RESUMEN
INTRODUCTION: The phase 2 RAMONA study demonstrated that second-line nivolumab ± ipilimumab immunotherapy was feasible and effective in older patients with advanced esophageal squamous cell cancer (ESCC). Here, we presented results from functional status (FS) and quality-of-life (QoL) analyses. MATERIALS AND METHODS: Patients aged ≥65 years with advanced ESCC and disease progression following first-line therapy were enrolled for study treatment with nivolumab ± ipilimumab. Geriatric assessments (GA) consisting of G8 and GoGo/SlowGo evaluation, and quality of life (QoL) assessments with EORTC QLQ-C30 questionnaires were conducted at baseline and during the treatment. A post hoc analysis was performed to compare therapy efficacy, toxicity, and QoL between age groups (≥70 years vs. <70 years) and functionality groups (G8 > 14 vs. ≤14 and GoGo vs. SlowGo). RESULTS: In 66 treated patients with a median age of 70.5 years, older patients had non-inferior overall survival and tumor response compared to younger patients, with no increased treatment-related adverse events. Fitter patients (G8 > 14, GoGo) had a clinically, yet not statistically significant, survival advantage than less fit patients (G8 ≤ 14, SlowGo) patients. Moreover, FS by G8 and GoGo/SlowGo significantly correlated with QoL. Overall, QoL was impaired at baseline but remained stable in all scales over the course of immunotherapy. DISCUSSION: The administration of nivolumab ± ipilimumab second-line immunotherapy in older patients with ESCC did not show age-dependent effects and maintained QoL. GA could identify functional deficits and limitations of QoL and should be implemented in the context of immunotherapy. CLINICALTRIALS: gov: NCT03416244.
RESUMEN
To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.
RESUMEN
BACKGROUND: Panel gene sequencing is an established diagnostic tool for precision oncology of solid tumors, but its utility for the treatment of cancers of the digestive system in clinical routine is less well documented. METHODS: We retrospectively identified patients with advanced or metastatic gastrointestinal, pancreaticobiliary or hepatic cancers who received panel gene sequencing at a tertiary university hospital from 2015 to 2022. For these cases, we determined the spectrum of genetic alterations, clinicopathological parameters and treatment courses. Assessment of actionability of genetic alterations was based on the OncoKB database, cancer-specific ESMO treatment guidelines, and recommendations of the local molecular tumor board. RESULTS: In total, 155 patients received panel gene sequencing using either the Oncomine Focus (62 cases), Comprehensive (91 cases) or Childhood Cancer Research Assay (2 cases). The mean age of patients was 61 years (range 24-90) and 37% were female. Most patients suffered from either colorectal cancer (53%) or cholangiocellular carcinoma (19%). 327 genetic alterations were discovered in 123 tumor samples, with an average number of 2.1 alterations per tumor. The most frequently altered genes were TP53, KRAS and PIK3CA. Actionable gene alterations were detected in 13.5-56.8% of tumors, according to ESMO guidelines or the OncoKB database, respectively. Thirteen patients were treated with targeted therapies based on identified molecular alterations, with a median progression-free survival of 8.8 months. CONCLUSIONS: Actionable genetic alterations are frequently detected by panel gene sequencing in patients with advanced cancers of the digestive tract, providing clinical benefit in selected cases. However, for the majority of identified actionable alterations, sufficient clinical evidence for targeted treatments is still lacking.
Asunto(s)
Neoplasias del Sistema Digestivo , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Adulto Joven , Neoplasias del Sistema Digestivo/genética , Neoplasias del Sistema Digestivo/patología , Neoplasias del Sistema Digestivo/terapia , Mutación , Medicina de Precisión/métodos , Terapia Molecular Dirigida/métodos , Biomarcadores de Tumor/genéticaRESUMEN
AIM: Cancer remains a disease with a significant impact on morbidity and mortality but also on quality of life. This prospective randomized pilot study investigated the effects of a sound intervention on physical and emotional well-being in outpatients with cancer. METHODS: Two self-applied sound interventions were used for this purpose, either active "music playing" with a body monochord or passive sound intervention with headphones to listen to a given music compilation. Interventions were carried out over a period of 4 weeks for at least 15 min in the evening before bedtime. The following self-assessment questionnaires were completed both at baseline and after 4 weeks to evaluate the response: the Pittsburgh Sleep Quality Index (PSQI), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), Visual Analogue Scale (VAS) for pain and fatigue, and the Fear of Progression (FoP) questionnaire. Primary endpoint of this exploratory trial was to describe the rate of patients with improvement in at least one dimension without worsening of any other. RESULTS: 73 patients (29 male, 44 female) were included in the study and randomized to either active (n = 34, 47%) or passive sound intervention (n = 39, 53%). Median age was 52.0 years (range 21-79). Fourteen patients (19%) stated that they were musically active. The sound intervention was carried out on a median of 26 days (range 5-28). A higher percentage of patients in the passive group reached the primary endpoint: n = 15 (39%) versus n = 9 (27%). Response differences in favour of the passive group were seen with the VAS fatigue and with QLQ-30 questionnaires. Overall, an improvement in QLQ-30 questionnaire was seen in 12 patients (31%) in the passive group versus 3 patients (9%). Moreover, sound intervention significantly improved social functioning and shortness of breath in the passive group according to QLQ-C30. Significant improvements were also noticed in the passive group in terms of affective reactions as a domain of the FoP questionnaire. No effects on pain or sleep quality could be observed. CONCLUSION: A 4-week self-administered sound intervention was feasible in outpatients suffering from cancer. Using a panel of 5 questionnaires, passive sound interventions appeared to be more likely to positively influence patient-reported outcomes. In particular, a positive impact was documented in social functioning and fatigue.
Asunto(s)
Neoplasias , Calidad de Vida , Humanos , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Proyectos Piloto , Neoplasias/terapia , Neoplasias/psicología , Dolor , Encuestas y Cuestionarios , Fatiga/terapiaRESUMEN
BACKGROUND: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population. METHODS: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244. FINDINGS: Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0-76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7-12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment. INTERPRETATION: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment. FUNDING: Bristol Myers Squibb.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Células Epiteliales , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Femenino , Humanos , Ipilimumab/efectos adversos , Masculino , Nivolumab/efectos adversosRESUMEN
INTRODUCTION: Colorectal cancer (CRC) is a disease of older patients, but evidence-based guidelines for chemotherapy in older patients are scarce. Geriatric assessment (GA) evaluates a patient's functional status (FS) and helps in decision-making when choosing chemotherapy for older patients. However, the change of FS during chemotherapy is rarely studied as GA is mostly performed once instead of sequentially. METHODS: We performed a subgroup analysis of a prospective, multicenter study EpiReal 75. Patients aged ≥75 years with gastrointestinal malignancy prior to initiation of chemotherapy or receiving palliative chemotherapy were screened. We defined geriatric core assessments including the Eastern Cooperative Oncology Group score, Barthel's activities of daily living (ADL) scale, Lawton's instrumental activities of daily living (IADL) scale, and G-8 questionnaire, which were performed at baseline and repeated every 3 months. Quality of life (QoL) assessed by QLQ-C30 questionnaire was also re-evaluated every 3 months. We defined any deterioration in any of the geriatric parameters as unstable in the corresponding function. RESULTS: 28 patients with CRC were enrolled between April 2014 and December 2018. 20 patients were evaluable for statistical analysis with a mean age of 78.5 years (range, 75-88). Most patients received chemotherapy in palliative setting. During 3 months of chemotherapy, 25% of patients became more dependent as measured by ADL or IADL. During a median follow-up of 15 months, patients with unstable ADL or IADL had a significantly shorter overall survival (OS) than those with stable ADL or IADL (plogrank = 0.0055 and 0.0253, respectively), without a significant difference in progression-free survival (PFS). Also, unstable IADL correlated with a deterioration in aspects of QoL such as role functioning and emotional functioning (p = 0.0189 and 0.0239, respectively). 20% of patients experienced treatment-related grade 3 adverse events (AEs), no grade 4-5 AEs occurred. CONCLUSION: Sequential GA revealed changes in FS in older patients with CRC receiving chemotherapy. A deterioration of FS during chemotherapy did not influence PFS but had a negative impact on OS and QoL. It is therefore important to maintain FS in older patients with cancer, and regular performance of geriatric core assessments should be encouraged in the clinical practice.
Asunto(s)
Neoplasias Colorrectales , Neoplasias Gastrointestinales , Anciano , Humanos , Evaluación Geriátrica , Calidad de Vida , Actividades Cotidianas , Estudios Prospectivos , Neoplasias Colorrectales/tratamiento farmacológicoRESUMEN
Lung carcinoids are neuroendocrine tumors representing 1 to 2% of lung cancers. This study outlines the case of a patient with a metastatic lung atypical carcinoid who presented with a pleural effusion and progression of liver metastases after developing resistance to conventional treatments. Personalized functional profiling (PFP), i.e. drug screening, was performed in ex-vivo spheroids obtained from the patient's liver metastasis to identify potential therapeutic options. The drug screening results revealed cediranib, an antiangiogenic drug, as a hit drug for this patient, from a library of 66 Food and Drug Administration (FDA)-approved and investigational drugs. Based on the PFP results and the reported evidence of clinical efficacy of bevacizumab and capecitabine combination in gastro-intestinal neuroendocrine tumors, this combination was given to the patient. Four months later, the pleural effusion and pleura carcinosis regressed and the liver metastasis did not progress. The patient experienced 2 years of a stable disease under the PFP-guided personalized treatment.
Asunto(s)
Tumor Carcinoide , Carcinoma Neuroendocrino , Neoplasias Hepáticas , Neoplasias Pulmonares , Neoplasias Primarias Secundarias , Tumores Neuroendocrinos , Derrame Pleural , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/patología , Carcinoma Neuroendocrino/patología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Pulmón/patología , Neoplasias Pulmonares/patología , Neoplasias Primarias Secundarias/patología , Tumores Neuroendocrinos/patología , Derrame Pleural/patologíaRESUMEN
BACKGROUND: Older patients with metastatic pancreatic cancer may suffer increased toxicity from intensive chemotherapy. Treatment individualization by geriatric assessment (GA) might improve functional outcome. METHODS: We performed a multicenter, phase IV, open label trial in patients ≥70 years with metastatic pancreatic adenocarcinoma. Patients underwent GA and were assigned to one of three categories based on their scores: Go-Go, Slow-Go, or Frail. These categories were intended to guide physician's treatment decisions when choosing to treat patients with nab-paclitaxel/gemcitabine (arm A), gemcitabine (arm B), or best supportive care (arm C). Primary objective was a stable (loss of five points or less) Barthel's Activities of Daily Living (ADL) score during chemotherapy; secondary endpoints included GA scores during therapy, safety, quality of life, response and survival rates. RESULTS: Thirty-two patients were enrolled in the trial in six centers in Germany (out of 135 planned), resulting in termination due to low recruitment. Fifteen patients were allocated to nab-paclitaxel/gemcitabine, fifteen to gemcitabine, and two to best supportive care by their physicians, although according to their GA scores 29 patients (91%) were categorized as Slow-Go and three (9%) as Go-Go. Thus, fifteen of 32 (47%) patients were misclassified and given a course of treatment inconsistent with their GA scores. Median progression-free survival (PFS) were 3.3 months and 9.1 months and median time to quality-of-life deterioration 13 days and 29 days in the nab-paclitaxel/gemcitabine and gemcitabine monotherapy arms, respectively. Serious adverse events were reported in 11 (78.6%) patients in the nab-paclitaxel/gemcitabine and 8 (53.3%) patients in the gemcitabine arm. CONCLUSIONS: Clinical evaluations by investigators differed markedly from geriatric assessments, leading to potential overtreatment. In our modest sample size study, those patients undergoing more intensive therapy had a less favorable course.
Asunto(s)
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Actividades Cotidianas , Adenocarcinoma/tratamiento farmacológico , Anciano , Albúminas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Evaluación Geriátrica , Humanos , Sobretratamiento , Paclitaxel , Neoplasias Pancreáticas/tratamiento farmacológico , Estudios Prospectivos , Calidad de Vida , Neoplasias PancreáticasRESUMEN
Pancreatic acinar cell carcinoma (ACC) is a rare malignant disease that displays distinct differences to pancreatic ductal adenocarcinoma. Here, we report the case of a patient with ACC and underlying breast cancer susceptibility gene 2 (BRCA2) germline mutation that developed severe pancreatic panniculitis (PP) during the course of the disease. The patient received a multimodal therapy including surgery, systemic chemotherapy, and targeted therapy with the PARP inhibitor olaparib, resulting in an overall survival of 47 months. Findings from this case are compared to the current knowledge on management of ACC and paraneoplastic PP.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Anticuerpos Monoclonales Humanizados , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Colangiocarcinoma/tratamiento farmacológico , Humanos , Compuestos de Fenilurea/uso terapéutico , QuinolinasRESUMEN
Perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is a mainstay in the treatment of esophagogastric adenocarcinomas (EGA). Trastuzumab improved survival when added to chemotherapy in patients with HER-2-positive metastatic EGA. We investigated the combination of trastuzumab and FLOT as perioperative treatment in patients with locally advanced EGA. A multicenter phase II study evaluated the efficacy and toxicity of perioperative FLOT (24-hours 5-FU 2600 mg/m2 , leucovorin 200 mg/m2 , oxaliplatin 85 mg/mg2 , docetaxel 50 mg/m2 , trastuzumab 6 mg/kg then 4 mg/kg d1, repeated d15 for four cycles preoperatively and postoperatively followed by 9 cycles of trastuzumab monotherapy) in patients with HER-2 positive EGA. Patients had ≥cT2, any N, M0 EGA. The primary endpoint was the rate of centrally assessed pathological complete response (pCR). Secondary endpoints comprised disease-free (DFS) and overall survival (OS), R0 resection rate, toxicity and surgical morbidity. Fifty-six evaluable patients (median age 62 years) were included; n = 40 had tumors originating from the esophagogastric junction; T stage was (cT2/3/4/unknown): 4/42/8/2; n = 50 patients had cN+ disease. Main adverse events grades 3-4: leukopenia (17.9%), neutropenia (46.6%) and diarrhea (17.0%). All patients underwent tumor resections. R0 resection rate was 92.9%. Eight patients had anastomotic leakage. One postoperative death occurred. pCR was found in 12 patients (21.4%) and a further n = 14 patients (25.0%) had near complete response. Median DFS was 42.5 months and the 3-year OS rate was 82.1%. The primary endpoint of achieving a pCR >20% was reached. No unexpected safety issues were observed. Survival data are promising.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Unión Esofagogástrica/patología , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/administración & dosificación , Docetaxel/uso terapéutico , Esquema de Medicación , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Periodo Perioperatorio , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Análisis de Supervivencia , Trastuzumab/administración & dosificación , Trastuzumab/uso terapéutico , Resultado del TratamientoRESUMEN
In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy, and these drugs have already become essential for the treatment of various noncurable tumors. However, monotherapy in advanced hepatocellular carcinoma (aHCC) failed to show statistically significant improvement.Recently, the combination of atezolizumab and bevacizumab demonstrated efficacy of combining ICI and VEGF inhibition, further substantiating previous data on synergistic mechanisms among respective substance classes.As TKI treatment is currently standard of care for aHCC, and ICIs are approved by the FDA and available in many areas of the world, numerous patients may have been treated with monotherapy of those drugs. However, it remains unclear if failure to monotherapy has an impact on combination therapy. We therefore report a patient well responding to combination therapy despite previous failures to TKI and ICI monotherapy.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Quimioterapia Combinada , Humanos , Resultado del TratamientoRESUMEN
Older patients (65 years and over) represent the majority of patients with a cancer diagnosis. For oesophageal carcinomas, the age peak is in the seventh to eighth decade of life. In gastric carcinoma, 1/3 of patients are older than 75 years and approximately 45â% of colon carcinoma patients are ≥â75 years old.Due to existing comorbidities, age-related changes and polypharmacy, older patients present a special challenge in tumor therapy.In studies, these patients are usually clearly under-represented and "elderly"-studies are rare.New surgical procedures with laparoscopy and also robotic provide advantages for esophageal and gastric carcinoma, which in the future can reduce postoperative morbidity in relation to cardiac and pulmonary complications for old and older patients. The selection of suitable patients is essential here.With regard to chemotherapy, fluoropyrimidines and oxaliplatin are well tolerated; triplet therapies should be avoided. Immunotherapy in particular offers an interesting alternative to standard chemotherapy due to its better side effect profile.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias del Colon/terapia , Neoplasias Esofágicas/terapia , Neoplasias Gastrointestinales/terapia , Inmunoterapia , Laparoscopía , Procedimientos Quirúrgicos Robotizados , Neoplasias Gástricas/terapia , Procedimientos Quirúrgicos Operativos , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/patología , Neoplasias Esofágicas/patología , Neoplasias Gastrointestinales/patología , Humanos , Oxaliplatino/uso terapéutico , Neoplasias Gástricas/patologíaRESUMEN
Chemotherapy combined with the angiogenesis inhibitor bevacizumab (BVZ) is approved as a first-line treatment in metastatic colorectal cancer (mCRC). Limited clinical benefit underpins the need for improved understanding of resistance mechanisms and the elucidation of novel predictive biomarkers. We assessed germline single-nucleotide polymorphisms (SNPs) in 180 mCRC patients (Angiopredict [APD] cohort) treated with combined BVZ + chemotherapy and investigated previously reported predictive SNPs. We further employed a machine learning approach to identify novel associations. In the APD cohort IL8 rs4073 any A carriers, compared to TT carriers, were associated with worse progression-free survival (PFS) (HR = 1.51, 95% CI:1.03-2.22, p-value = 0.037) and TBK1 rs7486100 TT carriers, compared to any A carriers, were associated with worse PFS in KRAS wild-type (wt) patients (HR = 1.94, 95% CI:1.04-3.61, p-value = 0.037), replicating previous findings. Machine learning identified novel associations in genes encoding the inflammasome protein NLRP1 and the ER protein Sarcalumenin (SRL). A negative association between PFS and carriers of any A at NLRP1 rs12150220 and AA for SRL rs13334970 in APD KRAS wild-type patients (HR = 4.44, 95% CI:1.23-16.13, p-value = 0.005), which validated in two independent clinical cohorts involving BVZ, MAVERICC and TRIBE. Our findings highlight a key role for inflammation and ER signalling underpinning BVZ + chemotherapy responsiveness.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Retículo Endoplásmico/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Anciano , Proteínas Reguladoras de la Apoptosis/genética , Estudios de Cohortes , Neoplasias Colorrectales/terapia , Terapia Combinada , Retículo Endoplásmico/metabolismo , Femenino , Estudios de Asociación Genética , Humanos , Inflamación/genética , Aprendizaje Automático , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas NLR , Evaluación de Procesos y Resultados en Atención de Salud/métodos , Polimorfismo de Nucleótido Simple , Supervivencia sin Progresión , Transducción de SeñalRESUMEN
Metastatic gastric cancer (GC) and oesophagogastric junctional (OGJ) adenocarcinoma have a poor clinical outcome with a high worldwide burden of disease. A 65-year old male patient with microcytic anemia was diagnosed with stage IV OGJ adenocarcinoma with multiple liver metastases. Immunohistochemical analysis revealed a high expression of HER2 (3+). Palliative chemotherapy with FLOT (oxaliplatin, 5-fluorouracil, leucovorin and docetaxel) in combination with trastuzumab was initiated. Due to severe adverse events, the therapy was de-escalated to trastuzumab monotherapy after six months of treatment. Initial restaging revealed partial response after the combination therapy of FLOT with trastuzumab. After reduction to trastuzumab monotherapy, the disease remained stable for two years until radiological complete response was observed. Trastuzumab monotherapy was continued for another two years to maintain complete response. Eleven months after the discontinuation of the therapy, no recurrence of the disease was detected. In conclusion, complete response can be achieved under trastuzumab monotherapy in exceptional responders.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/secundario , Receptor ErbB-2/metabolismo , Adenocarcinoma/metabolismo , Anciano , Esquema de Medicación , Neoplasias Esofágicas/metabolismo , Unión Esofagogástrica , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Masculino , Inducción de Remisión , Trastuzumab/administración & dosificaciónRESUMEN
BACKGROUND: The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA. METHODS: PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6â¯J Apcmin/+; BALB/c nu/nu xenografts) and CRC patients under combination chemotherapy with Beva. BMAL1 single nucleotide gene polymorphisms (SNPs) were analysed by DNA-microarray in clinical samples. BMAL1 functions were studied in human CRC cell lines using colorimetric growth, DNA-binding and reporter assays. FINDINGS: In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment. In CRC patients' tumours (nâ¯=â¯74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (*pâ¯=â¯.0061) and reduced progression-free survival (PFS) [*pâ¯=â¯.0223, Hazard Ratio (HR)â¯=â¯1.69]. BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *pâ¯=â¯.014, HRâ¯=â¯1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound aâ¯-â¯672â¯bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent to a BMAL1 DNA-binding motif (E-box) in the VEGFA gene promoter, resulting in increased VEGFA synthesis and proliferation of human CRC cell lines. INTERPRETATION: BMAL1 was associated with Beva resistance in CRC. Inhibition of REVERBA-BMAL1 signalling may prevent resistance to anti-angiogenic therapy. FUND: This work was in part supported by the European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]).
Asunto(s)
Factores de Transcripción ARNTL/genética , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Bevacizumab/efectos adversos , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/genética , Femenino , Xenoinjertos , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Supervivencia sin Progresión , Regiones Promotoras Genéticas/genéticaRESUMEN
Acne-like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream (Reconval K1) as prophylactic skin treatment in addition to doxycycline were explored in a double-blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1-treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender-specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)-related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non-parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm (Reconval K1) regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne-like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided.
Asunto(s)
Erupciones Acneiformes/prevención & control , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Vitamina K 1/administración & dosificación , Erupciones Acneiformes/inducido químicamente , Adulto , Anciano , Anciano de 80 o más Años , Cetuximab/efectos adversos , Método Doble Ciego , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/efectos adversos , Caracteres Sexuales , Crema para la Piel , Resultado del Tratamiento , Vitamina K 1/uso terapéuticoRESUMEN
Monitoring the mutational patterns of solid tumors during cancer therapy is a major challenge in oncology. Analysis of mutations in cell-free (cf) DNA offers a noninvasive approach to detect mutations that may be prognostic for disease survival or predictive for primary or secondary drug resistance. A main challenge for the application of cfDNA as a diagnostic tool is the diverse mutational landscape of cancer. Here, we developed a flexible end-to-end experimental and bioinformatic workflow to analyze mutations in cfDNA using custom amplicon sequencing. Our approach relies on open-software tools to select primers suitable for multiplex PCR using minimal cfDNA as input. In addition, we developed a robust linear model to identify specific genetic alterations from sequencing data of cfDNA. We used our workflow to design a custom amplicon panel suitable for detection of hotspot mutations relevant for colorectal cancer and analyzed mutations in serial cfDNA samples from a pilot cohort of 34 patients with advanced colorectal cancer. Using our method, we could detect recurrent and patient-specific mutational patterns in the majority of patients. Furthermore, we show that dynamic changes of mutant allele frequencies in cfDNA correlate well with disease progression. Finally, we demonstrate that sequencing of cfDNA can reveal mechanisms of resistance to anti-Epidermal Growth Factor Receptor(EGFR) antibody treatment. Thus, our approach offers a simple and highly customizable method to explore genetic alterations in cfDNA.
Asunto(s)
Ácidos Nucleicos Libres de Células/genética , Neoplasias Colorrectales/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación/genética , Ácidos Nucleicos Libres de Células/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Humanos , Biopsia Líquida , Reproducibilidad de los ResultadosRESUMEN
In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy and these drugs have already become essential for the treatment of various non-curable tumors. Compared to conventional chemotherapy or tyrosine kinase inhibitors, ICIs generally exhibit a favorable side effect profile further promoting their increasing prescription rate. However, increasing use of these substance made clear that ICI induced activation of the immune system may also lead to immune-related adverse events (irAEs). Common irAEs are dermatological, gastrointestinal, or endocrine side effects but further tissue types and organ systems may also be affected. A detailed knowledge of these potential side effects is important as early recognition is the key to successful treatment, reversibility of organ dysfunction and in some cases even prevention of fatal outcome. In more severe irAEs, immunosuppression may be necessary to cope with these side effects. To increase awareness of irAEs and support immediate and successful management, we provide a comprehensive review on most common irAEs of ICIs, their diagnosis, and treatment.
Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Neoplasias/tratamiento farmacológico , Animales , Comunicación Celular , Humanos , Terapia Molecular Dirigida/efectos adversos , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Transducción de Señal , Microambiente TumoralRESUMEN
BACKGROUND: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous cell carcinomas. Therefore, we assess combined nivolumab/ipilimumab as 2nd line therapy in elderly ESCC patients. METHODS: RAMONA is a multicenter open-label phase II trial. The primary objective is to demonstrate a significant survival benefit of nivolumab/ipilimumab in advanced ESCC compared to historical data of standard chemotherapy. Primary endpoint is therefore overall survival (OS). Major secondary objective is the evaluation of tolerability. Time to QoL deterioration will thus be determined as key secondary endpoint. Further secondary endpoints are tumor response, PFS and safety. We aim to recruit a total of n = 75 subjects that have to be > 65 years old. Eligibility is determined by the geriatric status (G8 screening and Deficit Accumulation Frailty Index (DAFI)). A safety assessment will be performed after a 3 cycle run-in phase of nivolumab (240 mg Q2W) to justify escalation for eligible patients to combined nivolumab (240 mg Q2W) and ipilimumab (1 mg/kg Q6W), while the other patients will remain on nivolumab only. RAMONA also includes translational research sub-studies to identify predictive biomarkers, including PD-1 and PD-L1 evaluation at different time points, establishment of organoid cultures and microbiome analyses for response prediction. DISCUSSION: The RAMONA trial aims to implement checkpoint inhibitors for elderly patients with advanced ESCC as second line therapy. Novel biomarkers for checkpoint-inhibitor response are analyzed in extensive translational sub-studies. TRIAL REGISTRATION: EudraCT Number: 2017-002056-86 ; NCT03416244 , registered: 31.1.2018.