Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma

AimTo present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination.MethodsHRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms.ResultsQuestionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6–13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy.ConclusionThis analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648).     

NRAS mutation status is an independent prognostic factor in metastatic melanoma

BACKGROUND:

There is a need for improved prognostic markers in melanoma. In this study, the authors tested the prognostic significance and clinicopathologic correlations of v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) mutations in patients with metastatic melanoma.

METHODS:

Clinical and pathologic data were collected retrospectively on melanoma patients who were clinically tested for BRAF (exon 15) and NRAS (exons 1 and 2) mutations at The University of Texas M. D. Anderson Cancer Center. Analyses were performed to identify significant associations of mutations with tumor and patient characteristics and with survival from the diagnosis of stage IV disease.

RESULTS:

The genotypes of the full cohort (n = 677) were 47% BRAF mutation, 20% NRAS mutation, and 32% wild‐type for BRAF and NRAS (“WT”). Tumor mutation status was associated (P = .008) with the risk of central nervous system involvement at the diagnosis of stage IV disease, with a higher prevalence observed in BRAF‐mutant (24%) and NRAS‐mutant (23%) patients than in WT patients (12%). Among patients with nonuveal melanoma who underwent mutation testing within 6 months of stage IV diagnosis (n = 313), patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis, which was shorter than the median survival of WT patients (15.1 months; P = .004). Multivariate analysis of this population incorporating age, sex, metastases (M1) category, serum lactate dehydrogenase level, and mutation status confirmed that NRAS mutations are associated independently with decreased overall survival (vs WT; P = .005; hazard ratio, 2.05).

CONCLUSIONS:

Patients with BRAF or NRAS mutations were more likely than WT patients to have central nervous system involvement at the time they were diagnosed with distant metastatic disease. NRAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma. Cancer 2012. © 2011 American Cancer Society.     

The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients

BackgroundMolecular markers in colon cancer are needed for a more accurate classification and personalized treatment. We determined the effects on clinical outcome of the BRAF mutation, microsatellite instability (MSI) and KRAS mutations in stage II and stage III colon carcinoma.Patients and methodsStage II colon carcinoma patients (n = 106) treated with surgery only and 258 stage III patients all adjuvantly treated with 5-fluorouracil chemotherapy were included. KRAS mutations in codons 12 and 13, V600E BRAF mutation and MSI status were determined.ResultsOlder patients (P < 0.001), right-sided (P = 0.018), better differentiated (P = 0.003) and MSI tumors (P < 0.001) were significantly more frequent in stage II than stage III. In both groups, there was a positive association between mutated BRAF and MSI (P = 0.001) and BRAF mutation and right-sided tumors (P = 0.001). Mutations in BRAF and KRAS were mutually exclusive. In a multivariate survival analysis with pooled stage II and stage III data, BRAF mutation was an independent prognostic factor for overall survival (OS) and cancer-specific survival [hazards ratio (HR) = 0.45, 95% confidence interval (CI) 0.25–0.8 for OS and HR = 0.47, 95% CI 0.22–0.99]. KRAS mutation conferred a poorer disease-free survival (HR = 0.6, 95% CI 0.38–0.97).ConclusionsThe V600E BRAF mutation confers a worse prognosis to stage II and stage III colon cancer patients independently of disease stage and therapy.     

Residual melanoma after an excisional biopsy is an independent prognostic factor for local recurrence and overall survival

The aim of this study was to evaluate the effect of a residual melanoma after an excisional biopsy on prognosis of patients with cutaneous melanoma.     

Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study

BackgroundThe clinical features and the prognostic relevance of vitiligo lesions in melanoma patients are still controversial. This prospective observational study was designed to characterise the clinical features of melanoma-associated vitiligo, to analyse the association with other autoimmune manifestations and to ascertain whether the development of vitiligo lesions carries a prognostic relevance on the clinical course of melanoma.Materials and methodsA total of 2954 consecutive patients have been included; multivariate analyses of distant metastasis-free survival (DMFS) and overall survival (OS) were carried out to ascertain the independent prognostic role of vitiligo as a time-dependent covariate.ResultsVitiligo was demonstrated in 83 of 2954 melanoma patients (2.8%). A significantly higher percentage of autoimmune diseases was demonstrated in vitiligo patients (7 of 83) with respect to patients without vitiligo (80 of 2871) (P = 0.004). Multivariate analyses selected the time-dependent covariate vitiligo as the favourable independent prognostic variable associated to a longer DMFS in stage III and a higher OS in both stage III and stage IV.ConclusionMelanoma-associated vitiligo should be considered as a distinct clinical entity, separate from vitiligo vulgaris, and identifies a subgroup of patients characterised by a high prevalence of immune-mediated diseases and by a favourable prognosis.     

Low socioeconomic status is a poor prognostic factor for survival in stage I nonsmall cell lung cancer and is independent of surgical treatment, race, and marital status

BACKGROUND: Racial minorities exhibit poor survival with nonsmall cell lung cancer (NSCLC) that generally is attributed to low socioeconomic status (SES). In this study, the authors investigated the role of SES in this survival disparity among patients with stage I NSCLC. METHODS: A case-only analysis was performed on California Cancer Registry (CCR) data (1989-2003). Univariate survival analyses were performed using the Kaplan-Meier method. Multivariate survival analyses were performed using Cox proportional hazards ratios. RESULTS: In total, 19,702 incident cases of stage I NSCLC were analyzed. Low SES was identified more commonly in African-American and Hispanic patients and was associated significantly with men, unmarried status, stage IB disease, squamous cell histology, poorly differentiated tumors, fewer surgical resections performed, and less overall treatment received. Reasons for no surgery were associated strongly with low SES and unmarried status but not with race. In multivariate analysis, each incremental improvement in SES quintile was associated with statistically significant decreases in the hazard ratios (HRs) for death (second SES quintile [SES2] vs SES1: HR, 0.91; 95% confidence interval [95% CI], 0.85-0.98; SES3 vs SES1: HR, 0.90; 95% CI, 0.84-0.97; SES4 vs SES1: HR, 0.83; 95% CI, 0.77-0.89; SES5 vs SES1: HR, 0.78; 95% CI, 0.72-0.84; P(trend) < .0001). African-American or Hispanic race was not an independent poor prognostic factor for survival after adjustment for surgery, SES, and marital status. CONCLUSIONS: Low SES was an independent poor prognostic factor for survival in patients with stage I NSCLC and was independent of surgery, race, and marital status.     

Heterogeneous chromosome 12p deletion is an independent adverse prognostic factor and resistant to bortezomib-based therapy in multiple myeloma

The deletion of 12p (del(12p)) has been described as a novel negative prognostic marker in multiple myeloma (MM) and has gained increasing attention in recent years. However, its impact on MM is still controversial. In this study, we comprehensively evaluated the clinical impact of 12p13 deletion using fluorescence in situ hybridization (FISH) on 275 newly diagnosed MM cases treated in a prospective, non-randomized clinical trial (BDH 2008/02). The results showed that deletion of 12p13 was detected in 10.5% of newly diagnosed cases and associated with multiple indicators for high tumor burden including ISS III, BM plasmacytosis larger than 50%, and renal lesion. Moreover, the cases with 12p13 deletion typically had higher incidence of del(17p), IGH translocation and t(4;14). Patients with del(12p) conferred significantly adverse prognosis for PFS and OS, even in patients subjected to bortezomib-based therapy. When adjusted to the established prognostic variables including del(13q), del(17p), t(4;14), amp(1q21), ISS stage and LDH, del(12p13) remained the powerful independent adverse factor for PFS (P = 0.007) and OS (P = 0.032). In addition, del(12p13) combined with high β2-MG, high LDH and bone lesion can further identify subpopulations with high-risk features. Our results strongly supported that del(12p13) can be used as a valuable prognostic marker in MM.     

p53 is an independent pre-treatment markers for long-term survival in stage II and III colorectal cancers: an analysis of interaction between genetic markers and fluorouracil-based adjuvant therapy

One hundred and thirty-eight stage II and III colorectal cancer patients were included to evaluate the prognostic significance of genetic markers (including mutations of the p53, K-ras genes, and microsatellite instability) on the response to 5-fluorouracil (FU)-based post-operative adjuvant therapies (PAT). When stratified by PAT and adjusting for other prognostic variables, presence of p53 mutation was associated with a poor outcome (hazard ratio (HR)=3.1, 95% confidence interval (CI), 0.9-11.0) among patients without PAT. Our data confirmed that p53 mutation is an independent pre-treatment factor in stage II and III colorectal cancer after curative resection.     

Accumulation of FOXP3+T-cells in the tumor microenvironment is associated with an epithelial-mesenchymal-transition-type tumor budding phenotype and is an independent prognostic factor in surgically resected pancreatic ductal adenocarcinoma

Here we explore the role of the interplay between host immune response and epithelial-mesenchymal-transition (EMT)-Type tumor-budding on the outcome of pancreatic adenocarcinoma (PDAC).CD4+, CD8+, and FOXP3+T-cells as well as iNOS+ (M1) and CD163+-macrophages (M2) were assessed on multipunch tissue-microarrays containing 120 well-characterized PDACs, precursor lesions (PanINs) and corresponding normal tissue. Counts were normalized for the percentage of tumor/spot and associated with the clinico-pathological features, including peritumoral (PTB) and intratumoral (ITB) EMT-Type tumor-budding and outcome.Increased FOXP3+T-cell-counts and CD163-macrophages and decreased CD8+T-cell-counts were observed in PDACs compared with normal tissues and PanINs (p < 0.0001). Increased peritumoral FOXP3+T-cell-counts correlated significantly with venous invasion, distant metastasis, R1-status, high-grade ITB, PTB and independently with reduced survival. Increased intratumoral FOXP3+T-cells correlated with lymphatic invasion, N1-stage, PTB and marginally with adverse outcome. High peritumoral CD163-counts correlated with venous invasion, PTB and ITB. High intratumoral CD163-counts correlated with higher T-stage and PTB.PDAC-microenvironment displays a tumor-favoring immune-cell composition especially in the immediate environment of the tumor-buds that promotes further growth and indicates a close interaction of the immune response with the EMT-process. Increased peritumoral FOXP3+T-cell density is identified as an independent adverse prognostic factor in PDAC. Patients with phenotypically aggressive PDACs may profit from targeted immunotherapy against FOXP3.     

Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer

BACKGROUND: Programmed cell death 4 (Pdcd4) inhibits malignant transformation, and initial studies of Pdcd4 suggested the regulation of Pdcd4 localization by protein kinase B (Akt). However, supporting patient tissue data are missing, and the diagnostic/prognostic potential of Pdcd4 rarely has been studied. The objectives of the current were 1) to determine Pdcd4 as a diagnostic marker in the adenoma-carcinoma sequence, 2) to support phosphorylated Akt (pAkt)-mediated Pdcd4 regulation in vivo, and 3) to obtain the first prognostic evidence of Pdcd4 in colorectal cancer. METHODS: Tumor samples and normal tissues from 71 patients with colorectal cancer who were followed prospectively (median follow-up, 36 months) and 42 adenomas were analyzed for Pdcd4, Akt, and pAkt in immunohistochemical and Western blot analyses. RESULTS: A significant reduction in Pdcd4 was observed between normal mucosa and adenomas and between adenomas and tumor samples (P < .01 and P < .01, respectively). Normal mucosa demonstrated strong nuclear Pdcd4, which was reduced significantly in adenomas (P < .01) and almost was lost in tumors (P < .01). pAkt was correlated inversely with Pdcd4 and with the transition of Pdcd4 from nucleus to cytoplasm (P < .01). Kaplan-Meier analysis (using the Mantel-Cox log-rank test) indicated a significant correlation between the loss of total and nuclear Pdcd4 in tumors and overall survival (P < .05 and P < .02, respectively) and disease-specific survival (P < .01 and P < .01, respectively). In multivariate analysis, loss of total or nuclear Pdcd4 was an independent predictor of disease-specific or overall survival. CONCLUSIONS: To the authors' knowledge, this is the first study to demonstrate an independent prognostic impact of Pdcd4 and its expression pattern in colorectal cancer. Data from this study support the regulation of Pdcd4 localization by pAkt in vivo. Pdcd4 immunohistochemistry may be useful as a supportive diagnostic tool for the transition between normal, adenoma, and tumor tissues.     

The level of manganese superoxide dismutase content is an independent prognostic factor for glioblastoma. Biological mechanisms and clinical implications

We address the issue of the role of manganese superoxide dismutase in tumorigenesis by studying a relatively homogeneous group of tumours for the correlation between amount of this anti-oxidant enzyme and prognosis. The clinical outcome of 30 patients affected by glioblastomas whose manganese superoxide dismutase content had been established at the time of first diagnosis is compared. When the survival of patients is stratified according to manganese superoxide dismutase level in the tumour, a link of these levels and prognosis can be observed. Patients with high levels of manganese superoxide dismutase show a median survival time of 6.11 months, while patients whose tumours display a low amount of MnSOD have a median survival time of 12.17 months. To assess the upstream mechanisms that sustain the increase in manganese superoxide dismutase content in brain neuroepithelial tumours, we also studied the expression of p53 in a series of 17 astrocytomas of various grading. In all tested astrocytomas, high manganese superoxide dismutase content is associated with cytoplasmic accumulation of p53. Thus glioblastomas can be divided into two distinct groups on the basis of their content of manganese superoxide dismutase, having 'better' or 'worse' prognosis, respectively. The use of this protein as a marker may help to define therapeutic strategies in the clinical management of glioblastoma.     

Tumour cyclic AMP binding proteins: an independent prognostic factor for disease recurrence and survival in breast cancer

Summary In two separate cohorts of breast cancer patients presenting without evidence of distant metastatic disease, high levels of tumour cyclic AMP binding proteins (> 8 pmol/mg cytosol protein) have been shown to be associated with poor prognosis in terms of both disease recurrence and overall survival. This association is independent of known established prognostic factors and allows the identification of a small subgroup of patients whose outlook warrants the implementation of aggressive systemic therapy.     

The kinetics of the visible growth of a primary melanoma reflects the tumor aggressiveness and is an independent prognostic marker: a prospective study

Primary melanoma (MM) could be a good model to test an intuitive concept: a cancer that is growing fast in its early phase is likely to have a high aggressiveness. Since MMs are visible tumors, many patients can provide information to indirectly assess the kinetics of their lesion. A prospective study was designed to assess if the kinetics of the visible growth of a primary MM, as described by the patient, could be a noninvasive prognostic marker. The ratio of MM thickness to delay between MM appearance and MM removal was used as a surrogate value for the kinetics of the MM growth. To assess the delay between MM appearance and removal, 362 patients with self-detected invasive MM fulfilled a detailed questionnaire, which provided 2 types of estimations of this delay and thus 2 melanoma kinetics indexes (MKI and MKI*). After a median follow-up of 4 years, univariate and multivariate analyses assessed whether relapse-free survival was linked to MKI or MKI*. MKI was significantly predictive of relapse-free survival (HR = 1.84 [1.51-2.25]) and relapse at 1 year (RR = 2.93 [1.84-4.69]), independently from Breslow thickness. MKI was retained in multivariate prognostic models, just after thickness and before other usual markers. MKI* was also a significant independent risk marker, although less predictive. In this model, the initial growth kinetics of a cancer reflects its aggressiveness and a high index predicts a short-term relapse. The "subjective" data obtained from patients about their MM history, although usually neglected, can thus provide a better prognostic marker than many "objective" tests.     

Sarcopenia is an independent unfavorable prognostic factor of non-small cell lung cancer after surgical resection: A comprehensive systematic review and meta-analysis

BackgroundWhether sarcopenia has any impact on long-term survival of patients with surgically treated non-small cell lung cancer (NSCLC) remains unclear. We conducted a meta-analysis focusing on current topic comprehensively for the first time.MethodsWe systematically searched relevant studies in PubMed, Embase, and Cochrane Library up to July 3, 2018. Data of 5-year overall survival (OS) and disease-free survival (DFS) rates as well as hazard ratio (HR) of OS were collected for analysis by using the STATA 12.0 package.ResultsA total of 6 cohort studies consisting of 1213 patients (422 patients with sarcopenia and 791 patients without) were included for analysis. Meta-analysis showed that patients with sarcopenia had a significantly lower 5-year OS rate (risk ratio (RR) = 1.63; 95% confidence interval (CI) = [1.13, 2.33]; P = 0.008) than those without, which was more prominent in patients with early-stage NSCLC. Sarcopenia was found to be an independent predictor of poor OS in patients with surgically treated NSCLC (HR = 2.85; 95%CI = [1.67, 4.86]; P < 0.001). With a limited sample size, there was no sufficient evidence of significantly different 5-year DFS rate between the two groups (RR = 1.14; 95%CI = [0.59, 2.17]; P = 0.70). However, in the subgroup of patients with early-stage NSCLC, sarcopenia was associated with a significantly lower 5-year DFS rate (RR = 1.59; 95%CI = [1.01, 2.52]; P = 0.046).ConclusionPatients with sarcopenia had a significantly worse prognosis than those without after surgical resection of NSCLC especially in those at early stage. Sarcopenia is an independent unfavorable prognostic factor for patients with surgically treated NSCLC. (246 words).     

Circulating angiopoietin-1 to angiopoietin-2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents

The circulating levels of several angiogenic cytokines [angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang-1/Ang-2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin-1/angiopoietin-2 ratio correlated with advanced disease features including international staging system (ISS)-3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin-2) we found that angiopoietin-2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang-1/Ang-2 ratio correlated with survival. Patients with circulating Ang-1/Ang-2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first-line therapy with novel agent-based regimens (65% of our patients). Furthermore, a subset of ISS-3 patients with serum Ang-1/Ang-2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang-1/Ang-2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50-2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.     

Combined flow cytometry determination of S-phase fraction and DNA ploidy is an independent prognostic factor in node-negative invasive breast carcinoma: analysis of a series of 271 patients with stage I and II breast cancer

Purpose. To assess the significance of S-phase fraction (SPF) and DNA ploidy evaluated by DNA flow cytometry as prognostic markers in stage I or II breast cancer.Patients and methods. A series of 271 patients, treated by surgery, radiotherapy ± systemic therapy was analyzed (median follow up: 64 months). Standardized flow cytometry cell preparation from frozen samples and consensus rules for data interpretation were followed. Three SPF classes were defined on the basis of tertiles after adjustment for ploidy. Four groups were defined based on combinations of DNA ploidy (DIP: diploid; ANEUP: aneuploid) and SPF: DIP and low SPF (DL, n=37), DIP and medium or high SPF (DMH, n=76), ANEUP and low SPF (AL, n=24), ANEUP and medium or high SPF (AMH, n=68). Local control rate (LCR), disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS) were correlated with DNA ploidy, SPF, DL to AMH groups, T and N stages, SBR grading, age, and hormonal status on univariate and multivariate analysis (Cox model).Results. On univariate analysis, DFS and LCR were higher for DIP tumours. High SPF values were associated with shorter DFS. LCR, MFS, DFS, and OS rates were significantly different with an increasingly poorer prognosis from DL to AMH. On multivariate analysis, groups DL to AMH, histological node involvement and T stage were independently associated with MFS, and DFS. In N(–) patients, DL to AMH remained independent for MFS and DFS. For SBR III tumours, MFS and OS were significantly different in DL to AMH groups. These results strongly support the use of combined evaluation of DNA ploidy and SPF as independent parameters in clinical trials for N(–) stage I and II breast cancer.