Ondrej Fiala

The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non–small cell lung cancer

The role of KRAS mutations in molecular targeted therapy by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) has not been fully understood. The present investigation is aimed at an elucidation of the role of specific KRAS mutation types in predicting outcomes of patients with advanced NSCLC receiving EGFR-TKI therapy. Initially, 448 NSCLC patients were tested for the presence of KRAS mutations, to obtain frequencies of specific KRAS mutation types. Subsequently, the clinical outcome of treatment was evaluated in a subgroup of 38 KRAS-positive patients receiving EGFR-TKI therapy. KRAS mutations were detected in 69 of 448 patients (15.4%), mostly in smokers (17.86% vs. 5.8%, P = 0.0048), and appeared more frequently in adenocarcinomas than in squamous cell NSCLC or NSCLC that is not otherwise specified (21% vs. 6.99% vs. 4.4%, P = 0.0004). The most frequent type of KRAS mutation was G12C. The progression-free survival (PFS) was doubled in a group of non-G12C patients compared with that of the G12C group (9.0 wk vs. 4.3 wk, P = 0.009). The overall survival (OS) was not significantly different between non-G12C and G12C groups (12.1 wk vs. 9.3 wk, P = 0.068). The G12C KRAS mutation is a strong negative predictor for EGFR-TKI treatment, whereas other KRAS mutation types have not negatively predicted treatment efficacy compared with that for the wild-type KRAS genotype.

Outcomes for Patients with Metastatic Renal Cell Carcinoma Achieving a Complete Response on Targeted Therapy: A Registry-based Analysis

BACKGROUND It is currently not known whether treatment with anti-vascular endothelial growth factor agents for metastatic renal cell carcinoma (mRCC) can be safely discontinued in patients achieving a complete response (CR). OBJECTIVE To assess outcomes for patients with mRCC achieving CR on targeted therapy (TT) and the survival of patients discontinuing TT after CR. DESIGN, SETTING, AND PARTICIPANTS A national registry was used to identify patients achieving CR during first-line TT using bevacizumab, sunitinib, sorafenib, or pazopanib. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Relationships with outcomes were analysed using a log-rank test. RESULTS AND LIMITATIONS A total of 100 patients achieving CR were identified out of 2803 patients. The median time to CR was 10.1 mo. Median progression-free survival (PFS) from TT initiation was 3.8 yr (95% confidence interval [CI] 2.9-4.6 yr) and the 5-yr overall survival (OS) was 80% (95% CI 70-91%). Patients discontinuing TT within 1 mo after achieving CR and those continuing TT beyond CR had similar OS (CI for difference in 2-yr post-CR OS -13% to 19%; p=0.3) and PFS (CI for difference in 2-yr post-CR PFS -29% to 17%; p=0.7). The limitations include the retrospective, registry-based data analysis. CONCLUSIONS Achievement of CR on TT for mRCC was associated with excellent long-term prognosis. No significant differences in post-CR survival were observed between patients discontinuing TT after the date of CR and those who continued on TT, although the wide CIs cannot exclude important differences between the groups. PATIENT SUMMARY According to this registry-based analysis, patients with metastatic renal cancer with no signs of disease (complete response) after treatment with targeted agents experience excellent long-term survival even if the treatment does not continue beyond the date of complete response.

Skin rash as useful marker of erlotinib efficacy in NSCLC and its impact on clinical practice.

Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor used in treatment of advanced NSCLC. Patients harboring EGFR or KRAS mutations represent minority of all patients in caucasian population and there is no available predictor for a predominant group of patients harboring the wild-type EGFR and wild-type KRAS genes. Skin rash is the most frequent manifestation of cutaneous toxicity of erlotinib. Rash is associated with a good therapeutic response. We aimed at the evaluation of rash as a predictor of therapeutic effect of erlotinib in patients harboring the wild-type EGFR and KRAS wild-type genes and to assess its possible usage in a clinical practice.Totally 184 patients with advanced stage NSCLC (IIIB, IV) harboring the wild-type EGFR and wild-type KRAS genes were analysed. Comparison of ORR, PFS and OS according to the occurrence of rash was performed. In order to assess the impact of rash in clinical practice it was conducted landmark analysis of the group of patients whose rash was observed during first month of treatment (n=124). Patients in whom progression was observed during the first month of treatment were excluded from the landmark analysis. The comparison of ORR was performed using Fishers exact test, visualization of survival was performed using Kaplan-Meier survival curves and the differences in survival were tested using the log-rank test. Median PFS in patients who were observed with rash during the treatment was 3.0 vs. 1.2 months in patients with no rash (p<0.001), median of OS in patients who were observed with rash during the treatment was 13.9 vs. 5.8 months in patients with no rash (p<0.001). ORR in patients who were observed with rash during the treatment was 17.4% vs. 3.3% in patients with no rash (p=0.001). Median of PFS after 1 month of treatment in patients who were observed with rash during the first month was 2.9 vs. 1.1 months in patients with no rash (p=0.027). Median of OS after 1 month of treatment in patients who were observed with rash during the first month was 13.8 vs. 9.9 months in patients with no rash (p=0.082). Rash is strongly associated with better survival and ORR in patients harboring wild-type EGFR and wild-type KRAS genes. Occurrence of rash during the first month of treatment is a useful predictor of better effect of erlotinib after one month of treatment. Patients who were not observed with rash during the first month of treatment are in high risk of progression. Optimization of the treatment of these patients can contribute restaging after two months of treatment, assessment of plasma levels of erlotinib and eventually attempt to dose escalation.

EEG correlates of a mental arithmetic task in patients with first episode schizophrenia and schizoaffective disorder

OBJECTIVE To evaluate the spectral power of the cortical bands in patients with first episode schizophrenia and schizoaffective disorder at rest and during the performance of a mental arithmetic task. METHODS We analyzed EEG spectral power (SP) in the resting state and subsequently while counting down from 200 in steps of 7, in 32 first episode schizophrenia patients (SZ), 32 patients with first episode schizoaffective disorder (SA) and healthy controls (HC, n=40). Behavioral parameters such as accuracy and counting speed were also evaluated. RESULTS Both SZ and SA patients were slower in counting than HC, no difference was obtained in the accuracy and counting speed in the patient groups. In the resting state patients showed elevated midline theta power, off-midline anterior beta 2 power and decreased central/posterior alpha power. The SA group occupied an intermediate position between the schizophrenia patients and controls. In task performance patients lacked a typical increase of midline theta, left anterior beta 2, and anterior gamma power; however, schizoaffective patients demonstrated a growing trend of power in the gamma band in left anterior off-midline sites similar to HC. Moreover, alpha power was less inhibited in schizoaffective patients and more pronounced in schizophrenia patients indicating distinct inhibitory mechanisms in these psychotic disorders. CONCLUSIONS Patients with SA demonstrate less alteration in the spectral power of bands at rest than SZ, and present spectral power changes during cognitive task performance close to the controls. SIGNIFICANCE Our study contributes to the present evidence on the neurophysiological distinction between schizophrenia and schizoaffective disorder.

Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: a registry-based analysis.

OBJECTIVES The aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS A national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs. RESULTS Median progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013. CONCLUSION PFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.

The association of miR-126-3p, miR-126-5p and miR-664-3p expression profiles with outcomes of patients with metastatic colorectal cancer treated with bevacizumab

MicroRNAs regulate the expression of genes involved in several important cancer-related processes including cell adhesion, proliferation, and tumour angiogenesis. Bevacizumab is routinely used in the treatment of patients with metastatic colorectal cancer, but, so far, no reliable biomarker predicting response to bevacizumab has been established. The aim of our retrospective study was to evaluate the association of miR-126-3p, miR-126-5p and miR-664-3p tumour expression levels with outcomes of patients with metastatic colorectal cancer treated with bevacizumab. The study included 63 patients. For the assessment of microRNA expression, gene-specific TaqMan assays were used. The median progression-free survival and overall survival for patients with low tumour expression of miR-126-3p were 8.8 and 20.6 months versus 13.5 months and median overall survival was not reached for patients with high expression (p = 0.0064 and p = 0.0027), respectively. The median progression-free survival and overall survival for patients with low tumour expression of miR-126-5p were 9.0 and 22.2 months versus 12.0 and 23.4 months for patients with high expression (p = 0.2113 and 0.6858), respectively. The median progression-free survival and overall survival for patients with low tumour expression of miR-664-3p were 9.1 and 22.5 months versus 8.8 and 23.4 months for patients with high expression (p = 0.2542 and p = 0.1922), respectively. The multivariable Cox proportional hazards model revealed that miR-126-3p expression was significantly associated with progression-free survival (hazard ratio = 0.28, p = 0.0053) and also with overall survival (hazard ratio = 0.18, p = 0.0046). In conclusion, the results of this study suggest that the expression of miR-126-3p in the tumour tissue was associated with outcome of metastatic colorectal cancer patients treated with bevacizumab.

Efficacy of sunitinib in patients with metastatic or unresectable renal cell carcinoma and renal insufficiency

AIM The aim of this retrospective, registry-based study was to analyse treatment outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib and renal insufficiency (RI). METHODS The cohort included 790 patients treated with sunitinib between 2006 and 2013. At the start of sunitinib therapy 22, 234, and 534 patients had severe (glomerular filtration rate [GFR] <30ml/min/1.73m(2)), moderate (GFR 30-60 ml/min/1.73m(2)) or mild RI/normal renal function (GFR >60ml/min/1.73m(2)), respectively. RESULTS For the three groups defined above, median progression-free survival (PFS) (95% confidence interval [CI]) was 5.3 months (0.1-18.5), 8.1 months (6.2-9.9) and 11.3 months (9.4-13.2) (p=0.244), and median overall survival (OS) was 26.3 months (1.2-51.4), 21.2 months (13.2-29.1) and 26.3 months (22.6-29.9) (p=0.443), respectively. The disease control rates were 45.5%, 56.4% and 59.2%, respectively (p=0.374). No unexpected toxicity was reported in the patients with RI, but the treatment was more frequently discontinued because of adverse events and the duration of therapy was significantly shorter in these patients (p=0.007). CONCLUSIONS Duration of first-line targeted treatment for mRCC was significantly shorter for patients with RI, and may have translated into a trend to shorter PFS. These results highlight the need for optimal management of side-effects in patients with mRCC and RI.

Parkin (PARK 2) Mutations Are Rare in Czech Patients with Early-Onset Parkinson's Disease

Objective The aim of the study is to determine the frequency of parkin allelic variants in Czech early-onset Parkinsons disease patients and healthy controls. Methods A total of 70 early-onset Parkinsons disease patients (age at onset ≤40 years) and 75 controls were screened for the sequence variants and exon rearrangements in the parkin gene. Results Parkin mutations were identified in five patients (7.1%): the p.R334C point mutation was present in one patient, four patients had exon deletions. The detected mutations were observed in the heterozygous state except one homozygous deletion of the exon 4. No mutations were obtained in control subjects. A novel sequence variant p.V380I (c.1138G>A) was identified in one control. Non-pathogenic polymorphisms p.S167N and p.D394N were seen in similar percentage in patients and controls, polymorphism p.V380L was almost twice as frequent in controls as in patients. Conclusions Our study contributes to the growing body of evidence on the low frequency of the parkin mutations in the early-onset Parkinsons disease suggesting the potential role of other genes in the pathogenesis of the disease.

Thyroid transcription factor 1 expression is associated with outcome of patients with non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy

Pemetrexed is an antifolate cytostatic agent targeting several folate-dependent enzymatic pathways, widely used in the treatment of locally advanced or metastatic stage non-small cell lung cancer. Aside from the non-squamous histology, there is still no available molecular biomarker predicting treatment efficacy of pemetrexed-based chemotherapy. The aim of our retrospective study was to evaluate the association of thyroid transcription factor 1 expression with outcome of a large cohort of patients with non-squamous non-small cell lung cancer treated with pemetrexed. We retrospectively analysed clinical data of 463 patients with advanced-stage non-small cell lung cancer (IIIB or IV) treated with pemetrexed-based chemotherapy. Thyroid transcription factor 1 expression was assessed using indirect immunohistochemical detection in formalin-fixed paraffin-embedded tumour tissue at the time of diagnosis. Thyroid transcription factor 1 expression was detected in the tumour tissue from 76.0% of patients, and tumours from 24.0% of patients were thyroid transcription factor 1 negative. The median progression-free survival and overall survival for patients with thyroid transcription factor 1 positive tumours were 4.8 and 11.8 months compared to 2.8 and 8.3 months for those with thyroid transcription factor 1 negative tumours (p = 0.001 and p < 0.001). The multivariable Cox proportional hazards model revealed that thyroid transcription factor 1 expression was significantly associated with progression-free survival (hazard ratio = 1.57, p < 0.001) and also with overall survival (hazard ratio = 1.73, p < 0.001). In conclusion, the results of the conducted retrospective study suggest that the thyroid transcription factor 1 expression was independently associated with progression-free survival and overall survival in patients with advanced-stage non-squamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

Outcomes of Patients With Long-Term Treatment Response to Vascular Endothelial Growth Factor-Targeted Therapy for Metastatic Renal Cell Cancer

Micro‐Abstract Although targeted therapies are the mainstay of treatment for metastatic renal cell carcinoma there are limited data on the outcomes of patients with long‐term responses. We report the outcomes of a registry‐based study of patients continuously treated with first‐line targeted therapy for at least 24 months. There were clinically important differences in survival between patients who achieved complete response and those with partial response or stable disease. These differences had not been described before and are important for treatment optimization of this patient subgroup. Background: Although targeted therapies with inhibitors of the vascular endothelial growth factor (VEGF) are the mainstay of treatment for metastatic renal cell carcinoma, there are limited data on the outcome of patients with long‐term response to this treatment. Patients and Methods: In a retrospective, registry‐based study, patients continuously treated with first‐line anti‐VEGF agents for at least 24 months were included. In total, 219 patients had evaluable data and were included in the outcome analysis. Results: Median progression‐free survival (PFS) after initiation of first‐line targeted therapy was 39.7 months (95% confidence interval [CI], 35.9‐43.5 months), with 5‐year PFS of 34.2% (95% CI, 27.2%‐41.2%). Median overall survival (OS) reached 79.1 months (95% CI, 65.2‐93.0 months) with the 5‐year OS of 62.1% (95% CI, 54.5%‐69.7%). In this cohort, 28, 103, and 88 patients achieved complete response (CR), partial response (PR), or stable disease (SD) as the best response, respectively. Median PFS and OS were comparable in patients with PR and SD, but significantly longer in patients with CR (log rank test P value for PFS difference < .001 and .009 for OS difference). Conclusion: There are marked differences in PFS and OS between patients who receive long‐term anti‐VEGF treatment, achieving CR and non‐CR as the best clinical response. Patients with non‐CR experienced a relatively high progression rate shortly after the landmark time point of 2 years.