RFS Hazard Ratio Research Articles

Para-aortic Lymph Node Dissection for Colorectal Cancer: Predicting Pathologic Lymph Node Positivity and Optimizing Outcomes.

In colorectal cancer, the presence of para-aortic lymph nodes (PALN) indicates extraregional disease. Appropriately selecting patients for whom PALN dissection will provide oncologic benefit remains challenging. This study identified factors to predict survival among patients undergoing PALN dissection for colorectal cancer. An institutional database was queried for patients who underwent curative-intent resection of clinically positive PALN for colorectal cancer between 2007 and 2020. Preoperative radiologic images were reviewed, and patients who did and did not have positive PALN on final pathology were compared. Survival analysis was performed to evaluate the impact of pathologically positive PALN on recurrence-free (RFS) and overall survival (OS). Of 74 patients who underwent PALN dissection, 51 had PALN metastasis at the time of primary tumor diagnosis, whereas 23 had metachronous PALN disease. Preoperative chemotherapy ± radiotherapy was given in 60 cases (81.1%), and 28 (37.8%) had pathologically positive PALN. Independent factors associated with positive PALN pathology included metachronous PALN disease and pretreatment and posttreatment radiographically abnormal PALN. On multivariable analysis, pathologically positive PALN was significantly associated with decreased RFS (hazard ratio 3.90) and OS (HR 4.49). Among patients with pathologically positive PALN, well/moderately differentiated histology was associated with better OS, and metachronous disease trended toward an association with better OS. Pathologically positive PALN are associated with poorer RFS and OS after PALN dissection for colorectal cancer. Clinicopathologic factors may predict pathologic PALN positivity. Curative-intent surgery may provide benefit, especially in patients with well-to-moderately differentiated primary tumors and possibly metachronous PALN disease.

Neutrophil-to-Lymphocyte Ratio as a Predictor of Postoperative Recurrence and Prognosis in Oesophageal Squamous Cell Carcinoma

Trimodal therapy is frequently used for patients with locally advanced, resectable oesophageal cancer. However, it does not provide a satisfactory prognosis. The neutrophil-to-lymphocyte ratio (NLR) is an important indicator of patients' inflammatory and immune statuses. We investigated the prognostic role of NLR values obtained at different treatment stages in patients with oesophageal squamous cell carcinoma. We evaluated the correlation between NLR values or their change and prognosis at each treatment point (before chemoradiotherapy; before surgery; and at 14 days, and 1 and 2 months postoperatively) in 163 patients with oesophageal squamous cell carcinoma who underwent oesophagectomy after neoadjuvant chemoradiotherapy from April 2003 to August 2018. The outcomes studied were overall (OS) and relapse-free (RFS) survival. The NLR at 1 month postoperatively showed the strongest correlation with prognosis, with an optimal cut-off value of 4.5 (area under the curve=0.7878; 95% confidence interval=0.70-0.85; p<0.0001). Univariate and multivariate analyses showed that NLR ≥4.5 was a significant factor for both RFS (hazard ratio=4.44, 95% confidence interval=2.69-7.34) and OS (hazard ratio=3.88, 95% confidence interval=2.38-6.32). Furthermore, NLR significantly stratified patients for the RFS and OS regardless of the pathological response (complete/non-complete response) and postoperative complications (Clavien-Dindo grade <IIIa/≥ IIIa). NLR measurement at 1 month postoperatively correlated with prognosis and was also a useful predictor of recurrence. Patients with high NLRs need more rigorous follow-up as they constitute a high-risk group. Postoperative adjuvant therapy may also be considered for such patients.

Predictive impact of residual disease detected using multiparametric flow cytometry on risk stratification of paediatric acute myeloid leukaemia with normal karyotype.

Residual disease (RD) detected using multiparametric flow cytometry (MFC) is an independent predictive variable of relapse in acute myeloid leukaemia (AML). However, RD thresholds and optimal assessment time points remain to be validated. We investigated the significance of RD after induction therapy in paediatric AML with normal karyotype between June 2008 and June 2018. Bone marrow samples from 73 patients were collected at the end of the first (BMA-1) and second (BMA-2) induction courses to monitor RD using MFC. Presence of RD after BMA-1 and/or BMA-2 correlated with poor relapse-free (RFS) and overall survival at 0.1% RD cutoff level. Receiver operating characteristic curve showed that RD cutoff levels of 1.3% and 0.5% after BMA-1 and BMA-2, respectively, predicted events with the highest sensitivity and specificity. In multivariable analysis, RD after BMA-2 was the strongest independent risk predictor for poor RFS (hazard ratio 2.934; 95% confidence interval: 1.106-7.782; P=.031). Our study therefore suggests that an RD level ≥0.5% after BMA-2 has a significant predictive impact on the prognosis of AML patients having normal karyotype and thus guide the stratification of treatment strategies.

Time interval from transurethral resection of bladder tumour to bacille Calmette-Guérin induction does not impact therapeutic response.

To investigate bacille Calmette-Guérin (BCG) tolerability and response with respect to the timing of BCG administration after transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). A review of patients with NMIBC at our institution managed with at least 'adequate BCG' (defined by the United States Food and Drug Administration as at least five of six induction instillations, with two additional instillations comprising either maintenance or repeat induction) at our institution from 2000 to 2018 was performed. Time from TURBT to first instillation of induction BCG was stratified by quartile and analysed as a continuous variable. Kaplan-Meier and log-rank tests analysed differences in recurrence-free (RFS) and progression-free survival (PFS). Cox proportional hazards regression models identified associations between risk factors and survival outcomes. A total of 518 patients received adequate BCG at a median (range) of 26(6-188)days from TURBT. Overall, 45 patients (9%) developed BCG intolerance at a median (range) 12 (7-33) instillations. When time from TURBT to BCG was stratified into quartiles, there was no difference with respect BCG intolerance (P=0.966), RFS (P=0.632) or PFS (P = 0.789). On both uni- and multivariate regression analysis for RFS and PFS, time from TURBT to BCG was not a significant predictor when analysed by quartile or as a continuous variable (the hazard ratio for RFS was 1.00, 95% confidence interval [CI] 0.99-1.00, P=0.449; and for PFS was 0.99, 95% CI 0.98-1.00, P=0.074). The rates of tolerability and response to adequate BCG are not predicated by the timing of induction BCG instillation after TURBT. Early administration in properly selected patients is safe and delays do not affect therapeutic response.

Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma

BackgroundAlterations in fibroblast growth factor receptor 3 (FGFR3) occur in ∼15% of muscle-invasive bladder cancers (MIBCs) and metastatic urothelial carcinomas (mUCs). ObjectiveTo determine the association between FGFR3 status and response to platinum-based chemotherapy in patients with MIBC or mUC. Design, setting, and participantsThe authors conducted a retrospective review and comparison of patients having (1) MIBC treated with neoadjuvant chemotherapy (NAC), (2) mUC treated with first-line platinum-based chemotherapy (M1 cohort), and (3) MIBC who were from The Cancer Genome Atlas (TCGA). InterventionPlatinum-based chemotherapy. Outcome measurements and statistical analysisPathologic response, recurrence-free (RFS) or progression-free (PFS) survival, and overall survival (OS) were compared between patients with FGFR3 alteration (FGFR3alt) and those without it (FGFR3wild type [FGFR3wt]) in the three cohorts. Results and limitationsNine of 72 NAC patients (13%) had FGFR3alt, of whom none had pathologic complete response and three had residual non-MIBC (carcinoma in situ, n = 1; pT1, n = 2). FGFR3alt was associated with shorter RFS (hazard ratio, 2.74; p = 0.044) but not OS. Among TCGA patients who underwent adjuvant chemotherapy (n = 74), FGFR3alt patients had shorter RFS as well. Conversely, among chemotherapy-naive TCGA patients, FGFR3alt was associated with longer RFS and OS. In the M1 cohort (FGFR3alt, n = 27; FGFR3wt, n = 81), FGFR3alt was associated with higher rates of pulmonary metastases and nonregional lymphadenopathy. Despite lower response rates among FGFR3alt patients (37% vs 49%; p = 0.056), PFS and OS were not significantly different from FGFR3wt patients. ConclusionsFGFR3 status is associated with lower responses to platinum-based chemotherapy, which may prompt exploration of nonchemotherapeutic approaches for perioperative management of FGFR3alt urothelial cancers. Patient summaryApproximately 15% of bladder cancers harbor mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Our findings suggest that FGFR3 mutations might be associated with lower responses and shorter time to recurrence among patients with muscle-invasive bladder cancer who received perioperative platinum-based chemotherapy. FGFR3 status does not significantly impact response to chemotherapy among those with metastatic urothelial cancers.

Clinical significance of colorectal liver metastases newly detected during hepatectomy

Background: Despite advances in imaging modalities, intraoperative detection of new legions (newly detected colorectal liver metastases : ND-CLM) is common in patients undergoing hepatectomy. However, clinical significance of ND-CLM is still unknown. Methods: Data of 171 patients who underwent initial hepatectomy for colorectal liver metastases after preoperative chemotherapy were reviewed from 2010 to 2015. ND-CLM were defined as metastases newly confirmed during hepatectomy by visual inspection, palpation, or intraoperative ultrasonography. Background characteristics and long-term outcomes of patients having ND-CLM were investigated. Results: Among 171 patients, ND-CLM were detected in 54 patients (31.6%). In patients having ND-CLM, the number of tumor was larger (P=0.0158) and the level of CEA was higher (P=0.0035) than in those without ND-CLM. Operative procedures were modified intraoperatively because of detection of ND-CLM in 23 patients (42.6 %). However , ND-CLM did not preclude curative resection in any patients. The 5-year recurrence-free (RFS) and overall survival (OS) rates in patients with ND-CLM (28.1% and 29.0%) were worse than those without ND-CLM (39.5% [p= 0.0079], 58.1% [p =0.0010]). In multivariate analysis, having ND-CLM was found to be an independent risk factor of impaired RFS (hazard ratio =1.81, p =0.0385) and OS (hazard ratio =2.06, p =0.0165 ). Conclusions: Detection of new lesions during hepatectomy negatively impacts on survival in patients undergoing surgery for colorectal liver metastases.

Exploration of tumour-infiltrating lymphocytes as a predictive biomarker for adjuvant endocrine therapy in early breast cancer

PurposeTumour-infiltrating lymphocytes (TILs) have been shown to be prognostic for disease-free survival and predictive for the benefit of chemotherapy in patients with early breast cancer, but have not been studied for endocrine therapy.Experimental designThe number of CD8-positive TILs was assessed in a subcohort of 236 patients in the Intergroup Exemestane Study. AQ After 2–3 years of adjuvant tamoxifen, AQpatients were randomized between the schemes of continuation for 5 years on tamoxifen and switching to exemestane. The numbers of CD8-positive TILs were analysed for correlations with disease-free survival (DFS) and overall survival (OS). A similar analysis was performed on 2596 patients in the TEAM trial who were randomized between the sequential scheme and the exemestane monotherapy.ResultsIn the first cohort, patients with low (below median) numbers of CD8-positive TILs had a univariate hazard ratio (HR) for DFS of 0.27 (95% CI 0.13–0.55) in favour of treatment with exemestane, whereas this benefit was not observed in patients with high numbers of CD8-positive TILs (HR 1.34, 95% CI 0.71–2.50, HR for interaction 5.02, p = 0.001). In the second cohort, patients with low numbers of CD8-positive TILs showed a benefit of exemestane treatment on recurrence-free survival (RFS HR 0.67, 95% CI 0.45–0.99), and not with above-median numbers of CD8-positive TILs (HR 0.86, 95% CI 0.59–1.26, HR for interaction 1.29, p = 0.36).ConclusionsThis study is the first to propose the number of CD8-positive TILs as potential predictive markers for endocrine therapy, with the low presence of CD8-positive TILs associated to benefit for exemestane-inclusive therapy. However, treatment-by-marker interactions were only significant in one cohort, indicating the need for further validation.

Optimal surrogate endpoint of survival for gastric cancer patients undergoing neoadjuvant chemotherapy.

141 Background: Surrogate endpoint of survival for gastric cancer patients undergoing neoadjuvant chemotherapy (NAC) has not been established yet. To determine the most optimal surrogate endpoint, we compared the validity of outcomes according to the endoscopic or histological response criteria and other histological factors in gastric cancer patients who underwent NAC. Methods: The target population in this study was 77 gastric cancer patients who underwent NAC followed by curative gastrectomy between January 2010 and December 2016. In histological response criteria, if necrosis or disappearance of the tumor was present in more than 2/3 of the primary lesion, the case was diagnosed as a histological responder. Hazard ratio (HR) for RFS in responders according to each factor was estimated, and survival curves were compared between responders and non-responders using log-rank test. Results: The number of patients in each regimen was as follows: docetaxel/cisplatin/S-1, 40; docetaxel/oxaliplatin/S-1, 16; cisplatin/S-1, 15; S-1/oxaliplatin, 4; docetaxel/S-1, 2. The endoscopic and histological response rates were 73% (56/77) and 16% (12/77), respectively. The proportions of patients with ypT0-1 and ypN0 were 17% (13/77) and 23% (18/77), respectively. HRs were 0.761 (log-rank p = 0.43) in the endoscopic response criteria, 0.879 (log-rank p = 0.77) in the histological response criteria, 0.703 (log-rank p = 0.46) in ypT0-1, and 0.121 (log-rank p = 0.001) in ypN0, respectively. Three-year RFS rates in ypN status were ypN0/1/2/3 = 93%/48%/43%/14%. Conclusions: Pathological ypN status was the most optimal surrogate endpoint of RFS for gastric cancer patients undergoing NAC. Patients with ypN0 would be expected for long relapse-free survival.

Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II-III Melanoma Adjuvant Therapy.

We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials. Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included. A two-level modeling approach was used for assessing Spearman's patient-level correlation (rho) of RFS and OS and the trial-level coefficient of determination (R²) of the treatment effects on RFS and on OS. The results were validated externally in 13 adjuvant studies without available IPD. We then tested the results on the European Organisation for Research and Treatment of Cancer (EORTC) 18071 double-blind trial comparing ipilimumab 10 mg/kg with placebo, which showed a statistically significant impact of the checkpoint inhibitor on RFS and OS. All statistical tests were two-sided. With a median follow-up of seven years, 12 of 13 trials showed a consistency between the IFN vs No IFN differences regarding RFS (hazard ratio [HR]RFS = 0.88) and OS (HROS = 0.91), but the small trial, Eastern Cooperative Oncology Group 2696, was an outlier (HRRFS = 0.72 vs HROS = 1.11). Therefore, even if rho was high, R² was low and could not reliably be estimated. Based on the 12 trials, rho remained high (0.89), and the hazard ratios for RFS and OS were strongly correlated (R² = 0.91). The surrogate threshold effect for RFS was estimated to be 0.77. For the EORTC 18071 trial, the hazard ratio for RFS was 0.75, predicting an effect of ipilimumab on OS. This was subsequently confirmed (HROS = 0.72, 95.1% confidence interval = 0.58 to 0.88, P = .001). In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS.

A randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel vs. carboplatin and paclitaxel for optimally debulked, advanced endometrial carcinoma.

5505 Background: Patients with stage III/IVA uterine cancer (UC) carry high risk of systemic and local recurrence. Chemotherapy was shown to reduce systemic recurrence, however the risk of local failure remains high. Methods: The primary endpoint of this open label, randomized phase III trial was to determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for 4 cycles (C-RT, experimental arm) reduces the rate of recurrence or death (i.e., increases recurrence-free survival, RFS) when compared to carboplatin and paclitaxel for 6 cycles (CT, control arm) in patients with stages III-IVA (&lt;2 cm residual disease) or FIGO 2009 stage I/II serous or clear cell UC and positive cytology. Secondary objectives were assessment of overall survival (OS), acute and late toxicities, and quality of life. A 28.5% reduction in the rate of recurrence or death was considered significant. Treatment randomization and analysis were stratified by gross residual tumor and age. Results: Between 6/2009 and 7/2014, 813 patients were enrolled and randomized (407 C-RT and 406-CT). Of those, 733 were eligible (344 C-RT and 360 CT), and 680 received the trial intervention (333 C-RT and 347 CT). Median follow up is 47 months. Patients characteristics were balanced between arms. There were 201 (58%) &gt; grd 3 toxicity events in the C-RT arm and 227 (63%) in the CT arm. The most common &gt; grd 3 events were myelosupression (40% vs. 52%), gastrointestinal (13% vs. 4%), metabolic (15% vs. 19%), neurological (7% vs. 6%), infectious (4% vs. 5%). Treatment hazard ratio for RFS was 0.9 (C-RT vs. CT; CI 0.74 to 1.10). C-RT reduced the incidence of vaginal (3% vs. 7%, HR = 0.36, CI 0.16 to 0.82), pelvic and paraaortic recurrences (10% vs. 21%, HR=0.43, CI 02.8 to 0.66) compared to CT, but distant recurrences were more common with C-RT vs. CT (28% vs. 21%, HR 1.36, CI 1 to 1.86). The analysis is premature for OS comparison. Conclusions: Although C-RT reduced the rate of local recurrence compared to CT; the combined modality regimen did not increase RFS in optimally debulked, stage III/IVA UC. Clinical trial information: NCT00942357.

Frequency, Characteristics and Prognostic Significance of RUNX1 mutations in Patients with Acute Myeloid Leukemia, Not Otherwise Specified

Background: Somatic mutations in RUNX1 gene have been identified in a substantial proportion of patients with de novo acute myeloid leukemia (AML). It is suggested as a new candidate molecular marker and, therefore, is suggested to be routinely performed at the diagnostic stage of AML. Despite its clinical importance, however, previous cohorts have been heterogeneous in terms of cytogenetic and molecular subtypes of AML. Here, the aim of this study was to evaluate the frequency, biologic characteristics, and prognostic significance of RUNX1 mutations focusing on patients with AML, not otherwise specified (NOS).Methods: Diagnostic samples from 202 patients with AML were analyzed for RUNX1 mutations. We excluded AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, and therapy-related AML because these entities have prognostic relevances of their own. RUNX1 mutations were detected using standard PCR techniques and direct sequencing.Results:RUNX1 mutations were found in 27 (13.4%) patients. The mutations were clustered in Runt homology domain (13, 48.1%) and transactivation domain (9, 33.3%). Frameshift mutations were most common (52.9%), followed by missense mutations (35.3%) and nonsense mutations (11.8%). As shown in Table 1, patients with RUNX1 mutations had a lower platelet count (P = 0.03), a higher rate of trisomy 8 (P = 0.02) and trisomy 13 (P = 0.039), and a trend toward older age (P = 0.063) than patients without mutations. Presence of RUNX1 mutations and NPM1 or CEBPA mutations were mutually exclusive. At the median follow-up of 12.1 months, RUNX1 mutations predicted for shorter overall survival (OS; P = 0.007) and relapse-free survival (RFS; P = 0.003). In the multivariate analysis, RUNX1 mutation was a significant marker for inferior OS (hazard ratio, 3.037; P = 0.014) and RFS (hazard ratio, 5.699; P = 0.001).Conclusion: The findings of our study further strengthen the previous data about RUNX1 mutations in AML. Furthermore, AML NOS with RUNX1 mutations is characterized by distinct biology and is associated with adverse clinical outcome. Our study supports the notion that RUNX1 mutational status would be integrated into diagnostic workup of AML, particularly for AML, NOS subgroup.Table 1Clinical and biologic features of the cohort by RUNX1 mutationsRUNX1 mutationsP -valueMutated, n (%)Wild type, n (%)Number27 (13.4)175 (86.6)Male sex17 (63.0)94 (53.7)0.489Median age, years (range)63 (14 - 80)55 (1 - 83)0.063WBC count, ¡¿109/L (median, range)7.9 (1.1 - 133.3)14.0 (0.8 - 231.3)0.636Hemoglobin, g/dL (median, range)8.6 (5.0 - 10.6)8.8 (4.1 - 17.3)0.376Platelet count, ¡¿109/L (median, range)35 (14 - 230)59 (9 - 900)0.03Blood blasts, % (median, range)29 (0 - 94)38.5 (0 - 93)0.312FAB subtypesM03 (11.1)11 (6.3)0.609M1, M221 (77.8)129 (73.7)0.831M4, M53 (11.1)27 (15.4)0.767M6, M708 (4.6)0.546Cytogenetic abnormalitiesNormal karyotype (%)11 (40.7)104 (59.4)0.106Trisomy 8 (%)5 (18.5)8 (4.6)0.02Trisomy 11 (%)1 (3.7)4 (2.3)0.823Trisomy 13 (%)3 (11.1)3 (1.7)0.039Trisomy 21 (%)1 (3.7)2 (1.1)0.866Distribution of other mutationsFLT3 -ITD5 (18.5)50 (28.6)0.39FLT3 -TKD1 (3.7)4 (2.3)0.823NPM1055 (31.4)0.002CEBPA017 (9.7)0.187MLL -PTD1 (3.7)14 (8.0)0.691 DisclosuresNo relevant conflicts of interest to declare.

Prognostic significance of p53 protein overexpression in localized gastrointestinal stromal tumors of the small intestine.

212 Background: Mutation of c-kit is a relatively early event in the tumorigenesis of gastrointestinal stromal tumors (GISTs). p53 alteration has been suggested as an additional genetic change that affects patient outcome in some studies. However there has been few studies in GISTs of the small intestine. The aim of this study was to determine the prognostic significance of p53 alterations in localized GISTs of the small intestine. Methods: We retrospectively reviewed 113 patients with completely resected localized GISTs in the small intestine who were not treated with adjuvant imatinib between 1994 and 2008. Immunohistochemical staining of CD117, CD34, S-100, SMA and p53 were performed in all patients and mutational analyses of c-kit exons 9, 11, 13 and 17 were conducted in 81 (56.6%) patients. Results: The median follow-up after diagnosis was 84 months (range, 40-146 months). Overexpression of p53 were observed in 38 patients (33.6%). p53 overexpression was strongly correlated with high mitotic index (p = 0.01) and higher risk groups based on the National Institutes of Health’s (NIH) risk category (p = 0.019). On univariate analysis, patients with p53 overexpression showed worse recurrence-free survival (RFS, p = 0.003). c-kit mutation status was not a prognostic factor (p = 0.411). Multivariate analysis indicated that p53 overexpression remained as independent poor prognostic factors for RFS (hazard ratio = 2.66, p = 0.026) as well as tumor size and mitosis. The p53 overexpression was marginally associated with poor RFS in the low or intermediate risk groups according to NIH's risk category (p = 0.081). Conclusions: Our results suggest that the p53 overexpression is an independent prognostic factor for RFS in localized GISTs of the small intestine. Additionally, p53 overexpression could be a helpful marker for selecting patients for further treatment in low or intermediate risk group patients.

The role of Cathepsin S as a marker of prognosis and predictor of chemotherapy benefit in adjuvant CRC: a pilot study

Background:The aim of this pilot retrospective study was to investigate the immunohistochemical expression of Cathepsin S (CatS) in three cohorts of colorectal cancer (CRC) patients (n=560).Methods:Prevalence and association with histopathological variables were assessed across all cohorts. Association with clinical outcomes was investigated in the Northern Ireland Adjuvant Chemotherapy Trial cohort (n=211), where stage II/III CRC patients were randomised between surgery-alone or surgery with adjuvant fluorouracil/folinic acid (FU/FA) treatment.Results:Greater than 95% of tumours had detectable CatS expression with significantly increased staining in tumours compared with matched normal colon (P>0.001). Increasing CatS was associated with reduced recurrence-free survival (RFS; P=0.03) among patients treated with surgery alone. Adjuvant FU/FA significantly improved RFS (hazard ratio (HR), 0.33; 95% CI, 0.12–0.89) and overall survival (OS; HR, 0.25; 95% CI, 0.08–0.81) among 36 patients with high CatS. Treatment did not benefit the 66 patients with low CatS, with a RFS HR of 1.34 (95% CI, 0.60–3.19) and OS HR of 1.33 (95% CI, 0.56–3.15). Interaction between CatS and treatment status was significant for RFS (P=0.02) and OS (P=0.04) in a multivariate model adjusted for known prognostic markers.Conclusion:These results signify that CatS may be an important prognostic biomarker and predictive of response to adjuvant FU/FA in CRC.

Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer

The purpose of this study was to characterize insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) expression in patients with nonsmall cell lung cancer (NSCLC). A total of 459 patients who underwent curative resection of NSCLC were studied (median follow-up duration, 4.01 years). Expression of the IR and IGF-1R protein in tumor specimens was assessed immunohistochemically using tissue microarrays. The cytoplasmic IR score was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC), whereas cytoplasmic IGF-1R score was higher in patients with SCC than those with ADC. Neither IR nor IGF-1R expression was associated with sex, smoking history, or clinical stage. Patients with positive IR or IGF-1R expression levels had poor recurrence-free (RFS) (3.8 vs 3.3 years; 3.8 vs 2.0 years, respectively), but similar overall survival (OS). Patients with high expression levels of IR and IGF-1R had shorter RFS and OS compared with those with low levels of IR and/or IGF-1R expression. Finally, a multivariate analysis revealed the impact of IR, but not of IGF-1R, as an independent predictive marker of NSCLC survival: hazard ratio (HR) for OS, 1.005 (95% confidence interval [CI], 1.001-1.010], HR for RFS, 1.005 (95% CI, 1.001-1.009), when IR score was tested as a continuous variable. Overexpression of IR predicts a poor survival among patients with NSCLC, especially those with SCC. These results might serve as future guidance to the clinical trials involving IR or IGR-1R targeting agents.

Prognostic role of ECOG performance status in patients with urothelial carcinoma of the upper urinary tract: an international study

To evaluate the prognostic role of ECOG Performance status (ECOG-PS) in a large multi-institutional international cohort of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. Data of 427 patients treated with radical nephroureterectomy at five international institutions in Asia, Europe and Northern America were collected retrospectively from 1987 to 2008. Logistic and Cox regression models were used for univariable and multivariable analyses. ECOG-PS was 0 in 272 of 427 (64%) patients. The median follow-up of the whole cohort was 32 months. The five-year recurrence-free (RFS), cancer-specific (CSS) and overall (OS) survival estimates were 71.7%, 74.9% and 68.5%, respectively, in patients with ECOG-PS 0 compared with 60.1%, 67.8%, and 51.4% respectively, in patients with ECOG-PS ≥1 (P value 0.08 for RFS, 0.43 for CSS, and <0.001 for OS, respectively). On multivariable Cox regression analyses, ECOG-PS was not an independent predictor of either RFS (hazard ratio 1.4; P = 0.107) or CSS (hazard ratio 1.2; P = 0.426) but was an independent predictor of OS (hazard ratio 1.5; P = 0.03). In this large multicentre international study, ECOG-PS was not significantly associated with RFS and CSS. Conversely we find a strong association with survival 1-month after surgery and OS. Further research is needed to ascertain the additive prognostic role of ECOG-PS in well-designed prospective multicentre studies.

Abstract 1122: Insulin receptor expression and survival of patients with non-small cell lung cancer

Abstract Purpose: The purpose of this study was to characterize insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) expression in patients with non-small cell lung cancer (NSCLC). Methods: A total of 459 patients who underwent curative resection of NSCLC were studied (median follow-up duration, 4.01 years). Expression of the IR and IGF-1R protein in tumor specimens was assessed immunohistochemically using tissue microarrays. Results: The cytoplasmic IR score was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC) whereas cytoplasmic IGF-1R was higher in patients with SCC than those with ADC. Neither IR nor IGF-1R expression was associated with sex, smoking history, or clinical stage. Patients with positive IR or IGF-1R expression levels had poor recurrence-free (3.8 vs. 3.3 years; 3.8 vs. 2.0 years, respectively) but similar overall survival durations. Patients with high expression levels both IR and IGF-1R had shorter recurrence-free and overall survival compared to those with low levels of IR and/or IGF-1R expression. IGF-1R and IR expressions were negatively correlated with survival duration of patients with ADC and SCC, respectively. Finally, a multivariate analysis revealed the impact of IR, but not IGF-1R, as an independent prognostic predictor of survival: hazard ratio (HR) for OS, 1.005 (95% confidence interval [CI], 1.001 – 1.010], HR for RFS, 0.608 (95% CI, 1.001 – 1.009) when tested as a continuous variable. Conclusions: Overexpression of IR, but not IGF-1R, appears to foretell a poor survival among patients with NSCLC, especially those with SCC. Thus, expression of IR has a negative prognostic value and future clinical trials with therapy interventions of IR regulation should be under the consideration for this patient population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1122. doi:10.1158/1538-7445.AM2011-1122

Long-term follow-up of women enrolled in a randomized trial of adjuvant chemotherapy for early stage ovarian cancer (ICON1)

5509 Background: ICON1 and a meta-analysis of all relevant trials demonstrated an improvement in 5 year recurrence-free and overall survival (RFS and OS) for women with early-stage epithelial ovarian cancer (ES EOC) treated with adjuvant chemotherapy compared to no adjuvant chemotherapy. We aimed to determine if this initial benefit is maintained long-term and whether benefit is different with different risk groups of patients defined by stage, grade and histology. Method: 477 women with ES EOC were recruited from centres in Italy (271 women) UK (195) Switzerland (11) between August 1991 and January 2000. 5-year results were presented at ASCO 2001. Systematic long-term follow up was planned and completed in May 2006. Results: With a median follow-up of 9.2 years, 168 women have developed recurrent disease or died and 144 women have died. The Hazard Ratio (HR) for RFS of 0.70 in favour of adjuvant chemotherapy (95% CI 0.52–0.95 p= 0.023) translated into an improvement of 10-year absolute RFS of 10% from 57 to 67%. For OS, HR was 0.74 (95% CI 0.53–1.02 p= 0.066), a corresponding improvement in 10-year absolute OS of 8% from 64% to 72%. 26% of patients died from causes other than ovarian cancer. Stage I patients were grouped as low (Ia, grade 1), medium (Ia grade 2, Ib or Ic grade 1) and high risk (Ia, grade 3, Ib or IC grade 2 or 3, any clear cell). The test of interaction between risk groups and adjuvant treatment for RFS and OS was 0.055 and 0.13, respectively. The HR, 95%CI and p value are summarised in the table . Conclusions The long-term benefit of adjuvant treatment on RFS is confirmed. There is clear evidence that adjuvant chemotherapy reduces the risk of recurrence/death or death alone in high-risk patients but not in the low-risk group. [Table: see text] [Table: see text]

Gene Mutations as Predicitive Markers for Postremission Therapy in Younger Adults with Normal Karyotype AML.

Background: Mutations in the genes encoding NPM1, FLT3 (FLT3 ITD, FLT3 TKD), CEBPA, MLL (PTD) and NRAS have been identified as molecular markers in acute myeloid leukemia (AML) exhibiting a normal karyotype. Most recent studies focused on the prognostic value of single markers not taking into account their potential interactions. In addition, little is known about the predictive value of these markers on postremission therapy.Aims: To evaluate the prognostic impact of NPM1, FLT3, CEBPA, MLL and NRAS gene mutations on response to induction therapy, relapse-free (RFS) and overall survival (OS) as well as the predictive impact of these mutations on RFS and OS following different postremission therapies.Methods: Patients [16 to 60 years of age] were entered on four AMLSG treatment trials [AML-2/95, AML-1/99, AML HD93, AML HD98A]. As a consistent feature, in all four trials a genetic randomization was performed assigning all patients with an HLA-matched family donor (MRD) to allogeneic stem cell transplantation (SCT) in first complete remission (CR). Leukemia cells were analyzed for mutations in the above genes as previously described.Results: Between 1993 and 2004, 872 patients exhibiting a normal karyotype were registered. Median age was 48 years; median follow-up time was 49 months. Mutations were identified as follows (total number of samples analyzed; incidence of mutations): NPM1 (n=526; 53%), FLT3-ITD (n=531; 31%), FLT3-TKD (n=617; 11%), CEBPA (n=509; 14%), MLL-PTD (640; 8%), and NRAS (641; 13%). CR rate was 76%. In a logistic regression model, the NPM1+/FLT3-ITD- (p<.0001) and the CEBPA+ genotypes (p=0.05) were associated with induction success. Of 666 patients achieving a CR after induction therapy, 171 had a MRD and 143 (84%) of these received an allogeneic SCT in first CR. In survival analyses, the variable “availability of a MRD” was included on a strict intent-to-treat basis. Cox proportional hazard models for RFS and OS revealed age <48 years (hazard ratio (HR) 0.72 and 0.62, respectively), availability of a MRD (HR 0.62 and 0.75), the CEBPA+ (HR 0.42 and 0.36) and the NPM1+/FLT3-ITD- (HR 0.34 and 0.43) genotype as prognostic factors. To better define the role of allogeneic SCT in first CR, subgroup analyses were performed according to the combined FLT3-ITD and NPM1 mutation status (NPM1+/FLT3-ITD- versus all other combinations). These analyses revealed a marked difference in HR estimation for the variable “availability of a MRD”. In the NPM1+/FLT3-ITD- subgroup, HR for RFS and OS were 0.89 (95%-CI 0.49–1.64) and 0.93 (95%-CI 0.51–1.67) translating into a nearly equivalent RFS after 4 years of 61% (MRD) and 57% (no MRD). In contrast, in the subgroup defined by all other combinations of FLT3-ITD and NPM1 mutations, HR for RFS and OS were 0.56 (95%-CI 0.39–0.81) and 0.69 (95%-CI 0.48–0.98) translating into a marked difference in 4 years RFS of 47% (MRD) and 23% (no MRD).Conclusions: Specific genotypes emerge as highly significant prognostic factors for response to induction therapy and for survival in AML patients exhibiting a normal karyotype. The genotypic marker constellation NPM1+/FLT3-ITD- also fulfils the criteria of a predictive marker indicating a strong beneficial effect of allogeneic SCT in first CR only in the subgroup of patients without the NPM1+/FLT3-ITD- marker constellation.

Tumor-Specific Expression of Vascular Endothelial Growth Factor Receptor 2 but Not Vascular Endothelial Growth Factor or Human Epidermal Growth Factor Receptor 2 Is Associated With Impaired Response to Adjuvant Tamoxifen in Premenopausal Breast Cancer

Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance. Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors. VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER-positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor-positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status. Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor-positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.