Abstract
The 3rd annual DGVS Spring Conference of the German Society for Gastroenterology (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten) was held at the Seminaris Campus Hotel in Berlin, Germany, on 8–9 May, 2009. The conference was organized by Roland Schmid and Matthias Ebert from the Technical University of Munich, Germany. The central theme of the meeting was ‘translational gastrointestinal oncology: towards personalized medicine and individualized therapy‘. The conference covered talks on markers for diagnosis, screening and surveillance of colorectal cancer, targets for molecular therapy, response prediction in clinical oncology, development and integration of molecular imaging in gastrointestinal oncology and translational research in clinical trial design. Owing to the broad array of topics and limitations of space, this article will focus on biomarkers, response prediction and the integration of biomarkers into clinical trials. Presentations mentioned in this summary were given by Matthias Ebert (Technical University of Munich, Germany), Esmeralda Heiden (Epigenomics, Berlin, Germany), Frank Kolligs (University of Munich, Germany), Florian Lordick (University of Heidelberg, Germany), Hans Jorgen Nielsen (University of Copenhagen, Denmark), Anke Reinacher-Schick (University of Bochum, Germany), Christoph Röcken (University of Berlin, Germany), Wolff Schmiegel (University of Bochum, Germany) and Thomas Seufferlein (University of Halle, Germany).
Molecular classification & biomarkers of colorectal cancer
Screening by fecal occult blood tests and colonoscopy can prevent colorectal cancer. However, fecal occult blood tests suffer from low sensitivity, and compliance with screening colonoscopy recommendations remains low. Recently, methylation of circulating DNA has gained attention as a marker for colorectal cancer. Matthias Ebert and Esmeralda Heiden reported on the two trials, EPITEK and Evaluation of SEPT9 Biomarker Performance for Colorectal Cancer Screening (PRESEPT), which are prospectively evaluating recently identified genes that have been found to be frequently aberrantly methylated in the blood of patients with colorectal cancers. The EPITEK study will analyze the gene ALX4Citation[1] in 4000 individuals prior to colonoscopy, whilst the PRESEPT study is currently recruiting a total of 7500 individuals in the USA and Germany. The PRESEPT study includes subjects aged 50 years or older who are at average risk for colorectal cancer, and who have been scheduled for screening colonoscopy. The trial analyzes the methylation status of the gene Septin 9 in blood drawn prior to colonoscopy. Septin 9 has previously been validated in case–control studies yielding a sensitivity of 68–72% for colorectal cancers at specificities of 89–93% Citation[2]. The availability of highly sensitive and specific noninvasive colorectal cancer screening and detection tests in the future will have the potential to increase compliance with current screening guidelines recommending screening initiation at the age of 50–55 years for the average-risk population.
The dominant molecular mechanisms underlying colorectal carcinogenesis include chromosomal instability (CIN), microsatellite instability (MSI), epigenetic instability (commonly referred to as the CpG island methylator phenotype – CIMP) and single-gene mutations. Frank Kolligs pointed out that while MSI is clearly defined by a five- to ten-marker consensus panel, no standardized methods or criteria for defining CIN and CIMP have been described. Currently, the most widely used marker for determining CIN is loss of heterozygosity of chromosome 18q. For the definition of CIMP, different marker panels have been proposed, but, to date, no consensus marker panel has been found. The two single-gene mutations currently gaining most attention are mutations of codons 12 and 13 of the Kras gene and mutation of codon 600 of the Braf gene (V600E). Kras and Braf mutations exclude each other in the same tumor and Braf, but not Kras, mutations are strongly associated with CIMP and MSI. Based on these molecular classifiers, currently five to seven diffenent types of colorectal cancers have been distinguished Citation[3,4]. The use of these molecular phenomena as biomarkers and classifiers of colorectal cancers is currently gaining great interest, and clinical studies are including the analysis of these genetic and epigenetic biomarkers.
Molecular markers & response prediction
Wolff Schmiegel and Matthias Ebert discussed recent studies demonstrating that patients carrying a mutated Kras allele in their tumors will most likely not respond to a therapy with the antibodies cetuximab and panitumumab which are both directed against the EGF receptor Citation[5,6]. Therefore, Kras mutation is the first predictive marker for colorectal cancer therapy. Current data support the notion that tumors carrying the V600E Braf mutation will also not respond to a therapy targeting the EGF receptor Citation[7]. However, further studies are required before Braf mutation analysis can be included into daily practice. Christoph Röcken pointed out that the total costs for palliative colorectal cancer therapy sum up to a mean of €50,000 per patient. As more and more molecular targeted therapeutics become available, predictive markers are essential in order to save costs and avoid unwanted side effects. In contrast to colorectal cancer, no predictive markers for pancreatic, gastric and esophageal cancer are available to date.
Florian Lordick presented an overview on clinical and pathological criteria for assessment of response in colorectal cancer treatment. Several studies have clearly demonstrated the strong correlation between the appearance of a skin rash and response to a therapy with anti-EGF-receptor agents in colorectal and other cancers. Therefore, among patients with metastasized colorectal cancers treated with cetuximab, those carrying wild-type Kras alleles in their tumors and who develop a skin rash will have the best therapeutic response and reveal the best prognosis compared with patients not developing a skin reaction and carrying a mutated Kras allele. Arterial hypertension occurring during antiangiogenic therapy has been correlated with the biological inhibition of the VEGF-related pathway. One recent study demonstrated that patients receiving bevacizumab in addition to chemotherapy with irinotecan and 5-fluorouracil had a better response to therapy, and a significantly longer progression-free survival when developing grade 2–3 hypertension compared with those patients without Citation[8]. Another study has demonstrated that the kinetics of carcinoembryonic antigen serum levels is strongly correlated to response to chemotherapy in patients with metastasized colorectal cancer Citation[9]. A strong association between the carcinoembryonic antigen slope and progression-free survival was found. Several studies have assessed the correlation between response to neoadjuvant chemotherapy in colorectal liver metastases and histological response as determined by tumor-regression grade. The grade of histological tumor regression was strongly associated with disease-free and overall survival. However, histological regression was more frequent in tumors treated with oxaliplatin than with irinotecan.
Translational research in clinical trial design
Thomas Seufferlein discussed the importance of integrating biomarkers in clinical trials and emphasized the necessity of quality control of biomarkers. The main issues include the analytical validity of the tests used as well as its clinical and economic utility. The further establishment of biomarkers in the management of cancer patients will result in individualized therapies that will no longer be based on population-based statistics, but on the specifics of the individual tumors. This will finally result in a setting where the phenotype of a tumor will no longer be sufficient for therapeutical decisions. However, the development of a biomarker from identification to clinical application is a great challenge. Therefore, the main aim of the Oncology Biomarker Qualification Initiative (OBQI), which is a collaboration between the National Cancer Institute (NCI), US FDA and Centers for Medicare and Medicaid Services (CMS), is to qualify biomarkers for use in clinical trials. It shall help to overcome technical, regulatory, economic and structural obstacles associated with the development of biomarkers.
In the case of colorectal cancer, 700 out of 1000 patients with stage II cancers will be cured by surgery alone and 300 will be at risk of recurrence. By contrast, out of 1000 patients with stage III cancers, only 350 will be cured by surgery and 100–150 will benefit with an improvement of survival by adjuvant therapy. Therefore, Hans Jorgen Nielsen pointed out that we are desperately in need not only of markers in the metastasized, but also in the curative situation, as we are not able to predict which patient will suffer disease recurrence after curative therapy. Anke Reinacher-Schick further emphasized the importance of the prospective evaluation of biomarkers and reported on the Eastern Cooperative Oncology Group E5202 trial. This trial, a randomized, Phase III study comparing 5-fluorouracil, leucovorin and oxaliplatin, with and without bevacizumab, in patients with stage II colon cancer at high risk for recurrence, prospectively evaluates the biomarkers microsatellite instability and 18q loss of heterozygosity. Only patients with tumors having lost one 18q allele and being microsatellite stable or revealing low-grade microsatellite instability are classified as of high risk of disease recurrence and randomized into the two treatment groups, while those with highly microsatellite instable tumors and carrying both 18q alleles are included in the observational arm. In order to progress to individualized cancer therapy, standardized bio-banking has to be established in every clinical trial. In the future, biomarkers will not only be analyzed in translational programs accompanying clinical studies, but will be included in clinical studies as primary end points along with efficacy measures.
In summary, the Spring Conference highlighted the current situation and future perspective of molecular-based individualized therapy of gastrointestinal cancers. Especially in the case of colorectal cancer, molecular markers are currently being intensively studied for screening, early diagnosis and assessment of prognosis. Kras mutation has become the first predictive biomarker in colorectal cancer therapy.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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