ATM mutation is associated with shorter overall survival in relapsed/advanced urothelial cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 370-370 ◽  
Author(s):  
Ming Yin ◽  
Petros Grivas ◽  
Amir Mortazavi ◽  
Paul Monk ◽  
Hamid Emamekhoo ◽  
...  

370 Background: Somatic mutations of ATM are frequently found in UC and have been associated with a better response to cisplatin-based neoadjuvant chemotherapy. However, we previously showed ATM mutations were associated with a short survival in UC (PMID: 29682192 ). In this study, we focused on prognostic values of mutations in ATM in tumors of patients with relapsed or advanced (TxN2-3M0-1) UC through three independent datasets. Methods: 81 UC pts who underwent FoundationOne genomic sequencing (315 cancer-related genes) were used as a discovery dataset. Results were then validated in additional 91 pts with UC who received FoundationOne test (collected separately) and 129 relapsed/advanced UC patients selected from 412 TCGA bladder cohort. Fisher Exact test was used to determine difference of ATM mutation rates. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. Results: The median ages of the 3 cohorts were 65 (44–84), 65 (21–91) and 67 (45–-90). The majority of pts were Caucasians (86.4%, 75.8% and 81.4%) and ever smokers (77.8%, 67% and 76.7%). ATM mutations were present in 14.8% (12/81), 11% (10/91) and 6.2% (8/129) of the three cohorts (Fisher Exact, p = 0.118). In all three groups of pts, ATM mutations consistently correlated with a significantly shorter OS (Discovery: HR = 2.25, 95% CI, 1.03–4.89, p = 0.041; Validation 1: HR = 3.15, 95% CI, 1.17–8.44, p = 0.023; and Validation 2: HR = 2.17, 95% CI, 0.99–4.75, p = 0.051). In 144 pts treated with cisplatin or carboplatin pooled from the three cohorts, ATM mutations correlated with a non-significantly higher objective response rate (OR = 1.54, 95% CI 0.44–5.35, p = 0.5), but were still associated with a poorer survival (HR = 1.95, 95% CI 1.00–3.83, p = 0.05). Conclusions: These results suggest that ATM mutations may be considered as a negative prognostic biomarker in relapsed/advanced UC pts. Further studies are required to determine the underlying mechanisms.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 438-438 ◽  
Author(s):  
Monika Joshi ◽  
Petros Grivas ◽  
Amir Mortazavi ◽  
Paul Monk ◽  
Steven K. Clinton ◽  
...  

438 Background: DDR gene alterations may contribute to higher tumor mutational burden (TMB) via genomic instability in addition to APOBEC mutagenesis. We previously showed that ATM mutations correlated with shorter OS in UC, while Teo et al. showed patients (pts) with DDR alterations benefited from PD-1/PD-L1 blockade in advanced UC. Here, we aimed to validate those findings and further explore the prognostic role of ATM mutations in advanced UC treated with anti-PD-1/PD-L1 agents. Methods: The study included 53 pts who had FoundationOne tumor tissue genomic sequencing and anti-PD-1/PD-L1 therapy. Fisher exact test was used to test difference in objective response rate (ORR). OS was measured from time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: The cohort had a median age of 66 (range 21–81) with 34% females and 64.2% platinum-based chemotherapy. DDR alterations (including ATM) were present in 49.1% pts (26/53) and favored a higher ORR (37.5% vs. 23.1%, p = 0.26). Compared with those without DDR alterations, pts with DDR alterations (excluding ATM) seemed to have longer OS, although significance was not reached likely due to a short follow-up time (HR = 0.53, 95% CI 0.20–1.38, p = 0.19). ATM alterations seemed to favor higher response rate to PD-1/PD-L1 blockade (ORR, 40% vs. 28.9%, p = 0.6), but was associated with significantly shorter OS (HR = 5.7, 95% CI 1.65–19.74, p = 0.006) in overall pts and in subgroups with/without platinum-based chemotherapy (data not shown). Pts with ≥ 3 DDR alterations (including ATM) had substantial higher TMB (13.9–72.2 perMb, median 22.6) and benefited the most from PD-1/PD-L1 blockade with 80% ORR vs. 24.4% ORR in pts with < 3 DDR alterations. Conclusions: Our study supported that DDR alterations are associated with higher response rate and prolonged OS in advanced UC pts receiving anti-PD-1/PD-L1 agents, likely from impact on TMB. However, ATM alterations correlated with poor prognosis also in those pts. Further studies are needed to assess the clinical utility of DDR alterations in directing therapies in UC.


2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 427-427 ◽  
Author(s):  
Ming Yin ◽  
Petros Grivas ◽  
Edmund Folefac ◽  
Steven K. Clinton ◽  
Hamid Emamekhoo ◽  
...  

427 Background: DDR defects play an important role in tumorigenesis, progression, treatment response and outcomes of BCa. We previously showed DDR mutations were associated with better prognosis in relapsed/advanced (TxN2-3M0-1) BCa. In this study, we aimed to update and validate our findings in 3 independent datasets. Methods: 81 BCa patients (pts) who had FoundationOne tumor tissue genomic sequencing (315 cancer-related genes) were used as discovery dataset. Validation dataset 1 consisted of additional 91 pts with FoundationOne test. Validation dataset 2 consisted of 129 relapsed/advanced pts from TCGA BCa cohort. Overall survival (OS) was measured from time of initial BCa diagnosis to death or last follow-up. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Logistic regression analysis was performed to calculate odds ratio (OR) and 95% CI. A panel of 32 DDR genes (excluding ATM) were used for analyses because ATM mutation was a negative prognostic factor in our prior study. Results: DDR mutations were present in 76.5% (62/81), 40.7% (37/91) and 51.2% (66/129) pts of the 3 datasets. They were associated with longer OS (adjHR = 0.39, 95% CI 0.21–0.73, p = 0.003) in the discovery dataset, which were confirmed in two validation datasets (Validation 1: adjHR = 0.51, 95% CI 0.26–1.03, p = 0.059; Validation 2: adjHR = 0.62, 95% CI 0.39–0.97, p = 0.038). There was a trend for longer OS with increased number of DDR mutations in individual pts. Pts carrying ≥3 DDR mutations had the best prognosis (data not shown). In 144 cisplatin or carboplatin-treated pts pooled from the 3 cohorts, pts with DDR mutations were more likely to have objective response (OR = 1.81, 95% CI 0.85–3.92 for any DDR mutations; OR = 3.65, 95% CI 0.91–14.7 for ≥3 DDR mutations) and longer overall survival (HR = 0.61, 95% CI 0.38–0.98 for any DDR mutations; HR = 0.49, 95% CI 0.19–1.27 for ≥3 DDR mutations). Conclusions: DDR mutations (excluding ATM gene and especially ≥3) correlated with better outcomes in relapsed/advanced BCa. Further exploration of the deleterious nature and functional impact of alterations is critical along with prospective validation in ongoing trials.


2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Aiying Lu ◽  
Haifeng Li ◽  
Yuming Zheng ◽  
Minzhong Tang ◽  
Jun Li ◽  
...  

The peripheral blood neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) have been reported to correlate with the prognosis of many malignancies. This study evaluated the prognostic value of pretreatment NLR, LMR, and PLR in nasopharyngeal carcinoma (NPC). A retrospective analysis of clinical and pathological data of 140 NPC patients without distant metastasis during initial treatment was conducted to identify correlations between NLR, LMR, and PLR and clinicopathological features, overall survival, and progression-free survival. Cox proportional hazard regression analysis was used to reveal the independent factors affecting the prognosis of NPC patients. NLR was associated with T staging, N staging, and overall clinical stage grouping of the NPC patients (P<0.05). NLR ≥ 2.28, LMR < 2.26, and PLR ≥ 174 were significantly associated with a relatively short overall survival (P<0.05). In addition, NLR ≥ 2.28 was significantly associated with a relatively short progression-free survival (P<0.05). Cox proportional hazard regression analysis showed that NLR was an independent prognostic factor in NPC. Pretreatment NLR, LMR, and PLR might be a useful complement to TNM staging in the prognostic assessment of NPC patients.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1445.1-1445
Author(s):  
F. Girelli ◽  
A. Ariani ◽  
M. Bruschi ◽  
A. Becciolini ◽  
L. Gardelli ◽  
...  

Background:The available biosimilars of etanercept are as effective and well tolerated as their bio originator molecule in the naive treatment of chronic autoimmune arthritis. More data about the switching from the bio originator are needed.Objectives:To compare the clinical outcomes of the treatment with etanercept biosimilars (SB4 and GP2015) naïve and after the switch from their corresponding originator in patients affected by autoimmune arthritis in a real life settingMethods:We retrospectively analyzed the baseline characteristics and the retention rate in a cohort of patients who received at least a course of etanercept (originator or biosimilar) in our Rheumatology Units from January 2000 to January 2020. We stratified the study population according to biosimilar use. Descriptive data are presented by medians (interquartile range [IQR]) for continuous data or as numbers (percentages) for categorical data. Drug survival distribution curves were computed by the Kaplan-Meier method and compared by a stratified log-rank test. A Cox proportional hazards regression analysis stratified by indication, drug, age, disease duration, sex, treatment line, biosimilar use and prescription year was performed. P values≤0.05 were considered statistically significant.Results:477 patients (65% female, median age 56 [46-75] years, median disease duration 97 [40.25-178.75] months) treated with etanercept were included in the analysis. 257 (53.9%) were affect by rheumatoid arthritis, 139 (29.1%) by psoriatic arthritis, and 81 (17%) by axial spondylarthritis. 298 (62.5%) were treated with etanercept originator, 97 (20.3%) with SB4, and 82 (17.2%) with GP2015. Among the biosimilars 90/179 (50.3%) patients were naïve to etanercept treatment. Among the 89 switchers we observed 8 treatment discontinuations: one due to surgical infection complication, three due to disease flare, two due to subjective worsening and one due to remission. The overall 6- and 12-month retentions rate were 92.8% and 80.2%. The 6- and 12-month retention rate for etanercept, SB4 and GP2015 were 92.7%, 93.4% and 90.2%, and 82%, 74.5% and 88.1% respectively, without significant differences among the three groups (p=0.374). Patients switching from originator to biosimilars showed and overall higher treatment survival when compared to naive (12-month retention rate 81.2% vs 70.8%, p=0.036). The Cox proportional hazard regression analysis highlighted that the only predictor significantly associated with an overall higher risk of treatment discontinuation was the year of prescription (HR 1.08, 95% CI 1.04 to 1.13; p<0.0001).Conclusion:In our retrospective study etanercept originator and its biosimilars (SB4 and GP2015) showed the same effectiveness. Patients switching from originator to biosimilar showed an significant higher retention rate when compared to naive. The only predictor of treatment discontinuation highlighted by the Cox proportional hazard regression analysis was the year of treatment prescription.Disclosure of Interests:Francesco Girelli: None declared, Alarico Ariani: None declared, Marco Bruschi: None declared, Andrea Becciolini Speakers bureau: Sanofi-Genzyme, UCB and AbbVie, Lucia Gardelli: None declared, Maurizio Nizzoli: None declared


2019 ◽  
Vol 34 (1) ◽  
pp. 41-46 ◽  
Author(s):  
Chuanxu Luo ◽  
Xiaorong Zhong ◽  
Zhu Wang ◽  
Yu Wang ◽  
Yanping Wang ◽  
...  

Purpose: A nomogram is a reliable tool to generate individualized risk prediction by combining prognostic factors. We aimed to construct a nomogram for predicting the survival in patients with non-metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer in a prospective cohort. Methods: We analyzed 1304 consecutive patients who were diagnosed with non-metastatic HER2 positive breast cancer between January 2008 and December 2016 in our institution. Independent prognostic factors were identified to build a nomogram using the COX proportional hazard regression model. The prediction of the nomogram was evaluated by concordance index (C-index), calibration and subgroup analysis. External validation was performed in a cohort of 6379 patients from the Surveillance, Epidemiology, and End Results (SEER) database. Results: Through the COX proportional hazard regression model, five independent prognostic factors were identified. The nomogram predicting overall survival achieved a C-index of 0.78 in the training cohort and 0.74 in the SEER cohort. The calibration plot displayed favorable accordance between the nomogram prediction and the actual observation for 3-year overall survival in both cohorts. The quartiles of the nomogram score classified patients into subgroups with distinct overall survival. Conclusion: We developed and validated a novel nomogram for predicting overall survival in patients with non-metastatic HER2 positive breast cancer, which presented a favorable discrimination ability. This model may assist clinical decision making and patient–clinician communication in clinical practice.


BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Gangqin Xi ◽  
Lida Qiu ◽  
Shuoyu Xu ◽  
Wenhui Guo ◽  
Fangmeng Fu ◽  
...  

Abstract Background Collagen fibers play an important role in tumor initiation, progression, and invasion. Our previous research has already shown that large-scale tumor-associated collagen signatures (TACS) are powerful prognostic biomarkers independent of clinicopathological factors in invasive breast cancer. However, they are observed on a macroscale and are more suitable for identifying high-risk patients. It is necessary to investigate the effect of the corresponding microscopic features of TACS so as to more accurately and comprehensively predict the prognosis of breast cancer patients. Methods In this retrospective and multicenter study, we included 942 invasive breast cancer patients in both a training cohort (n = 355) and an internal validation cohort (n = 334) from one clinical center and in an external validation cohort (n = 253) from a different clinical center. TACS corresponding microscopic features (TCMFs) were firstly extracted from multiphoton images for each patient, and then least absolute shrinkage and selection operator (LASSO) regression was applied to select the most robust features to build a TCMF-score. Finally, the Cox proportional hazard regression analysis was used to evaluate the association of TCMF-score with disease-free survival (DFS). Results TCMF-score is significantly associated with DFS in univariate Cox proportional hazard regression analysis. After adjusting for clinical variables by multivariate Cox regression analysis, the TCMF-score remains an independent prognostic indicator. Remarkably, the TCMF model performs better than the clinical (CLI) model in the three cohorts and is particularly outstanding in the ER-positive and lower-risk subgroups. By contrast, the TACS model is more suitable for the ER-negative and higher-risk subgroups. When the TACS and TCMF are combined, they could complement each other and perform well in all patients. As expected, the full model (CLI+TCMF+TACS) achieves the best performance (AUC 0.905, [0.873–0.938]; 0.896, [0.860–0.931]; 0.882, [0.840–0.925] in the three cohorts). Conclusion These results demonstrate that the TCMF-score is an independent prognostic factor for breast cancer, and the increased prognostic performance (TCMF+TACS-score) may help us develop more appropriate treatment protocols.


2020 ◽  
Author(s):  
Sudhir Bhandari ◽  
Amit Tak ◽  
Sanjay Singhal ◽  
Jyotsna Shukla ◽  
Bhoopendra Patel ◽  
...  

Abstract Objectives: The present study is aimed at estimating patient flow dynamical parameters and requirement of hospital beds. Secondly, the effects of age and gender on parameters were evaluated. Patients and Methods: In this retrospective cohort study, 987 COVID-19 patients were enrolled from SMS Medical College, Jaipur (Rajasthan, India). The survival analysis was carried out from 29 Feb to 19 May 2020 for two hazards – ‘Hazard 1’ was hospital discharge and ‘Hazard 2’ was hospital death. The starting point for survival analysis of the two hazards was considered to be hospital admission . The survival curves were estimated and additional effects of age and gender were evaluated using Cox proportional hazard regression analysis. Results: The Kaplan Meier estimates of lengths of hospital stay (Median =10 days, IQR =10 days) and median survival rate ( more than 60 days due to large amount of censored data) were obtained. The Cox Model for ‘Hazard 1’ showed no significant effect of age and gender on duration of hospital stay. Similarly, the Cox Model 2 showed no significant difference of gender on survival rate. The case fatality rate 8.1 % , recovery rate 78.8% , mortality rate 0.10 per 100 person--days and hospital admission rate 0.35 per 105 person-days were estimated.Conclusion : The study estimates hospital bed requirement based on patient flow dynamic parameters. Furthermore, study concludes that average length of hospital stay were similar for patients of both genders and all age groups.


2019 ◽  
Vol 25 (1) ◽  
pp. 57-64
Author(s):  
Susin Park ◽  
Nam Kyung Je

Background: Anticoagulation therapy is recommended for stroke prevention in high-risk patients with atrial fibrillation (AF). This study aimed to estimate the time to switch from warfarin to a direct oral anticoagulant (DOAC) and identify the factors associated with it. Methods: By using claims data, we studied 7111 warfarin-using patients with nonvalvular AF who were aged ≥65 years. The Kaplan-Meier analysis was performed to estimate the time to switch from warfarin to a DOAC, and Cox proportional hazard regression analysis was used to estimate the influencing factors. Results: Approximately one-third of the patients (2403, 33.8%) switched from warfarin to a DOAC during the study period. Female sex, aged between 75 and 79 years, having a Medical Aid or Patriots and Veterans Insurance, hypertension, and history of prior stroke, and transient ischemic attack or thromboembolism (prior stroke/TIA/TE) were associated with a significantly shorter time to switch. The odds of switching to a DOAC were increased by approximately 1.2-fold in the women and 1.4-fold in the patients with prior stroke/TIA/TE. Conclusions: Approximately one-third of the warfarin-using patients switched from warfarin to a DOAC within 6 months after the change in the DOAC reimbursement criteria. In the Cox proportional hazard regression analysis, the factors that affected anticoagulant switching from warfarin to a DOAC were female sex and history of prior stroke/TIA/TE.


2020 ◽  
Vol 7 (7) ◽  
Author(s):  
Berend J van Welzen ◽  
Colette Smit ◽  
Anders Boyd ◽  
Faydra I Lieveld ◽  
Tania Mudrikova ◽  
...  

Abstract Background The development of efficacious combination antiretroviral therapy (cART) has led to a dramatic decrease in mortality in HIV-positive patients. Specific data on the impact in HIV/hepatitis B virus (HBV)–coinfected patients are lacking. In this study, all-cause and cause-specific mortality risks stratified per era of diagnosis are investigated. Methods Data were analyzed from HIV/HBV-coinfected patients enrolled in the ATHENA cohort between January 1, 1998, and December 31, 2017. Risk for (cause-specific) mortality was calculated using Cox proportional hazard regression analysis, comparing patients diagnosed before 2003 with those diagnosed ≥2003. Risk factors for all-cause and liver-related mortality were also assessed using Cox proportional hazard regression analysis. Results A total of 1301 HIV/HBV-coinfected patients were included (14 882 person-years of follow-up). One-hundred ninety-eight patients (15%) died during follow-up. The adjusted hazard ratio (aHR) for all-cause mortality in patients diagnosed in or after 2003 was 0.50 (95% CI, 0.35–0.72) relative to patients diagnosed before 2003. Similar risk reduction was observed for liver-related (aHR, 0.29; 95% CI, 0.11–0.75) and AIDS-related mortality (aHR, 0.44; 95% CI, 0.22–0.87). Use of a tenofovir-containing regimen was independently associated with a reduced risk of all-cause and liver-related mortality. Prior exposure to didanosine/stavudine was strongly associated with liver-related mortality. Ten percent of the population used only lamivudine as treatment for HBV. Conclusions All-cause, liver-related, and AIDS-related mortality risk in HIV/HBV-coinfected patients has markedly decreased over the years, coinciding with the introduction of tenofovir. Tenofovir-containing regimens, in absence of major contraindications, should be strongly encouraged in this population.


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