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•4–29% of cancer patients may experience intense progression after immunotherapy.•Diagnosis of HPD relies on both RECIST criteria and dynamic parameters such as TGR.•HPD confers a ...worse prognosis to cancer patients.•Risk of HPD may be predicted by age, previous irradiation and metastatic load.•MDM2/4 amplification and EGFR aberrations are promising biomarkers of HPD.
Cancer research is living a time of unparalleled expectations around immunotherapy, a therapeutic strategy that materializes the elegant idea of weaponizing our immune system to eradicate tumor cells. In an everchanging standard of care, a growing number of studies have shown that immunotherapy may accelerate tumor progression in a significant subset of patients ranging from 4% to 29% across multiple histologies. The identification of hyperprogression poses a challenge for RECIST criteria, which fail to capture pre- and post-treatment tumor growth kinetics at early times of disease. To this end, parameters such as the TGR (Tumor Growth Rate), TGK (Tumor Growth Kinetics), and TTF (Time to Treatment Failure) have been proposed. Although the definition of hyperprogression is not consistent among research groups, it may be depicted as a RECIST progression at the first on-treatment scan with at least a doubling in growth pace when comparing pre- and post-treatment periods. Unlike pseudoprogression, patients displaying hyperprogression present worse survival outcomes. This phenomenon has been independently associated to older age, higher metastatic load, and previous irradiation, but remarkably failed to show association to tumor burden or aggressive pre-treatment growth. Despite the pivotal interest of recognizing subjects at increased risk of hyperprogression, only MDM2 amplification and EGFR aberrations have been described as potential biomarkers and require further validation. In addition, tumor mutation burden and circulating DNA may be valuable to this purpose. This work provides an update on epidemiology, clinical predictors, biomarkers, and a plausible molecular rationale of hyperprogressive disease after immunotherapy.
The importance of mutation identification for advanced colorectal cancer treatment with anti-epidermal growth factor receptor agents is well established. However, due to delays in turnaround time, ...low-quality tissue samples, and/or lack of standardization of testing methods a significant proportion of patients are being treated without the information that Kirsten rat sarcoma and neuroblastoma rat sarcoma (RAS) testing can provide. The detection of mutated circulating tumor DNA by BEAMing technology addresses this gap in care and allows these patients to receive international guideline-recommended expanded RAS testing with rapid turnaround times. Furthermore, the overall concordance between OncoBEAM RAS colorectal cancer testing and standard of care tissue testing is very high (93.3%). This article presents an overview of the clinical utility and potential applications of this minimally invasive method, such as early detection of emergent resistance to anti-epidermal growth factor receptor therapy. If appropriately implemented, BEAMing technology holds considerable promise to enhance the quality of patient care and improve clinical outcomes.
We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy ...in metastatic colorectal cancer.
NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 × 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed.
The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n=634; 2 × 2 factorial portion, n=1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85-1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83-1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4.
Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer.
This multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer.
Patients were assigned to 24 weeks ...of capecitabine 1250 mg/m2 twice daily on days 1–14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS).
The intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77–1.01 and overall survival (OS) (HR = 0.86; 95% CI 0.74–1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand–foot syndrome may be associated with better outcomes in capecitabine recipients.
Oral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.
This is the first study that seeks to establish the prognostic value of circulating tumor cell (CTC) (determined by CellSearch system) in patients with stage III CRC.
Our results suggest that given ...the low number of CTC in patients with localized CRC and the particular pattern of metastatic dissemination in patients with CRC, it is likely that CTC does not have a prognostic role in this setting.
The prognostic role of circulating tumor cells (CTC) in early colorectal cancer (CRC) has not been determined yet. We evaluated the potential prognostic value of CTC in stage III CRC patients.
Prospective multicenter study of 519 patients with stage III CRC recruited between January 2009 and June 2010. CTC were enumerated with the CellSearch System after primary tumor resection and before the start of adjuvant therapy. A total of 472 patients were included in the analysis.
CTC ≥1, ≥2, ≥3 and ≥5 were detected in 166 (35%), 93 (20%), 57 (12%) and 34 (7%) patients, respectively. Median follow-up was 40 months. In the overall population, CTC ≥1 (disease-free survival (DFS): HR 0.97,P = 0.85; overall survival (OS): HR 1.03,P = 0.89), ≥2 (DFS: HR 1.07,P = 0.76; OS: HR 1.02,P = 0.95), ≥3 (DFS: HR 0.96,P = 0.87; OS: HR 0.74,P = 0.41) and ≥5 (DFS: HR 0.72,P = 0.39; OS: HR 0.48,P = 0.21) were not associated with worse DFS and OS. No clinicopathological characteristics were significantly associated with the presence of CTC. In patients with disease relapse, the proportion with CTC ≥1 was not significantly different between those with single versus multiple metastatic locations (37.9% versus 31.4%,P = 0.761). In the multivariate analysis, CTC ≥1 was not an independent prognostic factor for DFS (HR 0.97,P = 0.87) and OS (HR 0.96,P = 0.89).
CTC detection was not associated with worse DFS and OS in patients with stage III CRC. Given the scarcity of CTC in these patients, it is likely that CTC determined by CellSearch system does not have a prognostic role in this setting. However, a longer follow-up is needed.
Familial colorectal cancer type X (FCCX) encompasses a group of families with dominant inheritance pattern of colorectal cancer (CRC) but no alteration in any known CRC susceptibility gene. ...Therefore, the explanation of their susceptibility is a priority to offer an accurate genetic counseling. We screened the 27 coding exons and exon–intron boundaries of BRCA2 in 48 FCCX probands. We identified 29 variants including a frameshift mutation. Deleterious variant c.3847_3848delGT p.(Val1283Lysfs*2) showed cosegregation with disease as well as loss of heterozygosity (LOH) in CRC tumor DNA. This is the first evidence of germline BRCA2 pathogenic mutation associated with CRC risk. Furthermore, missense variants c.502C>A p.(Pro168Thr), c.5744C>T p.(Thr1915Met) and c.7759C>T p.(Leu2587Phe) were proposed as candidate risk alleles based on cosegregation, LOH tumor analysis and in silico testing.
This multicentre, randomised, and phase II study evaluated mFOLFOX+cetuximab followed by maintenance mFOLFOX+cetuximab or single-agent cetuximab in metastatic colorectal cancer (mCRC) patients ...(NCT01161316).
Previously, untreated mCRC patients (wild-type KRAS) were randomised to receive cetuximab+mFOLFOX-6 (8 cycles for 2 weeks) followed by maintenance therapy: single-agent cetuximab (Arm-A) or mFOLFOX-6 + cetuximab (Arm-B) until progression. Primary endpoint was progression-free survival (PFS) at 9 months.
One hundred ninety-three patients (median range age 60 33–74 years) were randomised (2:1): 129 Arm-A versus 64 Arm-B. PFS at 9 months (95% confidence interval) showed non-inferiority between arms (Arm-A/Arm-B: 60 52, 69%/72 61, 83%, p non-inferiority<0.1). There were no statistically significant differences in the PFS (Arm-A/Arm-B: 9 95% CI 7, 10 months/10 7,13 months, hazard ratio HR = 1.19 0.80, 1.79) or overall survival (23 19, 28 months/27 18, 36 months, HR = 1.24 0.85, 1.79) between arms. The objective response rate was also similar (48 39, 57%/39 27, 52%). The safety profile was similar between arms, and all patients experienced at least one adverse event (AE) (Arm-A/Arm-B grade ≥III AEs: 70%/68%). The most common grade ≥III AEs were as follows: neutropenia (Arm-A/Arm-B: 28%/26%), rash acneiform (15%/24%) and sensory neuropathy (2%/15%) in any group. Arm-A was associated with less grade ≥III rash and sensory neuropathy and a lower rate of serious AEs (20%/27%).
This phase II exploratory trial with a non-inferiority design suggests that maintenance therapy with single-agent cetuximab following mFOLFOX+cetuximab induction could be a valuable option compared with mFOLFOX+cetuximab treatment continuation. We await phase III trials to confirm single-agent cetuximab as maintenance therapy in mCRC patients.
•Cetuximab alone could be a viable maintenance therapy option in metastatic colorectal cancer patients.•Progression-free survival (PFS) at 9 months was similar between cetuximab alone and FOLFOX+cetuximab.•PFS and overall survival were similar between cetuximab alone and FOLFOX+cetuximab.•Safety profile was similar between cetuximab alone and FOLFOX+cetuximab.
Background: The CellSearch System is a technique to detect circulating tumor cells (CTCs) in patients with cancer. Few data have been published concerning the role of CTCs detection by this method in ...colorectal cancer. The aim of this study was to correlate the presence of CTCs with the commonest clinical and morphological variables. Patients and methods: Blood samples were collected from 97 patients and 30 healthy volunteers. Quantification of CTCs in 7.5 ml of blood was carried out with the CellSearch System. The results were expressed as number of CTCs/7.5 ml and the cut-off of ≥2 CTCs/7.5 ml was chosen to define the test as positive. Results: Positive CTCs were detected in 34 of 94 patients (36.2%). Correlation was not found among positive CTCs and location of primary tumor, increased carcinoembryonic antigen level, increased lactate dehydrogenase level or grade of differentiation. Only stage correlated with positive CTCs (20.7% in stage II, 24.1% in stage III and 60.7% in stage IV, P = 0.005). Conclusions: CTCs detection by CellSearch is a highly reproducible method that correlates with stage but not with other clinical and morphological variables in patients with colorectal cancer. Colon cancer tumor cells are detectable in all stages. Further studies are warranted.
Background
Carpal osteochondral fragmentation and subsequent post‐traumatic osteoarthritis (PTOA) are leading causes of wastage in the equine athlete. Identification of synovial fluid biomarkers ...could contribute to the diagnosis and understanding of osteoarthritis (OA) pathophysiology.
Objective
The aim of this study was to identify differentially expressed metabolic and glycosylation pathways in synovial fluid from healthy horses and horses with naturally occurring carpal OA.
Study design
Cross‐sectional, in vivo metabolomics and glycomics study.
Methods
In cohort 1, carpal synovial fluid (n = 12 horses; n = 6 healthy, n = 6 OA) was analysed using high‐resolution liquid chromatography mass spectrometry (LC‐MS). In cohort 2 (n = 40 horses; n = 20 healthy, n = 20 OA), carpal synovial fluid was analysed using lectin microarrays and a lubricin sandwich ELISA.
Results
Metabolomic analysis identified >4900 LC‐MS features of which 84 identifiable metabolites were differentially expressed (P < .05) between healthy and OA joints, including key pathways related to inflammation (histidine and tryptophan metabolism), oxidative stress (arginine biosynthesis) and collagen metabolism (lysine metabolism). Principle Component Analysis and Partial Least Squares Discriminant Analysis demonstrated separation between healthy and OA synovial fluid. Lectin microarrays identified distinct glycosylation patterns between healthy and OA synovial fluid, including increased Core 1/Core 3 O‐glycosylation, increased α‐2,3 sialylation and decreased α‐1,2 fucosylation in OA. O‐glycans predominated over N‐glycans in all synovial fluid samples, and synovial fluid lubricin was increased in OA joints as compared to controls.
Main limitations
The sample size in cohort 1 was limited, and there is inherent variation in severity and duration of joint injury in naturally occurring OA. However, LC‐MS identified up to 5000 unique features.
Conclusions
These data suggest new potential diagnostic and therapeutic targets for equine OA. Future targeted metabolomic and glycomic studies should be performed to verify these results. Lectin microarrays could be investigated as a potential screening tool for the diagnosis and therapeutic monitoring of equine OA.
El objetivo principal de la investigación clínica aplicada en Oncología es trasladar los conocimientos derivados de la investigación básica a la práctica médica lo más rápido posible. Se trata de ...poner en marcha en toda su dimensión la oncofarmacogenómica y la oncofarmacogenética. Para ello, es preciso que los hospitales comprendan la importancia del desarrollo de unidades de investigación traslacional donde puedan encontrarse y participar los investigadores básicos y los clínicos.
The principal objective of the translational research in Oncology is to translate the knowledge derived from the basic research to the clinical practice as soon as possible. The goal is to develop and maximize the concepts of oncopharmacogenomic and oncopharmacogenetic. In this context it will be absolutely necessary that hospitals integrate the basic and clinical research in translational research units with the appropriate resources.
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