Liquid Biopsy in Progressing Prostate Cancer Patients Starting Docetaxel with or Without Enzalutamide: A Biomarker Study of the PRESIDE Phase 3b Trial.

BACKGROUND AND OBJECTIVE: The PRESIDE (NCT02288247) randomized trial demonstrated prolonged progression-free survival (PFS) with continuing enzalutamide beyond progression in metastatic castration-resistant prostate cancer (mCRPC) patients starting docetaxel. This study aims to test the associations of PFS and circulating tumor DNA (ctDNA) prior to and after one cycle (cycle 2 day 1 [C2D1]) of docetaxel and with a liquid biopsy resistance biomarker (LBRB; plasma androgen receptor [AR] gain and/or circulating tumor cells [CTCs] expressing AR splice variant 7 [CTC-AR-V7]) prior to continuation of enzalutamide/placebo. METHODS: Patients consenting to the biomarker substudy and donating blood before starting docetaxel with enzalutamide/placebo (N = 157) were included. Sequential plasma DNA samples were characterized with a prostate-cancer bespoke next-generation-sequencing capture panel (PCF_SELECT), and CTCs were assessed for AR-V7 (Epic Sciences, San Diego, CA, USA). Cox models, Kaplan-Meier, and restricted mean survival time (RMST) at 18 mo were calculated. KEY FINDINGS AND LIMITATIONS: There was a significant association of worse PFS with pre-docetaxel ctDNA detection (N = 86 (55%), 8.1 vs 10.8 mo hazard ratio [HR] = 1.78, p = 0.004) or persistence/rise of ctDNA at C2D1 (N = 35/134, 5.5 vs 10.9 mo, HR = 1.95, 95% confidence interval [CI] = 1.15-3.30, p = 0.019). LBRB-positive patients (N = 62) had no benefit from continuing enzalutamide with docetaxel (HR = 0.78, 95% CI = 0.41-1.48, p = 0.44; RMST: 7.9 vs 7.1 mo, p = 0.50). Conversely, resistance biomarker-negative patients (N = 87) had significantly prolonged PFS (HR = 0.49, 95% CI = 0.29-0.82, p = 0.006; RMST: 11.5 vs 8.9 mo, p = 0.005). Eight patients were unevaluable. An exploratory analysis identified increased copy-number gains (CDK6/CDK4) at progression on docetaxel. Limitations included relatively low detection of CTC-AR-V7. Validation of impact on overall survival is required. CONCLUSIONS AND CLINICAL IMPLICATIONS: Liquid biopsy gives an early indication of docetaxel futility, could guide patient selection for continuing enzalutamide, and identifies cell cycle gene alterations as a potential cause of docetaxel resistance in mCRPC. PATIENT SUMMARY: In the PRESIDE biomarker study, we found that detecting circulating tumor DNA in plasma after starting treatment with docetaxel (chemotherapy) for metastatic prostate cancer resistant to androgen deprivation therapy can predict early how long patients will take to respond to treatment. Patients negative for a liquid biopsy resistance biomarker (based on the status of androgen receptor (AR) gene and AR splice variant 7 in circulating tumor cells) benefit from continuing enzalutamide in combination with docetaxel, while patients positive for the resistance biomarker did not. Additionally, we identified alterations in the cell cycle genes CDK6 and CDK4 as a potential genetic cause of resistance to docetaxel, which may support testing of specific drugs targeting these alterations.

Relationship between malnutrition and the presence of symptoms of anxiety and depression in hospitalized cancer patients.

BACKGROUND: Anxiety and depression are a common issue in patients with cancer, yet understudied among hospitalized patients. The aim of this study was to estimate the prevalence of anxiety and depression symptomatology in cancer inpatients and its relationship with malnutrition. METHODS: Cross-sectional study in hospitalized cancer patients. A nutritional assessment was done using the Global Leadership Initiative on Malnutrition (GLIM) criteria to diagnose malnutrition. Data regarding anxiety and depression symptomatology was obtained with the Hospital Anxiety and Depression Scale (HADS). RESULTS: A total of 282 inpatients were assessed. GLIM criteria found 20% (66) of well-nourished and 80% (216) with malnutrition. HADS presented an average score of 8.3 ± 4.4 with respect to anxiety and an average score of 7.7 ± 4.6 with respect to depression. Up to 54% of the patients showed a possible presence of anxiety, and 45.3% of them showed a possible presence of depression. In malnourished patients, HADS score was non-significantly higher with respect to anxiety (8.5 ± 4.3 in malnourished vs 7.1 ± 4.6 in well-nourished; p = 0.06) and was significantly higher with respect to depression (8.2 ± 4.6 in malnourished vs 5.3 ± 4.0 in well-nourished; p < 0.001). After controlling for potential confounders, malnourished patients were 1.98 times more likely to present anxious symptomatology (95% CI 1.01-3.98; p = 0.049) and 6.29 times more likely to present depressive symptomatology (95% CI 1.73-20.47; p = 0.005). CONCLUSIONS: The presence of anxiety and depression symptomatology in oncological inpatients is high. There is an association between malnutrition and presenting anxious and depressive symptomatology in hospitalized cancer patients.

The economic cost of not coding disease-related malnutrition: A study in cancer inpatients.

BACKGROUND & AIMS: Disease-related malnutrition (DRM) coding rate is usually low in hospitalised patients. The objective of our study was to estimate the percentage of correct DRM coding in cancer inpatients and to calculate the economic losses caused by such lack of coding. METHODS: This was an observational, prospective study that was conducted in patients hospitalised in the Medical Oncology Unit of our hospital. A nutritional assessment was performed through subjective global assessment (SGA). The all patient refined-diagnosis related group (APR-DRG) weights were obtained at the moment of discharge; moreover, recalculation was done after including the diagnosis of malnutrition in the medical record of those patients in whom it had not been initially coded. The associated cost reimbursement were calculated based on the weight before and after revising the diagnosis of DRM. RESULTS: A total of 266 patients were evaluated. From them, 220 (82.7%) suffered from DRM according to the SGA. In 137 (51.5%) of these patients, diagnosis was coded, as opposed to 83 (31.2%) cases (33 subjects with moderate and 50 with severe DRM) in whom it was not coded. The sum of the APR-DRG weights before revising the diagnosis of malnutrition was 343.4 points (mean: 1.29 ± 0.89). Whereas, after revising the diagnosis, it increased up to 384.3 (1.44 ± 0.96). The total cost reimbursement for the hospital before revising the diagnosis of malnutrition was 1,607,861.21€ and after revision it increased up to 1,799,199.69€, which means that 191,338.48€ were not reimbursed to the hospital due to the lack of coding of malnutrition. The cost reimbursement for each admission increased an average of 719.32€. CONCLUSION: The prevalence of DRM in cancer inpatients is high. Nevertheless, the diagnosis is not coded in one third of patients, which results in important economic losses for the hospitals.

CT-Determined Sarcopenia in GLIM-Defined Malnutrition and Prediction of 6-Month Mortality in Cancer Inpatients.

Our objective was to evaluate the clinical application of third lumbar vertebra (L3)-computer tomography (CT)-determined sarcopenia as a marker of muscle mass in cancer inpatients diagnosed with malnutrition according to the Global Leadership Initiative on Malnutrition (GLIM) criteria and to establish its association with 6-month mortality. METHODS: This was an observational, prospective study in patients from an inpatient oncology unit. We performed a nutritional assessment according to GLIM criteria, including muscle cross-sectional area at L3 by CT and skeletal muscle index (SMI). Six-month mortality was evaluated. RESULTS: A total of 208 patients were included. The skeletal muscle cross-sectional area at L3 was 136.2 ± 32.5 cm2 in men and 98.1 ± 21.2 cm2 in women. The SMI was 47.4 ± 12.3 cm2/m2 in men and 38.7 ± 8.3 cm2/m2 in women. Sarcopenia (low SMI) was detected in 59.6% of the subjects. Using SMI as a marker of low muscle mass in application of GLIM criteria, we found 183 (87.9%) malnourished patients. There were 104 deaths (50%) at 6 months. The deceased patients had a lower skeletal muscle cross-sectional area (112.9 ± 27.9 vs. 126.1 ± 37.8 cm2; p = 0.003) and a lower SMI (41.3 ± 9.5 vs. 45.7 ± 12.9 cm2/m2; p = 0.006). An increased risk of 6-month mortality was found in malnourished patients according to GLIM criteria using SMI (HR 2.47; 95% confidence interval 1.07-5.68; p = 0.033). CONCLUSIONS: Low muscle mass, assessed by L3-CT, was observed to affect more than half of cancer inpatients. The deceased patients at 6 months had a lower skeletal muscle cross-sectional area and SMI. Malnutrition according to GLIM criteria using CT-determined sarcopenia was shown to adequately predict 6-month mortality.

GLIM Criteria Using Hand Grip Strength Adequately Predict Six-Month Mortality in Cancer Inpatients.

Protein-calorie malnutrition is very frequent in cancer patients and is associated with an increase in morbidity and mortality. Recently, the Global Leadership Initiative on Malnutrition (GLIM) criteria were proposed to standardize the diagnosis of malnutrition. Nevertheless, these criteria were not validated in prospective studies. Our objective is to determine the prevalence of malnutrition in cancer inpatients using different diagnostic classifications, including GLIM criteria, and to establish their association with length of stay and mortality. Hence, we designed a prospective study. Within the first 24 hours of admission to the Inpatient Oncology Unit, subjective global assessment (SGA) was carried out, and anthropometric data (body mass index (BMI), mid-arm circumference (MAC), arm muscle circumference (AMC), fat-free mass index (FFMI)) and hand grip strength (HGS) were obtained to assess the reduction of muscle mass according to GLIM criteria. Length of stay, biomarkers (albumin, prealbumin, C-reactive protein (CRP)), and in-hospital and six-month mortality were evaluated. Regarding the 282 patients evaluated, their mean age was 60.4 ± 12.6 years, 55.7% of them were male, and 92.9% had an advanced-stage tumor (17.7% stage III, 75.2% stage IV). According to SGA, 81.6% of the patients suffered from malnutrition (25.5% moderate malnutrition, and 56.1% severe malnutrition), and, based on GLIM criteria, malnutrition rate was between 72.2 and 80.0% depending on the used tool. Malnourished patients (regardless of the tool used) showed significantly worse values concerning BMI, length of stay, and levels of CRP/albumin, albumin, and prealbumin than normally nourished patients. In logistic regression, adjusted for confounding variables, the odds ratio of death at six months was significantly associated with malnutrition by SGA (odds ratio 2.73, confidence interval (CI) 1.35-5.52, p = 0.002), and by GLIM criteria calculating muscle mass with HGS (odds ratio 2.72, CI 1.37-5.40, p = 0.004) and FFMI (odds ratio 1.87, CI 1.01-3.48, p = 0.047), but not by MAC or AMC. The prevalence of malnutrition in advanced-stage cancer inpatients is very high. SGA and GLIM criteria, especially with HGS, are useful tools to diagnose malnutrition and have a similar predictive value regarding six-month mortality in cancer inpatients.