Jindrich Finek

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.

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.

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.

Erlotinib in the treatment of advanced squamous cell NSCLC

Erlotinib is an epidermal growth factor receptor tyrosine-kinase inhibitor. Clinical trials have shown its efficacy in advanced non-small cell lung cancer (NSCLC). We conducted a large retrospective study based on clinical experience aiming to prove erlotinibs efficacy and safety in patients with advanced-stage squamous cell NSCLC. Totally 375 patients with advanced-stage (IIIB, IV) squamous cell NSCLC were treated with erlotinib. Erlotinib was continued until disease progression or intolerable toxicity. 1 (0.3%) complete response (CR), 28 (7.5%) partial responses (PR) and 198 (52.8%) stable diseases (SD) were achieved. Overall response rate (ORR) and disease control rate (DCR) were 7.8% and 60.5%, respectively. Median progression-free survival (PFS) was 3.0 months and median overall survival (OS) was 7.6 months. PFS of patients with CR/PR, SD and PD were 7.6, 3.9 and 1.0 months, respectively (P<0.001). OS of patients with CR/PR, SD and PD were 13.3, 10.9 and 3.8 months, respectively (P<0.001).The most common adverse effects were rash and diarrhoea. In conclusion ertlotinib is effective and well-tolerated in patients with advanced-stage squamous cell NSCLC.

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.

The Usefulness of Tumor Markers in Patients with Colorectal Carcinoma for the Detection of Local Recurrences and Distant Metastases

AbstractAim: The aim of the study was to evaluate the usefulness of serum tumor marker assessment in patients with colorectal carcinoma for the early detection of local recurrences and distant metastases. Patients and Method: Tumor markers were examined in a group of 517 patients with clinically diagnosed and histologically verified colorectal carcinoma. The following tumor markers were assessed: CEA, CA 19-9, CA 72-4 and thimidinkinase. The statistical evaluation was performed using S.A.S.software (USA). Results: Serum values of all tumor markers were significantly increased in progression of the disease in comparison with those in remission. For detection of local recurrences the highest sensitivities were achieved by CA 19-9 (SN 57%, SP 90%), followed by CEA (SN 48%, SP 90%). For the detection of distant metastases the best seemed to be CEA (SN 63%, SP 90%) followed by CA 72-4 (SN 42%, SP 90%) and CA 19-9 (SN 37%, SP 90%). For the detection of liver metastases in progression the highest sensitivities were shown by CEA (SN 95%, SP 90%) followed by CA 19-9 (SN 72%, SP 90%). For the detection of lung metastases in progression the highest sensitivities were shown by CEA (SN 52%, SP 90%) followed by CA 19-9 (SN 33%, SP 90%). Conclusions: The classification of remission and the prediction of disease progression in patients during follow-up is possible with a high degree of probatility. For the detection of local recurrences CA 19-9 serum values seem to be the best. CEA showed the highest sensitivity for the detection of liver and lung metastases.ZusammenfassungZielsetzung: Ziel dieser Untersuchung war die Bewertung der Nützlichkeit von Serumtumormarkern bei Patienten mit kolorektalen Karzinomen für die frühe Entdeckung von Lokalrezidiven und Fernmetastasen. Patienten und Methode: Wir untersuchten die Tumormarker bei einer Gruppe von 517 Patienten mit klinisch diagnostizierten und histologisch verifizierten kolorektalen Karzinomen. Die folgenden Tumormarker wurden dabei bewertet: CEA, CA 19-9, CA 72-4 und Thimidinkinase. Die statistische Auswertung erfolgte mittels S.A.S.Software. Ergebnisse: Die Serumspiegel aller Tumormarker waren bei fortschreitender Erkrankung signifikant erhöht im Vergleich zu jenen im Remissionsstadium. Zur Entdeckung von Lokalrezidiven wurde die höchste Sensitivität mit dem CA 19-9 (SN 57%, SP 90%) erzielt, gefolgt von CEA (SN 48%, SP 90%). Zum Nachweis von Fernmetastasen schien das CEA die besten Ergebnisse zu bringen (SN 63%, SP 90%), gefolgt von CA 72-4 (SN 42%, SP90%) und CA 19-9 (SN 37%, SP 90%). Bei der Entdeckung von fortgeschrittenen Lebermetastasen zeigte CEA die höchste Sensitivität (SN 52%, SP 90%), gefolgt von CA 19-9 (SN 33%, SP 90%). Schlussfolgerungen: Die Klassifikation der Remission und die Verhersage der Erkrankungsprogression bei Patienten während der Nachuntersuchung ist mit hoher Wahrscheinlichkeit möglich. Zur Entdeckung von Lokalrezidiven zeigen CA 19-9-Serumspiegel die besten Ergebnisse. Das CEA zeigte dagegen bei der Entdeckung von Leber- und Lungenmetastasen die höchste Sensitivität.

An Assessment of Novel Biomarkers in Bone Metastatic Disease Using Multiplex Measurement and Multivariate Analysis

Aim: Current diagnostics of bone metastatic disease is not satisfactory for early detection or regular process monitoring. The combination of biomarkers and the multiparametric approach was described as effective in other oncology diagnoses. The aim of the study was to improve the difference diagnostics between bone-metastatic disease and solid tumors using mutivariate logistic regression model. Methods: We assessed the group of 131 patients with the following diagnoses: prostate cancer, breast cancer, lung cancer, and colorectal cancer. According to the results of scintigraphy, the cohort was divided into 2 groups based on the occurrence of bone metastases. Group 0 was a control group of 75 patients with no signs of bone metastases and group 1 included 56 patients with bone metastases. Results: We used stepwise selection multivariate logistic regression for choosing the multimarker formula for calculation of risk score for bone metastases diagnostics. For detection of bone metastasis, it was shown to be most effective measurement of 3 biomarkers: procollagen type 1 N-terminal propeptide, growth differentiation factor-15, and osteonectin and combining with calculation of risk score by designating measured concentrations in mathematical formula: bone risk score = procollagen type 1 N-terminal propeptide × 0.0500 + growth differentiation factor-15 × 1.4179 + osteonectin × 0.00555. Conclusion: We identified growth differentiation factor-15 as the best individual marker for bone metastasis diagnostics. The best formula for risk score includes levels of 3 biomarkers—procollagen type 1 N-terminal propeptide, growth differentiation factor-15, and osteonectin. The new score has better performance described by higher area under the curve than individual biomarkers. A further study is necessary to confirm these findings incorporating a larger number of patients.

Hybrid Imaging PET/CT with Application of18F-Fluorothymidine in Patients with Head and Neck Carcinoma Undergoing Radiotherapy

Aim: To introduce the possible benefits of the positron-emission tomography (PET)/computed tomography (CT) with 18F-3’-deoxy-3’-fluorothymidine (18F-FLT) in patients with orofacial carcinomas and its impact to patient management. Materials and Methods: Thirty-six patients with orofacial squamous cell carcinomas underwent 18F-FLT-PET/CT during radiotherapy. Examinations were performed after administration of 18F-FLT (1.8 MBq/kg) including full-diagnostic CT. Analysis of the radiotherapy effect was performed with possible prospect of repeated and focused irradiation. Results: Complete absence of 18F-FLT uptake was found in 20 patients, thus complete response to radiotherapy was reported. Persistence of focal 18F-FLT uptake was observed in 16 patients; in 11 patients, the measured activity was only mild. In five patients, a higher level of 18F-FLT uptake was measured and additional irradiation was performed in defined regions. Repeated follow-up proved complete regression 18F-FLT uptake. Conclusion: It was possible to assess the effect of radiotherapy with the use of 18F-FLT-PET/CT and findings are suitable for radiation dose-escalation planning.

Prognostic role of serum C-reactive protein in patients with advanced-stage NSCLC treated with pemetrexed

Pemetrexed is an intravenously administered antifolate cytostatic agent targeting several folate-dependent enzymatic pathways, widely used in the treatment of patients with advanced non-small cell lung cancer (NSCLC). It has been previously demonstrated that the superiority of pemetrexed is limited to patients with non-squamous histology. 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 baseline serum levels of C-reactive protein (CRP) with outcomes in a large cohort of patients with non-squamous NSCLC treated with pemetrexed. Clinical data of 325 patients were analysed. Serum samples were collected within one week before the initiation of treatment. The median progression-free (PFS) and overall survival (OS) for patients with high CRP was 2.1 and 9.5 compared to 4.2 and 20.5 months for those with normal CRP (p=0.002 and p<0.001, respectively). The multivariable Cox proportional hazards model revealed that serum CRP (HR=1.46, p=0.002) was significantly associated with PFS and also with OS (HR=1.95, p<0.001). In conclusion, the study results suggest that pretreatment serum CRP is associated with poor outcome of non-squamous NSCLC patients treated with pemetrexed.