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Journal of Clinical Oncology : Official... Jan 2023To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC).
PURPOSE
To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC).
METHODS
ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.
RESULTS
Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria.
RECOMMENDATIONS
Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti-vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti-epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive wild-type mCRC; chemotherapy and anti-vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated V600E-mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision making are recommended. Qualifying statements with further details related to implementation of guideline recommendations are also included.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Endothelial Growth Factors; Rectal Neoplasms; Practice Guidelines as Topic
PubMed: 36252154
DOI: 10.1200/JCO.22.01690 -
Signal Transduction and Targeted Therapy Mar 2023The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription... (Review)
Review
The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
Topics: Humans; Tumor Suppressor Protein p53; Apoptosis; Autophagy; Cell Cycle; Ferroptosis
PubMed: 36859359
DOI: 10.1038/s41392-023-01347-1 -
Cancer Treatment Reviews Dec 2022Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic... (Review)
Review
Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic review and multiple Bayesian network meta-analyses according to treatment line to establish an optimal therapeutic sequencing strategy for this lethal disease. We included 125 first-line trials (37,812 patients) and 33 s/further-lines trials (11,321 patients). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rates (ORR), overall survival (OS) and safety, for first and further lines, separately. We also estimated separate treatment rankings for the first and subsequent lines according to each endpoint, based on (surface under the cumulative ranking curve) SUCRA values. No first-line treatment was associated with superior PFS and OS than paclitaxel ± bevacizumab. Platinum-based polychemotherapies were generally superior in terms of ORR, at the cost of higher toxicity.. PARP-inhibitors in germline-BRCA1/2-mutant patients, and immunotherapy + chemotherapy in PD-L1-positive mTNBC, performed similar to paclitaxel ± bevacizumab. In PD-L1-positive mTNBC, pembrolizumab + chemotherapy was better than atezolizumab + nab-paclitaxel in terms of OS according to SUCRA values. In second/further-lines, sacituzumab govitecan outperformed all other treatments on all endpoints, followed by PARP-inhibitors in germline-BRCA1/2-mutant tumors. Trastuzumab deruxtecan in HER2-low mTNBC performed similarly and was the best advanced-line treatment in terms of PFS and OS after sacituzumab govitecan, according to SUCRA values. Moreover, comparisons with sacituzumab govitecan, talazoparib and olaparib were not statistically significant. The most effective alternatives or candidates for subsequent lines were represented by nab-paclitaxel (in ORR), capecitabine (in PFS) and eribulin (in PFS and OS).
Topics: Humans; Triple Negative Breast Neoplasms; Bevacizumab; Poly(ADP-ribose) Polymerase Inhibitors; Network Meta-Analysis; B7-H1 Antigen; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Paclitaxel; Algorithms
PubMed: 36202026
DOI: 10.1016/j.ctrv.2022.102468 -
European Journal of Cancer (Oxford,... Jul 2023Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK inhibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma.
METHODS
Randomised clinical trials of previously untreated, advanced melanoma were included if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivolumab and relatlimab/nivolumab, and these combinations with all the other first-line treatment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade ≥3 treatment-related adverse events (≥ G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events.
RESULTS
A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 [95% CI 0.75-1.31] and RR = 0.99 [95% CI 0.78-1.27], respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 [95% CI 0.37-0.84]) and ORR (RR = 3.07 [95% CI 1.61-5.85]). Ipilimumab/nivolumab showed the highest risk of developing ≥ G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of ≥ G3 TRAEs (RR = 0.71 [95% CI 0.30-1.67]) versus ipilimumab/nivolumab.
CONCLUSION
Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/nivolumab, with a trend for a better safety profile.
Topics: Humans; Nivolumab; Ipilimumab; Network Meta-Analysis; Proto-Oncogene Proteins B-raf; Antineoplastic Combined Chemotherapy Protocols; Melanoma; Mitogen-Activated Protein Kinase Kinases
PubMed: 37196485
DOI: 10.1016/j.ejca.2023.04.010 -
International Journal of Cancer Jun 2017Gefitinib, erlotinib and afatinib are three widely used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for treating advanced non-small cell lung... (Comparative Study)
Comparative Study Meta-Analysis Review
Gefitinib, erlotinib and afatinib are three widely used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for treating advanced non-small cell lung cancer (NSCLC) with proven efficacy. We undertook a systematic review and meta-analysis to synthesize existing studies with direct comparisons of EGFR TKIs in NSCLC in terms of both efficacy and safety. Eight randomized trials and 82 cohort studies with a total of 17,621 patients were included for analysis. Gefitinib and erlotinib demonstrated comparable effects on progression-free survival (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.95 to 1.04), overall survival (HR, 0.99; 95% CI, 0.93 to 1.06), overall response rate (risk ratio [RR], 1.05; 95% CI, 1.00 to 1.11), and disease control rate (RR, 0.98; 95% CI, 0.96 to 1.01), which did not vary considerably with EGFR mutation status, ethnicity, line of treatment, and baseline brain metastasis status. Gefitinib was associated with more grade 3/4 liver dysfunction, but tended to cause lower rates of dose reduction, treatment discontinuation, total grade 3/4 adverse events (RR, 0.78; 95% CI 0.65 to 0.94), and a number of specific adverse events such as rash and diarrhea. No solid evidence was found that afatinib had greater efficacy than gefitinib or erlotinib in first-line treatment of EGFR-mutant NSCLC. However, afatinib was more effective than erlotinib as second-line treatment of patients with advanced squamous cell carcinoma. The grade 3/4 adverse events rate of afatinib was comparable to that of erlotinib but higher than that of gefitinib.
Topics: Afatinib; Carcinoma, Non-Small-Cell Lung; Diarrhea; Disease-Free Survival; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Gefitinib; Humans; Lung Neoplasms; Mutation; Outcome Assessment, Health Care; Proportional Hazards Models; Protein Kinase Inhibitors; Quinazolines; Randomized Controlled Trials as Topic
PubMed: 28295308
DOI: 10.1002/ijc.30691 -
BioMed Research International 2022Over the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing... (Review)
Review
BACKGROUND
Over the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing 6% annually. PTC has become the malignant tumor with the highest growth rate in the world that fourteen PTC-related mutant genes have been identified. Whether the BRAF mutation related to more aggressive clinicopathologic features and worse outcome in PTC remains variable and controversial. We aim to investigate the risk factors that may predict the BRAF mutation potential of these lesions and new prevention strategies in PTC patients.
METHODS
A total of 9,908 papillary thyroid carcinoma patients with average 74.6% BRAF mutations were analyzed (RevMan 5.3 software) in this study. The PubMed, Embase, and ISI Web of Science databases were systematically searched for works published through December 15, 2021.
RESULTS
The following variables were associated with an increased risk of BRAF mutation in PTC patients: age ≥ 45 years (OR = 1.39, 95%CI = 1.21-1.60, < 0.00001), male gender (OR = 1.13, 95%CI = 0.99-1.28, = 0.06), multifocality (OR = 1.22, 95%CI = 1.07-1.40, = 0.004), lymph node metastasis (OR = 1.33, 95%CI = 0.79-2.23, = 0.28), extrathyroidal extension + (OR = 1.61, 95%CI = 1.06-2.44, = 0.03), vascular invasion + (OR = 2.04, 95%CI = 1.32-3.15, = 0.001), and tumor node metastasis stage (OR = 1.61, 95%CI = 1.38-1.88, < 0.00001). In addition, tumor size (>1 cm) (OR = 0.51, 95%CI = 0.32-0.81, = 0.005) and distant metastasis (OR = 0.69, 95%CI = 0.22-2.21, = 0.54) had no association or risk with BRAF mutation in PTC patients.
CONCLUSION
Our systematic review identified the following significant risk factors of BRAF mutation in PTC patients: age (≥45 years), gender (male), multifocality, lymph node metastasis, vascular invasion, extrathyroidal extension, and advanced tumor node metastasis stage (stages III and IV). Tumor size (>1 cm) and distant metastasis do not appear to be correlated with BRAF mutation in PTC patients.
Topics: Carcinoma, Papillary; Humans; Lymphatic Metastasis; Male; Middle Aged; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 35647194
DOI: 10.1155/2022/9959649 -
Current Oncology (Toronto, Ont.) Jan 2022Compound epidermal growth factor receptor () mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon mutations. We... (Review)
Review
Compound epidermal growth factor receptor () mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon mutations. We conducted a systematic review to investigate the available data on this patients' subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4-26% of total mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40-80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20-70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound mutations, taking into account different sensitivity profile of accompanying mutations for selecting the most adequate EGFR TKI for individual patients.
Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors
PubMed: 35049698
DOI: 10.3390/curroncol29010024 -
Human Reproduction Update Dec 2021Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic...
BACKGROUND
Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs.
OBJECTIVE AND RATIONALE
In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes.
SEARCH METHODS
We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'male infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org.
OUTCOMES
The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes.
WIDER IMPLICATIONS
Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human male infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.
Topics: Animals; Chromosome Deletion; Genetic Testing; Genomics; High-Throughput Nucleotide Sequencing; Humans; Infertility, Male; Male
PubMed: 34498060
DOI: 10.1093/humupd/dmab030 -
World Neurosurgery Jun 2022Isocitrate dehydrogenase (IDH) mutations are present in 70% of World Health Organization grade II and III gliomas. IDH mutation induces accumulation of the... (Review)
Review
BACKGROUND
Isocitrate dehydrogenase (IDH) mutations are present in 70% of World Health Organization grade II and III gliomas. IDH mutation induces accumulation of the oncometabolite 2-hydroxyglutarate. Therefore, therapies targeting reversal of epigenetic dysregulation in gliomas have been suggested. However, the utility of epigenetic treatments in gliomas remains unclear. Here, we present the first clinical systematic review of epigenetic therapies in treatment of IDH-mutant gliomas and highlight their safety and efficacy.
METHODS
We conducted a systematic search of electronic databases from 2000 to January 2021 following PRISMA guidelines. Articles were screened to include clinical usage of epigenetic therapies in case reports, prospective case series, or clinical trials. Primary and secondary outcomes included safety/tolerability of epigenetic therapies and progression-free survival/overall survival, respectively.
RESULTS
A total of 133 patients across 8 clinical studies were included in our analysis. IDH inhibitors appear to have the best safety profile, with an overall grade 3/grade 4 adverse event rate of 9%. Response rates to IDH-mutant inhibitors were highest in nonenhancing gliomas (stable disease achieved in 55% of patients). In contrast, histone deacetylase inhibitors demonstrate a lower safety profile with single-study adverse events as high as 28%.
CONCLUSION
IDH inhibitors appear promising given their benign toxicity profile and ease of monitoring. Histone deacetylase inhibitors appear to have a narrow therapeutic index, as lower concentrations do not appear effective, while increased doses can produce severe immunosuppressive effects. Preliminary data suggest that epigenetic therapies are generally well tolerated and may control disease in certain patient groups, such as those with nonenhancing lesions.
Topics: Brain Neoplasms; Epigenesis, Genetic; Glioma; Histone Deacetylase Inhibitors; Humans; Isocitrate Dehydrogenase; Mutation
PubMed: 35314408
DOI: 10.1016/j.wneu.2022.03.051 -
Neuro-oncology Advances 2022A comprehensive review and description of the clinical features that impact prognosis for patients with diffuse hemispheric glioma, H3 G34-mutant (G34-DHG) is needed....
BACKGROUND
A comprehensive review and description of the clinical features that impact prognosis for patients with diffuse hemispheric glioma, H3 G34-mutant (G34-DHG) is needed. Understanding survival and prognostic features is paramount for clinical advancements and patient care.
METHODS
PubMed, Embase, and Google Scholar were searched for English articles published between January 1, 2012 and June 30, 2021. Eligible studies included patient(s) of any age diagnosed with an H3 G34-mutant brain tumor with at least one measure of survival or progression. Patient-level data were pooled for analyses. This study was prospectively registered in PROSPERO (CRD42021267764) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.
RESULTS
Twenty-seven studies met the criteria with a total of 135 patients included. Median age at diagnosis was 15.8 years (interquartile range [IQR]: 13.3-22.0) with 90% having localized disease. Co-occurring alterations included mutation in 93%, mutation in 88%, and promoter methylation in 70%. Median time-to-progression was 10.0 months (IQR: 6.0-18.0) and median overall survival was 17.3 months (95% CI: 15.0 to 22.9). The median time from progression to death was 5.0 months (IQR: 3.0-11.7). Factors associated with survival duration were age, as patients ≥18 y/o demonstrated longer survival (hazard ratio [HR] =2.05, 95% CI: 1.16 to 3.62), and degree of upfront resection, as near or gross-total resection demonstrated longer survival compared to those with less than near-total resection (HR = 3.75, 95% CI: 2.11 to 6.62).
CONCLUSION
This systematic review highlights available clinical data for G34-DHG demonstrating poor outcomes and important prognostic features, while serving as a baseline for future research and clinical trials.
PubMed: 36105387
DOI: 10.1093/noajnl/vdac133