Risk Of Metastasis In Patients Research Articles

Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer.

The majority of clinical deaths in patients with triple-negative breast cancer (TNBC) are due to chemoresistance and aggressive metastases, with high prevalence in younger women of African ethnicity. Although tumorigenic drivers are numerous and varied, the drivers of metastatic transition remain largely unknown. Here, we uncovered a molecular dependence of TNBC tumors on the TRIM37 network, which enables tumor cells to resist chemotherapeutic as well as metastatic stress. TRIM37-directed histone H2A monoubiquitination enforces changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs triggered a positive feedback loop via ATM/E2F1/STAT signaling, amplifying the TRIM37 network in chemoresistant cancer cells. High expression of TRIM37 induced transcriptomic changes characteristic of a metastatic phenotype, and inhibition of TRIM37 substantially reduced the in vivo propensity of TNBC cells. Selective delivery of TRIM37-specific antisense oligonucleotides using antifolate receptor 1-conjugated nanoparticles in combination with chemotherapy suppressed lung metastasis in spontaneous metastatic murine models. Collectively, these findings establish TRIM37 as a clinically relevant target with opportunities for therapeutic intervention. SIGNIFICANCE: TRIM37 drives aggressive TNBC biology by promoting resistance to chemotherapy and inducing a prometastatic transcriptional program; inhibition of TRIM37 increases chemotherapy efficacy and reduces metastasis risk in patients with TNBC.

Young age increases the risk of lymph-node metastasis in patients with muscle-invasive bladder urothelial carcinoma

BackgroundThe risk of positive lymph nodes in patients with muscle-invasive bladder urothelial carcinoma (MIBC) can be used to guide treatment recommendations. However, little is known about the effect of age on lymph node positivity (LN+). This study aimed to evaluate the effect of age on LN+ in MIBC.MethodsWe analyzed patients with stage T2–T4 bladder urothelial carcinoma who had not received preoperative radiotherapy, had at least one lymph node examined, and underwent cystectomy between 1998 and 2015. The Cochran–Armitage trend test and logistic univariate and multivariate analyses were used to evaluate the effect of age on LN+ in all T stages.ResultsIn total, 15,624 patients with MIBC were identified, including 747 patients aged ≤50 years (4.78%), 2614 patients aged 50–59 years (16.73%), 4914 patients aged 60–69 years (31.45%), 5225 patients aged 70–79 years old (33.44%), and 2124 patients aged > 80 years (13.59%). In T2–T4 staging, LN+ was negatively correlated with age. After adjustment for several covariates, multivariate logistic regression analysis revealed that age was an independent risk factor for LN+.ConclusionsIn this large SEER analysis, Young patients with MIBC have a higher risk of lymph node metastasis. This finding is worthy of further study and may eventually affect the treatment decisions of young patients.

Prediction of Late Recurrence and Distant Metastasis in Early-stage Breast Cancer: Overview of Current and Emerging Biomarkers.

Recently, a significant number of breast cancer (BC) patients have been diagnosed at an early stage. It is therefore critical to accurately predict the risk of recurrence and distant metastasis for better management of BC in this setting. Clinicopathologic patterns, particularly lymph node status, tumor size, and hormonal receptor status are routinely used to identify women at increased risk of recurrence. However, these factors have limitations regarding their predictive ability for late metastasis risk in patients with early BC. Emerging molecular signatures using gene expression-based approaches have improved the prognostic and predictive accuracy for this indication. However, the use of their based-scores for risk assessment has provided contradictory findings. Therefore, developing and using newly emerged alternative predictive and prognostic biomarkers for identifying patients at high- and low-risk is of great importance. The present review discusses some serum biomarkers and multigene profiling scores for predicting late recurrence and distant metastasis in early-stage BC based on recently published studies and clinical trials.

111 - Risk of metastasis in patients with delayed biochemical recurrence 10 years after radical prostatectomy

111 - Risk of metastasis in patients with delayed biochemical recurrence 10 years after radical prostatectomy

Matched analysis of the prognosis of amelanotic and pigmented melanoma in head and neck

Background: The prognosis of mucosal melanoma is poor, and the difference in clinical prognosis between patients with and without pigment needs further study.Aim: To analyze data with head and neck mucosal melanoma, and compare the prognosis of patients with and without pigment.Material and methods: The patients of amelanotic melanoma were matched with pigmented type according to age, sex, stage, location of disease, treatment history, tobacco and alcohol history. The Kaplan–Meier and Cox proportional risk regression model was used for analyzation.Results: 46 patients of amelanotic melanoma and 46 of pigmented type were included in this study. The overall survival rate and progression-free survival rate of patients with pigmented melanoma were higher than in patients with amelanotic melanoma (HR = 0.533, p = .035, 95% CI = 0.296–0.957; HR = 0.530, p = .034, 95% CI = 0.294–0.953, respectively), and the risk of distant metastases in patients with amelanotic melanoma was significantly higher than that in patients with pigmented melanoma (HR = 0.474, p = .046, 95% CI = 0.228–0.987).Conclusions and significance: The prognosis and disease-free survival of amelanotic melanoma is worse than for the pigmented type group. More identifying the differences in clinical characteristics will help to further individualized treatment decisions.

Performance of a prognostic 31-gene expression profile test in patients with node-negative cutaneous melanoma.

e22071 Background: The National Comprehensive Cancer Network guidelines recommend considering sentinel lymph node biopsy (SLNB) for cutaneous melanoma (CM) patients with a 5-10% risk of SLN positivity and offering it to those with > 10% risk. However, SLNB limitations include identification of only 1/3 of patients who end up with distant metastasis and a regional metastasis false negative rate ranging from 5-21% indicating a need to detect the risk of metastasis in patients with a negative SLNB. The 31 gene expression profile (31GEP) test uses the molecular biology of the primary tumor to predict 5-year recurrence-free (RFS), distant metastasis-free (DMFS), melanoma-specific (MSS), and overall survival (OS). Therefore, the objective of this study is to determine whether the 31GEP can stratify risk for patients with SLN-negative results to help guide CM management. Methods: 607 primary CM tumors were collected from patients with SLN-negative status who were enrolled in multi-center IRB-approved studies. Tumors were staged according to the AJCC 8th edition and analyzed by 31GEP testing to differentiate low-risk (Class 1A), intermediate-risk (Class 1B/2A), and high-risk (Class 2B) tumor biology. Clinical data were recorded and Kaplan-Meier (KM) and Cox regression analyses were performed to assess the relationship between 31GEP class and patient outcomes including RFS, DMFS, MSS, and OS. Results: KM analysis for 5yr RFS, DMFS, MSS, and OS stratified by 31GEP class are listed in Table. Multivariate Cox regression analysis demonstrated that the 31GEP Class 2B status was an independent predictor of RFS, DMFS, MSS, and OS with hazard ratios of 4.4 (95% CI, 2.7-7.2; p < 0.001), 4.4 (95% CI, 2.3-8.5; p < 0.001), 15.6 (95% CI, 3.4-71.2; p < 0.001), and 5.4 (95% CI, 2.6-10.9; p < 0.001), respectively. Conclusions: The results indicate that the 31GEP can stratify risk for a subset of patients with SLNB-negative results with the highest 5-year survival rates being associated with a Class 1A result. Moreover, GEP Class 2B is a significant independent predictor of metastatic risk in patients who are node negative. [Table: see text]

Development and validation of the immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma

BackgroundThe tumor immune microenvironment has clinicopathological significance in predicting prognosis and therapeutic efficacy. We aimed to develop an immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma (NPC).MethodsUsing...

Ovarian cancer-derived copy number alterations signatures are prognostic in chemoradiotherapy-treated head and neck squamous cell carcinoma.

DNA copy number alterations (CNAs) are frequent in cancer, and recently developed CNA signatures revealed their value in molecular tumor stratification for patient prognosis and platinum resistance prediction in ovarian cancer. Head and neck squamous cell carcinoma (HNSCC) is also characterized by high CNAs. In this study, we determined CNA in 173 human papilloma virus‐negative HNSCC from a Dutch multicenter cohort by low‐coverage whole genome sequencing and tested the prognostic value of seven cancer‐derived CNA signatures for these cisplatin‐ and radiotherapy‐treated patients. We find that a high CNA signature 1 (s1) score is associated with low values for all other signatures and better patient outcomes in the Dutch cohorts and The Cancer Genome Atlas HNSCC data set. High s5 and s7 scores are associated with increased distant metastasis rates and high s6 scores with poor overall survival. High cumulative cisplatin doses result in improved outcomes in chemoradiotherapy‐treated HNSCC patients. Here we find that tumors high in s1 or low in s6 are most responsive to a change in cisplatin dose. High s5 values, however, significantly increase the risk for metastasis in patients with low cumulative cisplatin doses. Together this suggests that the processes causing these CNA signatures affect cisplatin response in HNSCC. In conclusion, CNA signatures derived from a different cancer type were prognostic and associated with cisplatin response in HNSCC, suggesting they represent underlying molecular processes that define patient outcome.

A Nomogram for Predicting Lymph Nodal Metastases in Patients with Appendiceal Cancers: An Analysis of SEER Database

Backgrounds Appendiceal cancers are usually diagnosed after appendectomy accidentally. The need for subsequent right hemicolectomy in these patients was determined by the potential risk of regional lymph node (LN) metastasis. Establishing a nomogram to forecast the potential risk of lymph node metastasis of appendiceal cancer could help in the next step of treatment. Methods Patients with appendiceal cancer undergoing surgery was queried in the American cancer database of Surveillance, Epidemiology and End Results database from 2004 to 2016. A nomogram was established based on Logistic regression model. Results Finally, 3,075 patients were diagnosed with appendectomy cancer from 2004 to 2016. Among them, there were 2028 (65.9%) cases with negative lymph nodes, 1047 (34.1%) cases with positive lymph nodes. Risk factors associated with lymph node metastasis include age, histological type, tissue grade, T stage, distant metastasis, and tumor size. We drew the ROC curves of the training group（0.754, P < 0.001） and the validation group （0.775, P < 0.001） respectively. C-index values of predictions were 0.772 (95%CI, 0.750-0.793) and 0.776 (95%CI, 0.746-0.807), and Brier score were 0.178 and 0.172 in training and validation group respectively. All of them showed excellent performance of the nomogram in our study. Conclusion A new nomogram was created to assess the potential risk of LN metastasis in patients of appendiceal cancer by utilizing age, tumor histology, tumor pathologic grade, tumor size, T-stage, and M-stage. The nomogram could provide a strong reference for the right hemicolectomy and facilitate clinic decision.

Effects of single-nucleotide polymorphisms in the mTORC1 pathway on the risk of brain metastasis in patients with non-small cell lung cancer

PurposeThe mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a vital role in cancer development and progression. This study aimed to investigate the relationship between genotype variants in mTORC1 pathway and the risk of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC).MethodsWe extracted genomic DNA from blood samples of 501 NSCLC patients and genotyped eight single-nucleotide polymorphisms (SNPs) in three core genes [mammalian target of rapamycin (mTOR), mammalian lethal with sec-13 protein 8 (mLST8) and regulatory-associated protein of mTOR (RPTOR)] of the mTORC1 pathway. The associations between these SNPs and the risk of BM development were assessed.ResultsThe AG/GG genotype of mLST8:rs26865 and TC/CC genotype of mLST8:rs3160 were associated with an increased risk of BM [hazard ratios (HR) 2.938, 95% confidence interval (CI) 1.664–5.189, p < 0.001 and HR = 2.490, 95% CI = 1.543–4.016, p < 0.001, respectively]. These risk polymorphisms had a cumulative effect on BM risk, with two risk genotypes exhibiting the highest increased risk (p < 0.001). Furthermore, these risk SNPs were associated with the lymph node metastasis (N2/3), body mass index (BMI) (≥ 25 kg/m2), high level of squamous cell carcinoma (SCC) antigen and Ki-67 proliferation index. Moreover, patients with AG/GG genotype of mLST8:rs26865 had significantly lower median overall survival than those with AA genotype (12.1 months versus 21.6 months, p = 0.04).ConclusionsOur results indicate that polymorphisms in mTORC1 pathway were significantly associated with increased risk of BM and may be valuable biomarkers to identify NSCLC patients with a high risk of BM.

Irradiation ganglionnaire prophylactique des cancers de prostate

The risk of lymph node invasion, in case of prostate cancer, increases with the clinical stage of the disease, the Gleason score of prostate biopsies and the value of PSA at diagnosis. Historically, beyond 15% risk of lymph node involvement, irradiation of the pelvic areas was performed with prostate radiotherapy (RT) to take into account the risk of occult lymph node metastasis in patients at risk, but the benefit of this therapeutic approach remains to be demonstrated. The data from surgical lymph node dissection seem to question the risk levels, the escalation of the dose on the prostate increases the survival without relapse, the contribution of image-guided radiotherapy, (IGRT) and modulation of intensity (IMRT), decreases the toxicity of pelvic RT. This article reviews the principles of prophylactic ganglion irradiation for prostate cancer and discusses its relevance, current uncertainties, and prospective trials.

PSA Doubling Time and Absolute PSA Predict Metastasis-free Survival in Men With Biochemically Recurrent Prostate Cancer After Radical Prostatectomy.

The aim of this study was to investigate the association of prostate-specific antigen (PSA) values on metastasis-free survival (MFS) in men with biochemically recurrent prostate cancer (BRPC) and PSA doubling time (PSADT)< 12 months. This datasetalso reflects an update with longer follow-up of our prior publications on the natural history of BRPC in the absence of treatment. In this report, we combined databases from the Center for Prostate Disease Research and Johns Hopkins University (CPDR/JHU). In the CPDR/JHU radical prostatectomy database (30,936 total patients), 656 men with BRPC (> 0.2 ng/mL) after prostatectomy and PSADT<12 months, who received no adjuvant/salvage androgen deprivation and/or radiation therapy, were prospectively followed until radiologic evidence of metastasis and are included in this analysis. Metastasis occurred in 250 of 656 patients with BRPC (median follow-up, 5 years). PSADT< 7.5 months and Gleason score were independent risk factors for distant metastasis in multivariable analysis. Risk of metastasis increased for PSADT 6.01 to 7.50, 4.51 to 6.0, 3.01 to 4.50, and≤ 3.0 months, after adjusting for Gleason score. A PSA value≥ 0.5 ng/mL significantly and independently increased risk of metastasis in patients with PSADT< 12 months (hazard ratio, 2.79; 95% confidence interval, 1.47-5.29; P= .001). In men with PSADT< 12 months, PSADT≤ 7.5 months, PSA≥ 0.5 ng/mL, and Gleason score are independent predictors of MFS on multivariable analysis.

The long-term survival characteristics of a cohort of colorectal cancer patients and baseline variables associated with survival outcomes with or without time-varying effects

BackgroundColorectal cancer is the third most common cancer in the world. In this study, we assessed the long-term survival characteristics and prognostic associations and potential time-varying effects of clinico-demographic variables and two molecular markers (microsatellite instability (MSI) and BRAF Val600Glu mutation) in a population-based patient cohort followed up to ~ 19 years.MethodsThe patient cohort included 738 incident cases diagnosed between 1999 and 2003. Cox models were used to analyze the association between the variables and a set of survival outcome measures (overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), metastasis-free survival (MFS), recurrence/metastasis-free survival (RMFS), and event-free survival (EFS)). Cox proportional hazard (PH) assumption was tested for all variables, and Cox models with time-varying effects were used if any departure from the PH assumption was detected.ResultsDuring the follow-up, ~ 61% patients died from any cause, ~ 26% died from colorectal cancer, and ~ 10% and ~ 20% experienced recurrences and distant metastases, respectively. Stage IV disease and post-diagnostic recurrence or metastasis were strongly linked to risk of death from colorectal cancer. If a patient had survived the first 6 years without any disease-related event (i.e., recurrence, metastasis, or death from colorectal cancer), their risks became very minimal after this time period. Distinct sets of markers were associated with different outcome measures. In some cases, the effects by variables were constant throughout the follow-up. For example, MSI-high tumor phenotype and older age at diagnosis predicted longer MFS times consistently over the follow-up. However, in some other cases, the effects of the variables varied with time. For example, adjuvant radiotherapy treatment was associated with increased risk of metastasis in patients who received this treatment after 5.5 years post-diagnosis, but not before that.ConclusionsThis study describes the long-term survival characteristics of a prospective cohort of colorectal cancer patients, relationships between baseline variables and a detailed set of patient outcomes over a long time, and time-varying effects of a group of variables. The results presented advance our understanding of the long-term prognostic characteristics in colorectal cancer and are expected to inspire future studies and clinical care strategies.

Frequency of somatic mutations in the KRAS gene in patients of the South Russia diagnosed with colorectal cancer.

e15081 Background: Colorectal cancer (CRC) is a common pathology in the world; the annual incidence rate reaches 1 million cases, and the annual mortality rate exceeds 500,000. The target therapy of EGFR with monoclonal drugs improves the survival of patients with this pathology. However, the effectiveness of therapy depends on the presence of mutations in genes involved in the EGFR signaling cascade, in particular KRAS. The purpose of this study was to determine the frequency of somatic mutations in the KRAS gene in tumor samples of patients from the South Russia diagnosed with colorectal cancer, as well as to analyze the effect of point mutations G12A, G12C, G12D, G12R, G12S, G12V and G13D on tumor metastasis. Methods: 744 patients diagnosed with colorectal adenocarcinoma were examined for mutations in 12th and 13th codons of KRAS. Somatic mutations in the KRAS gene were detected with reagent kit Biolink (Russia) using FFPE DNA samples of tumor tissues. Statistical analysis was performed using the method of binary logistic multiple regression and χ2-test. Results: Mutations in the KRAS gene were found in 32% of patients in the pooled sample; the most common mutation was the replacement of G12D in the KRAS gene (36%). Less common detectable mutations in the KRAS gene were G13D (18%), G12V (16%), G12A (10%), G12C (8%), G12S (10%), G12R (2%). Metastatic CRC was found in 86% of carriers of the wild-type allele and in 88% of carriers of the mutant allele. The presence of a G12V substitution almost 6 times increased the risk of metastasis in patients with CRC (OR = 5.89; 95% CI: 0.8-43.45; p = 0.049). Conclusions: Mutations in the KRAS gene were found in 32% of patients with CRC in the South of Russia. A significant association of G12V replacement with a high risk of metastasis was established. Further study of somatic mutations in the KRAS gene will allow to choose the most effective therapeutic strategies in the presence of one or another of the studied mutations.

Prophylactic cranial irradiation (PCI) significantly decreases risk of brain metastases in patients with bulky, higher stage small-cell urothelial cancer.

486 Background: Patients with bulky, higher-stage small cell urothelial cancer (≥T3b, N+, and/or M+) have a high risk of developing brain metastases. Siefker-Radtke et al reported a 50% risk of brain metastases in this patient population. Therefore, a prospective trial evaluating the potential benefit of PCI was undertaken. Methods: Thirty patients with stage ≥T3b, N+, and/or M+ disease (without brain metastases on MRI) were treated between 12/2008 and 5/2018 with PCI. Patients were treated to a total dose of 30 Gy in 2 Gy fractions over 3 weeks. The patient had baseline brain MRI and mini-mental status exam (MMSE) before the treatment began. After treatment, patients underwent MRI and MMSE every 3-4 months for one year and every 6 months thereafter. If the patients did not have M+ disease at diagnosis, they were also treated with neoadjuvant chemotherapy (usually consisting of cisplatin/etoposide alternating with Adriamycin/ifosfamide), followed by a radical cystectomy. The PCI was either given between the last cycle of chemotherapy and surgery or after the surgery. Both acute and chronic toxicity from PCI were measured using CTCAE 3.0. Change in the MMSE after PCI was evaluated using a t-test. Results: Twenty-nine patients were evaluable. Twenty-four patients had ≥T3b and/or N+ disease and 5 patients had M1 disease. Median follow-up was 22 months (range 8-103 months). Four patients have developed brain metastases with a median time of 11.5 months after PCI (range 3-23 months). Two of these patients have died. Nine other patients have died from progressive systemic disease, but they did not have evidence of brain metastases. PCI was well-tolerated, with no grade ≥2 toxicity seen. Acute grade 1 toxicity seen included headache, nausea, and dermatitis. MMSE were available for 19 patients with a median follow-up of 13 months (range 3-87 months). There was no significant change in the MMSE scores after the PCI when compared to baseline (p = 0.61). Conclusions: In this study, PCI decreased the risk of developing brain metastases in patients with bulky, higher-stage small cell urothelial cancer from 50% (historical) to 13.8% without significant toxicity. Clinical trial information: NCT00756639.

Individual prediction of lateral neck metastasis risk in patients with unifocal papillary thyroid carcinoma

IntroductionMuch controversy exists over whether to perform lateral neck dissection (LND) on patients with papillary thyroid carcinoma (PTC). This study aimed to build predictive nomograms that could individually estimate lateral neck metastasis (LNM) risk and help determine follow up intensity. Patients and methodsUnifocal PTC patients who underwent LND between April 2012 and August 2014 were identified. Clinical and pathological variables were retrospectively evaluated using univariate and stepwise multivariate logistic regression analysis. Variables that had statistical significance in final multivariate logistic models were chosen to build nomograms, which were further corrected using the bootstrap resampling method. ResultsIn all, 505 PTC patients were eligible for analysis. Among these, 178 patients (35.2%) had lateral neck metastasis. Two nomograms were generated: nomogram (c) and nomogram (c + p). Nomogram (c) incorporated four clinical variables: age, tumor size, tumor site, and extrathyroidal extension (ETE). It had a good discriminative ability, with a C-index of 0.79 (bootstrap-corrected, 0.78). Nomogram (c + p) incorporated two clinical variables and two pathological variables: tumor size, tumor site, extranodal extension (ENE), and number of positive nodes in the central compartment. Nomogram (c + p) showed an excellent discriminative ability, with a C-index of 0.86 (bootstrap-corrected, 0.85). ConclusionTwo predictive nomograms were generated. Nomogram (c) is a clinical model, whereas nomogram (c + p) is a clinicopathological model. Each nomogram incorporates only four variables and can give an accurate estimate of LNM risk in unifocal PTC patients, which may assist clinicians in patient counseling and decision making regarding LND.

Clinical significance of nuclear localisation of agrin in lung adenocarcinoma.

Agrin has recently been identified as anovel oncogene that is overexpressed in several types ofhuman cancers. However, its role in lung cancer has not yet been investigated. Thepurpose ofthecurrent study was to investigate agrin protein expression in lung cancer and evaluate its clinicopathological and prognostic significance. In this study, Atotal of86 lung adenocarcinoma samples paired with adjacent non-tumour tissue samples and eight lung adenocarcinoma non-paired samples were selected for immunohistochemical staining for agrin. Strong staining ofagrin in nuclei oflung adenocarcinoma tissues was observed, but not in thenuclei ofnormal lung tissues (p<0.001). Consistent with staining in lung adenocarcinoma tissues, thenuclei staining ofagrin was also detected in lung cancer cell lines by immunofluorescence. This is thefirst report demonstrating that agrin is highly expressed in nuclei oflung adenocarcinoma tissues and that it is strongly correlated with lymph node metastasis (p=0.002), clinical stage (p=0.024), and poor differentiation (p=0.022). Agrin-positive nuclear staining oflung adenocarcinoma cells could be used to identify greatly increased risk ofmetastasis in patients after surgery, which might serve as avaluable prognostic marker.

Smoking, age, nodal disease, T stage, p16 status, and risk of distant metastases in patients with squamous cell cancer of the oropharynx.

With an expectation of excellent locoregional control, ongoing efforts to de-intensify therapy for patients with human papillomavirus-associated squamous cell oropharyngeal cancer necessitate a better understanding of the metastatic risk for patients with this disease. The objective of this study was to determine what factors affect the risk of metastases in patients with squamous cell cancers of the oropharynx. Under a shared use agreement, 547 patients from Radiation Therapy Oncology Group 0129 and 0522 with nonmetastatic oropharyngeal squamous cell cancers who had a known p16 status and smoking status were analyzed to assess the association of clinical features with the development of distant metastases. The analyzed factors included the p16 status, sex, T stage, N stage, age, and smoking history. A multivariate analysis of 547 patients with a median follow-up of 4.8 years revealed that an age ≥ 50 years (hazard ratio [HR], 3.28; P = .003), smoking for more than 0 pack-years (HR, 3.09; P < .001), N3 disease (HR, 2.64; P < .001), T4 disease (HR, 1.63; P = .030), and a negative p16 status (HR, 1.60; P = .044) were all factors associated with an increased risk of distant disease. Age, smoking, N3 disease, T4 disease, and a negative p16 status were associated with the development of distant metastases in patients with squamous cell cancers of the oropharynx treated definitively with concurrent chemoradiation.

Intravenous Chemotherapy Plus Intra-Arterial Chemotherapy Versus Intra-Arterial Chemotherapy in Patients with Advanced Retinoblastoma Cancer: A Retrospective, Multicentre-Based Study

Background: Intra-arterial chemotherapy (IAC) was found to be effective for the management of advanced retinoblastoma. However, the value of the addition of intravenous chemotherapy (IVC) to IAC in advanced retinoblastoma is unclear. Methods: Kaplan-Meier analyses were performed to compare 2-year rates of ocular survival, overall survival and event-free survival between the groups. Cox proportional hazards model was used to test the independent significance of different factors. Details of enucleated eyes and their histopathological results were recorded. Findings: Between July 2008 and December 2016, 213 patients at five institutions in China with advanced retinoblastoma (group D and E eyes) were included for analysis. They were treated with IVC plus IAC (n=103) or IAC (n=110). The proportion of patients with ocular survival at 2 years was 68% (95%CI 57-76) in the IVC plus IAC group and 72% (95%CI 60-80) in the IAC group (hazard ratio [HR] 0.88 [95%CI 0.55-1.43], P=0.61).The proportion of patients with overall survival at 2 years was 97% (95%CI 92-99) in the IVC plus IAC group and 96% (95%CI 90-99) in the IAC group (HR 1.56 [95%CI 0.41-5.90], P=0.51). The proportion of patients with event-free survival at 2 years was 76% (95%CI 67-83) in the IVC plus IAC group and 79% (95%CI 69-86) in the IAC group (HR 0.96 [95%CI 0.56-1.65], P=0.89). Multivariate analyses showed eye staging and local therapy were significant prognostic factors of ocular survival. High-risk histopathologic features were identified in 10.5% (4/38) of the IVC plus IAC group and 16.7% (5/30) of the IAC group, with no statistical difference (P=0.46). Interpretation: Addition of IVC to IAC did not significantly improve survival outcomes and lower the risk of metastasis in patients with advanced retinoblastoma cancer. Longer follow-up is needed to determine long-term efficacy, but at present, additional IVC is not recommended for using outside the scope of clinical research. Funding Statement: The National Natural Science Foundation of China; the National Natural Science Foundation of Guangdong Province; the Science and Technology Planning Project of Guangdong Province; the Scientific Research General Project of Guangzhou Science Technology and Innovation Commission; and the China Postdoctoral Science Foundation. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Novel 18-gene signature for predicting relapse in ER-positive, HER2-negative breast cancer

BackgroundSeveral prognostic signatures for early oestrogen receptor-positive (ER+) breast cancer have been established with a 10-year follow-up. We tested the hypothesis that signatures optimised for 0–5-year and 5–10-year follow-up separately are more prognostic than a single signature optimised for 10 years.MethodsGenes previously identified as prognostic or associated with endocrine resistance were tested in publicly available microarray data set using Cox regression of 747 ER+/HER2− samples from post-menopausal patients treated with 5 years of endocrine therapy. RNA expression of the selected genes was assayed in primary ER+/HER2− tumours from 948 post-menopausal patients treated with 5 years of anastrozole or tamoxifen in the TransATAC cohort. Prognostic signatures for 0–10, 0–5 and 5–10 years were derived using a penalised Cox regression (elastic net). Signature comparison was performed with likelihood ratio statistics. Validation was done by a case-control (POLAR) study in 422 samples derived from a cohort of 1449.ResultsNinety-three genes were selected by the modelling of microarray data; 63 of these were significantly prognostic in TransATAC, most similarly across each time period. Contrary to our hypothesis, the derived early and late signatures were not significantly more prognostic than the 18-gene 10-year signature. The 18-gene 10-year signature was internally validated in the TransATAC validation set, showing prognostic information similar to that of Oncotype DX Recurrence Score, PAM50 risk of recurrence score, Breast Cancer Index and IHC4 (score based on four IHC markers), as well as in the external POLAR case-control set.ConclusionsThe derived 10-year signature predicts risk of metastasis in patients with ER+/HER2− breast cancer similar to commercial signatures. The hypothesis that early and late prognostic signatures are significantly more informative than a single signature was rejected.