Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up.

PURPOSE: As noninvasive biomarkers are an important unmet need for neuroendocrine neoplasms (NEN), biomarker potential of genome-wide molecular profiling of plasma cell-free DNA (cfDNA) was prospectively studied in patients with NEN. EXPERIMENTAL DESIGN: Longitudinal plasma samples were collected from patients with well-differentiated, metastatic gastroenteropancreatic and lung NEN. cfDNA was subjected to shallow whole-genome sequencing to detect genome-wide copy-number alterations (CNA) and estimate circulating tumor DNA (ctDNA) fraction, and correlated to clinicopathologic and survival data. To differentiate pancreatic NENs (PNEN) from pancreatic adenocarcinomas (PAAD) using liquid biopsies, a classification model was trained using tissue-based CNAs and validated in cfDNA. RESULTS: One hundred and ninety-five cfDNA samples from 43 patients with NEN were compared with healthy control cfDNA (N = 100). Plasma samples from patients with PNEN (N = 21) were used for comparison with publicly available PNEN tissue (N = 98), PAAD tissue (N = 109), and PAAD cfDNA (N = 96). Thirty percent of the NEN cfDNA samples contained ctDNA and 44% of the patients had at least one ctDNA-positive (ctDNA+) sample. CNAs detected in cfDNA were highly specific for NENs and the classification model could distinguish PAAD and PNEN cfDNA samples with a sensitivity, specificity, and AUC of 62%, 86%, and 79%, respectively. ctDNA-positivity was associated with higher World Health Organization (WHO) grade, primary tumor location, and higher chromogranin A and neuron-specific enolase values. Overall survival was significantly worse for ctDNA+ patients and increased ctDNA fractions were associated with poorer progression-free survival. CONCLUSIONS: Sequential genome-wide profiling of plasma cfDNA is a novel, noninvasive biomarker with high specificity for diagnosis, prognosis, and follow-up in metastatic NENs.

Cachexia in cancer: what is in the definition?

OBJECTIVE: This study aimed to provide evidence-based results on differences in overall survival (OS) rate to guide the diagnosis of cancer cachexia. DESIGN: Data collection and clinical assessment was performed every 3 months (5 visits): baseline data, muscle strength, nutritional and psychosocial status. 2 definitions on cachexia using different diagnostic criteria were applied for the same patient population. Fearon et al's definition is based on weight loss, body mass index (BMI) and sarcopenia. Evans et al nuances the contribution of sarcopenia and attaches additional attention to abnormal biochemistry parameters, fatigue and anorexia. The mean OS rates were compared between patients with and without cachexia for both definitions. RESULTS: Based on the population of 167 patients who enrolled, 70% developed cachexia according to Fearon et al's definition and 40% according to Evans et al's definition. The OS in the cachectic population is 0.97 and 0.55 years, respectively. The difference in OS between patients with and without cachexia is more significant using the diagnostic criteria of Evans et al. The focus of Fearon et al on weight loss and sarcopenia over-rates the assignment of patients to the cachectic group and OS rates have less prognostic value. CONCLUSION: This study presents a correlation with prognosis in favour of Evans et al' definition as a tool for cachexia diagnosis. This means that weight loss and BMI decline are both key factors in patients with cancer leading to cachexia but less decisive as stated by Fearon et al. Instead, extra factors gain importance in order to predict survival, such as chronic inflammation, anaemia, protein depletion, reduced food intake, fatigue, decreased muscle strength and lean tissue depletion. TRIAL REGISTRATION NUMBER: B300201112334.