Prognostic Groups Of Patients Research Articles

Determinants of prolonged survival for breast cancer patient groups with leptomeningeal metastasis (LM).

The study aimed to assess factors affecting survival of breast cancer patients suffering leptomeningeal metastasis (LM) and to compare survivals in patients with LM as the first and only site of metastases at presentation to patients with LM and metastases in other organs, along with selecting a patient group which had the best survival outcomes. Subject groups consisted of 187 patients consecutively referred during 1999-2015. A Cox proportional hazards model was used to identify factors associated with prolonged survival from LM. The Cox prognostic index was created to identify the group of patients with the most favorable prognosis. Median survival for all patients and for those with LM as the first site of metastases at presentation was 17 weeks and 1 year-survival was 15 and 16%, respectively. Factors beneficially affecting survival were: KPS ≥ 70, older age, biological subtype ER/PR+HER2-, systemic treatment, intrathecal treatment and radiation therapy. Based on these factors, 4 prognostic groups were found, with the most favorable group being 24 LM patients with median survival of 9.6months. In this group, all patients were treated systemically and all were irradiated, 88% had KPS ≥ 70, about 80% had luminal breast cancer, 75% were treated intrathecally and 58% were more than 53years old. Out of 4 prognostic groups of patients with LM, the most favorable group was selected. The median survival of breast cancer patients with the leptomeninges as the only site of metastases was comparable to those who had metastases in the leptomeninges and in other organs.

Significance of MMP-9 expression and MMP-9 polymorphism in prostate cancer.

The aim of the study was to assess the expression of the MMP-9 gene and -1562 C/T polymorphism in MMP-9 gene promoter in relation to clinicopathological parameters in predicting the clinical outcome of prostate cancer patients. A total of 82 patients with histopathologically diagnosed prostate cancer were enrolled in the study. MMP-9 gene expression was assessed by reverse transcription-PCR method. MMP-9 (-1562 C/T) polymorphism variants were determined by the polymerase chain reaction-based restriction fragment length polymorphism method. MMP-9 expression and MMP-9 -1562 polymorphism variants in relation to disease pathological stage (P = 0.006; P <0.0001, respectively), as well as to prognostic group (P = 0.019; P <0.0001, respectively), were statistically significant. Only MMP-9 -1562 polymorphism variants in relation to tumor differentiation grade (P = 0.044) were found to be statistically significant. Positive MMP-9 gene expression was associated with 5-year survival rate of prostate cancer patients with pathological stage III (P = 0.036) and for the patients in prognostic group III (P = 0.012). Patients with tumor differentiation grade G2 and with the identified CC variant had a significantly longer survival time than patients with the identified TT variant (P = 0.007). MMP-9 gene expression and MMP-9 -1562 polymorphism variants were associated with prostate cancer pathological stage and prognostic group. MMP-9 -1562 polymorphism CC variant was associated with prostate cancer tumor differentiation grade. Five-year survival analysis showed the relationship between MMP-9 gene expression and pathological stage III, as well as prognostic group III, whereas MMP-9 -1562 polymorphism variants, with tumor differentiation grade G2.

Clinical Usefulness of Double Biomarkers 18F-Flurodeoxyglucose-Positron Emission Tomography and Carbohydrate Antigen 19-9 for Survival Prediction in Locally Advanced Pancreatic Cancer Patients Treated with Chemoradiation Therapy

To investigate the clinical significance of 18F-Flurodeoxyglucose-positron emission tomography (FDG-PET) parameters and carbohydrate antigen 19-9 (CA 19-9) levels in stratifying prognostic groups in patients with locally advanced pancreatic cancer after concurrent chemoradiotherapy (CRT) From our institutional database, we selected 257 patients with locally advanced pancreatic cancer who underwent both pretreatment 18F-FDG PET and CA 19-9 test, and received concurrent CRT between January 2004 and December 2011. The maximum standardized uptake value (SUVmax) was calculated at regions of primary tumors from pre-CRT and post-CRT FDG-PETs. SUV parameters (pre- and post-CRT SUVmax), SUV decline rate (%), CA 19-9 levels (pre- and post-CRT CA 19-9), and CA 19-9 decline rate (%) were analyzed for comparing radiologic response and survival outcomes (progression-free survival (PFS), overall survival (OS)). Median OS and PFS were 14.6 months and 8.8 months from the date of first diagnosis, respectively, at a median follow-up time of 14.2 months (range, 2.3-133.8 months). Radiologic responses after CRT (complete or partial response) were firstly obtained in 17% of the patients (n=43). Of the 164 patients with recurrences after CRT, distant metastasis (DM) was the most common (n=141, 86%), followed by local recurrence (LR) (n=12, 7%), and LR+DM (n=11, 7%). Additional surgical resection, maintenance chemotherapy, post-CRT CA 19-9 <66, and CA 19-9 decline ratio ≥91.2% were independent predictors of favorable PFS (p=<0.001, <0.001, 0.001, and 0.003), and pre-CRT CA 19-9 <760, CA 19-9 decline ratio ≥91.2% were independent predictors of favorable OS (p=0.017, <0.001) in multivariate analysis. For the PET parameters, SUV decline ≥63% was the most significant prognostic factor (p=0.029 for PFS, 0.017 for OS). Patients with SUV decline ≥63% were included in the responder group more than in the non-responder group (12% vs. 2%, p=0.057). We also divided patients into 4 risk groups according to the number of positive favorable factors (SUV decline ratio ≥63%, pre-CRT CA 19-9 <760 (for OS groups) or post-CRT CA 19-9 <66 (for PFS groups), and CA 19-9 decline ratio ≥91.2%) (0: high-risk, 1: intermediate high-risk, 2: intermediate low-risk, 3: low risk). The low-risk group showed significantly favorable PFS than other groups (median 59.4 months, p=0.001, 0.014, and 0.005, respectively). The low-risk group also showed the most favorable OS than others (median 85.4 months, p=0.020, 0.043, and 0.109, respectively). In patients with locally advanced pancreatic cancer, the use of a combination of double biomarkers, SUVmax and CA 19-9, appears useful in predicting survival outcomes after CRT. In other words, three prognostic factors such as SUV decline ratio, pre or post-CRT CA 19-9, and CA 19-9 decline ratio seem to have substantial advantages over single-parameter by facilitating better treatment selection for locally advanced pancreatic tumors.

The sarculator stratified prognosis of patients with high-risk soft tissue sarcomas (STS) of extremities and trunk wall treated with perioperative chemotherapy in a randomised controlled trial (RCT).

11016 Background: Patients with extremity and trunk wall STS with high malignancy grade and size larger than 5cm are considered at high risk of death, but in fact this risk varies broadly depending on histologic subtype and size. The Sarculator, a nomogram for STS, can improve prognostic assessment of these patients. This tool was evaluated for stratifying risk of distant metastasis (DM) and overall survival (OS) in a RCT investigating perioperative chemotherapy. Methods: High-risk STS patients were randomly assigned to receive either three cycles of preoperative chemotherapy with epirubicin (120 mg/m2) and ifosfamide (9 g/m2) or the same three preoperative cycles followed by two further postoperative cycles. The Sarculator was used to stratify patient risk according to predicted 10-year cumulative incidence of DM and OS rates. Results: The Sarculator identified three different prognostic groups of patients at low (N = 101), intermediate (N = 102), and high (N = 107) risk. Cumulative incidence of DM was 0.26 (SE: 0.04), 0.31 (SE: 0.05), and 0.48 (SE: 0.05) for low, intermediate, and high risk patients, respectively. Similarly, OS rates were 0.78 (95%CI 0.68-0.85), 0.63 (95%CI 0.53-0.72), and 0.42 (95%CI 0.32-0.52), respectively. Patients in the low risk group were at significantly lower risk of death compared to those in the intermediate (HR 0.51, 95%CI 0.34-0.78, P = 0.002) and high (HR 0.28, 95%CI 0.17-0.46, P &lt; 0.001) risk groups. Subgroup analysis performed by jointly considering these three groups and the two study arms did not identify statistically significant survival differences between the treatment arms within each risk category. Conclusions: Patients with high-risk STS included in this RCT were not a homogeneous population. The Sarculator identified different risk groups for DM and OS even in patients included in a RCT investigating perioperative treatments. This tool should be considered for redefining high-risk STS and stratifying patient risk in future RCT investigating perioperative chemotherapy. Clinical trial information: 2004-003979-36.

Estimating Survival After Salvage Surgery for Recurrent Oral Cavity Cancer

Locoregional recurrence of oral cavity squamous cell carcinoma (OCSCC) continues to be a life-threatening and difficult clinical situation. Salvage surgery can result in significant morbidities, and survival following recurrence is poor. To outline prognostic factors influencing overall survival (OS) following salvage surgery for OCSCC to guide management of treatment for patients with locoregionally recurrent disease. The medical records of 293 patients presenting to the London Health Sciences Center with locoregionally recurrent OCSCC between October 5, 1999, and May 2, 2011, were retrospectively reviewed. The primary outcome was OS from salvage treatment to last follow-up or death. Univariate analyses were carried out using the Cox proportional hazards regression model. A recursive partitioning analysis was used to create risk groups based on prognosis. Analysis was conducted from December 8, 2015, to February 26, 2016. Of the 293 patients evaluated, 59 (20%) had recurrence identified after their initial OCSCC treatment; 39 (66%) were men, and the mean (SD) age at diagnosis was 62.2 (11.8) years. Thirty-nine (66%) of these patients underwent salvage surgery for locoregional recurrence with curative intent. Five-year OS from the time of salvage surgery was 43%. Recursive partitioning analysis identified 3 risk groups: (1) high risk (patients who received adjuvant chemoradiotherapy or radiotherapy after initial surgery) with 5-year OS rate of 10% (hazard ratio [HR], 9.41; 95% CI, 2.68-33.04), (2) intermediate risk (previous surgery alone, age ≥62 years) with a 5-year OS rate of 39% (HR, 2.95; 95% CI, 0.86-10.09), and (3) low risk (previous surgery alone, age <62 years) with 5-year OS rate of 74%. This recursive partitioning analysis identified 3 prognostic groups in patients undergoing salvage surgery for recurrent OCSCC. The marked differences in survival between these groups should be taken into consideration when counselling and managing treatment for patients with locoregionally recurrent disease.

Molecular-Based Recursive Partitioning Analysis Model for Glioblastoma in the Temozolomide Era

There is a need for a more refined, molecularly based classification model for glioblastoma (GBM) in the temozolomide era. To refine the existing clinically based recursive partitioning analysis (RPA) model by incorporating molecular variables. NRG Oncology RTOG 0525 specimens (n = 452) were analyzed for protein biomarkers representing key pathways in GBM by a quantitative molecular microscopy-based approach with semiquantitative immunohistochemical validation. Prognostic significance of each protein was examined by single-marker and multimarker Cox regression analyses. To reclassify the prognostic risk groups, significant protein biomarkers on single-marker analysis were incorporated into an RPA model consisting of the same clinical variables (age, Karnofsky Performance Status, extent of resection, and neurologic function) as the existing RTOG RPA. The new RPA model (NRG-GBM-RPA) was confirmed using traditional immunohistochemistry in an independent data set (n = 176). Overall survival (OS). In 452 specimens, MGMT (hazard ratio [HR], 1.81; 95% CI, 1.37-2.39; P < .001), survivin (HR, 1.36; 95% CI, 1.04-1.76; P = .02), c-Met (HR, 1.53; 95% CI, 1.06-2.23; P = .02), pmTOR (HR, 0.76; 95% CI, 0.60-0.97; P = .03), and Ki-67 (HR, 1.40; 95% CI, 1.10-1.78; P = .007) protein levels were found to be significant on single-marker multivariate analysis of OS. To refine the existing RPA, significant protein biomarkers together with clinical variables (age, Karnofsky Performance Status, extent of resection, and neurological function) were incorporated into a new model. Of 166 patients used for the new NRG-GBM-RPA model, 97 (58.4%) were male (mean [SD] age, 55.7 [12.0] years). Higher MGMT protein level was significantly associated with decreased MGMT promoter methylation and vice versa (1425.1 for methylated vs 1828.0 for unmethylated; P < .001). Furthermore, MGMT protein expression (HR, 1.84; 95% CI, 1.38-2.43; P < .001) had greater prognostic value for OS compared with MGMT promoter methylation (HR, 1.77; 95% CI, 1.28-2.44; P < .001). The refined NRG-GBM-RPA consisting of MGMT protein, c-Met protein, and age revealed greater separation of OS prognostic classes compared with the existing clinically based RPA model and MGMT promoter methylation in NRG Oncology RTOG 0525. The prognostic significance of the NRG-GBM-RPA was subsequently confirmed in an independent data set (n = 176). This new NRG-GBM-RPA model improves outcome stratification over both the current RTOG RPA model and MGMT promoter methylation, respectively, for patients with GBM treated with radiation and temozolomide and was biologically validated in an independent data set. The revised RPA has the potential to contribute to improving the accurate assessment of prognostic groups in patients with GBM treated with radiation and temozolomide and to influence clinical decision making. clinicaltrials.gov Identifier: NCT00304031.

The role of histology, grading, location of tumour and ploidy in evaluation of outcome in patients with liposarcoma.

Department of Tumour Pathology, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Kraków, Poland The review of literature indicates that several clinico-morphological factors such as location of the primary tumour as well as its size, histologic subtype, and grade or even selected molecular changes may significantly affect survival of liposarcoma (LPS) patients. Data concerning prognostic importance of DNA ploidy status in LPS cells are extremely limited and results of flow cytometry (FCM) studies have never been compiled with the current classification of malignant adipocytic tumours. Based on evaluation of material from 54 liposarcomas which was available for both histological and FCM analysis, we distinguished four prognostic groups of patients. The best prognosis was noticed for diploid and grade G1 well-differentiated or myxoid liposarcomas localised on extremities. None of the patients with lipoma-like WDLPS and myxoid liposarcoma grade 1 metastasised, while metastases were observed among patients with dedifferentiated LPS (70% of 5-year MFS) and cellular myxoid or round cell liposarcoma (20% of 5-year MFS, only). The metastasis-free survival curves for the above mentioned groups of patients differed significantly (p = 0.00001).

The Frequency of Occurrence of Minimal Residual Disease into Different Prognostic Groups of Patients with Chronic Lymphocytic Leukemia

Background. It is known, that genetic factors and the absence of minimal residual disease (MRD) are strongly affecting prognosis of chronic lymphocytic leukemia (CLL).Aim. To determine the influence of genetic abnormalities (GA) on achieving MRD-negative remissions in patients with CLL.Methods. Twenty-four adult pts (median age 57 years, range 35-67; male 14, female 10) with newly diagnosed CLL were included. The CLL was diagnosed according to the standard basic examination (complete blood count with differential, multicolor flow cytometry (MFC) of blood and bone marrow (BM), lymph node and BM immunohistochemistry (IHC), computered tomography). Cytogenetic studies were performed on blood samples using standard GTG-method. Interphase FISH analyses were performed according to the manufacturer's protocol using DNA probes: LSI 13(RB1)13q14, LSI ATM (11q22), CEP12, LSI TP53 (17p13.1) (Abbott). Immunophenotype (IFT) of CLL cells assessed with combinations: CD3/CD19, CD19/CD5, CD19/CD11c, CD19/CD20, CD19/CD22, CD19/CD23, CD19/CD25, CD19/CD38, CD19/CD43, CD19/CD81, CD19/HLA-DR, and CD19/CD5/CD23. We have used NCI revised guidelines (Hallek M, et al., 2008) for treatment initiation and assessment of response after completion of primary therapy with rituximab-based regimens (FCR or RB). All patients treated subsequently with rituximab maintenance. MRD was detected by MFC.Results. The frequency of GA in CLL was 50.0% (12/24): 15.0% (3/20) - by conventional karyotyping, 47.8% (11/23) - by FISH analyses and 9.5% (2/21) - using both methods. Stratification of patients into prognostic groups based on identified GA. Favorable prognosis (Group 1) - patients with del(13q) (n = 5); neutral prognosis (Group 2) - normal karyotype (n = 12) or trisomy of chromosome 12 (n = 3); unfavorable prognosis (Group 3) - del(11q) (n = 3) or the complex karyotype (n = 1).Statistically significant differences in the frequency of achieving MRD-negative remissions between FCR (5/11) vs. RB (5/13) were not detected (p<0.05).Complete remissions (CR) were reached in 37.5% (9/24) pts, partial remissions (PR) - 62.5% (15/24). The MRD-negative remissions were reached in 10 patients: in Group 1 - 2/5 (40%; CR - 1), in Group 2 - 5/15 (33.3%, CR - 6), in Group 3 - 75.0% (3/4; CR - 2).Statistically significant differences in PFS were detected between MRD-negative vs. MRD-positive groups (p=0.03). Median PFS in MRD-negative has not been reached. Median PFS MRD-positive was 33.1 month.Conclusions. Further researches aimed at examining the relationship between the presence or absence of MRD and genetic prognostic groups, will help to understand the most important factors affecting the overall and progression-free survival. DisclosuresNo relevant conflicts of interest to declare.

Phenotypic Characteristics of Tumor Cells in Patients with Chronic Lymphocytic Leukemia into Different Prognostic Groups

Background. The presence or absence of certain cluster of differentiation on the tumor cells of chronic lymphocytic leukemia may affect the course of the disease. Influence of genetic abnormalities on the prognosis of the disease was also proved.Aim. To determine the relationship of the phenotype of tumor cells with genetic prognostic groups of patients with chronic lymphocytic leukemia (CLL).Methods. Thirty-five adult pts (median age 61 year, range 44 - 82; male 24, female 11) with diagnosed CLL were included in the study. The CLL was diagnosed according to the standard basic examination (complete blood count with differential, multicolor flow cytometry (MFC) of blood and bone marrow (BM), lymph node and BM immunohistochemistry (IHC), computered tomography). Cytogenetic studies were performed on blood samples using standard GTG-method. Interphase FISH analyses were performed according to the manufacturer's protocol using DNA probes: LSI 13(RB1)13q14, LSI ATM (11q22), CEP12, LSI TP53 (17p13.1) (Abbott). Immunophenotype (IFT) of CLL cells assessed with combinations: CD3/CD19, CD19/CD5, CD19/CD11c, CD19/CD20, CD19/CD22, CD19/CD23, CD19/CD25, CD19/CD38, CD19/CD43, CD19/CD81, CD19/HLA-DR, and CD19/CD5/CD23.Results. Stratification of patients into prognostic groups was performed based on identified GA. Favorable prognosis - patients with del(13q) (n = 9); neutral prognosis - normal karyotype (n = 14) or trisomy of chromosome 12 (n = 4); unfavorable prognosis - del(17p) (n = 3), del(11q) (n = 3) and the complex karyotype (n = 2).Expression of CD20 was lower, and CD38 - higher in adverse group (51.0±16.31 % and 36.02±10.35 %, respectively) versus neutral or favorable groups (CD20+ - 83.17±5.52 % and 84.41±4.7 %; CD38 - 10.46±4.8 %, and 12.44±4.1 %, respectively, p <0.05). The expression level of CD20 and CD38 did not differ between the neutral and favorable groups.The number of patients with CD38 expression more than 10% was higher in the unfavorable group (7/8) versus favorable (4/8) (p <0.05). At the same time overexpression of CD38 was observed more frequently in patients with a lack of expression of CD23 on CD5 tumor cells (CD5+CD23-) (p<0.05).Expression of HLA-DR was higher in patients with MRD-negative remissions (3/4) versus patients with MRD-positive remissions (1/8) (p<0.05).Conclusions. The study of the influence of various factors on the prognosis and course of CLL requires a comprehensive approach. Further researches are needed to determine the relationship between CLL affecting factors like genetic abnormalities, phenotypic characteristics of the tumor cells and MRD. DisclosuresNo relevant conflicts of interest to declare.

Optimized Voronoi compartment determination using machine-learning to identify prognostic groups of patients based on cellular behavior in treated AML

Optimized Voronoi compartment determination using machine-learning to identify prognostic groups of patients based on cellular behavior in treated AML

Early post-operative magnetic resonance imaging in glioblastoma: correlation among radiological findings and overall survival in 60 patients.

To evaluate early post-operative magnetic resonance (EPMR) as a prognostic tool after resection of glioblastoma. Sixty EPMR examinations were evaluated for perioperative infarct, tumour growth between diagnosis and EPMR, contrast enhancement pattern, and extent of resection (EOR). The EOR was approached with the subjective evaluation of radiologists and by quantifying volumes. These parameters were tested as predictors of survival using the Kaplan-Meier method. Contrast enhancement was found in 59 patients (59/60; 98 %). Showing a thin-linear pattern of enhancement was the most favourable finding. Patients with this pattern survived longer than patients with thick-linear (median overall survival (OS) thin-linear=609 days; thick-linear=432 days; P = .023) or nodular (median OS = 318 days; P = .001) enhancements. The subjective evaluation of the EOR performed better than its quantification. Patients survived longer when resection was total (median OS total resection=609 days; subtotal=371 days; P = .001). When resection was subtotal, patients survived longer if it was superior to 95 % (median OS resection superior to 95 %=559 days; inferior to 95 %=256 days; P = .034). EPMR provides valuable prognostic information after surgical resection of glioblastomas. A thin-linear pattern of contrast enhancement is the most favourable finding. Further prognostic stratification may be obtained by assessing the EOR. • Some kind of contrast enhancement may be found in most EPMR examinations. • Thin-linear enhancements in the EPMR may be considered benign findings. • The EOR evaluated in the EPMR may stratify prognostic groups of patients. • The subjective evaluation of the EOR performs slightly better than its quantification.

DNA repair prognostic index modelling reveals an essential role for base excision repair in influencing clinical outcomes in ER negative and triple negative breast cancers.

Stratification of oestrogen receptor (ER) negative and triple negative breast cancers (TNBCs) is urgently needed. In the current study, a cohort of 880 ER- (including 635 TNBCs) was immuno-profiled for a panel of DNA repair proteins including: Pol β, FEN1, APE1, XRCC1, SMUG1, PARP1, BRCA1, ATR, ATM, DNA-PKcs, Chk1, Chk2, p53, and TOPO2. Multivariate Cox proportional hazards models (with backward stepwise exclusion of these factors, using a criterion of p < 0.05 for retention of factors in the model) were used to identify factors that were independently associated with clinical outcomes. XRCC1 (p = 0.002), pol β (p = 0.032) FEN1 (p = 0.001) and BRCA1 (p = 0.040) levels were independently associated with poor BCSS. Subsequently, DNA repair index prognostic (DRPI) scores for breast cancer specific survival (BCSS) were calculated and two prognostic groups (DRPI-PGs) were identified. Patients in prognostic group 2 (DRPI-PG2) have higher risk of death (p < 0.001). Furthermore, in DRPI-PG2 patients, exposure to anthracycline reduced the risk of death [(HR (95% CI) = 0.79 (0.64-0.98), p = 0.032) by 21-26%. In addition, DRPI-PG2 patients have adverse clinicopathological features including higher grade, lympho-vascular invasion, Her-2 positive phenotype, compared to those in DRPI-PG1 (p < 0.01). Receiver operating characteristic (ROC) curves indicated that the DRPI outperformed the currently used prognostic factors and adding DRPI to lymph node stage significantly improved their performance as a predictor for BCSS [p < 0.00001, area under curve (AUC) = 0.70]. BER strongly influences pathogenesis of ER- and TNBCs. The DRPI accurately predicts BCSS and can also serve as a valuable prognostic and predictive tool for TNBCs.

Dermoscopy for melanoma: don't forget to take a photo.

ORIGINAL ARTICLE, p 1269 After the first1 then, the more recent, second report on the MSLT1 trial2 it became clear that sentinel lymph node (SLN) biopsy in cutaneous melanoma cannot be considered as a therapeutic method despite the authors' conclusions.3 However, the histopathological status of the SLN has been clearly correlated with outcome and is, nowadays, considered to be a highly indicative prognostic indicator.4 5 SLN status in melanoma de facto creates new stage I–II and new stage III prognostic groups of patients with a survival rate at 5 years of approximately 91% and 41%, respectively. Better evaluation of the prognosis is part of the medical information that our patients deserve from us. This legitimates the fact that this procedure can be offered to selected patients with melanoma as a staging option after their informed consent. Moreover, relatively good prognosis of patients who have an SLN‐negative biopsy legitimates a nonaggressive follow‐up scheme mainly based on clinical examination as recommended in many international guidelines. In contrast, the high recurrence risk of patients who are SLN‐positive justifies the inclusion of these patients in adjuvant treatment clinical trials in the expectancy of, lastly, finding a significantly efficient treatment as well as more invasive (and irradiating) follow‐up policies with repeated imaging procedures. This latter option, recently reinforced by the favourable results of new therapeutic options offered in the case of visceral melanoma metastases, is probably, at least for immunotherapeutic options, more efficient in patients with good overall status.

Nottingham Clinico-Pathological Response Index (NPRI) after neoadjuvant chemotherapy (Neo-ACT) accurately predicts clinical outcome in locally advanced breast cancer.

There is a need to identify more sensitive clinicopathologic criteria to assess the response to neoadjuvant chemotherapy (Neo-ACT) and guide subsequent adjuvant therapy. We performed a clinicopathologic assessment of 426 patients who had completed Neo-ACT for locally advanced breast cancer (LABC) with a median follow-up of 70 months. Patients were divided into a training set treated with anthracycline combination chemotherapy (n = 172); an internal validation set treated with anthracycline and taxane (n = 129); and an external validation set treated with anthracycline with or without taxane (n = 125). A multivariate Cox regression model demonstrated the absence of fibrosis, presence of lymphovascular invasion, increasing number of lymph node metastases, and administration of hormone therapy were significantly associated with short breast cancer-specific survival (BCSS) and disease-free survival (DFS); Ps < 0.01, while reduction of tumor size was associated with DFS (P = 0.022). Nottingham Clinico-Pathological Response Indexes (NPRI) were calculated, and four prognostic groups (NPRI-PG) were identified. Patients in prognostic group 2 (NPRI-PG2) for BCSS (66 of 172; 38.4%) have the same prognosis as those who achieved pathologic complete response (pCR; NPRI-PG1; 15%). Receiver-operating characteristic (ROC) curves indicated that the NPRI outperformed the currently used prognostic factors and adding the NPRI improved their performance as a predictor for both BCSS (area under the curve [AUC], 0.88) and DFS (AUC, 0.87). The NPRI predicts BCSS and DFS, with a higher sensitivity than pCR. The NPRI can also improve the sensitivity and specificity of clinicopathologic response as a study endpoint, for assessing response to Neo-ACT, and can serve as a valuable tool for the discovery of future predictive molecular markers.

Comparison of pathologic stage in patients receiving esophagectomy with and without preoperative chemoradiation therapy for esophageal SCC.

The prognostic value for the post-chemoradiation therapy (CRT) pathologic stage is uncertain. The purpose of this study was to compare the pathologic stage in patients undergoing esophagectomy with and without preoperative CRT for esophageal squamous cell carcinoma (ESCC). This study retrospectively reviewed the data from 2151 patients with ESCC who underwent esophagectomy with or without preoperative CRT between 2008 and 2011 in Taiwan. Patients were divided into 2 groups. Group A consisted of patients treated with primary surgery without prior treatments (n=1301), and group B consisted of patients receiving preoperative CRT followed by esophagectomy (n=850). In group A, 679 patients received surgery alone, 92 received postoperative chemotherapy, 416 received postoperative chemoradiation therapy, and 114 received postoperative radiation therapy. In group A, the 3-year survival rates by pathologic stage were 82.2% for stage 0, 67.6% for stage I, 50.7% for stage II, 21.5% for stage III, and 14.8% for stage IV (P<.001). In group B, the 3-year survival rates of post-CRT pathologic stages 0, I, II, III, and IV were 59.4%, 46.0%, 40.3%, 19.1%, and 8.2%, respectively (P<.001). In multivariate analysis, the pathologic T, N, and M were all independent prognostic factors in both group A (esophagectomy alone) and B (CRT plus esophagectomy). The current, 7th edition of the esophageal TNM staging system could adequately stratify prognostic groups in patients with squamous cell carcinoma who were treated with preoperative CRT and esophagectomy.

Abstract 5179: Context-specific dependence of ovarian cancer on IKKϵ and CHEK1

Abstract Background: The IκB kinase, IKKϵ, was previously identified as an oncogene in breast cancer and was associated with poor clinical outcome in ovarian cancer. Recently, we demonstrated that IKKϵ is a key regulator of invasion and metastasis in ovarian cancer. A highly specific inhibitor of IKKϵ is not readily available for use as a tool compound to study pathway interactions in the preclinical setting. Therefore, we utilized dual shRNA technique to create IKKϵ-matched cell line pairs and performed sensitization screens to identify the key molecular targets influenced by the loss of IKKϵ expression. Results: We screened a previously established shRNA library targeting the human kinome, and identified 65 genes that further inhibited the survival of ovarian cancer cells in combination with IKKϵ depletion. In order to evaluate potential clinical significance associated with their overexpression, we examined the expression levels of these 65 genes in TCGA ovarian serous cystadenocarcinoma dataset. Strikingly, CHEK1 was overexpressed in 100% of TCGA ovarian cancers with a cut-off of 1.5 fold change compared to normal ovarian surface epithelium. Interestingly, CHEK1 loss also sensitized IKKϵ depleted A2780, a wild-type p53 containing ovarian cancer cell line. Next, we investigated whether chemical inhibitors could recapitulate the effects of shRNAs, although they are less specific than RNAi and are unable to interrogate kinase-independent functions of cellular proteins. Consistent with the initial screening methodology, inhibition of IKKϵ and CHEK1 activities by BX795 and PF00477736, respectively, in 6 ovarian cancer cell lines was critical to the cooperative decrease in cell viability. Thus, the co-inhibition of IKKϵ and CHEK1 activities, regardless of p53 status, was more effective in killing ovarian cancer cells than single treatment. The inhibition of IKKϵ activity alone induced dramatic G2/M arrest in all 6 cell lines without inducing a DNA damage response, while CHEK1 inhibition resulted in significant DNA damage response with abnormal S phase profile in cell cycle analysis and an increase in gamma-H2A.X level. This combined inhibition dramatically decreased CHEK1 level and further increased apoptosis compared to CHEK1 inhibitor alone. Conclusion: Our dual shRNA technique efficiently identified CHEK1 as an IKKϵ synthetic lethal gene in ovarian cancer. CHEK1 inhibitor as a single agent has not been successful in clinic, and this may be due to increased pro-survival signaling mediated by IKKϵ, which may contribute to resistance and subsequent relapse. Identification of IKKϵ dependent signaling will lead to development of context-specific therapeutics in the poor prognostic group of patients with a high level of IKKϵ expression. Citation Format: Marianne K. H. Kim, Dong Joon Min, George Wright, Christina M. Annunziata. Context-specific dependence of ovarian cancer on IKKϵ and CHEK1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5179. doi:10.1158/1538-7445.AM2014-5179

Identification of gene expression profiles associated with prognostic groups of patients with Merkel cell carcinoma

Background Merkel cell carcinoma (MCC) is an aggressive form of skin cancer mostly caused by the Merkel cell polyomavirus [1]. MCC although rare in incidence is associated with poor prognosis. Gene expression studies (GES) have identified a number of genes that are associated with risk of developing MCC. However, their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. There is a need to better understand the biology of MCC and to develop potential new targets with regard to cancer risk and prognostic value [2]. Gene expression profiling and pathway association analysis on GES data can elucidate relevant biological processes, and identify new candidate target genes. Materials and methods We sought to identify differential gene expression and functional associations in MCC. Differentially expressed genes with a P value ≤ 0.05 and a fold change ≥ 2.5 between prognostic groups were identified and pathway association analysis was done for a total of 38 differentially expressed genes from a gene expression profiling study [3] with prognostic groups of MCC patients. The over representation of gene-based associations in each pathway was calculated using Fisher’s exact test. Results Pathways involved in neuropathic pain signaling, glutamate receptor signaling and synaptic long term potentiation were found to be highly enriched with associations. These results suggest that gene expressions associated with these pathways may contribute to MCC development and prognosis.

Promoter CpG Island Methylation of Genes in Key Cancer Pathways Associates with Clinical Outcome in High-Grade Serous Ovarian Cancer

We aimed to identify DNA methylation biomarkers of progression-free survival (PFS) to platinum-based chemotherapy in high-grade serous ovarian cancer (HGSOC) within biologically relevant ovarian cancer-associated pathways. Association with PFS of CpG island (CGI) promoter DNA methylation at genes in the pathways Akt/mTOR, p53, redox, and homologous recombination DNA repair was sought with PFS as the primary objective in a prospectively collected ovarian cancer cohort (n = 150). Significant loci were validated for associations between PFS, methylation, and gene expression in an independent The Cancer Genome Atlas (TCGA) data set of HGSOC (n = 311). DNA methylation at 29 CGI loci linked to 28 genes was significantly associated with PFS, independent from conventional clinical prognostic factors (adjusted P < 0.05). Of 17 out of the 28 genes represented in the TCGA data set, methylation of VEGFB, VEGFA, HDAC11, FANCA, E2F1, GPX4, PRDX2, RAD54L, and RECQL4 was prognostic in this independent patient cohort (one-sided P < 0.05, false discovery rate < 10%). A multivariate Cox model was constructed, with clinical parameters (age, stage, grade, and histologic type) and significant loci. The final model included NKD1, VEGFB, and PRDX2 as the three best predictors of PFS (P = 6.62 × 10(-6), permutation test P < 0.05). Focussing only on known VEGFs in the TCGA cohort showed that methylation at promoters of VEGFA, VEGFB, and VEGFC was significantly associated with PFS. A three loci model of DNA methylation could identify two distinct prognostic groups of patients with ovarian cancer (PFS: HR = 2.29, P = 3.34 × 10(-5); overall survival: HR = 1.87, P = 0.007) and patients more likely to have poor response to chemotherapy (OR = 3.45, P = 0.012).

Clinical usefulness of double biomarkers AFP and PIVKA-II for subdividing prognostic groups in locally advanced hepatocellular carcinoma

In this study, we investigated the clinical usefulness of AFP and PIVKA-II in subdividing prognostic groups in patients with locally advanced HCC treated locally. Patients who had undergone local treatment for locally advanced HCC between 2001 and 2006 were enrolled. Response to treatment was defined as a reduction in AFP or PIVKA-II by more than 50% from baseline levels at 1 month after the treatment completion. Patients were divided according to their AFP and PIVKA-II response: A↓P↓ [AFP response (+) and PIVKA-II response (+)]; A↓P↑ [AFP response (+) and PIVKA-II response (-)]; A↑P↓ [AFP response (-) and PIVKA-II response (+)]; A↑P↑ [AFP response (-) and PIVKA-II response (-)]. Clinical characteristics and prognosis were compared between groups. Patients were subdivided into four groups by the change in the level of the biomarkers AFP and PIVKA-II, and the survival outcomes of each group were distinct. Among patients with an AFP response, further subdivision by PIVKA-II response revealed that those in the A↓P↓ group had a longer median progression-free survival (PFS) and overall survival (OS) compared with those in the A↓P↑ group (PFS: 16.2 vs. 5.1 months, P = 0.009; OS: 26.3 vs. 7.3 months, P = 0.017). Combination of AFP and PIVKA-II response showed a predictive power for PFS and OS comparable to radiological criteria and better than AFP response alone. In patients with locally advanced HCC, the use of a combination of two biomarkers, AFP and PIVKA-II, appears useful in predicting treatment outcomes through the subdivision of prognostic groups.

Significance of MMP-9 expression and MMP-9 polymorphism in prostate cancer

The aim of the study was to assess the expression of the MMP-9 gene and -1562 C/T polymorphism in MMP-9 gene promoter in relation to clinicopathological parameters in predicting the clinical outcome of prostate cancer patients. A total of 82 patients with histopathologically diagnosed prostate cancer were enrolled in the study. MMP-9 gene expression was assessed by reverse transcription-PCR method. MMP-9 (-1562 C/T) polymorphism variants were determined by the polymerase chain reaction-based restriction fragment length polymorphism method. MMP-9 expression and MMP-9 -1562 polymorphism variants in relation to disease pathological stage (P = 0.006; P <0.0001, respectively), as well as to prognostic group (P = 0.019; P <0.0001, respectively), were statistically significant. Only MMP-9 -1562 polymorphism variants in relation to tumor differentiation grade (P = 0.044) were found to be statistically significant. Positive MMP-9 gene expression was associated with 5-year survival rate of prostate cancer patients with pathological stage III (P = 0.036) and for the patients in prognostic group III (P = 0.012). Patients with tumor differentiation grade G2 and with the identified CC variant had a significantly longer survival time than patients with the identified TT variant (P = 0.007). MMP-9 gene expression and MMP-9 -1562 polymorphism variants were associated with prostate cancer pathological stage and prognostic group. MMP-9 -1562 polymorphism CC variant was associated with prostate cancer tumor differentiation grade. Five-year survival analysis showed the relationship between MMP-9 gene expression and pathological stage III, as well as prognostic group III, whereas MMP-9 -1562 polymorphism variants, with tumor differentiation grade G2.