Radiotherapy Response In Patients Research Articles

Characterization of DNA Damage Response-Associated Somatic Mutations in Borderline Resectable and Locally Advanced Pancreatic Cancer

The role of radiation for pancreatic cancer remains controversial, with recent studies showing conflicting results, highlighting the need to develop biomarkers of radiation response. Despite its potential utility in predicting radiosensitivity, the landscape of somatic mutations in borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), as related to DNA damage response (DDR), has not been well characterized. This study aimed to characterize the frequency of such mutations in a cohort of patients with BRPC/LAPC treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT). Mutational data was collected from patients with BRPC/LAPC treated at a single institution with neoadjuvant chemotherapy and SBRT, followed by surgical resection from 2016-2021. Chemotherapy consisted of modified FOLFIRINOX or gemcitabine/nab-paclitaxel, and patients were treated with SBRT in 33 Gy in 5 fractions. Genomic data was obtained from either endoscopic biopsy or surgical specimens, and next-generation sequencing was performed either in-house with a Solid Tumor Panel or with FoundationOne CDx. Specific emphasis was placed on the characterization of double-strand DNA break (DSB) repair genes, as this is the type of tumor cell damage traditionally induced by radiation therapy. Genes associated with the two main pathways of DSB repair, non-homologous end joining (NHEJ) and homologous repair (HR), were analyzed. Specific HR pathway mutations assessed were BLM, BRCA1/2, MRE11, NBN, PALB2, RAD50, RAD51B-D, and RAD54L, while PRKDC mutations were assessed for the NHEJ pathway. Mutations in ATM, an important initiator of DDR pathways, were also analyzed. Additionally, the frequency of mutations in TP53, CDKN2A and SMAD4 in patients with concomitant KRAS mutations was assessed. Eighty-five patients were included in the study. Five (5.9%) patients had mutations in the NHEJ pathway of the PRKDC gene. Twenty (23.5%) patients had mutations in the HR pathway, including BRCA2 (10/85; 11.8%), PALB2 (5/85; 5.9%), BRCA1 (3/85; 3.5%), and RAD50 (1/85; 1.2%). Six (7.1%) patients had mutations in ATM. No patients were found to have mutations in BLM, RAD51B-D, RAD54L, or NBN. Amongst patients with KRAS mutations (72/85), concomitant mutations were observed in TP53 (47/85; 55.3%), CDKN2A (16/85; 18.8%), and SMAD4 (9/85; 10.6%). Herein, we characterized the frequency of somatic mutations associated with DSB repair genes in patients with BRPC/LAPC. Data analysis on outcomes related to radiation response in patients with mutations in DDR pathways is ongoing, but will likely also benefit from multi-institutional efforts to increase the power to answer this question.

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma

BackgroundRadiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC.MethodsThis was a large‑scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC.ResultsAfter genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10− 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy.ConclusionOur study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients.Trial registration number: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546.

Inflammatory Markers and Radiotherapy Response in Patients With Painful Bone Metastases.

Inflammation is proposed to influence tumor response in radiotherapy (RT). Clinical studies to investigate the relationship between inflammatory markers and RT response is warranted to understand the variable RT efficacy in patients with painful bone metastases. To evaluate the association between inflammatory markers and analgesic response to RT in patients with painful bone metastases. Adult patients from 7 European study sites undergoing RT for painful bone metastases were included in this prospective and longitudinal analysis. The association between RT response and 17 inflammatory markers at baseline, as well as the association between RT response and the changes observed in inflammatory markers between baseline and three and eight weeks after RT, was analyzed with univariate regression analyses. Baseline analyses were adjusted for potential clinical predictors of RT response. None of the inflammatory markers were significantly associated with an upcoming RT response in the analysis of 448 patients with complete baseline data. In patients available for follow-up, the three-week change in TNF (P 0.017), IL-8 (P 0.028), IP-10 (P 0.032), eotaxin (P 0.043), G-CSF (P 0.033) and MCP-1 (P 0.002) were positively associated with RT response, while the three-week change in CRP (P 0.006) was negatively associated. Results from this study show an association between RT response and change in pro-inflammatory mediators and indicate that inflammation may be important to achieve an analgesic RT response in patients with painful bone metastases. None of the investigated inflammatory markers were found to be pre-treatment predictors of RT response.

Circadian as a prognostic factor for radiation responses in patients with cervical cancer: A nested case‑control study.

The radiation response of cervical cancer is thought to be enhanced by the levels of melatonin due to its roles in the circadian cycle and cancer growth. In the present study, the roles of circadian rhythms and melatonin levels as prognostic factors for predicting the radiation response in patients with cervical cancer were examined. In this nested case‑control study, patients with good and poor responses to radiotherapy were assessed in terms of the time‑of‑day radiation treatment was administered and further influencing factors. The radiation time was determined, as the subjects were either irradiated in the morning (06.00‑10.00am) or afternoon (04.00‑06.00pm). Data on tumour size and other biological parameters were collected and analysed by binary logistic regression. Among the 56patients examined, most subjects had good radiation responses. Most patients were <50years old with an initial body weight of >50kg, no pain prior to radiation, low erythrocyte sedimentation rates, normal intravenous urography results, moderate or good differentiation on pathology and histo‑pathologically non‑keratinised cells. According to the multivariate analysis, the irradiation time as a surrogate of the circadian cycle (morning vs. afternoon), the initial haemoglobin(Hb) level and the clinical tumour size were significant predictors of the radiation response. The circadian cycle, tumour size and Hb levels may affect the radiation response in patients with cervical cancer. In addition, the morning group had better 5‑year overall survival, but it was not significant, possibly due to the small cohort size. Further research is required to identify more relevant prognostic factors using different radiotherapy techniques [National Clinical Trial (NCT) no.NCT05511740, registration date, 08/20/2022].

Effect of molecular subtypes on radiotherapy response in patients with breast cancer brain metastasis

Objective: This study aimed to investigate survival and the response to radiotherapy (RT) among patients with molecular subtypes of breast cancer brain metastases. Patients and Methods: We retrospectively analyzed the data of 139 breast cancer patients with brain metastases treated with wholebrain radiotherapy (WBRT) or focal brain treatment (FBT) between 2006 and 2019. Overall survival (OS) and brain metastasis progression-free survival (BMPFS) were calculated from the first RT until death or the last follow-up. Survival analyses were performed using the Kaplan–Meier method. Prognostic factors were evaluated using the Cox proportional hazard model. Results: Twenty three (16.5%), 77 (55.4%), 14 (10.1%), and 25 (18%) patients were diagnosed with triple-negative, HER-2 (+), luminal-like A, and luminal-like B breast cancer, respectively. Of 139 patients, 66 (47.8%) underwent FBT, and 73 (52.5%) underwent WBRT. While the most preferred fraction was 10*300 Gy in WBRT, doses of 15-25 Gy in 1-5 fractions were preferred in local RT. We observed that age, Karnofsky performance scale (KPS) score, initial RT technique, extracranial disease, number of brain metastases impacted OS and BMPFS. Conclusion: Breast cancer brain metastasis is a different, complex, and challenging disease based on the molecular subtype of the tumor, despite various local treatments. Therefore, appropriate and tailored treatment approaches should be considered for the different molecular subtypes.

Development of a prediction model for radiotherapy response among patients with head and neck squamous cell carcinoma based on the tumor immune microenvironment and hypoxia signature.

The immune system and hypoxia are major factors influencing radiosensitivity in patients with different cancer types. This study aimed at developing a model to predict radiotherapy response in patients with head and neck squamous cell carcinoma (HNSCC) based on the tumor immune microenvironment and hypoxia signature. We first evaluated the hypoxia status and tumor immune microenvironment in the Cancer Genome Atlas (TCGA) cohort by using transcriptomic data. Differentially expressed genes (DEGs) were identified between the "high immunity and low hypoxia" and "low immunity and high hypoxia" groups and those DEGs significantly associated with disease-specific survival in the univariate Cox regression analysis were selected as the prognostic DEGs. We selected the immune hypoxia-related genes (IHRGs) by intersecting prognostic DEGs with immune and hypoxia gene sets. We used the IHRGs to train a multivariate Cox regression model in the TCGA cohort, based on which we calculated the IHRG prognostic index (IHRGPI) for each patient and validated its efficacy in predicting radiotherapy response in the Gene Expression Omnibus cohorts. Furthermore, we explored potential mechanisms and effective combinational treatment strategies for different IHRGPI groups. Five IHRGs were used to construct the IHRGPI, which was used to dichotomize the cohorts. The patients with lower IHRGPI showed a better radiotherapy response across different cohorts and endpoints, including overall survival, progression-free survival, and recurrence-free survival (p < 0.05). Patients with higher IHRGPI showed greater hypoxia and lesser immune cell infiltration. A lower IHRGPI indicated a better immunotherapy response, while a higher IHRGPI indicated a better chemotherapy response. IHRGPI is promising for predicting radiotherapy response and guiding combinational treatment strategies in patients with HNSCC.

Radiosensitivity-Specific Proteomic and Signaling Pathway Network of Non-Small Cell Lung Cancer (NSCLC)

An unmet clinical need in non-small cell lung cancer (NSCLC) management is the accurate prediction of radiation response in patients receiving radical radiation therapy. We explored the intrinsic radiosensitivity of NSCLC from the proteomic profiles of NSCLC cell lines and paraffin-embedded human samples. To uncover radiosensitivity-specific proteomic and signaling pathways, we performed quantitative proteomics by data-independent acquisition mass spectrometry assay on 29 human NSCLC cell lines and 13 paraffin-embedded human NSCLC samples. We validated closely interacting radioresistant proteins by western blotting, immunofluorescence, real-time quantitative polymerase chain reaction in NSCLC cell lines, and immunohistochemistry in paraffin-embedded human samples. We validated the functions of 3 key hub proteins by lentivirus transfection, clonogenic survival assay, and flow cytometry. The proteomic profiling of NSCLC showed that the intrinsic radiosensitivity of NSCLC is mainly modulated by signaling pathways of proteoglycans in cancer, focal adhesion, and regulation of the actin cytoskeleton. We identified 71 differentially expressed proteins and validated 8 closely interacting proteins as radioresistant proteins of NSCLC. Moreover, we also validated the functionality of integrin-linked protein kinase, p21-activated kinase 1, and Ras GTPase-activating-like protein IQGAP1 in the radiation response of NSCLC cell lines. Finally, with the NSCLC radiosensitivity-specific proteins, we delineated the atlas network of NSCLC radiosensitivity-related signaling pathways. Radiosensitivity-specific proteins could guide individualized radiation therapy in clinical practice by predicting the radiation response of patients with NSCLC. Moreover, the NSCLC radiosensitivity-related signaling pathway atlas could guide further exploration of the underlying mechanism.

Radiotranscriptomics signature‐based predictive nomograms for radiotherapy response in patients with nonsmall cell lung cancer: Combination and association of CT features and serum miRNAs levels

PurposeWe aimed to establish radiotranscriptomics signatures based on serum miRNA levels and computed tomography (CT) texture features and develop nomogram models for predicting radiotherapy response in patients with nonsmall cell lung cancer (NSCLC).MethodsWe first used established radioresistant NSCLC cell lines for miRNA selection. At the same time, patients (103 for training set and 71 for validation set) with NSCLC were enrolled. Their pretreatment contrast‐enhanced CT texture features were extracted and their serum miRNA levels were obtained. Then, radiotranscriptomics feature selection was implemented with the least absolute shrinkage and selection operator (LASSO), and signatures were generated by logistic or Cox regression for objective response rate (ORR), overall survival (OS), and progression‐free survival (PFS). Afterward, radiotranscriptomics signature‐based nomograms were constructed and assessed for clinical use.ResultsFour miRNAs and 22 reproducible contrast‐enhanced CT features were used for radiotranscriptomics feature selection and we generated ORR‐, OS‐, and PFS‐ related radiotranscriptomics signatures. In patients with NSCLC who received radiotherapy, the radiotranscriptomics signatures were independently associated with ORR, OS, and PFS in both the training (OR: 2.94, P < .001; HR: 2.90, P < .001; HR: 3.58, P = .001) and validation set (OR: 2.94, P = .026; HR: 2.14, P = .004; HR: 2.64, P = .016). We also obtained a satisfactory nomogram for ORR. The C‐index values for the ORR nomogram were 0.86 [95% confidence interval (CI), 0.75 to 0.92] in the training set and 0.81 (95% CI, 0.69 to 0.89) in the validation set. The calibration‐in‐the‐large and calibration slope performed well. Decision curve analysis indicated a satisfactory net benefit.ConclusionsThe radiotranscriptomics signature could be an independent biomarker for evaluating radiotherapeutic responses in patients with NSCLC. The radiotranscriptomics signature‐based nomogram could be used to predict patients’ ORR, which would represent progress in individualized medicine.

Radiotranscriptomics Signature-Based Predictive Nomograms for Radiotherapy Response in Patients with Non-Small Cell Lung Cancer: Combination and Association of CT Features and Serum miRNAs Levels

Radiotranscriptomics Signature-Based Predictive Nomograms for Radiotherapy Response in Patients with Non-Small Cell Lung Cancer: Combination and Association of CT Features and Serum miRNAs Levels

In Vivo Imaging Markers for Prediction of Radiotherapy Response in Patients with Nasopharyngeal Carcinoma: RESOLVE DWI versus DKI

In this prospective study, we compared the performance of readout segmentation of long variable echo trains of diffusion-weighted imaging (RESOLVE DWI) and diffusion kurtosis imaging (DKI) for the prediction of radiotherapy response in patients with nasopharyngeal carcinoma (NPC). Forty-one patients with NPC were evaluated. All patients underwent conventional MRI, RESOLVE DWI and DKI, before and after radiotherapy. All patients underwent conventional MRI every 3 months until 1 year after radiotherapy. The patients were divided into response group (RG; 36/41 patients) and no-response group (NRG; 5/41 patients) based on follow-up results. DKI (the mean of kurtosis coefficient, Kmean and the mean of diffusion coefficient, Dmean) and RESOLVE DWI (the minimum apparent diffusion coefficient, ADCmin) parameters were calculated. Parameter values at the pre-treatment period, post-treatment period, and the percentage change between these 2 periods were obtained. All parameters differed between the RG and NRG groups except for the pretreatment Dmean and ADCmin. Kmean-post was considered as an independent predictor of local control, with 87.5% sensitivity and 91.3% specificity (optimal threshold = 0.30, AUC: 0.924; 95% CI, 0.83–1.00). Kmean-post values of DKI have the potential to be used as imaging biomarkers for the early evaluation of treatment effects of radiotherapy on NPC.

Comparison of high-resolution diffusion-weighted imaging and diffusion kurtosis imaging for prediction of radiotherapy response in patients with nasopharyngeal carcinoma

Objective In this prospective study, the performance between high-resolution diffusion-weighted imaging (DWI) and diffusion kurtosis imaging (DKI) for prediction of radiotherapy response in patients with nasopharyngeal carcinoma was compared. Methods Forty-one patients pathologically diagnosed with NPC received IMRT. All patients underwent conventional MRI, high-resolution DWI and DKI before and after radiotherapy (1-2 d after the plan dose was administered). All patients received conventional MRI during follow-up at 3, 6, 9 and 12 months after radiotherapy. According to the RECIST 1.1(response evaluation criteria in solid tumors), all patients were divided into the response group (RG; n=36) and non-response group (NRG; n=5). The mean kurtosis coefficient (Kmean) and the mean diffusion coefficient (Dmean) of DKI and apparent diffusion coefficient (ADC) of DWI were analyzed before and after radiotherapy. Results Among 41 patients, 36 cases were assigned into the RG group and 5 in the NRG group. Before and after radiotherapy, all parameters significantly differed between two groups (P=0.000-0.013) except for the Dmean and ADC prior to radiotherapy. At the end of radiotherapy, the sensitivity of Kmean was calculated as 87.5% and the specificity was 91.3% for predicting local control (optimal threshold=0.30, AUC: 0.924; 95%CI: 0.83-1.00). Conclusion Kmean value after radiotherapy is a potential biomarker for the early evaluation of clinical efficacy of radiotherapy in NPC patients. Key words: Nasopharyngeal neoplasm/radiotherapy; Diffusion-weighted imaging; Diffusion kurtosis imaging

Neoadjuvant olaparib targets hypoxia to improve radioresponse in a homologous recombination-proficient breast cancer model.

Clinical trials are studying the benefits of combining the PARP-1 inhibitor olaparib with chemotherapy and radiotherapy treatment in a variety of cancer increasing the therapeutic ratio for olaparib may come from its ability to modify the tumour microenvironment by targeting homologous recombination-deficient, hypoxic tumour clonogens, and/or increasing tumour-associated vasodilation to improve oxygenation. Herein, we investigated the effect of prolonged neoadjuvant exposure to olaparib on the tumor microenvironment using a genetically-engineered mouse p53−/− syngeneic breast cancer model, which is proficient in homology-directed DNA repair. We observed increased in vivo growth delay and decreased ex vivo clonogenic survival following pre-treatment with olaparib 50 mg/kg bid Olaparib for 7 days ending 48 hours prior to a radiation dose of 12Gy. This increased in vivo radioresponse was associated with a decreased hypoxic fraction. This study suggests that the radiation response in patients can be improved with limited toxicity if olaparib is given in a purely neoadjuvant setting to modify the tumor microenviroment prior to the start of the radiotherapy treatment. Consequently a significant gain can be achieved in therapeutic window and clinical studies are needed to confirm this preclinical data.

The value of insulin-like growth factor-1 receptor for predicting early glottic carcinoma response to radiotherapy.

The optimal management of laryngeal carcinoma requires tumor treatment and preservation of laryngeal functions, such as swallowing and voice quality. Radiotherapy (RT) can fulfill both criteria, although it remains important to identify predictors of radioresistance and reduce unnecessary irradiation. Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane receptor that plays a key role in cancer development, although its prognostic value after RT remains unknown. We evaluated the predictive value of IGF-1R expression for RT response in patients with early glottic squamous cell carcinoma. We retrospectively reviewed 43 patients with T1N0 and T2N0 glottic squamous cell carcinoma who were treated with RT alone. Biopsy specimens were stained using an anti-IGF-1R antibody, and we evaluated the relationships between IGF-1R expression and T classification or tumor recurrence. We also evaluated the loco-regional control (LRC) rate and the prognostic value of various clinical factors. All cases achieved complete response after the initial RT, and 10 (23.3%) patients experienced local tumor recurrence. Twenty-five patients (58.1%) exhibited high IGF-1R expression, although the level of IGF-1R expression was not correlated with T classification. Local recurrence was observed in 36% (9/25) of patients with high IGF-1R expression and in only 5% (1/18) of patients with low IGF-1R expression (p<0.05). The 2-year LRC rate was 94.1% for the low IGF-1R expression group, compared to 49.8% for the high IGF-1R expression group (p=0.04). Anterior commissure involvement and IGF-1R expression were independent adverse factors for LRC. High IGF-1R expression was more common among patients with recurrent early glottic carcinoma, which suggests that there is a biological relationship between IGF-1R expression and RT response. Thus, IGF-1R may be a useful screening parameter for RT response in laryngeal carcinoma.

Association between CCND1 G870A polymorphism and radiotherapy response in high-risk human papillomavirus-related cervical cancer

To investigate the correlation of cyclin D1 (CCND1) G870A single nucleotide polymorphism (SNP) with radiotherapy response in patients with high risk human papillomavirus (HR-HPV) related cervical cancer. A total of 273 patients with cervical cancer, who were confirmed by histopathology and hybrid capture 2 (HC-2) assay and treated by radiotherapy, were enrolled for this study. The correlation of CCND1 G870A polymorphism with tumor response in patients was assessed. Compared with patients with AA genotype, the patients with GG genotype and AA genotype showed lower sensitivity to radio-therapy treatment (adjusted ORGA=2.69, 95% CI 1.28-5.67 and adjusted ORGG=3.28, 95% CI 1.47-7.29, respectively), an increase in risks of recurrence/metastasis (adjusted ORGA=2.52, 95% CI 1.12-5.63 and adjusted ORGG=3.95, 95% CI 1.68-9.26, respectively), and shorter recurrence/metastasis-free survival (PGA=0.010 and PGG=0.045). G870A polymorphism is a frequent variation that could be used for evaluate the radio-sensitivity and prognosis for patients with HR-HPV related cervical cancer.

Nuclear expression of WRAP53β is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma

Today there are no reliable predictive markers for radiotherapy response in head and neck squamous cell carcinoma (HNSCC), leading to both under- and over-treatment of patients, personal suffering, and negative socioeconomic effects. Inherited mutation in WRAP53β (WD40 encoding RNA Antisense to p53), a protein involved in intracellular trafficking, dramatically increases the risk of developing HNSCC. The purpose of this study was to investigate whether WRAP53β can predict response to radiotherapy in patients with HNSCC. Tumor biopsies from patients with HNSCC classified as responders or non-responders to radiotherapy were examined for the expression of the WRAP53β protein and single nucleotide polymorphisms in the corresponding gene employing immunohistochemistry and allelic discrimination, respectively. In addition, the effect of RNAi-mediated downregulation of WRAP53β on the intrinsic radiosensitivity of two HNSCC cell lines was assed using crystal violet and clonogenic assays. Nuclear expression of WRAP53β was significantly associated with better response to radiotherapy and improved patient survival. Downregulation of WRAP53β with siRNA in vitro enhanced cellular resistance to radiation. Our findings suggest that nuclear expression of WRAP53β promotes tumor cell death in response to radiotherapy and is a promising predictor of radiotherapy response in patients with HNSCC.

Phosphatidylinositol 3-kinase CB association with preoperative radiotherapy response in rectal adenocarcinoma.

To examine the correlation of phosphatidylinositol 3-kinase (PIK3) CB expression with preoperative radiotherapy response in patients with stage II/III rectal adenocarcinoma. PIK3CB immunoexpression was retrospectively assessed in pretreatment biopsies from 208 patients with clinical stage II/III rectal adenocarcinoma, who underwent radical surgery after 30-Gy/10-fraction preoperative radiotherapy. The relation between PIK3CB expression and tumor regression grade, clinicopathological characteristics, and survival time was statistically analyzed. Western blotting and in vitro clonogenic formation assay were used to detect PIK3CB expression in four colorectal cancer cell lines (HCT116, HT29, LoVo, and LS174T) treated with 6-Gy ionizing radiation. Pharmacological assays were used to evaluate the therapeutic relevance of TGX-221 (a PIK3CB-specific inhibitor) in the four colorectal cancer cell lines. Immunohistochemical staining indicated that PIK3CB was more abundant in rectal adenocarcinoma tissues with poor response to preoperative radiotherapy. High expression of PIK3CB was closely correlated with tumor height (P < 0.05), ypT stage (P < 0.05), and high-degree tumor regression grade (P < 0.001). High expression of PIK3CB was a potential prognostic factor for local recurrence-free survival (P < 0.05) and metastasis-free survival (P < 0.05). High expression of PIK3CB was also associated with poor therapeutic response and adverse outcomes in rectal adenocarcinoma patients treated with 30-Gy/10-fraction preoperative radiotherapy. In vitro, PIK3CB expression was upregulated in all four colorectal cancer cell lines concurrently treated with 6-Gy ionizing radiation, and the PIK3CB-specific inhibitor TGX-221 effectively inhibited the clonogenic formation of these four colorectal cancer cell lines. PIK3CB is critically involved in response to preoperative radiotherapy and may serve as a novel target for therapeutic intervention.

Radiosensitizing biological modifiers enhancing efficacy in non-small-cell lung cancer treated with radiotherapy

251 ISSN 1758-1966 10.2217/LMT.13.25 © 2013 Future Medicine Ltd Lung Cancer Manage. (2013) 2(4), 251–255 The leading cause of cancer-related mortality worldwide is lung cancer, with an average 5-year overall survival rate of only 10–15%, taking all clinical stages together [1]. Lung cancer can be divided into two major histological groups: non-small-cell lung cancer (NSCLC) and small-cell lung cancer. NSCLC is the dominating group in Sweden, comprising more than 85% of all newly diagnosed lung cancer patients; the rest of this article will focus on this tumor entity. Treatments for these patients are based on surgery if the tumor has not spread and is technically removable, and these patients display a better 5-year survival [2]. However, many patients present with locally advanced disease (stage IIIb), metastatic disease (stage IV) or comorbidities, rendering less than 20% of the patients medically operable [3]. Thus, curatively intended radiotherapy, alone or in combination with chemotherapy, offers in many cases the only possibility of cure in localized NSCLC. The effect of radiotherapy depends on the absorption of radiation, which occurs by interaction with orbital electrons in the atoms that are being exposed [4]. Radiation produces a variety of damage to macromolecular components by altering DNA and RNA bases and sugars, inducing DNA–protein and DNA–DNA crosslinks and further by inducing singleand doublestrand breaks [5]. However, despite this induced damage, the cell is fully capable of repairing itself by using five major DNA repair systems: nucleotide excision repair [6]; base excision repair [7]; mismatch repair [8]; homologous recombinational repair [9]; and nonhomologous end joining [10]. Unfortunately for patients with NSCLC, these systems are well functioning and NSCLC is considered as a relatively radioresistant tumor. In a retrospective study by Holgersson et al., which was a collaborative effort among all the Swedish oncology departments, clinical data were collected for 1146 patients with diagnosed NSCLC subjected to curatively intended irradiation (>50 Gy) during the years 1990–2000 [11]. Among the 1146 patients with nonsmall-cell carcinoma eligible for ana lysis,

Strong expression of survivin is associated with positive response to radiotherapy and improved overall survival in head and neck squamous cell carcinoma patients

Head and neck squamous cell carcinoma (HNSCC) is a malignancy that is associated with severe mortality despite advances in therapy. Today's standard treatment most commonly includes radiotherapy, often combined with chemotherapy or surgery. There are so far no established biomarkers to predict response to radiation, and thus the aim of this study was to investigate a series of markers that could potentially identify HNSCC patients who would benefit from radiotherapy. The selected markers, both proteins (epidermal growth factor receptor, survivin and p53), and single nucleotide polymorphisms (SNPs) in the genes of XRCC3, XRCC1, XPC, XPD, MDM2, p53 and FGFR4 were correlated to the response to radiotherapy and overall survival. Investigations were performed on pretreatment tumor biopsies from patients classified as responders or nonresponders to radiotherapy. Protein expression was examined using immunohistochemistry and the genotyping of specific SNPs was analyzed using PCR-RFLP or pyrosequencing. We found that survivin expression was significantly stronger in the responder group (p = 0.003) and that patients with a strong survivin expression had a significantly better overall survival (p < 0.001). Moreover, downregulation of survivin by siRNA in two HNSCC cell lines significantly decreased their sensitivity to radiation. Among the SNPs analyzed, patients with the XPD Lys751Gln SNP had a significantly shorter overall survival (p = 0.048), and patients with the FGFR4 Gly388Arg SNP had a significantly longer overall survival (p = 0.010). In conclusion, our results suggest that survivin plays an important role in the response to radiotherapy and may be a useful marker for predicting radiotherapy response in patients with HNSCC.

Galectin-7 levels predict radiation response in squamous cell carcinoma of the cervix

ObjectiveWe previously found that galectin-7 was upregulated in patients with cervical cancer who remained recurrence-free after chemoradiation. We hypothesized that pretreatment levels of galectin-7 predict radiation response in patients with squamous cell carcinoma (SCC) of the cervix. MethodsGalectin-7 expression was assessed by immunohistochemical staining of a tissue microarray of paraffin-embedded specimens from 161 patients with cervical SCC treated with definitive radiation therapy in 1980–1999. Galectin-7 expression was scored as absent or present. Distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were computed using the Kaplan–Meier method and log-rank tests. ResultsThe median age at diagnosis was 45years (range 21–85) and median follow-up interval was 71months (range 0–285). Of the 161 patients, 105 (65%) had FIGO stage IB disease, 18 (11%) stage IIA, and 38 (24%) stage IIB. Median tumor diameter was 5.5cm (range 3.5–8). Seven patients (4%) received concurrent chemotherapy; 139 patients (86%) had galectin-7-positive tumors and 22 (14%) galectin-7-negative tumors. Five-year DMFS rates for patients with galectin-7-positive versus -negative tumors were 73% and 55% (p=0.05); DSS, 65% and 36% (p=0.004); and OS, 64% and 36% (p=0.005). In multivariate analysis adjusting for age, stage, and tumor diameter, galectin-7 expression remained a significant predictor of DMFS (hazard ratio [HR]=0.43, p=0.03), DSS (HR=0.34, p=0.001), and OS (HR=0.34, p=0.001). ConclusionsElevated galectin-7 expression is associated with improved outcomes after radiation therapy for cervical cancer. Further studies are required to validate these findings and clarify the role of galectin-7 in disease progression and radiation response.

Swedish Lung Cancer Radiation Study Group: Predictive value of age at diagnosis for radiotherapy response in patients with non-small cell lung cancer

Introduction. The aim of the present study was to investigate the impact of age at diagnosis on prognosis in patients treated with curatively intended radiotherapy for NSCLC. Material and methods. This is a joint effort among all the Swedish Oncology Departments that includes all identified patients with a diagnosed non-small cell lung cancer that have been subjected to curatively intended irradiation (≥50 Gy) treated during 1990 to 2000. Included patients had a histopathological/cytological diagnosis date as well as a death date or a last follow-up date. The following variables were studied in relation to overall and disease-specific survival: age, gender, histopathology, time period, smoking status, stage and treatment. Results. The median overall survival of all 1146 included patients was 14.7 months, while the five-year overall survival rate was 9.5%. Younger patients (<55 years), presented with a more advanced clinical stage but had yet a significantly better overall survival compared with patients in the age groups 55–64 years (p = 0.035) and 65–74 years (p = 0.0097) in a multivariate Cox regression analysis. The overall survival of patients aged ≥75 years was comparable to those aged <55 years. Conclusion. In this large retrospective study we describe that patients younger than 55 years treated with curatively intended radiotherapy for NSCLC have a better overall survival than patients aged 55–64 and 65–74 years and that younger patients seem to benefit more from the addition of surgery and/or chemotherapy to radiotherapy. Due to the exploratory nature of the study, these results should be confirmed in future prospective trials.