant associated with NSCLC distant metastasis.

Gene Expression Profile-Guided Personalized Intraperitoneal Chemotherapy for Gastric Cancer Peritoneal Carcinomatosis.

Background: Peritoneal carcinomatosis (PC) is one of the most unfavorable sites of metastasis for malignant tumors of various localizations, especially gastric cancer (GC). According to the literature, synchronous PC in GC is common in 15-52% of patients. The purpose of this study was to examine the long-term results using personalized systemic and intraperitoneal chemotherapy as part of the combined treatment of stomach cancer presenting with synchronous PC. Methods: Cytoreductive surgical treatment was performed for 70 patients at the first stage. The control group (n = 35) received standard postoperative chemotherapy according to the FOLFOX scheme. Personalized postoperative systemic and intraperitoneal chemotherapy was administered in the basic group (n = 35), based on the expression levels of the eight genes in the primary tumor, lymph node, and peritoneal metastases. Results: The median progression-free survival was 14.9 months in the basic group, and in the control group it was 11.2 months (P < 0.001). The median life expectancy in the basic group was 16.8 (13.7 - 18.8) months, in the control group it was 12.5 (11.3 - 13.1) months (P < 0.001). Conclusions: Developing algorithms of personalized systemic and intraperitoneal chemotherapy in patients with GC with synchronous carcinomatosis, based on the analysis of molecular genetic characteristics of the tumor and metastases, allows to improve the long-term results of combined treatment.

Personalized Prescription of Chemotherapy Based on Assessment of mRNA Expression of BRCA1, RRM1, ERCC1, TOP1, TOP2α, TUBß3, TYMS, and GSTP1 Genes in Tumors Compared to Standard Chemotherapy in the Treatment of Non-Small-Cell Lung Cancer

Objectives: A growing body of evidence suggests the important role of chemosensitive gene expression in the prognosis of patients with lung cancer. However, studies on combined gene expression assessments for personalized prescriptions of chemotherapy regimens in patients have not yet been conducted. The aim of this work was to conduct a prospective study on the appointment of personalized chemotherapy in patients with non-small-cell lung cancer. Materials and methods: The present study analyzed 85 patients with lung cancer (stage IIB-IIIB). Within this group, 48 patients received individualized chemotherapy, and 37 patients received classical chemotherapy. In the individualized chemotherapy group, the mRNA expression levels of ERCC1, RRM1, TUBB3, TYMS, TOP1, TOP2α, BRCA1, and GSTP1 in lung tissues were measured by quantitative real-time PCR (qPCR), and an individual chemotherapy regimen was developed for each patient according to the results. Patients in the classical chemotherapy group received the vinorelbine/carboplatin regimen. Survival analyses were performed using the Kaplan−Meier method. Prognostic factors of metastasis-free survival (MFS) and overall survival (OS) of patients were identified via Cox's proportional hazards regression model. Results: MFS and OS were significantly better in the personalized chemotherapy group compared to the classic chemotherapy group (MFS, 46.22 vs. 22.9 months, p = 0.05; OS, 58.6 vs. 26.9 months, p < 0.0001). Importantly, the best metastasis-free survival rates in the group with personalized ACT were achieved in patients treated with the paclitaxel/carboplatin regimen. Based on an assessment of chemosensitivity gene expression in the tumors, the classical chemotherapy strategy also increased the risk of death (HR = 14.82; 95% CI: 3.33−65.86; p < 0.000) but not metastasis (HR = 1.95; 95% CI: 0.96−3.98; p = 0.06) compared to the group of patients with chemotherapy. Conclusions: The use of combined ERCC1, RRM1, TUBB3, TYMS, TOP1, TOP2α, BRCA1, and GSTP1 gene expression results for personalized chemotherapy can improve treatment efficacy and reduce unnecessary toxicity.

Premalignant Changes in the Bronchial Epithelium Are Prognostic Factors of Distant Metastasis in Non-Small Cell Lung Cancer Patients.

BACKGROUND: The study assessed the possibility of dividing patients into groups based on the assessment of morphological changes in the epithelium of small-caliber bronchi located near the primary tumor in order to predict high and low risks of distant metastasis of non-small cell lung cancer. METHODS: In 171 patients with non-small cell lung cancer (T1-4N0-3M0) in small-caliber bronchi taken at a distance of 3-5 cm from the tumor, various variants of morphological changes in the bronchial epithelium (basal cell hyperplasia (BCH), squamous cell metaplasia (SM), and dysplasia (D)) were assessed. Long-term results of treatment, namely, distant metastasis, were assessed after 2 and 5 years. RESULTS: During the follow-up period, distant metastases were found in 35.1% (60/171) of patients. Most often, they were observed in patients of the high-risk group: BCH+SM-D- (51.6%, 40/95) and BCH-SM+D+ (54.4%, 6/11). Less often, distant metastases were observed in low-risk group patients: BCH+SM+D- (6.7%, 3/45) and BCH-SM-D- (10.0%, 2/20). Tumor size, grade, and stage were significant predictors of metastasis only in the high-risk group. The 5-year metastasis-free survival was better in the low-risk group of distant metastases. CONCLUSIONS: Isolated BCH or dysplasia in small bronchi distant from foci of tumor is associated with a high-risk distant metastasis and less 5-year metastasis-free survival.

Prognostic significance of ERCC1, RRM1, TOP1, TOP2A, TYMS, TUBB3, GSTP1 AND BRCA1 mRNA expressions in patients with non-small-cell lung cancer receiving a platinum-based chemotherapy.

PURPOSE: Currently, more researchers are attracted by the possibility of assessing the sensitivity of a lung tumor to certain chemotherapy drugs and their personalized choice based on an assessment of this sensitivity. The purpose of this study was to explore the prognostic significance of the level of 8 chemosensitivity genes' expression in patients with non-small cell lung cancer (NSCLC). METHODS: The study included 59 patients with NSCLC IIB-IIIA stage. RNA was isolated from the surgical material of the tumor and normal lung tissue. The expression level of 8 chemosensitivity genes BRCA1, RRM1, ERCC1, TOP1, TOP2a, TUBB3, TYMS, GSTP1 was evaluated using RT-PCR. RESULTS: Cases with higher metastasis-free survival rates showed a significantly low level of expression of the ERCC1, BRCA1, GSTP1 genes (p=0.0004, p=0.01, p=0.01). In addition, analysis of the overall survival revealed that the highest rates were achieved in patients with overexpression of the ERCC1 gene. The overall survival in these patients was 86%, versus 55% in the other group and the differences were statistically significant (p=0.002). No statistically significant differences were found for the remaining genes. CONCLUSION: Thus, a comprehensive assessment of the chemosensitivity genes expression is important not only from the point of view of understanding the heterogeneity and complexity in the field of molecular biology of NSCLC, but also for a more accurate prognosis and course of the disease.

Neoadjuvant chemotherapy combined with intraoperative radiotherapy is effective to prevent recurrence in high-risk non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Basal cell hyperplasia (BCH) and squamous metaplasia (SM) in the small bronchi distant from the tumor is associated with a high risk of non-small cell lung cancer (NSCLC) recurrence. Here, we assessed whether neoadjuvant chemotherapy (NAC), intraoperative radiotherapy (IORT), or adjuvant chemotherapy (AC) is effective to prevent recurrence in NSCLC patients (n=171) with different premalignant lesions in the small bronchi. METHODS: BCH, SM, and dysplasia (D) were identified in the samples of lung tissue distant from the tumor. NSCLC patients were treated by surgery, different combinations of NAC and IORT, and AC. RESULTS: Based on the type of bronchial lesions, NSCLC patients were classified into four groups: BCH+SM-D- (55.6%, 95/171), BCH+SM+D- (26.3%; 45/171), BCH-SM+D+ (6.4%, 11/171), and BCH-SM-D- (11.7%, 20/171). During 5 years, recurrent carcinoma was found in 13.4% (23/171) of patients and represented by metachronous metastases in the thoracic lymph nodes (82.6%, 19/23) and by a relapse in the bronchial stump (17.4%, 4/23). Recurrence was frequent in BCH+SM+D- patients (87.0%, 20/23), rare in BCH+SM-D- and BCH-SM-D- patients (13.0%, 3/23), and absent in BCH-SM+D+ patients (0/23). The 5-year recurrence-free survival was also shorter in BCH+SM+D- patients (HR 27.35; 95% CI: 6.31-118.48; P<0.0001). In the high-risk (BCH+SM+D-) group, recurrence occurred mainly in cases without NAC and IORT (88.2%, 15/17) and was absent (0/15) when these therapies were combined. NAC- and IORT-negative patients also showed poor overall survival (HR 4.35; 95% CI: 1.96-9.66; P<0.0001) and tended to have decreased recurrence-free survival (P=0.075). Importantly, the recurrence rate was not different between AC-treated and AC-naïve BCH+SM+D- patients. CONCLUSIONS: The combination of NAC and IORT is an effective strategy to prevent recurrence in high-risk NSCLC patients.