Therapeutic Panitumumab-FOLFOX4 intervention with KRAS exon 2 mutation in colorectal cancer.

My partner Tien Lu and I are conducting our cancer project on how mutations in RAS can affect the of anti-epidermal growth factor receptor (EGRF) in colorectal cancer. EGRF is a cell-surface receptor that stimulates protein-tyrosine kinase activity when dimerized. EGRF can activate KRAS, and has been identified as an oncogene. Oncogenes can cause cells selected for apoptosis to survive and proliferate. A RAS mutation can be any KRAS or NRAS mutation in exon 2, 3, or 4. In some instances, it is possible that wildtype RAS allow for antibodies to target EGRF and reduce tumor size in colorectal cancer. Thus, there is the question on how patients with metastatic colorectal cancer with KRAS mutations in exon 2 that are given anti-epidermal growth factor therapy will fare compared to their wildtype counterparts. These mutations can then be used as predictive biomarkers to allow Doctor's to supply more individualized treatment to specific patients. In a clinical trial for the efficacy and safety of Panitumumab conducted by Dr. Douillard of ICO, patients were treated with FOLFOX4 and FOLFOX4 + Panitumumab. Panitumumab, compared to FOLFOX4, is more highly selective for EGRF.

The control group of patients were given only FOLFOX4, a combination of the drugs oxaliplatin, fluorouracil, and lucovorin. The variable group was given FOLFOX4 and Panitumumab. 1183 patients were treated in total (1096 were assessed for RAS mutations), with 60 percent (656 patients) without KRAS mutations in exon 2 and 40 percent (440 patients) with a KRAS mutation on exon 2. All patients were diagnosed with metatatic colorectal cancer. The study was conducted through prospective-retrospective analysis. The results can best be ascertained through the look at two of the figures of the paper. Figure 1 displays the Hazard ratio of the disease development or death based on the RAS mutation.

Figure 1: Hazard Ratio for Disease Progression or Death and Hazard Ratio for
Death from Any Cause, According to KRAS and RAS Mutation Status.

           The hazard ratio was 37.98% greater for the patients with muatated KRAS exon 2 (Figure 1, A). Even more profound was the effect in the prospective-retrospective analysis with a 46.6% increase in hazard ratio in those with mutated KRAS exon 2 (Figure 1, B). Meaning those with the mutation had a nearly 2 fold increase in chance of death. However it is important to note something that is not presented in the figure, that 52% of patients died after the primary analysis, making retrospective analysis impossible. Thus the data is much less succinct for the prospective-retrospective analysis due to having less than half the sample size. Moreover, the figure demonstrates that while Panitumumab was better at treating those with wildtype KRAS, FOLFOX4 alone was better at treating those with the mutation exon 2 (and other RAS mutations). Since panitumumab is more selective towards anti-EGRF antibodies, it appears that a mutation in KRAS exon 2 hinders the ability for the EGRF oncogene to be halted. The results further point to the patients with RAS mutations developing a resistance to Panitumumab, explaining its ineffectiveness with FOLFOX4 in RAS mutated patients. Since other RAS mutations are also deemed Panitumumab ineffective, other RAS mutations may be negative predictive biomarkers along with KRAS exon 2.             In the non-mutated RAS subgroup, the progression-free survival was increased on an average of 1.6 months and overall survival by 7.4 months with Panitumumab-FOLFOX4 therapy versus FOLFOX4 alone. However, in mutated KRAS exon 2 the average progression-free survival with Panitumumab-FOLFOX4 was 7.3 months compared to 8.8 of FOLFOX4 alone (P=0.02). Further pointing to KRAS (and other RAS mutations) providing resistance to anti-EGRF therapy. Figure 2 of the article further shows the efficacy of Panitumumab in nonmutated patients.

Figure 2 Kaplan–Meier Estimates of Progression-free Survival in the Primary-Analysis Population and Overall Survival in the Primary-Analysis and Updated-Analysis Populations, According to Treatment Group.

            Panitumumab-FOLFOX4 shows a increase in the survival of non-mutated patients versus FOLFOX4 alone with a high degree of certainty (95% confidence interval). Not only in the primary analysis but also the updated analysis that features prospective-retrospective review. The safety of Panitumumab is not strictly defined in the research. It simply states that there are no new adverse effect compared to FOLFOX4 therapy. However I would like to see the adverse effects being truly defined. Then the side effects of FOLFOX4, a common chemotherapy, would not be assumed. 

            Nevertheless, mutated RAS patients fared better with FOLFOX4 alone. The question I would have liked the article to adress is commonalities between patients with mutated KRAS exon 2. We cannot ascertain how patients attain KRAS exon 2 mutation. On one hand the data supports the notion that KRAS exon 2 mutation is a negative predictive biomarker (Figure 1), so doctors should refrain from using anti-EGRF therapy on patients with such mutations. On the other hand we do not know how to prevent these mutations that build anti-EGRF therapy resistance. I would like to know whether the mutations are caused by predominantly environmental factors or genetic disposition (or the natures of a combination of the two). Then preventing the KRAS mutation can allow treatments like Panitumumab-FOLFOX4 to be used that are more effective then, for example, FOLFOX4 alone (Figure 2). Providing Panitumumab-FOLFOX4 to patients with unmutated RAS will significantly improve the benefit-risk profile.


Sources:

1.  Kaz, AM; Brentnall, TA (2006). Genetic testing for colon cancer. Nature Clinical                            Practice Gastroenterology & Hepatology, 3:670-9.
2. "Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer — NEJM." New England Journal of Medicine. N.p., n.d. Web. 14 May 2014.
3. "Annals of Oncology." ESMO Consensus Guidelines for Management of Patients with Colon and Rectal Cancer. A Personalized Approach to Clinical Decision Making. N.p.,n.d. Web. 14 May 2014