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This month we will be focusing on data from the recent 2009 Gastrointestinal Cancers Symposium. This multidisciplinary meeting was held in San Francisco in mid-January. The program included a number of didactic presentations as well as 563 abstracts, both oral, poster and published. Nearly 3000 attendees were present at this year’s meeting, including a large international contingent of attendees.
In this issue:
Colorectal Cancer and Gastrointestinal Cancers
Dr Jeffrey Meyerhardt from Dana-Farber Cancer Institute discussed non-standard interventions in the adjuvant therapeutic management of colorectal cancer.
Patients frequently ask what they can do to decrease their risk of relapse after completing adjuvant chemotherapy. Dr Meyerhardt and his associates at the Dana-Farber Cancer Institute have looked at numerous potential risk factors for colorectal cancer (CRC). Factors that appear to increase the risk of developing CRC include family history of CRC, inflammatory bowel disease, diabetes mellitus, obesity, ingestion of red meat, the Western diet, alcohol consumption and smoking. Factors that may reduce the risk of developing CRC include aspirin, exercise, calcium & vitamin D, screening procedures and postmenopausal estrogen. As far as recurrence of and mortality from resected CRC is concerned, exercise seems to be associated with a decreased risk regardless of age, gender, or stage. The authors have carefully examined the lifestyles and recurrence patterns of patients participating in a large cooperative group trial. The Cancer and Leukemia Group B (CALGB) 89803 was an adjuvant trial comparing 5-FU/leucovorin to irinotecan, 5FU, and leucovorin (IFL). The CALGB investigators looked at recurrence patterns and lifestyle patterns among patients participating in this trial. Disease-free survival (DFS) appeared to be significantly better among those patients who ate a prudent diet as opposed to those who ate a Western diet with increased amounts of red meat, processed food, sweets and high-fat foods. The risk of recurrence was 4 times as high in those patients eating the Western diet. Obesity is a major health problem in the US. Both National Surgical Adjuvant Breast and Bowel Project (NSABP) and CALGB adjuvant trials in CRC have demonstrated a worse outcome for patients with BMI over 35 with the hazard ratio (HR) for BMI >35 being 1.25.
Aspirin and COX2 inhibitors have been shown to decrease recurrence and increase DFS in patients with resected CRC. In CALGB 89803, patients with stage III colon cancer who took aspirin during and for at least 6 months following adjuvant therapy had a 54% increase in DFS compared to non-aspirin users. Smoking early in life has also been shown to decrease survival from CRC. Patients in CALGB 89803 who had at least 12 pack-years of smoking history prior to age 30 had a HR for DFS of 1.37 compared to non-smokers. Finally, the importance and value of vitamin D use and vitamin D levels in risk of mortality from cancer has also been noted in CRC. Data from the Nurses’ Health Study and Health Professionals Follow-up Study have shown that patients with CRC who had adequate vitamin D levels prior to diagnosis had a significantly improved survival compared to those who had low vitamin D levels prior to diagnosis.
Dr Alan Venook from the University of California, San Francisco gave a very interesting talk about colorectal cancer titled Progress Towards an Individualized Approach to Therapy.
Dr Venook focused on a number of mutational changes and pharmacogenetic differences that can impact therapy and prognosis. Examples that he discussed included the numerous polymorphisms of UGT1A1 that can affect glucuronidation of SN-38, the active metabolite of irinotecan. These fairly common polymorphisms can lead to indirect hyperbilirubinemia as well as excess toxicity from irinotecan. K-ras mutational status has become a recognized predictive biomarker for response to anti-EGFR monoclonal antibody therapy in CRC. Several randomized phase III clinical trials have now examined the impact of K-ras mutational status and response to cetuximab or panitumumab in CRC. Tumors that are K-ras mutated do not respond to anti-EGFR monoclonal antibodies and may do worse when treated with chemotherapy plus anti-EGFR therapy. Recent data suggests a predictive role also for B-raf mutations. Tumors with K-ras wild-type, but B-raf mutated, do not appear to respond to anti-EGFR monoclonal antibodies. The role of EGFR copy number or EGFR amplification remains uncertain as conflicting data regarding its predictive value has been presented or published. Loss of PTEN, an important EGFR downstream signal, may also have a negative predictive and prognostic effect on patients with CRC. Loss of heterozygosity for chromosome 18q is a known negative prognostic factor for CRC and also predicts for poor response to flouropyrimidine therapy. Clinical trials in the future may be stratified for a number of biomarkers as increasing information regarding the importance of these factors comes to light.
Abstract 288: Correlation of molecular markers in colon cancer with stage specific prognosis: Results of the translational study on the PETACC 3 – EORTC 40993-SAKK 60-00 trial
Investigators from the European colon cancer adjuvant trial, PETACC 3, reported the results of an analysis of the incidence of certain molecular makers in stage II and stage III colon cancer from patients in this large adjuvant trial. They included expression of p53, SMAD4, thymidylate synthetase (TS), hTERT, mutations of K-ras and B-raf, microsatellite instability (MSI), and 18qLOH. They were able to analyze the incidence of biomarkers from 420 patients with stage II disease and 984 patients with stage III disease. Significant differences in frequency per stage were found for all markers except K-ras and B-raf. Multivariate analysis found that T-stage and MSI were independently significant clinical predictors in stage II. Nodal stage, T-stage, SMAD4 and p53 were independently significant clinical predictors for stage III. 18qLOH was prognostic for stage II, but not for stage III. SMAD4 and p53 were prognostic in stage III, but not in stage II. The authors concluded that the possibility that stage II and stage III colon cancer were actually 2 different diseases, rather than sequential steps in the evolution of a single cancer, should be considered.
Abstract 293: Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer
One of the themes of this year’s Gastrointestinal Cancers Symposium was the increasing recognition of the prognostic and predictive importance of biomarkers in colorectal cancer. A group of investigators from Greece and M. D. Anderson Cancer Center examined the contribution of various mutations to PFS following front-line therapy for metastatic colorectal cancer. They evaluated 168 primary colon cancer tumors for mutations of K-ras, B-raf and PI3KCA. K-ras, B-raf and PI3KCA mutations were present in 37%, 8% and 15% of patients, respectively. All patients received 5-FU based chemotherapy, 71% in combination with oxaliplatin, and 34% in combination with irinotecan. Bevacizumab was added to chemotherapy in 58%. Progression-free survival was similar between patients whose tumors carried mutant or wild-type K-ras or PI3KCA. Patients with mutant B-raf had lower PFS. Among the 100 patients who eventually received cetuximab either front-line or for salvage therapy, K-ras mutation predicted for lower response rates and lower PFS. B-raf and PI3KCA mutations also predicted for lowered efficacy in patients treated with second-line cetuximab based therapy. Mutational profiling continues to demonstrate increasing potential for identification of patients whose tumors differ in their prognostic and predictive profiles.
Abstract 294: Use of gene expression signatures to target therapies in metastatic colorectal cancer
Dr David Hsu from Duke University presented data from a gene expression analysis of 40 metastatic colorectal cancer tumors. Hierarchical clustering of the colorectal cancer data set based on pathway deregulation identified 3 distinct gene clusters. Cluster 1 did not appear to have any distinct patterns of oncogenic pathway deregulation. Cluster 2 was characterized by increased deregulation of the Myc and PI3 kinase pathways and was found to be more likely resistant to oxaliplatin and sensitive to irinotecan. Cluster 3 was characterized by increased deregulation of the beta-catenin and Src pathways and appeared to have a higher probability of being sensitive to oxaliplatin and resistant to irinotecan. The authors discovered a positive correlation between predicted oxaliplatin sensitivity and Src deregulation of cluster 3, suggesting that patients whose tumors are sensitive to oxaliplatin might also be sensitive to a Src inhibitor, such as dasatinib or bosutinib. The authors have developed murine xenografts in SCID mice from resected colorectal tumors and are planning to use them to determine the effects of multi-agent therapeutic regimens.
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