Prevalence and biopsychosocial indicators of fatigue in cancer patients.

INTRODUCTION: Symptoms of cancer-related fatigue (CRF) can have a significant impact on patients' quality of life and treatment adherence. We aimed to investigate the relationship between CRF and multiple psychosocial and somatic indicators within a large mixed cancer sample. METHODS: In this cross-sectional study, N = 1787 outpatients with cancer were assessed for CRF, pain, anxiety, and depression using validated screening instruments. We further obtained clinical parameters (Hb, CRP, creatinine, leukocytes, ASAT, and ALAT), sociodemographic data (age, gender, income, education level, marital status, parenthood, and living area), and lifestyle factors. Multivariate linear regression models were applied to estimate the impact of each indicator on CRF. RESULTS: Overall, 90.6% of patients experienced some CRF, with 14.8% experiencing severe CRF. No gender difference was found in the prevalence of CRF. Patients with higher levels of pain, depressive symptoms, and lower Hb levels had significantly higher levels of CRF (ps <0.001). Lower levels of CRF were observed in patients who had children (p = 0.03), had less education (p < 0.001), and were physically active for more than 2 h per week before their oncological diagnosis (p = 0.014). The latter was only a significant indicator in the male subsample. CONCLUSION: The present results demonstrate a high prevalence of CRF and highlight that not only somatic and psychosocial factors, but also lifestyle factors prior to diagnosis appear to be associated with the etiology and persistence of CRF. To effectively treat CRF, a biopsychosocial, personalized approach is recommended.

Thalidomide for the Management of Gastrointestinal Bleeding in a Palliative Care Setting.

BACKGROUND: Palliative care patients frequently present with clinically significant gastrointestinal bleeding. Due to the existence of confounding comorbidities and a remarkably reduced state of general health in many cases, the management of gastrointestinal bleeding in this population is often challenging. SUMMARY: This review summarizes and discusses the role of thalidomide in gastrointestinal bleeding with a special focus on palliative care patients. In addition, an illustrative case report is presented. Thalidomide may be beneficial in gastrointestinal bleeding by exerting antiangiogenic effects. The drug has an acceptable safety profile. Side effects like neurotoxicity may limit its use but can be monitored safely. Due to thalidomide's thrombin generation potential, patients managed with thalidomide-containing regimes should be closely monitored for deep venous thrombosis. Given its teratogenicity, thalidomide should not be administered to women of childbearing potential who are not using adequate contraception. KEY MESSAGE: Physicians caring for patients in a palliative care setting should be aware of thalidomide as an effective therapeutic option when endoscopy fails to find a bleeding source or for those patients who cannot or refuse to undergo endoscopy but present with recurrent or obscure gastrointestinal bleeding.

On dying alone in prison and the social responsibility of medicine: a pilot interview study of physicians caring for terminally ill incarcerated patients in Austria and the United States.

BACKGROUND: This group of physicians is difficult to reach and small in number. While studies of palliative care and end-of-life (EOL) issues in prison have increased, especially in the United States and since the coronavirus disease 2019 (COVID-19) pandemic, they are still limited due to the constraints of carrying out research in carceral contexts. At present, there is very little knowledge of the experiences of physicians providing EOL care in prisons. The aim of this pilot study was to examine the experiences of doctors caring for terminally ill patients inside prisons. METHODS: Three expert qualitative interviews were conducted in March and April 2021 with physicians working in carceral institutions in New York State and Austria. The interviews were audio-recorded and transcribed verbatim. Braun and Clarke's thematic analysis was used to examine the data. RESULTS: The following five themes were found: (I) a lack of training and support; (II) interrupted relationships; (III) limitations on visits and saying one's goodbyes; (IV) security as a main concern; and (V) the possibility of release. CONCLUSIONS: The study reveals the difficulties physicians face when caring for dying incarcerated patients. Provider-patient relationships are hardly continuous. The findings represent a starting point for further research. Support from the medical and palliative care community is needed for adequate provision of EOL care within prisons, improved post-release conditions, and help for physicians working in existing structures.

Routine laboratory parameters to support decision on parenteral nutrition in palliative care.

Introduction: Parenteral nutrition (PN) is widely used in palliative care (PC), but there is limited evidence to support its use at the end of life (EOL). This aim of this was to investigate the relationship between routine laboratory parameters and survival in patients receiving PN, and to develop a decision tree model to support clinicians decide whether to start or forgo PN. Methods: The laboratory parameters of 113 patients with advanced diseases who were admitted to a specialized palliative care unit (PCU) were analyzed at two points in time: T0 = before PN, T1 = two weeks after initiation of PN. Univariate Mann-Whitney U-tests and multivariate linear regression models, as well as a decision tree analysis were computed; all in relation to survival time. Results: The final regression model was significant with p = 0.001 (adjusted R2 = 0.15) and included two predictors for survival time after PN initiation: the CRP/albumin ratio and urea at T1 (ps = 0.019). Decision tree analysis revealed three important predictors for classification of survival time after PN initiation: CRP, urea, and LDH (all at T0). Discussion: The decision tree model may help to identify patients likely to benefit from PN, thus supporting the clinical decision whether or not to start PN.

The impact of COVID-19 and socioeconomic status on psychological distress in cancer patients.

Objective: We aimed to investigate the impact of the COVID-19 pandemic on psychological symptom burden against the socioeconomic background of cancer patients using data from routine assessments before and during the pandemic. Method: In this cross-sectional study, standardised assessment instruments were applied in N = 1,329 patients to screen for symptoms of anxiety, depression, post-traumatic stress, and fatigue from 2018 to 2022. Two MANOVAs with post-hoc tests were computed. First, only time was included as predictor to examine the isolated impact of the pandemic. Second, income level and education level were included as further predictors to additionally test the predictive power of socioeconomic factors. Results: In the final model, only income had a significant impact on all aspects of psychological symptom burden, with patients with low income being highly burdened (partial η² = .01, p = .023). The highest mean difference was found for depressive symptoms (MD = 0.13, CI = [0.07; 0.19], p < .001). The pandemic had no further influence on psychological distress. Conclusions: Although the pandemic is a major stressor in many respects, poverty may be the more important risk factor for psychological symptom burden in cancer outpatients, outweighing the impact of the pandemic.

Interactions of EGFR/PTEN/mTOR-Pathway Activation and Estrogen Receptor Expression in Cervical Cancer.

(1) Objective: Late-line chemotherapy rechallenge in recurrent cervical cancer is associated with modest therapy response but significant side effects. As mTOR pathways modulate cellular growth via estrogen receptor (ER) signaling and combined mTOR and ER inhibition previously demonstrated survival benefits in breast cancer, this exploratory study evaluates mTOR pathway and ER expression interactions in a preclinical cervical cancer model. (2) Methods: Immunostaining of a 126-tumor core tissue microarray was performed to assess phosphorylated-mTOR and ER expression. To identify tumor subsets with different clinical behavior, expression results were matched with clinicopathologic patient characteristics, and both univariate and multivariable survival statistics were performed. (3) Results: phosphorylated-mTOR correlates with ER (r = 0.309, p < 0.001) and loss of PTEN expression (r = -2.09, p = 0.022) in tumor samples across stages but not in matched negative controls. Positive ER expression is observed significantly more often in phosphorylated-mTOR positive samples (30.0% vs. 6.3%, p = 0.001). In the subgroup of phosphorylated-mTOR positive tumors (n = 60), ER expression is associated with improved survival (p = 0.040). (4) Conclusion: ER expression appears closely intertwined with EGFR/PTEN/mTOR-pathway activation and seems to define a subgroup with clinically distinct behavior. Considering limited therapeutic options in recurrent cervical cancer, further validation of combined mTOR and ER inhibition in selected patients could appear promising.

Risk as a pattern over time: Delineation of time-dependent risk factors in biological, psychological, and social variables in cancer patients.

BACKGROUND: Survival in cancer patients is associated with a multitude of biological, social, and psychological factors. Although it is well established that all these factors add to overall mortality, it is not well understood how the predictive power of these parameters changes in a comprehensive model and over time. METHODS: Patients who attended the authors' outpatient clinic were invited to participate. The authors followed 5180 mixed cancer patients (51.1% female; mean age, 59.1 years [SD = 13.8]) for up to 16 years and analyzed biological (age, sex, cancer site, anemia), psychological (anxiety, depression), and social variables (marital status, education, employment status) potentially predicting overall survival in a Cox proportional hazards model. RESULTS: The median survival time for the entire sample was 4.3 years (95% confidence interval, 4.0-4.7). The overall survival probabilities for 1 and 10 years were 76.8% and 38.0%, respectively. Following an empirical approach, the authors split the time interval into five periods: acute, subacute, short-term, medium-term, and long-term. A complex pattern of variables predicted overall survival differently in the five periods. Biological parameters were important throughout most of the time, social parameters were either time-independent predictors or tended to be more important in the longer term. Of the psychological parameters, only depression was a significant predictor and lost its predictive power in the long-term. CONCLUSIONS: The findings of this study allow the development of comprehensive patient-specific models of risk and resilience factors addressing biopsychosocial needs of cancer patients, paving the way for a personalized treatment plan that goes beyond biomedical cancer care.

The potential of medical comics to teach palliative care skills: a cross-sectional study of 668 medical students.

BACKGROUND: Palliative care (PC) skills are important when caring for patients with advanced illness in a broad range of settings. Students need to be trained in communication and empathy, both representing essential PC skills. Therefore, creative approaches could promote the understanding of relevant PC skills. METHODS: In an online lecture about graphic medicine, different medical comics (MC) were used to introduce the field of graphic medicine and to illustrate relevant skills in PC. After the lecture, an online survey was conducted. The survey consisted of each respondent`s sociodemographic profile and a questionnaire on multiple aspects related to the field of MC. Spearman correlation coefficients and Cohen's effect sizes were used for statistical analysis. RESULTS: The survey respondents comprised 668 students, 337 female, 326 male and 5 diverse. The results showed that the students had never (27.2%) or had very rarely (31.9%) been involved in with the field of MC. The largest number would rate their interest as somewhat or very interested (58.8%). When considering the use of MC to understand different perspectives, the students mainly rated them as useful (54.6%) or very useful (23.4%). Women had a more positive attitude towards MC than men (P<0.001). Students who placed more importance on PC skills were more likely to recommend the use of MC in general medical education (r=0.11, P=0.005). The majority of the students (58.8%) moderately or strongly agreed on the use of MC as a teaching method in PC. CONCLUSIONS: After a single lecture on graphic medicine, the students were positive about using MC for teaching PC skills. Since the lecture was short and the majority of the medical students stated that they had not been previously exposed to the field of MC, this study demonstrates that it is promising to further use and evaluate a set of visual and narrative illustrations as a teaching method in PC.

Challenges in Palliative Care Nursing at a University Hospital: A Qualitative Interview Study.

We examined the perception of palliative care nurses regarding challenges, coping strategies, resources, and needs when working in a university hospital in Austria. A qualitative descriptive design was applied, using semistructured interviews with 8 female and 2 male nurses. All interviews were recorded as digital audio and transcribed verbatim. We used thematic analysis and MAXQDA. In our analysis, 6 themes emerged: Four themes related to challenges: ( a ) lack of a supporting structural framework, ( b ) conflict in interdisciplinary work, ( c ) conflict with caregivers, and ( d ) dealing with death in a highly specialized university environment. One theme related to ( e ) individual solutions and coping strategies, and 1 theme comprised ( f ) needs and suggestions for improvements. Taking care of the family of a dying person, handling threatening situation, and working with inexperienced physicians were among the most important challenges reported by nurses. A supportive team, professional counseling, and training related to communication skills and to culturally specific needs of families are perceived to be necessary to provide high-quality palliative care. Addressing the needs of nurses can substantially improve their working condition and has an impact not only on the nurses themselves but also on the quality of patient care.

Latent structure and measurement invariance of the Hospital Anxiety and Depression Scale in cancer outpatients.

Background/Objective: The aim of the present study was to compare competing psychometric models and analyze measurement invariance of the Hospital Anxiety and Depression Scale (HADS) in cancer outpatients. Method: The sample included 3,260 cancer outpatients. Latent structure of the HADS was analyzed using confirmatory factor analysis (CFA) with robust maximum likelihood estimation (MLR). Measurement invariance was tested for age, time of response, gender, and cancer type by comparing nested multigroup CFA models with parameter restrictions. Results: Except for the one-factor solutions, all models showed acceptable model fit and measurement invariance. The model with the best fit was the originally proposed two-factor model with exclusion of two items. The one-factor solutions showed inacceptable model fit and were not invariant for age and gender. Conclusions: The HADS has a robust two-factor structure in cancer outpatients. We recommend excluding item 7 and 10 when screening for anxiety and depression.

Determination of Extravasation Effects of Nal-Iri and Trabectedin and Evaluation of Treatment Options for Trabectedin Extravasation in a Preclinical Animal Model.

Background: Extravasation during chemotherapy administration can lead to dangerous adverse effects ranging from pain to tissue necrosis. Evidence-based data about prevention and treatment of extravasation injuries of some clinically used compounds still remains elusive. This work aimed to investigate, in a preclinical mouse model, the effects of extravasation of two chemotherapeutic agents, nanoliposomal irinotecan (nal-Iri) and trabectedin. In addition, we aimed to study treatment options for injuries induced by extravasation of these substances. Methods: Mice were subcutaneously injected with nal-Iri or trabectedin applied in clinically used concentration. Doxorubicin was used as a positive control. In subsequently performed experiments, hyaluronidase, DMSO and tacrolimus were tested as potential treatments against extravasation-induced injuries by trabectedin. Systemic effects were analyzed by observation and documentation of the health status of mice and local reactions were measured and graded. In addition, hematoxylin-eosin stained histological sections of the treated skin areas were analyzed. Results: Of the two tested substances, only trabectedin showed vesicant effects. Subcutaneous injection of trabectedin caused erythema formation in mice by day two that was progressing to skin ulcerations by day five. Furthermore, we found that topical treatment of mice with tacrolimus or DMSO reduced the vesicant effects of trabectedin. The results observed in vivo were supported microscopically by the analysis of histological sections. Conclusions: We recommend classifying trabectedin as a vesicant agent and nal-Iri as a non-vesicant agent. Furthermore, our results obtained in a preclinical model suggest that tacrolimus and DMSO might be suitable treatment options of trabectedin extravasations, a finding that might be further utilized in clinical studies.

The HDL particle composition determines its antitumor activity in pancreatic cancer.

Despite enormous efforts to improve therapeutic options, pancreatic cancer remains a fatal disease and is expected to become the second leading cause of cancer-related deaths in the next decade. Previous research identified lipid metabolic pathways to be highly enriched in pancreatic ductal adenocarcinoma (PDAC) cells. Thereby, cholesterol uptake and synthesis promotes growth advantage to and chemotherapy resistance for PDAC tumor cells. Here, we demonstrate that high-density lipoprotein (HDL)-mediated efficient cholesterol removal from cancer cells results in PDAC cell growth reduction and induction of apoptosis in vitro. This effect is driven by an HDL particle composition-dependent interaction with SR-B1 and ABCA1 on cancer cells. AAV-mediated overexpression of APOA1 and rHDL injections decreased PDAC tumor development in vivo. Interestingly, plasma samples from pancreatic-cancer patients displayed a significantly reduced APOA1-to-SAA1 ratio and a reduced cholesterol efflux capacity compared with healthy donors. We conclude that efficient, HDL-mediated cholesterol depletion represents an interesting strategy to interfere with the aggressive growth characteristics of PDAC.

Expression of CD98hc in Pancreatic Cancer and Its Role in Cancer Cell Behavior.

Background: Cluster of differentiation 98 heavy chain (CD98hc) is a transmembrane protein, which functions both as a coreceptor of ß-integrins, enhancing intracellular integrin-dependent downstream signaling, and as a transporter of branched-chain and aromatic amino acids. As such, it is pivotal in cell cycle regulation and protection of oxidative, nutritional and DNA replication stress. Overexpression of CD98hc occurs widely in cancer cells and is associated with poor clinical prognosis. The role of CD98hc in pancreatic cancer remains to be elucidated. The aim of this study was to determine the expression of CD98hc in pancreatic ductal adenocarcinoma and to define its potential functional role in cancer cell biology. Methods: Immunohistochemical staining for CD98hc was performed on 222 tissue samples of patients with pancreatic ductal adenocarcinoma. The pancreatic cancer cell lines PANC-1 and BxPC-3 were used to determine the effect of CD98hc expression on cancer cell behavior using cell adhesion, cell trans-migration and cell spreading assays. Flow cytometry was performed to study the rate of apoptosis after detachment or serum starvation. shRNA-lentiviral constructs were used to knock down or reconstitute full length or mutated CD98hc. Results: Up to 20% of pancreatic ductal adenocarcinomas express CD98hc in the acinar cells (13%) and islet cells (20%) embedded in tumor tissue. Although expression of CD98hc in tumor tissue was not associated with a particular tumor stage or grade, our data show a trend towards longer overall survival of pancreatic cancer patients without CD98hc expression as compared to those with immunohistochemical positivity. In vitro downregulation of CD98hc in the pancreatic cancer cell lines PANC-1 and BxPC-3 significantly inhibits cell proliferation (p<0.05), self-renewal (p<0.05) and anchorage-independent growth (p<0.05). Conclusion: CD98hc is expressed in a remarkable percentage of pancreatic ductal adenocarcinomas. Due to its important role in cell behavior and malignant cell transformation, it may be a promising molecular target for potential new therapeutic approaches in pancreatic cancer in the future.

The cancer survival index-A prognostic score integrating psychosocial and biological factors in patients diagnosed with cancer or haematologic malignancies.

OBJECTIVE: We aimed to investigate whether (1) psychological and social indicators influence survival in patients diagnosed with cancer or haematologic malignancies when important biological aspects are controlled for, (2) psychological, social and biological indicators can be utilised to design one collated index for survival, usable in clinical practice to identify patients at risk of shorter survival and to improve personalised healthcare provision. METHODS: In this cross-sectional study, 2263 patients with cancer or haematologic malignancies participated. We analysed 15 biological, psychological and social indicators as risk factors for survival with a Cox proportional hazards model. Indicators significantly associated with survival were combined to compute models for the identification of patient groups with different risks of death. The training sample contained 1122 patients. Validation samples included the remaining 1141 patients, the total sample, as well as groups with different cancer entities. RESULTS: Five indicators were found to significantly impact survival: Cancer site (HR: 3.56), metastatic disease (HR: 1.88), symptoms of depression (HR: 1.34), female sex (HR: 0.73) and anaemia (HR: 0.48). Combining these indicators to a model, we developed the Cancer Survival Index, identifying three distinct groups of patients with estimated survival times of 47.2 months, 141 months and 198.2 months (p < 0.001). Post hoc analysis of the influence of depression on survival showed a mediating effect of the following four factors, related to both depression and survival: previous psychiatric conditions, employment status, metastatic disease and haemoglobin levels. CONCLUSIONS: Psychosocial and biological factors impact survival in various malignancies and can be utilised jointly to compute an index for estimating the survival of each patient individually-the Cancer Survival Index.

C-reactive protein and white blood cell count are adverse prognostic markers for patients with advanced cancer on parenteral nutrition in a palliative care unit setting: A retrospective cohort study.

BACKGROUND: Parenteral nutrition is controversial in patients with advanced cancer. Nevertheless, this treatment is common practice near the end of life. AIM: We aimed to identify factors which were associated with the outcome of patients on parenteral nutrition at an academic tertiary palliative care unit. DESIGN: In this retrospective cohort study patients were assigned to two groups according to parenteral nutrition treatment. Inferential statistics were used to assess whether the dynamics of laboratory variables over 2 weeks of parenteral nutrition were associated with survival. SETTING/PARTICIPANTS: Patients admitted to the Department of Palliative Medicine at the Medical University of Vienna between 2016 and 2018 were included in this study. RESULTS: Of 443 patients, 113 patients received parenteral nutrition. Patients had a lower body mass index, lower levels of bilirubin, γ-glutamyltransferase, alkaline phosphatase, and were of younger age compared to patients which did not receive parenteral nutrition. No difference in survival as measured from admission to death was found when comparing the two groups. Levels for γ-glutamyltransferase, alkaline phosphatase, and C-reactive protein significantly increased during 2 weeks of parenteral nutrition. Among patients with parenteral nutrition, an increase in C-reactive protein or white blood cell count levels was associated with lower survival. CONCLUSION: Patients who responded with an increase of C-reactive protein or white blood cell count during 2 weeks after reinitiation or start of parenteral nutrition had a worse survival. Our findings might support clinicians and patients in their decision to forgo parenteral nutrition in a palliative care setting.

Kidney Function Worsening Is Linked to Parenteral-Nutrition-Dependent Survival in Palliative Care Patients.

BACKGROUND: Parenteral nutrition (PN) is frequently administered in palliative care patients suffering from cachexia. The evidence regarding the use of PN in terminally ill patients is scarce. Routine laboratory parameters might help to decide whether to start or forgo PN, which could decrease overtreatment at the end of life. Kidney failure was frequently associated with survival. However, a relation between kidney function parameters and parenteral nutrition has not been observed thus far. The aim of this retrospective cohort study was to analyze kidney function parameters in palliative care patients under PN, as well as the relation between these parameters and overall survival. METHODS: Patients who were admitted to the Department of Palliative Medicine at the Medical University of Vienna were screened for PN treatment. Whether kidney function parameters at baseline or their dynamics over the course of two weeks were associated with survival was assessed with descriptive and interferential statistics. RESULTS: In total, 113 of 443 palliative care patients were administered parenteral nutrition for the first time. The overall survival (OS) for all patients with increased kidney function parameters at baseline was lower (creatinine: hazard ratio (HR) = 1.808, p < 0.001; urea: HR = 1.033, p < 0.001; uric acid HR = 1.055, p = 0.015). No significant increase in creatinine blood levels was observed in the first 2 weeks after the initiation of PN when compared to the non-PN group (p = 0.86). However, if creatinine blood levels increased within the PN group, lower overall survival was found (HR = 2.046, p = 0.007). CONCLUSION: Increased kidney function parameters, such as creatinine, urea and uric acid, might be used as negative prognostic markers in palliative care patients under PN. Moreover, an increase in creatinine during the administration of parenteral nutrition in the first 2 weeks is linked to worse outcomes. These findings may help future studies to establish objective markers for clinicians to determine whether to start or end PN in palliative cancer patients and decrease potential overtreatment at the end of life.

The impact of COVID-19 on cancer care of outpatients with low socioeconomic status.

Patients with low socioeconomic status (SES) are among the most underserved groups of people regarding cancer care. Analyzing the impact of the coronavirus-induced disease 2019 (COVID-19) pandemic on health care disparities and calling attention to inequalities in cancer care is crucial to justify and initiate adequate countermeasures. We aimed to determine whether the COVID-19 pandemic aggravated health care disparities of cancer outpatients related to their SES and analyzed patient data of the largest university center providing services for patients with hematologic and oncologic disorders in Austria from 2018 to 2021. SES was assessed using three indicators: monthly net household income, level of education and occupational prestige. In total, 1217 cancer outpatients (51.1% female) with a mean age of 59.4 years (SD = 14.2) participated. In the first year of the pandemic, the relative proportion of individuals with low income, low education level and low occupational prestige seeking cancer care at our outpatient center decreased significantly (P ≤ .015). The strongest indicator was income, with a consistent effect throughout the first pandemic year. Countermeasures and specific interventions to support cancer patients with low SES in their access to health care should be initiated and prioritized.

Bead-Based Isolation of Circulating Tumor DNA from Pancreatic Cancer Patients Enables High Fidelity Next Generation Sequencing.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and poses a challenge to the treating clinician. With the emergence of genomic profiling technologies, circulating tumor DNA (ctDNA) is increasingly recognized as a versatile biomarker for risk stratification and disease monitoring. We aimed to compare two commercially available NGS panels in a cohort of patients with advanced PDAC undergoing palliative chemotherapy. METHODS: CtDNA was isolated with a magnetic bead-based protocol from two consecutive blood samples before and during chemotherapy in 21 patients with PDAC. Mutations were assessed by using a panel covering 15 (GP15) or 50 (GP50) cancer-associated genes. Results were compared to tumor tissue (GP15), if available. RESULTS: Isolation of ctDNA resulted in a high mean value of 1.9 ng/µL (total volume of ~40 µL). Although the same number of patients were positive for at least one mutation (76%), the most commonly mutated oncogene in PDAC, KRAS, was detectable in an additional 25% of all patients with the GP15 panel due to a higher coverage. The genomic concordance rate between tissue DNA and ctDNA analyses was 65.22%. DISCUSSION: Our study demonstrates the feasibility of an NGS-based approach for ctDNA analysis and underlines the importance of using a disease-specific panel with a sufficiently high coverage.

A higher ctDNA fraction decreases survival in regorafenib-treated metastatic colorectal cancer patients. Results from the regorafenib's liquid biopsy translational biomarker phase II pilot study.

The predictive effect of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) treatment is still highly discussed. The primary objective of our study was to investigate a possible prognostic/predictive value of ctDNA under regorafenib treatment. This prospective multicenter translational biomarker phase II pilot study enrolled 30 metastatic CRC patients (67% men, 33% women) treated with regorafenib. ctDNA was assessed in plasma before treatment start and at defined time points during administration. Measurement of tumor fraction as well as mutation and copy number analysis of CRC driver genes were performed by next-generation sequencing approaches. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and Eastern Cooperative Oncology Group. Disease control rate was 30%. Median tumor fraction at baseline was 18.5% (0-49.9). Mutations in CRC driver genes or genes involved in angiogenesis were identified in 25 patients (83.3%). KRAS mutations were detected in 13 of 14 KRAS-positive tumors; in three patients without KRAS mutation in the respective tumors, acquired mutations as a consequence of prior anti-EGFR treatment were detected. In a subset of patients, novel occurring mutations or focal amplifications were detected. A tumor fraction of 5% and higher at baseline was significantly associated with a decreased OS (P = .022; hazard ratio 3.110 (95% confidence interval: 1.2-8.2). ctDNA is detectable in a high proportion of mCRC patients. Higher ctDNA levels are associated with survival among regorafenib treatment. Moreover, our data highlight the benefit of a combined evaluation of mutations and somatic copy number alterations in advanced cancer patients.