Colorectal cancer (CRC) is still a leading cause of cancer-related deaths in the United States and worldwide, despite recent improvements in cancer management. CRC, like many malignancies, is a ...heterogeneous disease, with subtypes characterized by genetic alterations. One common mutation in CRC is in the BRAF gene (most commonly V600E substitution). This occurs in ∼10% of patients with metastatic CRC (mCRC) and is a marker of poor prognosis.
Herein, we review the clinical and translational literature on the role of the BRAF V600E mutation in the pathogenesis of mCRC, its mechanisms as a prognostic marker, and its potential utility as a predictive marker of treatment response. We then summarize the current evidence-based recommendations for management of BRAF V600E-mutated mCRC, with a focus on recent clinical research advances in this setting.
The current standard therapies for first-line treatment of BRAF-mutated mCRC are chemotherapy with bevacizumab as well as 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab in patients with a good performance status. Combination strategies involving mitogen-activated protein kinase (MAPK) pathway blockade have shown promising results for the treatment of patients with BRAF V600E-mutated mCRC. The Binimetinib, Encorafenib, And Cetuximab cOmbiNed to treat BRAF-mutant ColoRectal Cancer (BEACON CRC) study represents the largest study in this population to date and has given strong clinical evidence to support BRAF and epidermal growth factor receptor inhibition with the combination of encorafenib plus cetuximab.
The treatment of BRAF-mutated mCRC has evolved rapidly over the last several years. Recently, combination strategies involving MAPK pathway blockade have shown promising results in BRAF V600E-mutated mCRC, and other potential targets continue to be explored. In addition, a greater understanding of the role of BRAF V600E mutation in the pathogenesis of CRC should also continue to fuel advances in the management of patients with mCRC harboring this genetic aberration.
•CRC remains a leading cause of cancer-related deaths globally, despite improvements in management.•Mutations in the BRAF gene are seen in 10% of patients with mCRC, particularly due to V600E substitution.•V600E substitution is a marker of poor prognosis and reduced response to treatment in patients with mCRC.•Combination treatment involving MAPK pathway blockade has shown promise for patients with BRAF V600E-mutated mCRC.•Continued research is needed to further improve outcomes in these patients.
Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated ...a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed.
Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8–1.1Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRC patients was analyzed to define the relevance of the identified TMB cut-point.
A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P<0.001) and PFS, by univariate (P<0.001) and multivariate analysis (P<0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18months) while the median PFS for TMBlow was 2months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point.
TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.
This study addresses the problem of the high‐dimensionality of quantitative structure‐activity relationship (QSAR) classification modeling. A new selection of descriptors that truly affect biological ...activity and a QSAR classification model estimation method are proposed by combining the sparse logistic regression model with a bridge penalty for classifying the anti‐hepatitis C virus activity of thiourea derivatives. Compared to other commonly used sparse methods, the proposed method shows superior results in terms of classification accuracy and model interpretation.
For high‐dimensional quantitative structure activity relationship (QSAR) classification model, a study typically contains a large number of irrelevant and redundant descriptors. In this paper, a new designing descriptor selection and QSAR classification model estimation method is proposed by combining the sparse logistic regression model with bridge penalty. The experimental results of classifying the anti‐hepatitis C virus activity of thiourea derivatives demonstrate that the proposed QSAR classification model performs effectively and competitively compared with other existing sparse methods of classification performance in both the training and the testing datasets. Moreover, it is noteworthy that the results obtained in terms of applicability domain provide a robust QSAR classification model. It is evident from the results that the developed QSAR classification model could conceivably be used for further high‐dimensional QSAR classification studies.
Identifying mutations in the KRAS gene has become increasingly important in the treatment of colorectal cancer with many prognostic and therapeutic implications. However, efforts to develop drugs ...that target KRAS mutations have not been successful until more recently with the introduction of the KRASG12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849). Both agents have demonstrated safety and promising efficacy in preclinical studies and early phase trials, but it appears that not all tumor types harboring the KRASG12C mutation are sensitive to monotherapy approaches. In particular, patients with colorectal cancer (CRC) derive less benefit compared to those with non-small cell lung cancer (NSCLC), likely due to rapid treatment-induced resistance through increased epidermal growth factor receptor (EGFR) signaling. As a result, combination therapy trials with EGFR inhibitors are currently underway. Here, we will review the available clinical trial data on KRASG12C inhibitors in KRASG12C-mutated CRC, possible mechanisms of resistance to monotherapy, the research studying why available agents are proving to be less efficacious in CRC compared to NSCLC, and future directions for these promising new drugs.
The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, plays an important role in the control of cell growth and differentiation. Disruption of its ...signaling leads to neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis.EGFR is overexpressed in a variety of solid tumors, including colorectal cancer (CRC), and its overexpression is associated with poorer prognosis. One class of agents that is currently used to target EGFR in the treatment of metastatic CRC (mCRC) is the monoclonal antibodies. While the monoclonal antibody EGFR inhibitors lack many of the severe side effects commonly observed with cytotoxic chemotherapy, they are associated with a set of unique dermatological toxicities. This paper reviews the safety profile of the anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of mCRC.
The study presented here investigated the impact of initial antibiotic choice (beta-lactams vs vancomycin) on the outcome of 342 patients with Staphylococcus aureus bacteremia (50.9% with ...methicillin-resistant isolates) encountered between 1 January 2002 and 30 June 2003. Initial antibiotics were inappropriate (beta-lactams) in 60 (34.5%) methicillin-resistant cases and suboptimal (vancomycin) in 62 (36.9%) methicillin-susceptible cases. Time to effective antibiotic therapy was longer in methicillin-resistant cases (25.5+/-28.6 vs 9.6+/-16.6 h; p<0.0005). All-cause in-hospital mortality was higher with inappropriate therapy (35.0 vs 20.9%; p=0.02). Initial vancomycin treatment was associated with a higher incidence of delayed clearance (>or=3 days) of methicillin-susceptible bacteremia (56.3 vs 37.0%; p=0.03). The results indicate inappropriate initial therapy is associated with higher in-hospital mortality and initial vancomycin may delay clearance.
Abstract Study question How many cycles are needed to get at least one blastocyst in patients of different AMH levels and varied ages? Summary answer Age and AMH determine the number of cycles, which ...ranges from 1 cycle in young patients up to 10 cycles in over-44-year-old patients. What is known already AMH secretion by ovarian granulosa cells initiates during the 36th week of gestation in pre-antral and antral follicles. This persists throughout a woman’s reproductive lifespan. AMH serves as a biomarker for assessing ovarian reserve and forecasting the ovarian response to stimulation. AMH is strongly associated with the quantity of antral follicles and the production of oocytes. AMH can be utilised to determine the initial dosage of FSH in an IVF cycle, as well as serving as a quantitative indicator of the number of oocytes produced. Study design, size, duration In this retrospective cohort study, data was collected from 16,417 ICSI cycles with Preimplantation Testing for Aneuploidy (PGT-A) conducted at three referral fertility centers from Jan 2019 to Dec 2023. We excluded cycles without serum AMH, endocrinopathies or recurrent pregnancy loss, males with total sperm count of less than 5 million and total motility less than 30%, and those with parental chromosomal abnormalities. Participants/materials, setting, methods Patients were stratified into three different categories of AMH (ng/ml), low (< 1.1 ng/mL), intermediate (>1.1 to < 3.0 ng/mL) and high (> 3.0 ng/mL). Each category was subdivided into 6 age sub-categories as follow (< 35), (35 to < 38), (38 to < 40), (40 to < 42), (42 to < 44), (> 44). All of the cycles underwent blastocyst stage biopsy and PGT-A utilising next generation sequencing (NGS). Main results and the role of chance Euploidy rate was statistically insignificant for all AMH levels in the same age group. However, euploid embryo numbers vary significantly. Euploid embryos numbers are shown in low, medium, and high AMH by age group. In the (<35) years was 1.9±1.5, 2.9±2.3, and 4.7±3.5, p < 0.0001. In the (35 to > 38) years was 1.3±0.8, 2.1±1.8, and 3.2±2.6, p < 0.0001. In the (38 to > 40) years was 0.9±0.8, 1.7±1.4, and 2.6±1.7, p < 0.0001. In the (40 to > 42) years was 0.6±0.5, 0.9±0.7, and 1.5±1.4, p < 0.0001. In the (42 to > 44) year was 0.26±0.2, 0.49±0.38, and 0.6±53, p < 0.0001. In the (≥44) years was 0.10±0.10, 0.23±0.21, and 0.40±0.37, p = 0.0170. We calculated the number of cycles needed to produce at least one grade BB or higher euploid blastocyst from the mean number of euploid embryos per cycle: The number of cycles is presented in low, medium, and high AMH. In the (<35) and (35 to > 38), 1 cycle is needed. In (38 to > 40) years, 2 cycles, 1 cycle and 1 cycle. In the (40-42) group 2 cycles, 2 cycles and 1 cycle. In the (42 to < 44) group 4 cycles, 3 cycles and 2 cycles. In the (≥44) group 10 cycles, 5 cycles and 3 cycles. Limitations, reasons for caution The retrospective nature of the study is the main limitation. Wider implications of the findings The study offers valuable insights for patient counselling regarding the required number of cycles to achieve euploid embryos, as well as for financial budgeting for both patients and insurance companies. Trial registration number Not applicable
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