Prognostic impact of early ctDNA dynamics during chemotherapy of metastatic cancer.

Aim: Clinical utility of the dynamics of ctDNA is sparse. This study aimed at evaluating the prognostic impact of early ctDNA dynamics in patients with metastatic cancer treated with chemotherapy. Materials & methods: The ctDNA dynamics were evaluated in 595 patients with metastatic cancer using droplet digital PCR. Results: Patients with an increase in ctDNA after one treatment cycle (n = 73; 12.2%) had an overall survival of 5.6 months compared with 8.6 months in patients with stable or decreasing ctDNA (n = 328; 55.1%) and 21.0 months in patients with undetectable ctDNA (p < 0.001; hazard ratio: 0.47; 95% CI: 0.41-0.53). Conclusion: Early ctDNA dynamics hold important prognostic information and have great implications for evaluation with the perspective of a more individualized treatment strategy.

The Soluble Urokinase-Type Plasminogen Activator Receptor as a Biomarker for Survival and Early Treatment Effect in Metastatic Colorectal Cancer.

The soluble urokinase-type plasminogen activator receptor (suPAR) is prognostic for overall survival (OS) in colorectal cancer (CRC). Our study explored the association between baseline suPAR and OS and progression-free survival (PFS) in metastatic CRC (mCRC). It is also the first study to explore the association between the initial change in suPAR level and OS, PFS and the first CT response evaluation. The study included 132 patients with mCRC treated with chemotherapy (FOLFIRI) with or without an EGFR-inhibitor. Blood samples were drawn before the first treatment cycle and in between the first and second treatment cycle. suPAR levels were determined using an ELISA assay. Using the Kaplan-Meyer method, we demonstrated a significantly shorter OS for patients with suPAR levels above the median (HR = 1.79, 95%CI = 1.10-2.92, p = 0.01). We also showed association between plasma suPAR level, gender and performance status (PS). However, we could not show any association with PFS, and analysis on the change in suPAR level provided no significant results. The results showing association between baseline suPAR and OS are in line with previous findings.

Early ctDNA response to chemotherapy. A potential surrogate marker for overall survival.

AIM: The aim of the study was to compare ctDNA response rate and objective response rate as surrogate markers for overall survival (OS) in patients with metastatic cancer treated with chemotherapy. METHODS: The study included 420 patients distributed in five cohorts with colorectal, ovarian, and non-small cell lung cancer. It represents a retrospective analysis of patients enrolled in prospective biomarker studies and clinical trials. All patients had ctDNA measured before start of treatment and at the first evaluation of objective response. ctDNA response rate was defined as the fraction of patients converting from a measurable level at baseline to an unmeasurable level at the first evaluation of objective response. Aberrant, tumour specific, methylated DNA was measured in plasma. The method involves DNA isolation, bisulphite conversion and droplet digital PCR. The primary outcome measure was the correlation between ctDNA response rate, overall response rate (ORR) and median survival. RESULTS: There was moderate correlation between ctDNA response rate and objective response at first evaluation (R2 = 0.68). The same applied to ctDNA response rate and ORR (R2 = 0.57). ctDNA held prognostic information in all the investigated tumour types (p < 0.05). There was a high correlation between ctDNA response and median survival across the included tumour types and treatments (R2 = 0.99) clearly outperforming both response at first evaluation and ORR (R2 = 0.70 and 0.57, respectively). CONCLUSION: The results suggest that ctDNA response might serve as a surrogate marker for OS. If validated, it may have great implications on the approval of new drugs.

Early identification of treatment benefit by methylated circulating tumor DNA in metastatic colorectal cancer.

BACKGROUND: The early identification of treatment effect is wanted in several settings, including the management of metastatic colorectal cancer (mCRC). A potential universal marker is circulating tumor DNA (ctDNA). Our prospective study explored the association between progression-free survival (PFS) and overall survival (OS), and early change of ctDNA after one cycle of chemotherapy in patients with mCRC. METHODS: The study included mCRC patients receiving standard first line combination chemotherapy with 5-Fluorouracil (FU), oxaliplatin, and bevacizumab. Hypermethylated neuropeptide Y (NPY) ctDNA (meth-ctDNA) served as a marker analyzed by droplet digital polymerase chain reaction (PCR). The meth-ctDNA level was analyzed in plasma before treatment start and again before cycle two. The patients were divided into two groups according to the dynamics of meth-ctDNA. Low ctDNA (LctDNA) included patients with zero or values of meth-ctDNA decreasing to a level including zero in the 95% confidence interval. High ctDNA (HctDNA) included all other patients (stable, increasing, or slightly decreasing values). The two groups were compared as to PFS and OS. RESULTS: The study included 123 patients. The PFS in the two groups differed significantly with a median of 9.2 and 6.7 months in LctDNA and HctDNA, respectively (p = 0.0005). This translated into a 12-month difference in OS with a median of 25.4 and 13.5 months, respectively (p = 0.0001). CONCLUSIONS: Early therapeutic reconsideration is of utmost importance. A low level of meth-ctDNA after one cycle of chemotherapy in the first line setting is a potential marker for excellent clinical outcomes. The clinical utility should be confirmed in randomized clinical trials.

Correlation Between Natural Killer Cell Activity and Treatment Effect in Patients with Disseminated Cancer.

INTRODUCTION: The aim of the present study was to analyze the possible correlation between Natural Killer (NK) cell activity as measured by the NK Vue assay and treatment efficacy in patients with disseminated cancer. MATERIALS AND METHODS: The study included four trials encompassing palliative treatment, i.e. one trial on prostate- and ovarian cancer, respectively, and two trials on colorectal cancer. The current results are based on 93 patients with mature data on treatment effect. Blood samples were collected at baseline and prior to each treatment cycle into NK Vue. Following 24 hours of stimulation the level of interferon-gamma (IFNγ) in the plasma was measured as a surrogate for NK cell activity. RESULTS: The relationship between NK cell activity and treatment response was similar across tumor types and treatment. The IFNγ either remained at or dropped to an abnormal level (<200 pg/mL) during treatment in group 1 (n = 35). In group 2 (n = 30) the level remained within a normal range (>200 pg/mL), while in group 3 (n = 28) it increased from an abnormal to a normal level. The response rate was 14%, 47%, and 82%, respectively, P < .001. The median progression free survival was 2.6 months (95% confidence interval (CI) 2.1-3.9), 10.0 months (95% CI 6.5-11.1), and 8.3 months (95% CI 6.5-8.7), respectively, P < .001 (log-rank). CONCLUSION: Patients lacking the ability to mount an immune response during the first 2 months of treatment have a poor prognosis, and their clinical benefit of the treatment is questionable.