Each presentation is built upon "real-life" interactive, patient case studies where participants are immediately engaged with the faculty, and are involved with patient therapy and patient management decisions via ARS throughout the symposium. And for each of the patient case study sessions a faculty member will present a didactic lecture addressing and reinforcing the evidence-based data supporting the optimal patient management decisions related to the colorectal cancer cases.

Incorporating Anti-EGFR Strategies into Therapy for Improving Colorectal Cancer Patient Outcomes For years, the standard treatment of metastatic colorectal cancer has been with a combination of a biologic agent plus a chemotherapy backbone. Two of the most commonly used regimens historically included FOLFOX (oxaliplatin-based chemotherapy) plus the "biologic" agent bevacizumab, and FOLFIRI (irinotecan-based chemotherapy) plus bevacizumab. In 2004 the FDA approved the use of the first of two commercially available anti-EGFR monoclonal antibodies, cetuximab, in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy, and also as a single agent. In 2006 the FDA approved another anti-EGFR monoclonal antibody, panitumumab, for third-line therapy of metastatic colorectal cancer. Panitumumab is not approved for use in combination with chemotherapy.

Binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased vascular endothelial growth factor production. EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over-expression of EGFR is found in most patients with colorectal cancer and is also detected in other human cancers including those of the head and neck and lung cancer.

The commercial availability of two distinct anti-EGFR antibodies, plus the anti-angiogenic agent, bevacizumab, and two chemotherapy "backbones" – irinotecan and oxaliplatin, have enabled investigators to evaluate several clinical strategies including the "change in chemotherapy" strategy and the "change in biologic strategy" e.g., using anti-EGFR versus anti-angiogenesis. For colorectal cancer patients, which clinical strategies to use and on which patients they should be used, especially in the first-line setting remain as questions in practice, although an increasing amount of data is becoming available showing the improvement in patient outcomes when treating colorectal cancer with an anti-EGFR-based regimen. These include the invaluable data from the CRYSTAL, OPUS, PRIME, COIN and most recently, the EREBUS trials, although the COIN data did not show a benefit of adding anti-EGFR to chemotherapy. The CRYSTAL trial originally showed that adding cetuximab to FOLFIRI reduces the risk of metstatic colorectal cancer growth by 15%. Currently, the US Intergroup is conducting a trial comparing cetuximab versus bevacizumab in first-line therapy in the KRAS wild type population. In Europe a trial with about 800 patients with KRAS wild type is ongoing comparing chemotherapy plus cetuximab versus chemotherapy plus bevacizumab in the up front setting. Data from both of these trials is eagerly awaited. And at ASCO 2011 Dr. Van Cutsem updated his CRYSTAL data showing that the addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type metastatic colorectal cancer. BRAF tumor mutation is an indicator of poor prognosis.

A novel tyrosine kinase inhibitor, brivanib, targets both the vascular endothelial and fibroblast growth factor receptors (VEGFR/FGFR). At ASCO 2011 results from a study designed to evaluate dual biologic therapy (anti-EGFR plus anti VEGFR/FGFR) to overcome resistance to cetuximab therapy for colorectal cancer patients. The preliminary results of this trial by Shapiro et al, and from a correlative trial by the NCIC, the C0.20 trial may be of benefit to helping overcome resistance to cetuximab. As of August 2011 other studies are underway evaluating brivanib for metastatic GI cancers. One is irinotecan plus brivanib in metastatic colorectal cancer (mCRC), another is a Phase I/II combination trial with irinotecan and cetuximab in mCRC, and the other is brivanib plus cetuximab in advanced GI malignancies.

In April 2011, data was published in the Journal of the National Cancer Institute demonstrating the effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. Addition of simvastatin to cetuximab reduced cell proliferation of KRAS mutant but not of BRAF mutant colorectal cancer cells in vitro. Treatment of KRAS mutant cells with simvastatin reduced BRAF activity and induced apoptosis. Treatment with cetuximab and simvastatin reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone.

The last few years have witnessed the rapid and ongoing development of biomarkers that show significant promise in the field of colorectal cancer management. This creates challenges to knowledgeably integrate these biomarkers into care plans for our patients. Several molecular biomarkers are now well established in colorectal cancer and are a valuable tool for clinicians regarding patient prognosis and therapy selection. These include the KRAS and BRAF oncogenes, and PI 3-Kinase. Mutations associated with these three molecular markers are indicative of resistance to anti-EGFR therapy. Mutations in the KRAS gene are associated with resistance to both cetuximab and panitumumab and account for approximately 30% to 40% of resistant patients. KRAS has traditionally been the most important marker to identify. And KRAS wild type occurs in approximately 60% of all colorectal cancers. Moreover, multiple studies have demonstrated that patients with wild-type KRAS may benefit from anti-EGFR antibody therapy either as monotherapy or in combination with chemotherapy.

Recently BRAF and PI 3 Kinase have become increasingly more important to identify sub populations of colorectal cancer patients who may benefit from anti-EGFR-directed therapy, especially in the up front or first-line setting. Combining an anti-EGFR antibody with chemotherapy indeed increases the response rate and progression free survival over anti-EGFR antibody therapy alone according to tumor KRAS and BRAF mutation status.

In 2009, the PETACC-3 Study (Pan-European Trials in Alimentary Tract Cancers) was a phase III trial that correlated various markers with stage-specific prognosis of colorectal cancer. The markers included KRAS, BRAF p53 and a few others. PETACC-3 compared 420 stage II patients and 984 stage III patients. The most interesting finding from this sub study is the strikingly different changes in molecular marker expression between the two groups (stage II and stage III). This suggests that stage II and stage III colorectal cancer develop through distinctly different molecular pathways and, thus, may represent different biological and clinico-pathologic entities, instead of the conventional idea that stage III cancers progress sequentially from stage II cancers. Studies such as PETACC-3 and others e.g., EORTC 40993 and SAKK 60-00 have implications for not only for identifying stage II patients who could be candidates for chemotherapy but for screening.

At ASCO 2011 a heterogenous predictive marker treatment effect with cetuximab was demonstrated according to KRAS mutation status. Patients with KRAS G13D mutant metastatic colorectal cancer appear to benefit from the addition of cetuximab to first-line chemotherapy.

Tumor gene expression has also demonstrated an ability to predict response to cetuximab in patients with KRAS wild type metastatic colorectal cancer. In a study published in early 2011 , 110 candidate gene expression markers in primary tumours from 144 KRAS wild type metastatic colorectal cancer patients (mCRC) received monotherapy with the anti-EGFR antibody cetuximab. Results were correlated with multiple clinical endpoints: disease control, objective response, and progression-free survival (PFS). Expression of many of the tested candidate genes, including EREG and AREG, strongly associated with all clinical endpoints. Using multivariate analysis with two-layer five-fold cross-validation, we constructed a four-gene predictive classifier. Patients below the classifier cut point had PFS and disease control rates similar to those of patients with KRAS mutant mCRC. Gene expression appears to identify KRAS wild type mCRC patients who receive little benefit from cetuximab.

The OPUS study data published in 2011 confirmed the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirmed KRAS mutation status as an effective predictive biomarker. However, in this study, the small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.

And in January 2011, although the COIN study failed to demonstrate benefit of adding cetuximab to chemotherapy it did suggest a prognostic role for EGFR immunohistochemistry in advanced colorectal cancer by measuring KRAS wild type.

At ASCO in 2011 a very important analysis was presented by Dr. Kohne who evaluated efficacy according to treatment by metastatic site of disease. Kohne showed that adding cetuximab to first-line chemotherapy improved clinical outcome in metastatic colorectal cancer patients with both liver-limited and non-liver limited disease. And in non-liver-limited disease he addition of cetuximab to FOLFIRI increased overall survival by 5 months.

Earlier in 2011, at the ASCO Gastrointestinal Cancer Symposium Dr. Jocelin Huang presented data showing that adjuvant FOLFIRI/cetuximab improves survival in patients with stage III colon cancer. Dr. Huang’s data was a subanalysis of the phase III N0147 clinical trial. It suggests that adding cetuximab to the chemotherapy regimen FOLFIRI may result in statistically significant improvements in outcomes for patients with stage III resected colon cancer, compared to treatment with FOLFIRI alone. Overall survival was also improved in these patients, from 85.2% with FOLFIRI alone to 92% with the addition of cetuximab, although the difference was not statistically significant. Thus, stage of disease in patients with mCRC may be another way to personalize systemic therapy with anti-EGFR strategies.