Clinical benefit from trastuzumab and other anti-human epidermal growth factor receptor-2 (HER2) therapies in patients with HER2-positive gastric cancer (GC) remains limited by primary or acquired ...resistance. We aimed to investigate the impact of concomitant molecular alterations to HER2 amplification on the clinical outcome of trastuzumab-treated patients. Using immunohistochemistry (IHC), copy number variations (CNVs), and Ion Ampliseq Cancer Panel, we analyzed the status of concomitant alterations in 50 HER2-positive advanced GC patients treated with trastuzumab in combination with other chemotherapeutic agents. The percentage of tumor samples with at least one concomitant alteration was 40% as assessed by IHC, 16% by CNVs, and 64% by Ampliseq sequencing. Median progression-free survival (PFS) was 8.0 months (95% confidence interval, 4.8-11.3). Patients were divided into two subgroups according to PFS values with a cutoff point of 8 months; results show that concomitant genomic alterations do not correlate with trastuzumab response. However, CNVs of CCNE1 significantly correlated (p < 0.05) with a shorter survival time. Our findings indicate that additional alterations implemented for prediction of clinical benefit from HER2-targeting agents in GC remained unclear. Further studies will be needed to elucidate the role of each specific biomarker and to optimize therapeutic approaches.
Background
Statins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic ...synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer.
Methods
Patients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000 mg/m
2
on days 1, 8, and 15 plus simvastatin 40 mg once daily) or GP (gemcitabine 1,000 mg/m
2
on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP).
Results
Between December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4 months (95 % CI 0.7–4.1 months) and 3.6 months (95 % CI 3.1–4.1 months) in the GS and GP arms, respectively (
P
= 0.903). The overall disease control rate was 39.7 % (95 % CI 12.2–33.8 %) and 57.1 % (95 % CI 19.8–44.2 %) in the GS and GP arms, respectively (
P
= 0.09). The 1-year expected survival rates were similar (27.7 and 31.7 % in the GS and GP arms, respectively;
P
= 0.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis.
Conclusions
Adding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer.
We assessed the performance of F-18 fluorodeoxyglucose positron emission tomography (FDG PET)-based radiomics for the prediction of tumor mutational burden (TMB) and prognosis using a machine ...learning (ML) approach in patients with stage IV colorectal cancer (CRC).
Ninety-one CRC patients who underwent pretreatment FDG PET/computed tomography (CT) and palliative chemotherapy were retrospectively included. PET-based radiomics were extracted from the primary tumor on PET imaging using the software LIFEx. For feature selection, PET-based radiomics associated with TMB were selected by logistic regression analysis. The performances of seven ML algorithms to predict high TMB were compared by the area under the receiver's operating characteristic curves (AUCs) and validated by five-fold cross-validation. A PET radiomic score was calculated by averaging the z-score of each radiomic feature. The prognostic power of the PET radiomic score was assessed using Cox proportional hazards regression analysis.
Ten significant radiomic features associated with TMB were selected: surface-to-volume ratio, total lesion glycolysis, tumor volume, area, compacity, complexity, entropy, correlation, coarseness, and zone size non-uniformity. The k-nearest neighbors model obtained the good performance for prediction of high TMB (AUC: 0.791, accuracy: 0.814, sensitivity: 0.619, specificity: 0.871). On multivariable Cox regression analysis, the PET radiomic score (Hazard ratio = 4.498, 95% confidential interval = 1.024-19.759;
= 0.046) was a significant independent prognostic factor for OS.
This study demonstrates that PET-based radiomics are useful image biomarkers for the prediction of TMB status in stage IV CRC. PET radiomic score, which integrates significant radiomic features, has the potential to predict survival in stage IV CRC patients.
Abstract Background Biliary tract carcinoma (BTC) is rare in the West, but not uncommon in Asia and is a highly fatal malignancy. VEGF expression is related with poor outcome in patients with BTC. ...Therefore, we conducted a phase II study to evaluate the efficacy and safety of sunitinib as second-line treatment. Methods This was a prospective, single-arm, multicentre, multinational study. Patients with unresectable, metastatic BTC who progressed after first-line chemotherapy were eligible. Sunitinib was administered at 37.5mg once daily continuously with 4-week cycle. The primary end point was the time to progression (TTP). Results Between May 2009 and October 2010, a total of 56 patients were enrolled from three countries. The median age was 55 years (range 38–75) and male to female ratio was 37:19. Median TTP was 1.7 months (95% confidence interval (CI) 1.0–2.4). The objective response rate was 8.9% (5 partial response) and disease control rate was 50.0%. (23 stable disease) Grade 3–4 toxicities were observed in 46.4% of the patients with neutropenia and thrombocytopenia being the most frequent (21.4%). Conclusions This phase II study suggests that sunitinib monotherapy demonstrated marginal efficacy in metastatic BTC patients although toxicity should be concerned in Asian population.
Clinical features of Asian melanoma patients are distinct from those of Western patients. This study was designed to determine the molecular and clinical characteristics of Asian melanoma patients ...treated with anti-PD-1 antibody.
Patients with recurrent or metastatic melanoma who began anti-PD-1 antibody therapy between January 2015 and April 2018 were retrospectively reviewed. Patients who underwent next-generation sequencing were also analyzed.
A total of 152 patients were included. The median age was 61 years, and 53% of patients were female. A total of 56 patients (37%) received immunotherapy as second-line or greater chemotherapy. Primary sites were acral (38%), mucosal (31%), cutaneous (24%), uveal (2%), and unknown (5%). The overall response rate was 17% (95% CI, 11-22%), and disease control rate was 60% (95% CI, 52-68%). The median progression-free survival (PFS) was 4.2 months (95% CI, 1.8-6.6 months), and median overall survival (OS) was 32.9 months (95% CI, 20.0-45.7 months). However, BRAF
and KIT mutational statuses were not associated with response or survival. High neutrophil-lymphocyte ratio (NLR) was associated with poor PFS (median PFS 6.9 vs. 2.4 months, p = 0.015) and OS (median OS NR vs. 10.4 months, p < 0.001). In multivariate analysis, high NLR independently predicted poor survival.
This study includes the largest set of integrated genomic data analyzing Asian patients with melanoma treated with immunotherapy. BRAF
and KIT mutational statuses were not associated with response or survival, and high NLR was a strong predictor of poor response to and survival with anti-PD-1 therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite comprehensive genomic analyses, no targeted therapies are approved for bladder cancer. Here, we investigate whether a single and combination therapy with targeted agents exert antitumor ...effects on bladder cancer cells through genomic alterations using a three-dimensional (3D) high-throughput screening (HTS) platform. Seven human bladder cancer cell lines were used to screen 24 targeted agents. The effects of 24 targeted agents were dramatically different according to the genomic alterations of bladder cancer cells. BEZ235 (dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor) showed antitumor effects against most cell lines, while AZD2014 (mTOR inhibitor) had an IC50 value lower than 2 μM in 5637, J82, and RT4 cell lines. AZD5363 (protein kinase B (AKT) inhibitor) exerted antitumor effects on 5637, J82, and 253J-BV cells. J82 cells (PI3KCA and mTOR mutations) were sensitive to AZD5363, AZD2014, and BEZ235 alone or in AZD5363/AZD2014 and AZD5363/BEZ235 combinations. Although all single drugs suppressed cell proliferation, the combination of drugs exhibited synergistic effects on cell viability and colony formation. The synergistic effects of the combination therapy on the PI3K/Akt/mTOR pathway, apoptosis, and EMT were evident in Western blotting. Thus, the 3D culture-based HTS platform could serve as a useful preclinical tool to evaluate various drug combinations.
Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 ...clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients with natural killer T (NK/T) -cell lymphomas have poor survival outcome, and for this condition there is no optimal therapy. The purpose of this study was to design a prognostic model ...specifically for extranodal NK/T-cell lymphoma, which can identify high-risk patients who need more aggressive therapy.
This multicenter retrospective study was comprised of 262 patients who were diagnosed with NK/T-cell lymphoma.
After a median follow-up duration of 51.2 months, 5-year overall survival rate in 262 patients was 49.5%. Prognostic factors for survival were "B" symptoms (P = .0003; relative risk, 2.202; 95% CI, 1.446 to 3.353), stage (P = .0006; relative risk, 2.366; 95% CI, 1.462 to 3.828), lactate dehydrogenase (LDH) level (P = .0005; relative risk, 2.278; 95% CI, 1.442 to 3.598), and regional lymph nodes (P = .0044; relative risk, 1.546; 95% CI, 1.009 to 2.367). Of 262 patients, 219 had complete information on four parameters. We identified four different risk groups: group 1, no adverse factor; group 2, one factor; group 3, two factors; and group 4, three or four factors. The new model showed a superior prognostic discrimination as compared with the International Prognostic Index (IPI). Notably, the distribution of patients was balanced when a new model was adopted (group 1, 27%; group 2, 31%; group 3, 20%; group 4, 22%), whereas 81% of patients were categorized as low or low-intermediate risks using IPI.
The newly proposed model for extranodal NK/T-cell lymphoma demonstrated a more balanced distribution of patients into four groups with better prognostic discrimination as compared with the IPI.
The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate ...methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r=0.465, P<0.0001), increased copy number gain (r=0.393, P=0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324-2.395; P<0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227-2.541; P=0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r=0.274, P=0.002), copy number gain or survival (P>0.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors.
Failure to proper transition of patients to subsequent therapies after disease progression on first-line treatment can risk exposing patients to worsening performance status, an upsurge of tumor ...burden, and exacerbation of toxicity due to the ineffective therapy. ...pre-treatment prediction of response to first-line chemotherapy is highly important for guiding patients to an optimal therapeutic approach and avoiding unnecessary toxicity. Using a response probability score derived from the logistic regression model, we developed a heatmap of the cluster analysis for miRNA expression in relation to treatment response, which showed a separated clustering of expression between the two groups (Fig. 1D). The 2-miRNA biomarker panel robustly stratifies prognosis of patients with mGC We dichotomized patients into groups with high- or low-probability of chemo-responsiveness, according to cutoff threshold values derived from the identical 2-miRNA prediction model and the proportion of responders was significantly higher in high-probability group than low-probability group (78.6% vs. 26.7%, P = 0.006). PFS in patients with a high probability of chemo-responsiveness was significantly better compared to PFS in a low probability group (median PFS: 4.3 vs. 2.8 months, P = 0.009), with a hazard ratio of 0.31 (95% CI: 0.13–0.74, P = 0.008) (Fig. 2E).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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