The response to neoadjuvant chemoradiotherapy with 5-fluorouracil in locally advanced rectal cancer patients: a predictive proteomic signature.

BACKGROUND: Colorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard treatment for patients with locally advanced non-metastatic rectal cancer is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU) followed by surgery, but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance. METHODS: From twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic rectal cancer patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-three patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups. RESULTS: We have highlighted 384 differentially abundant proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially abundant proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Data are available via ProteomeXchange with identifier PXD008440. CONCLUSIONS: From these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic rectal cancer. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment.

Radiomics strategies for risk assessment of tumour failure in head-and-neck cancer.

Quantitative extraction of high-dimensional mineable data from medical images is a process known as radiomics. Radiomics is foreseen as an essential prognostic tool for cancer risk assessment and the quantification of intratumoural heterogeneity. In this work, 1615 radiomic features (quantifying tumour image intensity, shape, texture) extracted from pre-treatment FDG-PET and CT images of 300 patients from four different cohorts were analyzed for the risk assessment of locoregional recurrences (LR) and distant metastases (DM) in head-and-neck cancer. Prediction models combining radiomic and clinical variables were constructed via random forests and imbalance-adjustment strategies using two of the four cohorts. Independent validation of the prediction and prognostic performance of the models was carried out on the other two cohorts (LR: AUC = 0.69 and CI = 0.67; DM: AUC = 0.86 and CI = 0.88). Furthermore, the results obtained via Kaplan-Meier analysis demonstrated the potential of radiomics for assessing the risk of specific tumour outcomes using multiple stratification groups. This could have important clinical impact, notably by allowing for a better personalization of chemo-radiation treatments for head-and-neck cancer patients from different risk groups.

Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVES: Patients treated for head and neck carcinomas experience a significant deterioration of their quality of life during treatments because of severe side effects. Nabilone has many properties that could alleviate symptoms caused by radiotherapy and improve patients' quality of life. The aim of the present study was to compare the effects of nabilone versus placebo on the quality of life and side effects during radiotherapy for head and neck carcinomas. METHODS: Fifty-six patients were randomized to nabilone or placebo. Patients filled the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ-H&N35; three independent questionnaires assessing appetite, nausea, and toxicity; and a visual analog scale for pain. These data were collected before radiotherapy, each week during radiotherapy, and 4 weeks after radiotherapy. Patients were weighed every week. RESULTS: Nabilone did not lengthen the time necessary for a 15% deterioration of quality of life (P = .4279), and it was not better than placebo for relieving symptoms like pain (P = .6048), nausea (P = .7105), loss of appetite (P = .3295), weight (P = .1454), mood (P = .3214), and sleep (P = .4438). CONCLUSION: At the dosage used, nabilone was not potent enough to improve the patients' quality of life over placebo.

Validation of genetic sequence variants as prognostic factors in early-stage head and neck squamous cell cancer survival.

PURPOSE: From the published literature, we identified 23 germ line sequence variants in 17 genes from hypothesis-generating studies that were associated with prognosis of head and neck cancer, including sequence variants of DNA repair (ERCC1, ERCC4, ERCC5, MSH2, XPA, ERCC2, XRCC1, XRCC3), DNA methylation (DNMT3B), cell cycle and proliferation (CCND1, TP53), xenobiotic metabolism (GSTM1, GSTT1, CYP2D6), metastatic -potential (MMP3), immunologic (CTLA4), and growth factor pathways (FGFR4). The purpose of this study was to validate the role of these 23 sequence variants for overall (OS) and disease-free survival (DFS) in a large, comprehensive, well-annotated data set of patients with head and neck cancer. EXPERIMENTAL DESIGN: We genotyped these sequence variants in 531 patients with stage I and II radiation-treated head and neck cancer (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention study), and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors. RESULTS: Two OS associations were statistically significant for each variant allele when compared with the wild-type: CTLA4: A49G [rs231775; adjusted HR (aHR), 1.32 (1.1-1.6); P = 0.01] and XRCC1: Arg339Gln [rs25487; aHR, 1.28 (1.05-1.57); P = 0.02]. Both of these sequence variants had significant results in the opposite direction as prior published literature. Two DFS associations were of borderline significance in the same direction as prior literature: ERCC2: Lys751Gln [rs13181; aHR, 0.80 (0.6-1.0); P = 0.05] and TP53: Arg72Pro [rs1042522; aHR, 1.28 (1.0-1.6); P = 0.03], comparing number of variant alleles with reference of zero variants. CONCLUSIONS: None of the prognostic sequence variants previously published was validated for OS in our patients with early-stage radiation-treated head and neck cancer, though rs1381and rs1042522 had borderline significant association with DFS.

Genetic sequence variants and the development of secondary primary cancers in patients with head and neck cancers.

BACKGROUND: Secondary primary cancers (SPCs), a major cause of morbidity and mortality in head and neck cancers (HNCs), are commonly associated with field cancerization. We comprehensively evaluated 23 germline sequence variants (from published literature) in 17 genes from 7 biological pathways associated with the HNC survival. Because cancer prognosis correlates with disease aggressiveness, the factors that determine aggressive disease may influence field cancerization process to favor SPC development. We thus hypothesized that the same sequence variants associated with HNC survival can also be associated with SPC. METHODS: Germline DNA from 531 stage I-II radiation-treated HNC patients (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention clinical trial) were genotyped, and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors. RESULTS: The majority of SPCs were of lung and HNCs. Median follow-up time was 5 years. SPCs were diagnosed in 21% of patients. The 5-year SPC-free survival was 79%. All but 1 evaluated sequence variant were not associated with SPC. There was a strong association of the DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) sequence variant, DNMT3B:C149T (rs2424913) with SPC: the adjusted hazard ratio (aHR) for TT versus CC was 2.23 (1.32-3.78; P = .003), whereas each variant T allele was associated with an aHR of 1.49 (1.15-1.95; P = .003). CONCLUSIONS: A functional sequence variant in DNMT3B is associated with the development of SPCs in HNC early stage patients treated with radiation. Aberrant DNA methylation may be an important modulator of SPC development in at-risk individuals with HNCs.

Expression of thymosin beta10 and its role in non-small cell lung cancer.

The exact role of thymosin beta10 in lung cancer progression remains unclear. We investigated by immunohistochemistry the expression of thymosin beta10 protein in tumors and tumor-adjacent tissues from 69 patients with non-small cell lung cancer. The relationship of thymosin beta10 expression with vascular endothelial growth factor, vascular endothelial growth factor-C, microvessel density, and lymphatic vessel density was determined; clinicopathologic factors and surgical treatment outcome were also studied. The results showed that thymosin beta10 was mainly expressed in the cytoplasm of lung cancer cells, and the overexpression of thymosin beta10 was correlated with advanced clinical stage (P = .026), distant metastases (P = .016), lymph node metastases (P = .007), poor degree of differentiation (P = .03), and poor postoperative survival (P = .004). Furthermore, thymosin beta10 overexpression was associated with vascular endothelial growth factor (P = .004), vascular endothelial growth factor-C (P = .017), microvessel density (P = .000), and lymphatic vessel density (P = .002). The lowest survival rate was observed in the patients with high thymosin beta10, positive vascular endothelial growth factor, and high microvessel density (P = .007) or in the patients with high thymosin beta10, positive vascular endothelial growth factor-C, and high lymphatic vessel density (P = .005). These results suggest that thymosin beta10 might induce microvascular and lymphatic vessel formation by up-regulating vascular endothelial growth factor and vascular endothelial growth factor-C in lung cancer tissues, thus promoting the distant and lymph node metastases and being implicated in the progression of non-small cell lung cancer.