Circulating Tumor DNA Monitoring Reveals Molecular Progression before Radiologic Progression in a Real-life Cohort of Patients with Advanced Non-small Cell Lung Cancer

Purpose: The clinical potential of liquid biopsy in patients with advancedcancer is real-time monitoring for early detection of treatment failure.Our study aimed to investigate the clinical validity of circulating tumorDNA (ctDNA) treatment monitoring in a real-life cohort of patients withadvanced non–small cell lung cancer (NSCLC).Experimental Design: Patients with advanced or noncurative locallyadvanced NSCLC were prospectively included in an exploratory study(NCT03512847). Selected cancer-specific mutations were measured inplasma by standard or uniquely designed droplet digital PCR assays beforeevery treatment cycle during first-line treatment until progressive disease(PD). Correlation between an increase in ctDNA (= molecular progres-sion) and radiologic PD was investigated, defined as lead time, and thecorresponding numbers of likely futile treatment cycles were determined.Utility of ctDNA measurements in clarifying the results of nonconclusiveradiologic evaluation scans was evaluated.Results: Cancer-specific mutations and longitudinal plasma sampling werepresent in 132 of 150 patients. ctDNA was detectable in 88 (67%) of132 patients treated by respectively chemotherapy (n = 41), immunotherapy(n = 43), or combination treatment (n = 4). In 66 (90%) of 73 patients ex-periencing PD, a ctDNA increase was observed with a median lead time of1.5 months before radiologic PD. Overall, 119 (33%) of 365 treatment cy-cles were administered after molecular progression. In addition, ctDNAmeasurements could clarify the results in 38 (79%) of 48 nonconclusiveradiologic evaluations.Conclusions: ctDNA monitoring leads to earlier detection of treatmentfailure, and clarifies the majority of nonconclusive radiologic evaluations,giving the potential of sparing patients from likely futile treatments andneedless adverse events.Significance: Treatment monitoring by ctDNA has the clinical potentialto reveal PD before radiologic evaluation and consequently spare patientswith advanced cancer from likely ineffective, costly cancer treatments andadverse events

Widespread glacial erosion on the Scandinavian passive margin

The topography in Scandinavia features enigmatic high-elevation low-relief plateau regions dissected by deep valleys and fjords. These plateau regions have long been interpreted as relict landforms of a preglacial origin, whereas recent studies suggest they have been modified significantly by glacial and periglacial denudation. We used late Pliocene–Quaternary source-to-sink analyses to untangle this scientific conundrum. We compared glacier-derived offshore sediment volumes with estimates of erosion in onshore valleys and fjords and on the inner shelf. Our results suggest that onshore valley and fjord erosion falls 61%–66% short of the offshore sink volume. Erosion on the inner shelf cannot accommodate this mismatch, implying that the entire Scandinavian landscape and adjacent shelf have experienced significant glacial erosion.publishedVersio

Quantification of Cell-free HER-2 DNA in Plasma from Breast Cancer Patients: Sensitivity for Detection of Metastatic Recurrence and Gene Amplification

The purpose of this study was to quantify the free-circulating plasma HER-2 DNA (cfHER-2 DNA) and to assess the ability of analysis to discriminate between patients with primary breast cancer and healthy controls in order to detect metastatic recurrence in comparison with serum HER-2 protein and also HER-2 gene amplification. The study population consisted of 100 patients with primary breast cancer and 50 healthy female donors. An additional 22 patients with metastases were subsequently included. cfHER-2 DNA was quantified with a quantitative PCR method together with a reference gene. Results: Using a cut-off of 2.5 for the ratio of the cfHER-2 DNA/reference gene, three (of 15) tissue HER-2-positive patients had a ratio >2.5 prior to the detection of metastatic disease. In the post-metastatic/pre-chemotherapy setting, 11 (of 23) tissue HER-2-positive patients with metastases had a ratio >2.5. There was no difference between absolute preoperative cfHER-2 DNA values for patients with primary breast cancer and those for healthy controls. There was no difference between cfHER-2 DNA values taken within nine months of development of the metastatic disease and the levels in patients without metastases, but there was a significant difference in the corresponding serum HER-2 protein levels in the tissue HER-2-positive patient group. Conclusion: Amplified HER-2 DNA can be detected in plasma when using a ratio comparison between cfHER-2 DNA and a reference gene. cfHER-2 DNA could not be used to discriminate between patients with primary breast cancer and healthy controls, and could not predict the development of metastatic disease

The Importance of Feasibility Assessment in the Design of ctDNA Guided Trials – Results From the OPTIPAL II Study

Introduction: Both quantitative and molecular changes in ctDNA can hold important information when treating metastatic colorectal cancer (mCRC), but its clinical utility is yet to be established. Before conducting a large-scale randomized trial, it is essential to test feasibility. This study investigates whether ctDNA is feasible for detecting patients who will benefit from treatment with epidermal growth factor receptor inhibitors and the prognostic value of circulating tumor DNA (ctDNA) response. Materials and methods: Patients with mCRC, who were considered for systemic palliative treatment and were eligible for ctDNA analysis. Mutational testing on cell-free DNA (cfDNA) was done by ddPCR. ctDNA response from baseline to the third treatment cycle was evaluated in patients with detectable ctDNA at baseline. ctDNA maximum response was defined as undetectable ctDNA at the third treatment cycle, ctDNA partial response as any decrease in the ctDNA level, and ctDNA progression as any increase in the ctDNA level. Results: Forty-nine patients were included. The time to test results for mutational testing on cfDNA was significantly shorter than on tumor tissue (p &lt; .001). Progression-free survival were 11.2 months (reference group), 7.5 months (HR = 10.7, p= .02), and 4.6 months (HR = 11.4, p= .02) in patients with ctDNA maximum response, partial response, and progression, respectively. Overall survival was 31.2 months (reference group), 15.2 months (HR = 4.1, p= .03), and 9.0 months (HR = 2.6, p= .03) in patients with ctDNA maximum response, partial response, and progression, respectively. Conclusion: Pretreatment mutational testing on cfDNA in daily clinic is feasible and can be applied in randomized clinical trials evaluating the clinical utility of ctDNA. Early dynamics in ctDNA during systemic treatment hold prognostic value.</p