Introduction: We investigated the safety and efficacy of pemetrexed with gemcitabine in heavily pre-treated, chemotherapy refractory, KRAS mutated colorectal cancer (mCRC) and the prognostic value of quantitative leve...Introduction: We investigated the safety and efficacy of pemetrexed with gemcitabine in heavily pre-treated, chemotherapy refractory, KRAS mutated colorectal cancer (mCRC) and the prognostic value of quantitative levels of cell free DNA (cfDNA) in plasma. Methods: Inclusion criteria comprised;histopathologically verified, KRAS mutant, chemotherapy resistant mCRC, adequate organ function and performance status. Patients received pemetrexed (initially 500 mg/m2 q3w) + gemcitabine (1250 mg/m2 days 1 and 8) until progression or unacceptable toxicity. RECIST version 1.1, NCI-CTCAE version 4.0 and Kaplan-Meier statistics were used for endpoint evaluation. Cell free DNA was quantified from pre-treatment EDTA plasma-samples by an in-house qPCR. Results: Forty patients were included. The median number of cycles was 3 (range 0 - 12). Thirty-six percent obtained disease stabilisation, but?no objective response was observed. Median PFS and OS were 2.8 (range 2.1 - 4.0) and 5.4 (range 4.3 - 7.0) months, respectively. Adverse events caused immediate discontinuation of treatment or delay of the next cycle and consequently discontinuation in 5 patients. Translational research revealed a shorter PFS and OS with increasing levels of cfDNA. The median PFS in patients with cfDNA levels above the 75 percentile was 2 months compared to 4 months in the remaining patients, HR 3.23 (1.05 - 9.89), p = 0.0008. The median OS was 3 and 6 months, respectively, HR 2.9 (95%CI 0.98 - 8.34). Cox regression analysis confirmed that cfDNA remained a significantly independent prognostic factor for both PFS and OS. Conclusion: Pemetrexed and gemcitabine did not prove sufficient benefit and unacceptable toxicity was observed. The potential value of cfDNA should be investigated further.展开更多
Background: Cell-free DNA (cfDNA) holds promise as a tumor marker of clinical importance. We aimed to investigate the prognostic value of baseline cfDNA in non small-cell lung cancer (NSCLC). Material and Methods: Dur...Background: Cell-free DNA (cfDNA) holds promise as a tumor marker of clinical importance. We aimed to investigate the prognostic value of baseline cfDNA in non small-cell lung cancer (NSCLC). Material and Methods: During a three-year period, patients with newly diagnosed, previously untreated advanced NSCLC were included in a consecutive, prospective marker-trial. Plasma was isolated from a pre-treatment peripheral blood sample and the level of total cfDNA was measured by an in-house assay qPCR-method. The treatment comprised carboplatin (AUC 5) intravenously day 1), and vinorelbine (30 mg/m2 intravenously day 1 and 60 mg/m2 perorally day 8) q3w for a maximum of six cycles. The primary end-point was overall survival (OS). Secondary end-points were progression free survival (PFS) and overall response rate (ORR). Results: 245 patients were included and received a minimum of 1 cycle of chemotherapy (median 4). The median OS was 8.9 months, the median PFS by intention to treat 5.4 months and the ORR was 25%. The patients were divided into four groups based on quartiles of cfDNA and subsequently dichotomized by the 75th percentile revealing a significantly worse prognosis for patients in the upper 75th percentile (median OS 4.9 months) compared to patients with lower levels (10.0 months) (HR 2.1, 95%CI 1.4 - 3.1, p 0.0001). A multivariate analysis confirmed the independent prognostic value of cfDNA. A subgroup analysis of patients with high cfDNA and poor performance status (PS = 2) identified a group of patients with even worse prognosis (median OS 2.0 versus 9.1 months, HR 3.6, 95%CI 1.4 - 9.2, p 0.0001). Similar and significant results were found when comparing level of cfDNA and PFS. Conclusions: High pre-treatment level of cfDNA seems to have a strong prognostic impact in patients with newly diagnosed advanced NSCLC. Combined with PS it identifies a patient group with minimal or no benefit of chemotherapy.展开更多
Most colorectal cancers evolve through an adenoma-carcinoma sequence with mutations in the KRAS/BRAF pathway as an early event. Mutation analyses are usually performed on tissue samples, but during the last couple of ...Most colorectal cancers evolve through an adenoma-carcinoma sequence with mutations in the KRAS/BRAF pathway as an early event. Mutation analyses are usually performed on tissue samples, but during the last couple of years the same analysis in blood has been facilitated. Our aim was to investigate the correlation between BRAF/KRAS mutations in tissue and plasma from colorectal adenomas and adenocarcinomas. Out of 22 patients with adenomas 10 had a mutation in the tissue, but no mutations were detected in the plasma. In 10 of 26 adenocarcinomas a mutation was found in the tumor and in four of these, the mutation was also detected in the plasma. Our results confirm previous findings that mutated DNA in plasma can be detected in approximately 50%?of non-metastasized adenocarcinomas. The difference between adenomas and adenocarcinomas suggests that appearance of mutated DNA in plasma associates with invasion.展开更多
文摘Introduction: We investigated the safety and efficacy of pemetrexed with gemcitabine in heavily pre-treated, chemotherapy refractory, KRAS mutated colorectal cancer (mCRC) and the prognostic value of quantitative levels of cell free DNA (cfDNA) in plasma. Methods: Inclusion criteria comprised;histopathologically verified, KRAS mutant, chemotherapy resistant mCRC, adequate organ function and performance status. Patients received pemetrexed (initially 500 mg/m2 q3w) + gemcitabine (1250 mg/m2 days 1 and 8) until progression or unacceptable toxicity. RECIST version 1.1, NCI-CTCAE version 4.0 and Kaplan-Meier statistics were used for endpoint evaluation. Cell free DNA was quantified from pre-treatment EDTA plasma-samples by an in-house qPCR. Results: Forty patients were included. The median number of cycles was 3 (range 0 - 12). Thirty-six percent obtained disease stabilisation, but?no objective response was observed. Median PFS and OS were 2.8 (range 2.1 - 4.0) and 5.4 (range 4.3 - 7.0) months, respectively. Adverse events caused immediate discontinuation of treatment or delay of the next cycle and consequently discontinuation in 5 patients. Translational research revealed a shorter PFS and OS with increasing levels of cfDNA. The median PFS in patients with cfDNA levels above the 75 percentile was 2 months compared to 4 months in the remaining patients, HR 3.23 (1.05 - 9.89), p = 0.0008. The median OS was 3 and 6 months, respectively, HR 2.9 (95%CI 0.98 - 8.34). Cox regression analysis confirmed that cfDNA remained a significantly independent prognostic factor for both PFS and OS. Conclusion: Pemetrexed and gemcitabine did not prove sufficient benefit and unacceptable toxicity was observed. The potential value of cfDNA should be investigated further.
文摘Background: Cell-free DNA (cfDNA) holds promise as a tumor marker of clinical importance. We aimed to investigate the prognostic value of baseline cfDNA in non small-cell lung cancer (NSCLC). Material and Methods: During a three-year period, patients with newly diagnosed, previously untreated advanced NSCLC were included in a consecutive, prospective marker-trial. Plasma was isolated from a pre-treatment peripheral blood sample and the level of total cfDNA was measured by an in-house assay qPCR-method. The treatment comprised carboplatin (AUC 5) intravenously day 1), and vinorelbine (30 mg/m2 intravenously day 1 and 60 mg/m2 perorally day 8) q3w for a maximum of six cycles. The primary end-point was overall survival (OS). Secondary end-points were progression free survival (PFS) and overall response rate (ORR). Results: 245 patients were included and received a minimum of 1 cycle of chemotherapy (median 4). The median OS was 8.9 months, the median PFS by intention to treat 5.4 months and the ORR was 25%. The patients were divided into four groups based on quartiles of cfDNA and subsequently dichotomized by the 75th percentile revealing a significantly worse prognosis for patients in the upper 75th percentile (median OS 4.9 months) compared to patients with lower levels (10.0 months) (HR 2.1, 95%CI 1.4 - 3.1, p 0.0001). A multivariate analysis confirmed the independent prognostic value of cfDNA. A subgroup analysis of patients with high cfDNA and poor performance status (PS = 2) identified a group of patients with even worse prognosis (median OS 2.0 versus 9.1 months, HR 3.6, 95%CI 1.4 - 9.2, p 0.0001). Similar and significant results were found when comparing level of cfDNA and PFS. Conclusions: High pre-treatment level of cfDNA seems to have a strong prognostic impact in patients with newly diagnosed advanced NSCLC. Combined with PS it identifies a patient group with minimal or no benefit of chemotherapy.
文摘Most colorectal cancers evolve through an adenoma-carcinoma sequence with mutations in the KRAS/BRAF pathway as an early event. Mutation analyses are usually performed on tissue samples, but during the last couple of years the same analysis in blood has been facilitated. Our aim was to investigate the correlation between BRAF/KRAS mutations in tissue and plasma from colorectal adenomas and adenocarcinomas. Out of 22 patients with adenomas 10 had a mutation in the tissue, but no mutations were detected in the plasma. In 10 of 26 adenocarcinomas a mutation was found in the tumor and in four of these, the mutation was also detected in the plasma. Our results confirm previous findings that mutated DNA in plasma can be detected in approximately 50%?of non-metastasized adenocarcinomas. The difference between adenomas and adenocarcinomas suggests that appearance of mutated DNA in plasma associates with invasion.
