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Hi, my name is Federico Innocenti, and I'm an associate professor at University of North Carolina, Chapel Hill and the Lineberger Comprehensive Cancer Center. It is really my pleasure to show you the highlights of a study that we have conducted in metastatic colorectal cancer patients that have been profiled for somatic DNA mutations in testing the association with the survival of patients in the trial.
So, the study was conducted in the clinical trial CALGB/SWOG 80405. Patients have been treated in the first line metastatic setting and the study has compared the effect of the biologics bevacizumab and cetuximab for overall survival. The study has enrolled about 1000 patients and, despite the fact that there were no statistically significant differences in overall survival, samples have been collected from the patients. Tumor samples have been collected from the patients and have been studied to find molecularly defined profiles of patients that might respond better to the therapies and potentially might benefit from additional interventions when they would progress.
So, the aims of this study are to determine the mutational profile of metastatic colorectal cancer patients in CALGB/SWOG 80405, to evaluate the prognostic value of these mutations, to evaluate the relative benefit of bevacizumab versus cetuximab, in relation to these mutations, and to identify molecularly defined groups that would benefit from personalized therapy.
The study again is in first line metastatic setting, patients were randomized to receive cetuximab or bevacizumab on the backbone of chemotherapy FOLFIRI and FOLFOX. These are a KRAS wild type of population for codons 12 and 13, the paper is recently accepted in press in JAMA. DNA is extracted from 500 patients, tumor specimens, the DNA mutations have been categorizing 12 genes, and you see here beta catenin, EGFR, BRAF, All RAS, TP53 and others. We have also categorized the MSI-high status of patients by microsatellites, and we have applied next generation sequence through FoundationOne® to categorize the mutational load of each tumor.
This is one of the main findings. We see very strong negative prognostic effect of the BRAF mutations in patients that are positive of these mutations. We see that patients with BRAF mutations have a median overall survival of 13 months versus patients that do not have BRAF mutations and they have a survival of 34 months.
We see the hazard ratio is 1.67 or a P-value of .0035. Because of the effect of tumor location on the prognosis of this patient, when we do remove tumor location from the multi verb analysis, we still see a very strong effect of BRAF, with a hazard ratio of 1.82 and a P-value of .0001.
The other main finding is that the MSI status of patients does not impact the overall survival. MSI-high patients were fine in about 7% of this population. You can see here, from the graph, patients that have the MSI-high status had a median overall survival of 30 months and patients that are MS stable, the MSS group, have a median overall survival of 32 months. The hazard ratio is .84 and the P-value is .50. When stratified by the BRAF positivity for mutations, you can see that patients that are in the MSI-high group have a much higher frequency of BRAF mutations, 52% versus 11% in the MSS group.
The other key finding that we have discovered is that when we look at the interaction of the MSI status with biologics we can see that patients in the MSS group ... There's no difference between the effect of bevacizumab and cetuximab, each of them having a median overall survival of about 30 months, but patients in the MSI-high group, they seem to benefit from bevacizumab compared to cetuximab. Patients treated with bevacizumab in the MSI-high have a median survival of 30 months, where those patients in the cetuximab are having a median survival of 12 months. This is interaction between the MSI status and the treatment of ... For a P-value for interaction of .0002.
When solified by BRAF status, the BRAF positive patients in this bevacizumab arm were 61% and the BRAF positive patients in the cetuximab arm were 46%. This is consistent with the previous studies conducted in the adjuvant setting for colorectal cancer identifying the patients with bevacizumab that were MSI-high, benefit from bevacizumab compared to just chemotherapy alone.
When we look at the mutational load in the MSS group of patients, we see that patients that tend to have a higher mutational load in their tumors, they tend to survive longer and they have a median survival of 36 months, versus patients that have a low value for mutational load and they tend to survive less, such as 30 months. This is a hazard ratio of .67 and a P-value of .02.
The main conclusions for MSI-high. The MSI-high patients seem to have improved survival when treated with bevacizumab compared to cetuximab. This will be in agreement with the sub-set analysis of the C-08 clinical trial that has been published recently in the adjuvant setting. Although, due to the small number of patients, the findings require confirmatory studies in the metastatic setting. Regarding the mutational load in MSS patients, this is the first large series indicating an effect of improved overall survival load of patients with a higher mutational load in their tumors, at least, to the best of our knowledge. The optimized cut off of eight for mutational load requires additional validation and combined with other types of molecular profiling of the tumor of patients, and for each and every mutational load in MSS patients biding for the selection of immune based interventions.
It has been a pleasure presenting these highlights on behalf of all the authors contributing to this work and thanks for your attention.