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Chinese Clinical Oncology May 2024Patients with surgically resectable BRAF-mutated colorectal liver metastases (CRLM) or limited extrahepatic disease constitute a highly selective subgroup among...
BACKGROUND
Patients with surgically resectable BRAF-mutated colorectal liver metastases (CRLM) or limited extrahepatic disease constitute a highly selective subgroup among BRAF-mutated patients, characterized by a more indolent disease biology. This is evident in their suitability for surgical resection. However, initial studies from a decade ago presented a discouraging outlook for these patients, citing early, frequent, multifocal recurrences and a very limited median overall survival (OS) of less than two years. Our objective was to provide an updated, comprehensive, and critically assessed review of the current literature on the prognostic impact of BRAF variants in CRLM, as well as to explore optimal treatment strategies for these patients through a systematic search.
METHODS
A systematic literature search of the Medline, Scopus, and CENTRAL databases for studies reporting long-term outcomes of patients with a known BRAF status was performed.
RESULTS
A total of 386 unique studies were screened during the study selection process. After applying the exclusion criteria, a total of 18 studies published between 2012 and 2023 were deemed eligible for inclusion.
CONCLUSIONS
In contrast to older studies, more recent studies, with larger sample sizes, have revealed that the rate of extrahepatic recurrence is comparable between BRAF-mutated and wild-type patients. Furthermore, they have reported significantly improved survival outcomes, with OS extending up to 52 months. Notably, patients with non-V600E BRAF mutations may even achieve outcomes comparable to those with wild-type BRAF CRLM. Additionally, a few recent studies have compared surgery and systemic therapies, indicating that surgery is associated with improved survival rates, even for patients with the V600E mutation. This challenges the previous belief that BRAF mutations are absolute contraindications to surgical treatment. Surgical denial for technically resectable patients may now be reserved for specific clinical scenarios, such as the presence of a BRAF V600E mutation and concurrent extrahepatic disease.
PubMed: 38859602
DOI: 10.21037/cco-23-128 -
BMC Cancer Jun 2024Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting.
METHOD
We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation.
RESULTS
Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE.
CONCLUSION
PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen.
TRIAL REGISTRATION
CRD42023454079.
Topics: Humans; Poly(ADP-ribose) Polymerase Inhibitors; Bayes Theorem; Prostatic Neoplasms, Castration-Resistant; Mutation; Male; Phthalazines; Network Meta-Analysis; Piperazines; BRCA2 Protein; Recombinational DNA Repair; Antineoplastic Combined Chemotherapy Protocols; Randomized Controlled Trials as Topic; Progression-Free Survival; Indoles; BRCA1 Protein; Treatment Outcome; Quinazolines
PubMed: 38851712
DOI: 10.1186/s12885-024-12388-2 -
Heliyon Jun 2024FBXW7 is a tumour suppressor gene that functions as E3-ubiquitin-ligase, targeting numerous oncoproteins for degradation, i.e., Cyclin-E, c-Myc, and Notch. FBXW7...
UNLABELLED
FBXW7 is a tumour suppressor gene that functions as E3-ubiquitin-ligase, targeting numerous oncoproteins for degradation, i.e., Cyclin-E, c-Myc, and Notch. FBXW7 performs a pivotal role in regulating cell cycle progression. FBXW7 mutation is frequently implicated in various cancers.
METHODOLOGY
A systematic review and meta-analysis done on several studies using "Preferred Reporting Items for Systemmatic Reviews and Meta-Analysis (PRISMA)" criteria and registered with PROSPERO (registration-number-CRD42023388845). The preliminary search comprises 1182 articles; however, 58 studies were subsequently chosen after eliminating non-eligible studies. To explore the prevalence of FBXW7 mutation among colorectal cancer patients, data were analysed using "OpenMeta Analyst and comprehensive meta-analysis-3.0 (CMA-3.0)" software.
RESULTS
This meta-analysis involves 13,974 respondents; most were males 7825/13,974, (56.0 %). Overall prevalence of FBXW7 mutations was 10.3 %, (95%CI: 8.6-12.4), I2 = 90.5 %, (P < 0.001). The occurrence of FBXW7 mutations was highest in Russia [19.0 %, (95%CI: 9.8-33.7)] and Taiwan [18.8 %, (95%CI: 8.7-35.9)], P-values< 0.05 while the least prevalence was reported in Netherland (4 %) and Italy (5 %), both P-values< 0.001. Overall prevalence of FBXW7 abberation was greatest amongst male gender: "53.9 %, (95%CI: 8.3-62.0 %)", Tumour location (colon): 59.8 %, (95%CI: 53.9-65), tumour site (left): 61.6 %, (95%CI: 53.8-68.9), Tumour-grade (Moderate): 65.9 %, (95%CI: 54.9-75.4 %), and Tumour late-stage: 67.9 %, (95%CI: 49.7-84.3 %), all P-values< 0.001. When stratified according to study-period, an increasing trend was noted from 2018 till present with the highest mutation rate recorded in 2022 (15.3 %).
CONCLUSION
Overall prevalence of FBXW7 mutations was 10.3 % with male gender, left side, and late-stage being most mutated, and these outcomes conform with severally published articles on FBXW7 mutation.
PubMed: 38845996
DOI: 10.1016/j.heliyon.2024.e31471 -
World Journal of Surgery May 2024Several doubts remain regarding the optimal use of neoadjuvant imatinib in gastrointestinal stromal tumors (GISTs), such as ideal treatment duration, patient selection,... (Review)
Review
BACKGROUND
Several doubts remain regarding the optimal use of neoadjuvant imatinib in gastrointestinal stromal tumors (GISTs), such as ideal treatment duration, patient selection, and long-term survival outcomes. This manuscript provides a comprehensive review on neoadjuvant imatinib treatment outcomes and facilitate evidence-based decision-making for the use of imatinib therapy in GISTs.
METHODS
Four databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched from inception to September 9, 2023. Meta-analyses of proportions were performed for the outcomes of R0 resection, disease responses, and 1-year, 3-year, and 5-year overall survival (OS) as well as 1-year, 3-year, and 5-year disease free survival (DFS). Sensitivity analyses in the form of leave-one-out analyses, meta-regression, and subgroup analyses were performed for outcomes with substantial statistical heterogeneity.
RESULTS
The search yielded 1254 articles, and 36 studies were included in our analysis. Meta-analysis of proportions revealed that 1-year, 3-year, and 5-year OS was 100%, 94%, and 88%, while 1-year, 3-year and 5-year DFS was 99%, 89%, and 79%, respectively. An R0 resection rate of 89% and a disease response rate of 67% was achieved after a mean duration of treatment of 8.41 ± 0.367 months. KIT exon 9 mutation was significantly associated with poorer 5-year DFS.
CONCLUSION
This study quantified key outcomes for neoadjuvant imatinib in locally advanced and metastatic or recurrent GIST. Patients with gastric and rectal tumous stand to benefit from neoadjuvant imatinib with an optimal treatment duration of 8 months. Furthermore, the potential utility of mutational analysis in guiding treatment with neoadjuvant imatinib was demonstrated.
PubMed: 38757916
DOI: 10.1002/wjs.12210 -
Endocrine May 2024Approximately 45% of anaplastic thyroid cancer (ATC) patients harbor a BRAF mutation and are eligible for target therapy (TT) with BRAF and MEK inhibitors (BRAFi/MEKi),...
PURPOSE
Approximately 45% of anaplastic thyroid cancer (ATC) patients harbor a BRAF mutation and are eligible for target therapy (TT) with BRAF and MEK inhibitors (BRAFi/MEKi), nevertheless, few data advocate for this. Hence, we've conducted a systematic review and meta-analysis investigating the effectiveness and safety of BRAFi/MEKi in BRAF ATC patients.
METHODS
PubMed, Embase, and the Cochrane Library were systematically searched for BRAFi/MEKi TT in BRAF ATC patients. Outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response (DOR) and adverse events (AEs).
RESULTS
Nine studies with 168 patients were included. Median follow-up ranged from 2.0 to 47.9 months. 75% of patients had stage IVc. In a pooled analysis, ORR was 68.15% (95% CI 55.31-80.99, I = 47%) and DCR was 85.39% (95% CI 78.10-92.68, I = 0), with a median DOR of 14.4 months (95% CI 4.6-14.4) and a median PFS of 6.7 months (95% CI 4.7-34.2). Moreover, 1-year OS rate was 64.97% (95% CI 48.76-81.17, I = 84%) and 2-years OS rate was 52.08% (95% CI 35.71-68.45, I = 79%). Subgroup analysis showed patients in the neoadjuvant setting had higher rates of 1 and 2-years OS and observational studies tended to report higher rates of ORR than clinical trials. No new or unexpected adverse events were found.
CONCLUSIONS
Our study demonstrated BRAFi/MEKi have a decent activity for BRAF ATC patients, especially in the neoadjuvant setting, with a tolerable safety profile. However, further clinical trials are warranted to investigate these findings.
PubMed: 38709445
DOI: 10.1007/s12020-024-03845-w -
Journal of Neuropathology and... Apr 2024SMARCA4 alterations can be encountered in a variety of human neoplasms, and metastases to the central nervous system (CNS) are rare, offering a challenge to...
SMARCA4 alterations can be encountered in a variety of human neoplasms, and metastases to the central nervous system (CNS) are rare, offering a challenge to neuropathologists despite not representing a distinct diagnostic entity. To better understand the clinical and histologic presentation of such neoplasms, we report an observational case series and systematic review of 178 unique articles that yielded 15 published cases and 7 cases from institutional files. In the systematic review, the median age was 58 years, the male-to-female ratio was 2:1, and the most common diagnosis was lung adenocarcinoma; all CNS metastases were discovered within 1 year of presentation. In the case series, the median age was 58 years, the male-to-female ratio was 6:1, and all known metastases originated from the lung. Most patients had a smoking history and died of disease. GATA-3 positivity was seen in most case series examples. Concurrent TP53 mutations (83.3%) and a high tumor mutation rate (60%) were common. To our knowledge, this is the only case series and systematic review in the English literature aimed at assessing SMARCA4-altered metastases in the CNS and vertebral column. We highlight the challenges of neuropathologic evaluation of such tumors and provide observational evidence of early metastases, histologic appearances, and immunohistochemical findings, including previously unreported GATA-3 positivity.
PubMed: 38687619
DOI: 10.1093/jnen/nlae039 -
Frontiers in Immunology 2024At present, several important trials have been published show that perioperative immunotherapy combined with chemotherapy can improve the prognosis of patients with... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of neoadjuvant immunotherapy plus chemotherapy followed by adjuvant immunotherapy in resectable non-small cell lung cancer: a meta-analysis of phase 3 clinical trials.
OBJECTIVE
At present, several important trials have been published show that perioperative immunotherapy combined with chemotherapy can improve the prognosis of patients with resectable non-small cell lung cancer, which further optimizes treatment options. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of perioperative immunotherapy combined with chemotherapy in resectable non-small cell lung cancer.
METHODS
The following databases were searched for relevant studies: PubMed, EMBASE, Cochrane library (updated 12 October 2023). All randomized trials comparing perioperative immunotherapy combined with chemotherapy versus chemotherapy alone in resectable non-small cell lung cancer were eligible for inclusion. Data were analyzed using Review Manager 5.4.1 (Cochrane collaboration software). Primary outcomes and measures included overall survival (OS), event-free survival (EFS), pathological complete response (pCR), major pathological response (MPR), R0 resection rate, rate of underwent surgery and adverse events (AEs).
RESULTS
A total of 2912 patients (1453 receiving perioperative immunotherapy plus chemotherapy and 1459 receiving chemotherapy alone) were included in this systematic review and meta-analysis. The result showed that compared with chemotherapy alone, combined therapy significantly improved OS (HR = 0.68;95% CI: 0.56-0.83), EFS (HR = 0.58;95% CI: 0.51-0.65), pCR (OR = 7.53;95% CI: 4.63-12.26), MPR (OR = 5.03;95% CI: 3.40-7.44), R0 resection (OR = 1.58;95% CI: 1.152.18) and rate of underwent surgery (OR = 1.25;95% CI: 1.04-1.49). However, combination therapy was associated with higher risk of severe adverse event (OR = 1.46;95% CI: 1.19-1.78; P=0.0002), grade 3 and higher treatment-related adverse event (TRAE) (OR = 1.25;95% CI: 1.06-1.49; P=0.010), TRAE that led to interruption (OR = 1.90;95% CI: 1.34-2.68; P=0.0003) and immune-related adverse event (OR = 2.78;95% CI: 2.18-3.55; P<0.00001). Significant benefits were observed across most subgroups of EFS and pCR. However, no statistical differences were observed for EFS of never smoked (HR = 0.73;95% CI: 0.51-1.05) and EGFR-mutation positive (HR = 0.35;95% CI: 0.04-3.03).
CONCLUSION
This systematic review and meta-analysis found superior efficacy associated with perioperative immunotherapy plus chemotherapy compared with chemotherapy alone in both tumor regression and prolonged survival in resectable NSCLC, but increased the risk of TRAE, so monitoring for adverse events is warranted.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, identifier (CRD42023476786).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Immunotherapy; Lung Neoplasms; Neoadjuvant Therapy; Treatment Outcome
PubMed: 38646542
DOI: 10.3389/fimmu.2024.1359302 -
Peptides Jul 2024In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1-42) in human studies with... (Review)
Review
In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1-42) in human studies with administration of synthetic human GIP. We searched the PubMed database for all trials investigating synthetic human GIP(1-42) administration. A total of 67 studies were included. Study duration ranged from 30 min to 6 days. In addition to healthy individuals, the studies included individuals with impaired glucose tolerance, type 2 diabetes, type 1 diabetes, chronic pancreatitis and secondary diabetes, latent autoimmune diabetes in adults, diabetes caused by a mutation in the hepatocyte nuclear factor 1-alpha gene, end-stage renal disease, chronic renal insufficiency, critical illness, hypoparathyroidism, or cystic fibrosis-related diabetes. Of the included studies, 78% did not mention safety events, 10% of the studies reported that no safety events were observed in relation to GIP administration, and 15% of the studies reported safety events in relation to GIP administration with most frequently reported event being a moderate and transient increased heart rate. Gastrointestinal safety events, and changes in blood pressure were also reported. Plasma concentration of active GIP(1-42) increased linearly with dose independent of participant phenotype. There was no significant correlation between achieved maximal concentration of GIP(1-42) and reported safety events. Clearance rates of GIP(1-42) were similar between participant groups. In conclusion, the available data indicate that GIP(1-42) in short-term (up to 6 days) infusion studies is generally well-tolerated. The long-term safety of continuous GIP(1-42) administration is unknown.
Topics: Humans; Gastric Inhibitory Polypeptide; Peptide Fragments; Diabetes Mellitus, Type 2; Glucose Intolerance; Diabetes Mellitus, Type 1
PubMed: 38615716
DOI: 10.1016/j.peptides.2024.171214 -
European Journal of Surgical Oncology :... Jun 2024Mutations in the BRAF gene (BRAFmut) are associated with an unfavorable prognosis in patients with metastatic colorectal cancer (CRC). The aim of this meta-analysis was... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Mutations in the BRAF gene (BRAFmut) are associated with an unfavorable prognosis in patients with metastatic colorectal cancer (CRC). The aim of this meta-analysis was to evaluate the prognosis of colorectal cancer (CRC) patients with liver metastases and the potential benefits of liver resection in patients with BRAFmut CRC.
MATERIAL AND METHODS
A systematic search of PubMed, Cochrane Central Controlled Trials, and Embase databases was conducted on May 31, 2023. The inclusion criteria were as follows:1) reporting of outcomes in patients with BRAFmut CRC who underwent surgery for liver metastases and/or comparison of outcomes between those who underwent and those who did not undergo resection; 2) reporting of survival information as hazard ratios (HR); and 3) publication in English.
RESULTS
34 studies were included. Median follow up was 48 months for prognostic BRAF status meta-analysis. BRAFmut status showed a significantly increased risk of mortality (hazard ratio [HR] = 2.56, 95% confidence interval [CI] 2.04-3.22; P < 0.01) and relapse (HR = 1.97, 95% CI 1.44-2.71; P < 0.01). Resection of liver metastases was associated with a survival benefit (median follow up 46 months). The HR for survival was 0.44 (95% confidence interval [CI] 0.33-0.59; P < 0.01) in favor of surgery.
CONCLUSIONS
and Relevance: Our analysis indeed confirms that BRAF mutation is associated with poor survival outcomes after liver resection of CRC metastases. However, upon quantitatively assessing the survival benefit of surgical intervention in patients with BRAF-mutated CRC liver metastases, we identified a significant 56% reduction in the risk of death.
Topics: Humans; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Liver Neoplasms; Mutation; Hepatectomy; Prognosis; Survival Rate
PubMed: 38603866
DOI: 10.1016/j.ejso.2024.108306 -
Clinical Breast Cancer Jul 2024Poly-ADP ribose polymerase inhibitor (PARPi) is approved for HER2-negative advanced breast cancer with BRCA1/2 mutation. In recent years, many studies have explored the... (Meta-Analysis)
Meta-Analysis
Poly-ADP ribose polymerase inhibitor (PARPi) is approved for HER2-negative advanced breast cancer with BRCA1/2 mutation. In recent years, many studies have explored the application of PARPi in neoadjuvant therapy, but failed to reach a unified conclusion. PubMed, Clinicaltrials.gov, Cochrane CENTRAL, Embase, and key oncological meetings for trials were searched for studies reporting neoadjuvant regimens with PARPi in HER2-negative breast cancer. Pathological complete response (pCR), residual cancer burden (RCB), breast-conservation surgery rate (BCSR), clinical response, and adverse events were extracted and pooled in a meta-analysis using the Mantel Haenszel random/fixed effects model. Subgroup analyses of pCR were conducted according to BRCA1/2 status, and hormone receptor (HR) status. Five studies (N = 1223) were included, the addition of PARPi to neoadjuvant regimens significantly increased pCR rates (HR 1.45, 95%CI 1.09-1.92, P = .01, I = 86%). In subgroup analysis, the addition of PARPi increased the pCR rate both in HR-positive (n = 383) and HR-negative (n = 431) subgroups, which showed a dominant effect of PARPi regardless of HR status (HR 2.07, 95%CI 1.33-3.23, P = .001, I = 0%; HR 1.85, 95%CI 1.39-2.26, P < .0001, I = 0%, respectively). However, when we performed a subgroup analysis based on the status of BRCA1/2, no further benefit for PARPi was found. Adverse reactions were generally tolerable. Other outcome indexes, including RCB, clinical response, BCSR, and PARPi did not show a clinical benefit. Regardless of BRCA1/2 status, PARPi in neoadjuvant therapy, can improve the pCR rate of HER2-negative breast cancer, especially in HR-positive patients. Thus, we should have performed larger randomized trials and provided a stronger evidence-based basis.
Topics: Female; Humans; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Neoadjuvant Therapy; Poly(ADP-ribose) Polymerase Inhibitors; Receptor, ErbB-2; Treatment Outcome
PubMed: 38580572
DOI: 10.1016/j.clbc.2024.02.020