Cancer-Related Fatigue and Circulating Biomarkers in Breast Cancer Survivors.

PURPOSE: Cancer-related fatigue (CRF) is the most common and disruptive symptom experienced by cancer survivors and because of its frequency and severity is especially worrisome in breast cancer survivors (BCS). Despite a great deal of research, the mechanisms underlying CRF have not been determined. The present study aims to describe associations between CRF in BCS and different blood biomarkers. METHODS: A descriptive and cross-sectional study was conducted. A set of biomarkers assessing inflammation were measured in BCS: C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR), IL-1ß, IL-6, IL-8, IL-10, tumor necrosis factor (TNF); HPA axis dysfunction (cortisol), autonomic dysfunction (noradrenaline); oxidative stress (8-OH deoxyguanosine); insulin resistance markers (insulin, IGF-I, IGFBP3) and sexual hormones (estrogens, progesterone, testosterone). RESULTS: NLR (p = .00) and cortisol (p = .02) were positive and negatively associated with CRF, respectively. The rest of the blood markers were not associated with CRF. CONCLUSION: Our results increase the evidence on pathophysiological mechanisms driving CRF in BCS. However, longitudinal studies are needed to explore the role of these factors as potential causal mechanisms.

Biological mechanisms of cancer-related fatigue in breast cancer survivors after treatment: a scoping review.

PURPOSE: Cancer-related fatigue (CRF) is the most common symptom experienced by cancer survivors. It is a multidimensional symptom affecting physical, emotional, and/or cognitive spheres, different from other types of fatigue. Characteristically is not alleviated by sleep or rest. CRF could have specific features in breast cancer survivors (BCS), because of sex, hormones, and distinct treatments. On the other hand, more than 25% of BCS report persistent CRF for 10 years or more after the diagnosis. The present study aims to recapitulate the knowledge about the biological mechanisms that potentially drive CRF in BCS after treatment. METHODS: To answer a broad question, a scoping review methodology was used. Data were collated from three bibliographic databases: PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Studies were selected if they had included more than 20 BCS, after finishing their treatment, fatigue was measured with a quantitative scale and biomarkers were analyzed. RESULTS: The final database was composed of 1896 records. Sixty-four studies finally met the eligibility criteria. Inflammation (61%), hypothalamic-pituitary-adrenal (HPA) axis dysregulation (14%), autonomic nervous system (ANS) dysfunction (11%), and diet (9%) were the biological pathways most frequently studied. Unfortunately, results from studies about inflammation and HPA axis show many inconsistencies. CONCLUSION: More research about the role of ANS dysfunction and diet on the pathogenesis of CRF would be warranted according to the results of the review. There are some fields such as endocannabinoid systems, mitochondrial dysfunction, gut microbiota, and oxidative stress that have been insufficiently explored. IMPLICATIONS FOR CANCER SURVIVORS: To widen the scope of future research in the physiopathology of CRF, it is necessary to identify mechanisms that would be potentially involved and have been insufficiently explored. Because of the high prevalence of CRF in BCS and the tremendous impact that fatigue has in their quality of life, it is essential to improve the efficacy of the treatments through a good knowledge of the biological basis of CRF.

"To be myself again": Perceived benefits of group-based exercise for colorectal cancer patients.

PURPOSE: To explore the perceived benefits of a group-based exercise program for patients with colorectal cancer (CRC) undergoing chemotherapy treatment. METHODS: In-depth semi-structured interviews were conducted with all participants (n = 27) at the end of the exercise program (patients, relatives and healthcare professionals). The exercise instructor in charge of the exercise program with CRC patients also collected observational field notes throughout a research diary. RESULTS: Three main themes related to exercise as a coping strategy were obtained: (a) physical recovery; (b) psychosocial well-being, and (c) reconnection with their embodied selves and normal lives. Physical recovery included a perceived increase in fitness and a reduction in physical side-effects. Psychosocial well-being included perceived benefits in self-confidence, sense of control, reduced fear, feeling of being useful, sense of achievement, positive thinking and avoiding depression. All the physical and psychosocial benefits helped patients reconnect with their embodied selves, engage in activities practised before the diagnoses, improve their body image, avoid stigma, and increase their social life beyond cancer diagnoses. In this sense, some patients held on to their past selves, trying to keep or recover normality in their lives, while others acknowledged that they might not be the same person anymore, with exercise being part of this new identity. CONCLUSIONS: This study shows that exercise is a coping strategy that benefitted CRC patients in several ways related to their physical and psychosocial quality of life.

Impact of the COVID-19 Lockdown on Physical Activity Levels and Health Parameters in Young Adults with Cancer.

The lockdown of the COVID-19 pandemic impacted physical activity (PA) levels around the world, affecting health parameters in young adults with cancer (YAC). To our knowledge, there is no evidence of the impact of the lockdown on the Spanish YAC. To analyse the changes in PA levels before, during, and after the lockdown of the YAC and its impact on health metrics in Spain, in this study, we utilized a self-reported web survey. PA levels decreased during the lockdown, and a significant increase in PA was observed after the lockdown. Moderate PA had the largest reduction (49%). Significant increases in moderate PA were noted after the lockdown (85.2%). Participants self-reported more than 9 h of sitting per day. HQoL and fatigue levels were significantly worse during the lockdown. The impact of the COVID-19 pandemic in this cohort of Spanish YAC showed a decrease in PA levels during the lockdown, affecting sedentarism, fatigue and HQoL. After lockdown, PA levels partially recovered, while HQoL and fatigue levels remained altered. This may have long-term physical effects such as cardiovascular comorbidities associated with sedentarism and psychosocial effects. It is necessary to implement strategies such as cardio-oncology rehabilitation (CORE), an intervention that can be delivered online, potentially improving participants' health behaviours and outcomes.

ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer.

PURPOSE: The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170). ANCHOR CRC aimed to evaluate efficacy, safety, and quality of life with first-line encorafenib + binimetinib + cetuximab in BRAFV600E-mutated mCRC. METHODS: In this multicenter, open-label, single-arm study, patients with BRAFV600E-mutated mCRC received oral encorafenib 300 mg once daily and binimetinib 45 mg twice daily in 28-day cycles, plus intravenous cetuximab 400 mg/m2 once on day 1 of cycle 1, then 250 mg/m2 once weekly for the first seven cycles, and 500 mg/m2 once on Days 1 and 15 from cycle 8 onward. The primary end point was locally assessed confirmed objective response rate (cORR), and secondary end points included centrally assessed cORR, progression-free survival, overall survival (OS), quality of life, and safety and tolerability. RESULTS: Among 95 patients, the locally assessed cORR was 47.4% (95% CI, 37.0 to 57.9) with all partial responses. Since the lower limit of the 95% CI exceeded 30%, the primary end point was met. With a median follow-up duration of 20.1 months, the median progression-free survival on the basis of local assessments was 5.8 months and the median OS was 18.3 months. Treatment was well tolerated, with no unexpected toxicities. Using Patient Global Impression of Changes, substantial improvement in symptoms was consistently reported in ≥ 30% of patients from cycle 3 to cycle 10. CONCLUSION: The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAFV600E-mutated mCRC with a manageable safety profile. Further first-line evaluation is ongoing (ClinicalTrails.gov identifier: NCT04607421).

A Phase I-II multicenter trial with Avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients; GEMCAD 1602 study.

BACKGROUND: Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. METHODS: This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. RESULTS: A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1-5.3 months] and overall survival was 12.2 months [3.2-23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. CONCLUSIONS: The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.

Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial.

BACKGROUND: Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE). METHODS: Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed. RESULTS: In total, 101 patients were followed for a median of 12 (6-17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was <1941 versus ≥1941 pg/mL (9 versus 4 months). Patients with VEGF-A < 1941 pg/mL showed longer median OS (19 versus 8 months), TTP (9 versus 4 months) and TTF (8 versus 4 months), along with higher ORR (26% versus 9%) and DCR (81% versus 55%). No differences were identified according to ACE levels. CONCLUSIONS: This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes.

C-Reactive Protein Is Associated with Physical Fitness in Breast Cancer Survivors.

Background: Physical fitness (PF) is an expression of the physiological functioning of multiple body components. PF is an important prognostic factor in terms of cardiovascular mortality, cancer mortality, and all-cause mortality. PF has been related to some biomarkers in the general population but not in breast cancer survivors (BCS). Purpose: To evaluate the effects of PF on biomarkers potentially related to physical activity (PA) in a sample of BCS. Methods: Cross-sectional study. A total of 84 BCS (mean age 54) who had finished their treatment were recruited. Different components of PF were evaluated, namely body composition (anthropometry), cardiorespiratory fitness (one-mile walk test), muscular (handgrip and sit-to-stand timed test), and motor (gait speed) components. Sexual hormones, inflammation, and insulin resistance biomarkers were measured. Results: C-Reactive Protein (CRP) was associated with every component of physical fitness: cardiorespiratory fitness (p-value = 0.002), muscular (sit-to-stand timed test, p-value = 0.002) and motor (gait speed, p-value = 0.004) components, and body composition (body mass index, p-value = 0.003; waist, p-value < 0.000; and waist-to-hip index, p-value = 0.012). CRP also was associated with "poor physical condition," a constructed variable that encompasses all components of physical fitness (p-value < 0.001). Insulin was associated with cardiorespiratory fitness and gait speed (p-values = 0.002 and 0.024, respectively). Insulin-like Growth Factor-1 was negatively associated with waist perimeter and waist-to-hip ratio. Conclusions: CRP can also be considered an indicator of poor PF in BCS. Implications for cancer survivors: in case of elevation of CRP indicating cardiovascular risk, health professionals should recommend lifestyle changes to improve BCS physical condition.

Early Clinical Experience with Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: The ROS Study.

Trifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience programme in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently enhanced OS: ≤2 metastatic sites, no liver metastasis, alkaline phosphatase < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5. Grade ≥ 3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropaenia (23.2%), anaemia (12.1%), and thrombocytopaenia (5.3%). This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers.

Prevalence and correlates of cancer-related fatigue in breast cancer survivors.

PURPOSE: To identify potential correlates of cancer-related fatigue (CRF) after curative breast cancer (BC) treatment. The hypothesis was that fatigue would be more severe among women treated with cardiotoxic drugs, with poor physical condition and those who exercised less. METHODS: Observational cross-sectional design. Fatigue was evaluated through PERFORM Questionnaire (multi-item, multi-dimensional). Patient-reported assessments and objective information regarding clinical data, physical activity (PA) and physical condition were analysed as potential correlates of CRF. RESULTS: One hundred eighty women who remained free of disease were recruited. The prevalence of fatigue interfering with quality of life was 43%. Weight, resting and recovery heart rate were positively associated with fatigue. Age and time from diagnosis were negatively associated. Previous therapies, objectively assessed weekly PA, cardiorespiratory condition, muscular strength and adherence to Mediterranean diet were not associated with CRF. CONCLUSIONS: CRF is a prevalent problem after BC treatment. Objectively assessed PA, cardiorespiratory fitness and muscular strength did not predict CRF. The association of heart rate and fatigue deserves a further insight. Future research should include longitudinal studies and determination of biomarkers. IMPLICATIONS FOR CANCER SURVIVORS: BC survivors, especially younger and overweight women, should be informed about fatigue as a potential persistent symptom through all stages of the cancer trajectory and into survivorship. They also should be routinely screened for CRF.

Cancer-related Fatigue in Breast Cancer Survivors: A Review.

Fatigue has been the most distressing and frequent symptom in breast cancer (BC) survivors after treatment. Although fatigue can occur in other cancer survivors, women with a history of BC might share some distinctive features. The present study aimed to recapitulate the knowledge about risk factors and correlates of cancer-related fatigue (CRF) in BC survivors after oncologic therapy. An electronic data search was conducted in PubMed using the terms "fatigue," "breast," "cancer," and "survivors." Records were included if they were original articles, available in English, had used a quantitative scale, had > 100 participants, and had excluded women with BC relapse. BC survivors were required to have finished their treatments ≥ 2 months before, except for hormonal therapy. The physiopathology and other interventions were considered beyond the scope of our review. The correlates were subsequently classified into 7 main categories: (1) sociodemographic data, (2) physical variables, (3) tumor- and treatment-related variables, (4) comorbidities, (5) other symptoms, (6) psychological issues, and (7) lifestyle factors. Fatigue was consistently greater in younger, obese, and diabetic women. Women reporting fatigue often communicated symptoms such as pain, depression, insomnia, and cognitive dysfunction. Coping strategies such as catastrophizing could play an important role in the persistence of fatigue. However, tumor characteristics, previous treatments received, and physical activity were not consistently reported. CRF was a strong predictor of the quality of life of BC survivors after treatment. In conclusion, we found CRF was a frequent and serious symptom that severely affects the quality of life of BC survivors after treatment. Health practitioners require more awareness and information about CRF.

Metastatic Colorectal Cancer. First Line Therapy for Unresectable Disease.

Colorectal cancer (CRC) is a commonly diagnosed malignancy. The prognosis of patients with unresectable, metastatic colorectal cancer (mCRC) is dismal and medical treatment is mainly palliative in nature. Although chemotherapy remains the backbone of treatment, the landscape is changing with the understanding of its heterogeneity and molecular biology. First-line therapy relies on a combination of chemotherapy and targeted therapies, according to clinical patient characteristics and tumor molecular profile. Here we review current evidence from randomized clinical trials for using chemotherapy doublets or triplets, and for the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents. Novel therapies developed for small, selected populations are also discussed.

A European survey on the insights of patients living with metastatic colorectal cancer: the patient journey before, during and after diagnosis - an Eastern European perspective.

BACKGROUND: Despite being highly preventable and treatable if diagnosed early, colorectal cancer (CRC) remains the second leading cause of cancer-related death in Europe. Limited information is available from the patient perspective on the persisting unmet needs of the journey of the patient with CRC. OBJECTIVE: To capture European metastatic CRC (mCRC) patients' insights during the patient journey (prediagnosis; diagnosis; postdiagnosis) through a patient survey. METHODS: In total, 883 patients from 15 European countries participated. Participants were divided into four groups from Hungary, Poland, Serbia and 'other European countries' (n=103, 163, 170 and 447 patients, respectively). RESULTS: General awareness of CRC and its symptoms prediagnosis varied among groups, with patients from Poland recording the lowest levels. Screening practices and attitudes also varied; while more patients from Serbia had been invited to CRC screening (~15%) compared with the other groups, the ones not invited claimed mostly (~20%) that would not have attended if they had been invited. Whereas most patients were diagnosed within a month after the first consultation/positive screening, the percentages varied substantially being lowest among patients in Poland (~30%) and Serbia (~25%). Although CRC-related information provision varied, with most informed patients from Hungary (~90%) and least from Serbia (~50%), all groups requested an easier-to-understand language by the healthcare team. Approximately 50% of patients from Eastern Europe had to wait longer than a month to receive treatment, in contrast to ~30% from other European countries. All groups emphasised the unmet need for support from psychologists and other patients. CONCLUSIONS: Our survey reveals the key aspects of the journey of the patient with mCRC and highlights the areas of similarities and differences between patients with mCRC from Eastern Europe versus those from other European countries as well as among patients from different Eastern European countries, calling for improvement particularly around awareness, screening, treatment availability, communication and support networks.

Correlation of RECIST, Computed Tomography Morphological Response, and Pathological Regression in Hepatic Metastasis Secondary to Colorectal Cancer: The AVAMET Study.

Background: The prospective phase IV AVAMET study was undertaken to correlate response evaluation criteria in solid tumors (RECIST)-defined response rates with computed tomography-based morphological criteria (CTMC) and pathological response after liver resection of colorectal cancer metastases. Methods: Eligible patients were aged ≥18 years, with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and histologically-confirmed colon or rectal adenocarcinoma with measurable liver metastases. Preoperative treatment was bevacizumab (7.5 mg on day 1) + XELOX (oxaliplatin 130 mg/m2, capecitabine 1000 mg/m2 bid on days 1-14 q3w). After three cycles, response was evaluated by a multidisciplinary team. Patients who were progression-free and metastasectomy candidates received one cycle of XELOX before undergoing surgery 3-5 weeks later, followed by four cycles of bevacizumab + XELOX. Results: A total of 83 patients entered the study; 68 were eligible for RECIST, 67 for CTMC, and 51 for pathological response evaluation. Of these patients, 49% had a complete or partial RECIST response, 91% had an optimal or incomplete CTMC response, and 81% had a complete or major pathological response. CTMC response predicted 37 of 41 pathological responses versus 23 of 41 responses predicted using RECIST (p = 0.008). Kappa coefficients indicated a lack of correlation between the results of RECIST and morphological responses and between morphological and pathological response rates. Conclusion: CTMC may represent a better marker of pathological response to bevacizumab + XELOX than RECIST in patients with potentially-resectable CRC liver metastases.

Concurrent Exercise Interventions in Breast Cancer Survivors with Cancer-related Fatigue.

This study compared the effects of two supervised concurrent training interventions in breast cancer survivors with cancer-related fatigue at baseline. Twenty-three female breast cancer survivors (50±8 years) were randomized to a high- (n=13) or a moderate-intensity (n=10) training program. Both interventions lasted 16 weeks and included the same resistance exercises, but the aerobic component was supervised and more intense in the former (i.e., rating of perceived exertion of 7-8 vs. 6 on a 1-10 scale for the high and moderate-intensity intervention, respectively). The primary endpoint was fatigue perception. Endpoints were assessed at baseline and after 16 weeks. The p-value for statistical significance was set at 0.004 after Bonferroni correction for multiple comparisons. The high-intensity training program increased lower-limb muscle strength significantly (p=0.002) and tended to improve fatigue perception (p=0.006), waist circumference (p=0.013), neutrophil-to-lymphocyte ratio (p=0.028) and some quality of life items (p=0.011). Although the moderate-intensity training program did not provide such benefits in general (i.e., higher p-values for pre vs post-intervention comparisons), no significant differences were found between interventions (all p>0.004). Further research is needed to elucidate if the benefits provided by high-intensity concurrent training are superior to those elicited by moderate-intensity training in breast cancer survivors.