Abstract
Background
KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer; however, their impact in the adjuvant setting has not yet been ...established.
Methods
We performed a meta-analysis of adjuvant phase III trials in patients with stage II and III colon cancer with available data on the impact of KRAS or BRAF mutations on both disease-free survival (DFS) and overall survival (OS). Trials were subgrouped based on whether adjustment for microsatellite instability (MSI) was performed and the subgroup effect was analyzed through a meta-regression. To increase the precision of the estimates, a joint DFS–OS (so-called “multivariate”) meta-analysis was performed. All statistical tests were 2-sided.
Results
Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10 893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled hazard ratio HR = 1.36, 95% confidence interval CI = 1.15 to 1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03 to 1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00 to 1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31 to 1.70, P < .001). The effect of the mutations on outcome was enhanced in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15 to 1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03 to 1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22 to 2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37 to 2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (Pinteraction = .02). This interaction was even more pronounced in the DFS–OS multivariate meta-analysis.
Conclusions
Both KRAS and BRAF mutations were statistically significantly associated with both DFS and OS, with the mutation effect being enhanced by MSI adjustment. Effective adjuvant treatment for microsatellite-stable BRAF or KRAS-mutated colon cancer represents an unmet clinical need, and exploring the use of recently available BRAF and KRAS inhibitors in this setting would be highly desirable.
The debate on the optimal drug combination for treating chemotherapy-nave patients with metastatic colorectal cancer has recently become particularly heated.The present editorial will review recent ...data on this topic.The FIRE-3 and PEAK trials have shown a 7.5 to 12 mo survival advantage with the use anti-epidermal growth factor receptor(anti-EGFR)antibodies.The CALGB 80405 has shown no difference between anti-EGFR and anti-vascular endothelial growth factor agents.All three trials have consistently shown a significant increase in objective response rate.These data suggest that there is a subset of metastatic colorectal cancer patients,rigorously selected by molecular profiling,who particularly benefit from an anti-EGFR-based regimen in the first-line setting.
The aim of the present review is to discuss the potential link between RAS, BRAF and microsatellite instability (MSI) mutational patterns and chemotherapeutic agent efficacy Irinotecan (IRI) vs. ...Oxaliplatin (OXA), and how this can potentially influence the choice of the chemotherapy backbone.
Following a review of the research literature, all pertinent articles published in the core journals were selected for the study. The inclusion criteria regarded relevant clinical and pre-clinical studies on the topic of interest (Relationship of OXA and IRI to KRAS/BRAF mutations and MSI).
Excision repair cross complementation group 1 (ERCC1) expression is inhibited by KRAS mutation, making tumor cells more sensitive to OXA. Results from OPUS, COIN and PRIME trials support that no conclusive data are available for BRAF mutant population because of the small number of patients. Enhanced IRI cytotoxicity to MSI cell lines is due to the participation of some of the mismatch repair (MMR) components in various DNA repair processes and their role in the maintenance of the pro-apoptotic effect of IRI and G2/M cell arrest.
OXA and IRI are indispensable drugs for mCRC treatment and their selection must be as careful as that of targeted agents. We suggest taking into consideration the interaction between known genomic alterations and OXA and IRI activity to personalize chemotherapy in mCRC patients.
The interplay between the immune system and chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) is complex and multifaceted. In COPD, chronic inflammation and ...oxidative stress can lead to immune dysfunction that can exacerbate lung damage, further worsening the respiratory symptoms. In NSCLC, immune cells can recognise and attack the cancer cells, which, however, can evade or suppress the immune response by various mechanisms, such as expressing immune checkpoint proteins or secreting immunosuppressive cytokines, thus creating an immunosuppressive tumour microenvironment that promotes cancer progression and metastasis. The interaction between COPD and NSCLC further complicates the immune response. In patients with both diseases, COPD can impair the immune response against cancer cells by reducing or suppressing the activity of immune cells, or altering their cytokine profile. Moreover, anti-cancer treatments can also affect the immune system and worsen COPD symptoms by causing lung inflammation and fibrosis. Immunotherapy itself can also cause immune-related adverse events that could worsen the respiratory symptoms in patients with COPD-compromised lungs. In the present review, we tried to understand the interplay between the two pathologies and how the efficacy of immunotherapy in NSCLC patients with COPD is affected in these patients.
Background: Aromatase inhibitors (AI) are widely used for treating hormone-sensitive breast cancer (BC). Obesity, however, due to aromatase-mediated androgen conversion into estradiol in the ...peripheral adipose tissue, might impair AI inhibitory capacity. We aimed at identifying a cut-off of body mass index (BMI) with significant prognostic impact, in a cohort of stage I-II BC patients on systemic adjuvant therapy with AI. Methods: we retrospectively evaluated routinely collected baseline parameters. The optimal BMI cut-off affecting disease-free survival (DFS) in AI-treated BC patients was identified through maximally selected rank statistics; non-linear association between BMI and DFS in the AI cohort was assessed by hazard-ratio-smoothed curve analysis using BMI as continuous variable. The impact of the BMI cut-off on survival outcomes was estimated through Kaplan−Meier plots, with log-rank test and hazard ratio estimation comparing patient subgroups. Results: A total of 319 BC patients under adjuvant endocrine therapy and/or adjuvant chemotherapy were included. Curve-fitting analysis showed that for a BMI cut-off >29 in AI-treated BC patients (n = 172), DFS was increasingly deteriorating and that the impact of BMI on 2-year DFS identified a cut-off specific only for the cohort of postmenopausal BC patients under adjuvant therapy with AI. Conclusion: in radically resected hormone-sensitive BC patients undergoing neoadjuvant or adjuvant chemotherapy and treated with AI, obesity represents a risk factor for recurrence, with a significantly reduced 2-year DFS.
Background Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) ...adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone. Methods RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status. Results Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3-4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients. Conclusions These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets. Keywords: FLOT, Perioperative chemotherapy, Gastric cancer, Gastro-oesophageal junction adenocarcinoma, pCR, MSI
Venous thromboembolism (VTE) is a commonly diagnosed multifactorial condition with significant morbidity and mortality, occurring in up to 20% of cancer patients. Indeed, patients with cancer are in ...a higher pro-thrombotic state due to alterations in their haemostatic- coagulative system, stasis and blood flow slowdown, endothelial dysfunction, vascular inflammation and platelet activation. Moreover, several cancer-dependent factors can sum up to trigger a first episode of VTE or to cause its recurrence in the course of anticoagulant treatment. Such a pro-thrombotic condition is further worsened by additional favoring risks such as immobilization, infection, surgery, or insertion of a central venous catheter, and anti-cancer therapy. Furthermore, in the secondary prevention setting, the anticoagulant therapy is accompanied by a high incidence of bleeding complications. Given the above, understanding and identifying the factors associated with the incidence and clinical outcome of VTE in cancer patients might be of great value in the prevention and management of VTEattributable complications, including death. Differences associated to gender on cancerrelated VTEs are not yet fully defined; many of the studies that addressed the question have been biased by erroneous/non homogeneous inclusion criteria. In the present review, we analyzed the potential differences in VTEs occurrence in cancer patients, by reporting the most significant findings in the recent literature. The identification of a differential clinical approach according to patient sex, might prompt the design of personalized treatment options tailored and optimized according to algorithms for oncological VTE prevention.
Advanced, metastatic colorectal cancer (CRC) is associated with high rate of mortality because of its poor responsiveness to chemotherapy/immunotherapy. Recent studies have shown that hepcidin, a ...peptide hormone produced mainly by hepatocytes, is expressed by and enhances the growth of tumor cells. We here assessed whether hepcidin expression helps identify subsets of CRC with advanced and aggressive course. By integrating results of in vitro/ex vivo studies with data of bioinformatics databases, we initially showed that hepcidin RNA and protein expression was more pronounced in tissue samples taken from the tumor area, as compared to the macroscopically unaffected, adjacent, colonic mucosa of CRC patients. The induction of hepcidin in the colonic epithelial cell line HCEC-1ct by interleukin (IL)-6, IL-21 and IL-23 occurred via a Stat3-dependent mechanism and, in primary CRC cells, hepcidin co-localized with active Stat3. In CRC tissue, hepcidin content correlated mainly with macrophage accumulation and IL-10 and CD206 expression, two markers of regulatory macrophages. Consistently, both IL-10 and CD206 were up-regulated by hepcidin in blood mononuclear cells. The highest levels of hepcidin were found in metastatic CRC and survival analysis showed that high expression of hepcidin associated with poor prognosis. Moreover, hepcidin expression correlated with markers of epithelial-to-mesenchymal transition and the silencing of hepcidin in CRC cells reduced epithelial-to-mesenchymal transition markers. These findings indicate that hepcidin is markedly induced in the advanced stages of CRC and suggest that it could serve as a prognostic biomarker in CRC.
AIM To investigate the clinical significance of routinely used glycemic parameters in a cohort of colorectal cancer(CRC) patients.METHODS Pre-treatment fasting blood glucose, insulin, Hb A1 c and ...homeostasis model of risk assessment(HOMA-IR) were retrospectively evaluated in a case-control study of 224 CRC and 112 control subjects matched for sex, obesity and diabetes frequency and blood lipid profile.Furthermore, the prognostic value of routinely used glycemic parameters towards progression-free(PFS) and overall survival(OS) was prospectively evaluated.RESULTS Fasting blood glucose, insulin, HOMA-IR and HbA 1c(all P < 0.0001) levels were higher in non-diabetic CRC patients compared with obesity-matched controls. All parameters were associated with increased CRC risk at ROC analysis, but no relationship with clinical-pathological variables or survival outcomes was observed for glycemia, insulinemia or HOMA-IR. Conversely, advanced CRC stage(P = 0.018) was an independent predictor of increased Hb A1 c levels, which were also higher in patients who had disease progression compared with those who did not(P = 0.05). Elevated Hb A1 c levels showed a negative prognostic value both in terms of PFS(HR = 1.24) and OS(HR = 1.36) after adjustment for major confounders, which was further confirmed in a subgroup analysis performed after exclusion of diabetic patients.CONCLUSION HbA 1c might have a negative prognostic value in CRC, thus suggesting that glycemic metabolic markers should be carefully monitored in these patients, independently of overt diabetes.
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