Dynamic nature of BRAF or KRAS p.G12C mutations in second-line therapy for advanced colorectal cancer patients: do early and late effects exist?

INTRODUCTION: The mitogen-activated protein kinase (MAPK) signalling network aberrations in metastatic colorectal cancer (mCRC) generate intrinsic dynamic effects and temporal variations that are crucial but often overlooked in clinical trial populations. Here, we investigate the time-varying impact of MAPK pathway mutation genotype on each treatment line's contribution to the overall clinical course. METHODS: The PROMETEO study focused on mCRC patients undergoing second-line treatment at 20 hospitals. We evaluated genotypes and employed flexible models to analyse the dynamic effect of each mutation. RESULTS: We examined data derived from 1160 patients. The effects of KRAS G12C or G12V, and BRAF V600E are clearly time-varying, with unexpected consequences such as the deleterious effect of BRAF V600E vs other genotypes dissipating over time when subjects receive antiangiogenics, or KRAS G12V and G12C showing increasing aggressiveness over time. Thus, contrary to expectations, the 12-month survival rate from the second line for those who survived >6 months was 49.9% (95% CI, 32.7-67.3) for KRAS G12C and 59% (95% CI, 38.5-80.6) for BRAF V600E. CONCLUSIONS: The dynamic perspective is essential for understanding the behaviour of tumours with specific genotypes, especially from the second line onward. This may be relevant in patient monitoring and treatment decision-making, particularly in cases with distinct mutations.

EGFR-mutated advanced lung cancer. Data from a single institution, the Hospital of Leon, in Spain.

INTRODUCTION: 10-16% of non-small cell lung cancer (NSCLC) cases have the epidermal growth factor receptor (EGFR) amplified and/or mutated. Studies show that EGFR tyrosine kinase inhibitors (TKIs) significantly prolong progression-free survival (PFS) in patients with advanced NSCLC compared to those treated with platinum-based chemotherapy (CT) doublets. Our aim is to perform a real-world survival analysis of patients treated with TKI as first-line therapy at the Hospital of Leon (CAULE) in Spain. The impact on global survival rates and responses to clinical and histopathological factors were also analyzed. MATERIAL AND METHODS: We retrospectively reviewed patients diagnosed with EGFR-mutated NSCLC who received treatment with EGFR-TKI in the Department of Oncology at the University of Leon Health Center complex between March 2011 and June 2018. Data was analyzed with Kaplan-Meier and Cox regression models to show overall survival (OS), progression-free survival (PFS), and the associated variables. RESULTS: 53 patients were included in the study, 50% (n = 27) were treated with gefitinib, 32% (n = 18) with erlotinib and 10% (n = 6) with afatinib. The median OS and PFS were 27.7 months (95% CI: 21-33.8 months) and 18 months (95% CI 14.25-21.89 months), respectively. The variables associated with OS and with PFS were exon19 deletion as a protective factor and presence of extrathoracic metastasis as a risk factor. The most frequent adverse effects were rash, diarrhea, asthenia, and conjunctivitis. CONCLUSIONS: Real-world analysis of this data confirms that treatment with TKI is beneficial for patients diagnosed with EGFR-mutated NSCLC. Our OS outcomes were similar to those reported in clinical trials.

Sleep duration and napping in relation to colorectal and gastric cancer in the MCC-Spain study.

Sleep duration is a novel and potentially modifiable risk factor for cancer. We evaluated the association of self-reported sleep duration and daytime napping with odds of colorectal and gastric cancer. We included 2008 incident colorectal cancer cases, 542 gastric cancer cases and 3622 frequency-matched population controls, recruited in the MCC-Spain case-control study (2008-2013). Sleep information, socio-demographic and lifestyle characteristics were obtained through personal interviews. Multivariable adjusted logistic regression models were used to estimate odds ratios (OR) with 95% confidence intervals (CI) for cancer, across categories of sleep duration (≤ 5, 6, 7, 8, ≥ 9 hours/day), daytime napping frequency (naps/week) and duration (minutes/nap). Compared to 7 hours of sleep, long sleep was associated with increased odds of colorectal (OR≥9 hours: 1.59; 95%CI 1.30-1.94) and gastric cancer (OR≥9 hours: 1.95; 1.37-2.76); short sleep was associated with increased odds of gastric cancer (OR≤5 hours: 1.32; 0.93-1.88). Frequent and long daytime naps increased the odds of colorectal (OR6-7 naps/week, ≥30 min: 1.32; 1.14-1.54) and gastric cancer (OR6-7 naps/week, ≥30 min: 1.56; 1.21-2.02). Effects of short sleep and frequent long naps were stronger among participants with night shift-work history. Sleep and circadian disruption may jointly play a role in the etiology of colorectal and gastric cancer.

Prognostic Nomogram and Patterns of Use of FOLFIRI-Aflibercept in Advanced Colorectal Cancer: A Real-World Data Analysis.

INTRODUCTION: The VELOUR study evaluated the efficacy and safety of adding aflibercept to FOLFIRI (fluorouracil, leucovorin, irinotecan) in second-line therapy for metastatic colorectal cancer (mCRC). However, a nomogram that can stratify patients according to prognosis is unavailable, and the frequency and effect of the pragmatic use of modified schedules in actual practice remains unknown. METHOD: The sample consists of 250 patients with mCRC treated with aflibercept and irinotecan-based chemotherapy at nine Spanish academic centers between January 2013 and September 2015. The result of a Cox proportional hazards model regression for overall survival (OS), adjusted for covariates available in daily practice, was represented as a nomogram and web-based calculator. Harrell's c-index was used to assess discrimination. RESULTS: The prognostic nomogram for OS includes six variables: Eastern Cooperative Oncology Group performance status, tumor location, number of metastatic sites, mutational status, better response to previous treatment(s), and carcinoembryonic antigen. The model is well calibrated and has acceptable discriminatory capacity (optimism-corrected c-index, 0.723; 95% confidence interval [CI], 0.666-0.778). Median OS was 6.1 months (95% CI, 5.1-8.8), 12.4 months (95% CI, 9.36-14.8), and 22.9 months (95% CI, 16.6-not reached) for high-, intermediate-, and low-risk groups, respectively. Age, comorbidity, or use of modified FOLFIRI regimens did not affect prognosis in this series. Grade 3-4 adverse events were less common following modified schedules. The admission rate because of toxicity was higher in ≥65 years (9.7% vs. 19.6%; odds ratio, 2.26; p = .029). CONCLUSION: We have developed and internally validated a prognostic model for use in individuals with colorectal cancer initiating therapy with FOLFIRI-aflibercept to predict both OS and the effect of pragmatic modifications of the classic regime on efficacy and safety. This can aid in decision making and in designing future trials. IMPLICATIONS FOR PRACTICE: In this study, the authors developed and conducted the internal validation of a prognostic nomogram that makes it possible to stratify patients who are eligible for second-line FOLFIRI-aflibercept based on their probability of survival. This model was developed in a multicenter sample from nine Spanish hospitals. Furthermore, to increase the study's validity, the practical use of aflibercept in this setting was investigated, including doses or pragmatic modifications. The results suggest that the modified schedules often used in this daily clinical practice-based patient population are associated with less severe toxicity without apparent detriment to survival endpoints. It is believed that these data complement the information provided by the VELOUR trial and are relevant for the oncologist in treating colon cancer in the second-line setting.

Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study.

The potential protective effect of renin-angiotensin system (RAS) inhibitors is a subject of increasing interest due to their possible role as chemopreventive agents against colorectal cancer (CRC). To evaluate this association, we conducted a case-control study with 2165 cases of colorectal cancer, diagnosed between 2007 and 2012, and 3912 population controls frequency matched (by age, sex and region) from the Spanish multicenter case-control study MCC-Spain. We found a significant protective effect of the angiotensin-converting enzyme Inhibitors (ACEIs) against CRC, limited to the under-65years group (OR=0.65 95%CI (0.48-0.89)) and to a lesser degree to men (OR=0.81 95%CI (0.66-0.99). In contrast, the angiotensin receptor blockers (ARBs) did not show a significant effect. Regarding the duration of use, a greater protection was observed in men as the length of consumption increases. In contrast, in the under-65 stratum, the strongest association was found in short-term treatments. Finally, by analyzing ACEIs effect by colon subsite, we found no differences, except for under 65years old, where the maximum protection was seen in the proximal intestine, descending in the distal and rectum (without statistical significance). In conclusion, our study shows a protective effect on CRC of the ACEis limited to males and people under 65years old, which increases in proximal colon in the latter. If confirmed, these results may suggest a novel approach to proximal CRC prevention, given the shortcomings of colonoscopy screening in this location.