Introduction
Although this book is addressed to medical doctors, in this chapter, we have tried to look at the scientific literature with the eyes of someone who has an FAP or has a family member with this disease, in order to understand, for those who so urgently seek it, what lies just “around the corner” in terms of breaking news.
The Disease
Familial adenomatous polyposis (FAP) is a syndrome affecting 1:10 000 people and accounts for approxi- mately 1% of colorectal cancer. It is an autosomal dominant syndrome caused by a germline mutation of the adenomatous polyposis coli gene (APC) locat- ed at chromosome 5q21. The disorder is charac- terised by the development of hundreds of colorectal adenomas during adolescence. Colorectal cancer will develop in nearly all affected persons by the sixth decade of life if prophylactic colectomy is not per- formed. Most cases begin as benign adenomatous colonic polyps.
One widely held opinion is that cancer is a genetic disease that arises from an accumulation of muta- tions that leads to the selection of cells with increas- ingly aggressive behaviour. These mutations may lead either to a gain of function by oncogenes or to a loss of function by tumour suppressor genes. Most mutations in cancer are somatic and are found only in the cancer cells. Most of our information on human cancer genes has been gained from hereditary cancers. In the case of hereditary cancers, the indi- vidual carries a particular germline mutation in every cell. In the past decade, more than 30 genes for auto- somal dominant hereditary cancers have been identi- fied.
Emergent Issues and Trends in Research
The ideal gold standard would be a gene technique that would allow the removal of the diseased gene and implant a disease-free gene. At present this is still pure speculation. Most of the research deals with systems for screening the germline mutations in the adenoma- tous polyposis coli (APC) gene that predisposes the disease susceptibility in familial adenomatous polypo- sis. Nowadays, there are technical systems that detect the mutations in APC gene. They might be useful in the molecular diagnosis of presymptomatic cases in FAP family. The clinical features of FAP patients may be related to the genotypes of their APC gene. Howev- er, there are other interesting ways of approaching the problem of a presymptomatic carrier risk assessment in familial adenomatous polyposis such as the com- bined use of molecular- and biomarkers. Predictive carrier testing for the inherited disorder of familial adenomatous polyposis can be conducted using DNA markers linked to the FAP locus. The presence of characteristic hypertrophic retinal lesions has been advocated as useful biomarkers for FAP. Bapat et al.
[1] have compared molecular linkage and retinal screening techniques by evaluating the presympto- matic carrier risk of 40 at-risk individuals from 15 FAP families. Linkage analysis was informative in all the cases as was retinal lesion analysis in 25 cases. For identification of the at-risk population, predictive diagnosis by both techniques was completely concor- dant and identified 15 members at “high” and 10 at
“low” risk of inheriting FAP. Another relevant matter regarding future trends in FAP research are the bio- markers for carcinogenesis and the use of drugs to prevent the evolution to the final stage of cancer.
Progression Markers during the Intestinal Carcinogenesis:Intermediate Biomarkers
Colon carcinogenesis is a multistep process in which an accumulation of genetic events within a single cell
Emergent Issues and Future Trends in Familial Adenomatous Polyposis
Gian Gaetano Delaini, Marco Scaglia, Gianluca Colucci, Tom Öresland
line leads to a progressively dysplastic cellular appearance, deregulated cell growth, and, finally, carcinoma. The “adenoma-carcinoma sequence”
occurs through a series of mutations in cancer-caus- ing genes and usually takes about 11 years. These genes (oncogenes, tumour suppressor genes, DNA mismatch repair genes) encode proteins that control vital cell functions such as growth and survival.
Development of intermediate markers for chemopre- vention trials is important. Premalignant lesions are a potential source of intermediate markers. Monitor- ing intermediate markers that correlate with a reduc- tion in cancer incidence would allow a more expedi- tious evaluation of potentially active chemopreven- tive agents. If a disappearance of these lesions can be correlated with a reduction in cancer incidence, then markers of premalignancy may serve as intermediate endpoints for chemoprevention trials.
Intermediate biomarkers of abnormal cell growth and development have recently been used in chemo- prevention trials in attempts to identify the efficacy of chemopreventive agents in human subjects. Mea- surements carried out include those related to cell proliferation, differentiation, and gene structure and expression in the colon. Among the modified pat- terns of cell proliferation identified by microautora- diographic or immunoperoxidase assays, a charac- teristic expansion in the size of the proliferative com- partment has been observed in normal-appearing colorectal mucosa of human subjects with disease increasing cancer risk; the same patterns have been induced by chemical carcinogens in rodents. More- over, this intermediate biomarker has been modulat- ed by chemopreventive agents in both rodents and humans. Newer intermediate biomarkers being stud- ied for application to human chemopreventive pro- grams include normal and abnormal patterns of expression of mucins, intermediate filaments and cytoskeletal proteins, and the structure and expres- sion of a variety of genes associated with normal and abnormal cell development. The application of these various intermediate biomarkers to chemopreven- tion studies is increasing the ability of investigators to analyse the effects of novel chemopreventive agents in the colon and in other organs.
H
ow to Prevent the Carcinogenic Progression b y Chemical A gents:the Chemoprevention
Cancer chemoprevention, as first defined by Sporn in 1976 [2], uses natural, synthetic, or biological chemi- cal agents to reverse, suppress, or prevent carcino- genic progression. It is based on the concepts of mul- tifocal field carcinogenesis and multistep carcino- genesis. In field carcinogenesis, diffuse epithelial
injury in tissues such as the aerodigestive tract, results from generalised carcinogen exposure throughout the field and clonal proliferation of mutated cells. Genetic changes exist throughout the field and increase the likelihood that one or more premalignant and malignant lesions may develop within that field. Multistep carcinogenesis describes a stepwise accumulation of alterations, both geno- typic and phenotypic. Arresting one or several of the steps may impede or delay the development of can- cer. This has been described particularly well in stud- ies involving precancerous and cancerous lesions of the head and neck, which focus on oral premalignant lesions (leukoplakia and erythroplakia) and their associated increased risk of progression to cancer. In addition to histologic assessment, intermediate markers of response are needed to assess the validity of these therapies in a timely and cost-efficient man- ner.
N
on-steroidal A nti-Inflammatory A gents for Colon Cancer Prevention
Colon cancer prevention has now focused on novel targeted therapies, such as non-steroidal anti-inflam- matory agents (NSAIDs). Aspirin, an inhibitor of COX-1 and -2, has been studied in several large ran- domised studies, but the effect on colorectal cancer prevention is unclear. The US Physician’s Health Study, which enrolled 22 071 physicians as partici- pants, reported that aspirin had no effect on the inci- dence of polyps or colon cancer [3]. However, Baron et al. conducted the Aspirin/Folate Polyp Prevention Study, a randomised, double-blind, placebo-con- trolled trial of daily aspirin (325 mg and 8 mg) and daily folate (1 mg) in 1121 patients with a recent his- tory of colon adenomas [4]. This trial demonstrated that the 81-mg dose of aspirin prevented recurrence of colorectal adenomas (47% placebo vs. 38% aspirin 81 mg vs. 45% aspirin 325 mg; p=0.04). This translat- ed into a relative-risk reduction of 19% in the 81-mg aspirin group and a non-significant reduction of 4%
in the 325-mg aspirin group. This study also report- ed a relative-risk reduction of 40% in the 81-mg aspirin group for advanced lesions. In addition, Sandler et al. [5] reported on the Colorectal Adenoma Pre- vention Study, which randomised 635 patients with prior colorectal cancer to 325-mg aspirin or placebo.
Twenty percent of the placebo group developed recurrent adenomas compared with 17% in the aspirin arm (p=0.0004), for an adjusted relative risk of 0.65. Aspirin intervention delayed the develop- ment of recurrent adenoma and also decreased the number of recurrent adenomas.
Although the role of aspirin remains debated, the
benefit of NSAIDs in chemoprevention has clearly been defined in certain high-risk subgroups [6]. In clinical trials of patients with FAP, sulindac (150 mg twice a day for 9 months) was shown to decrease the number of polyps by 44% and decrease the diameter of the polyps by 35% (p=0.014 and p<0.001, respec- tively) [7]. In a study, 77 patients with FAP (more than 5 polyps 2 mm in size) were randomised to receive placebo, 100 mg, or 400 mg of celecoxib twice daily [8]. Celecoxib is a selective COX-2 inhibitor.
Response to treatment was reported as the mean per- cent change from baseline. After 6 months, the 30 patients assigned to 400 mg of celecoxib had a 28%
reduction in the mean number of colorectal polyps (p=0.003) and a 30.7% reduction in the polyp burden (p=0.001) compared with 4.5 and 4.9% in the placebo group, respectively. This positive result led to the FDAs approval of celecoxib in the treatment of patients with FAP.
Other Agents under Trial
Other agents under investigation in colorectal chemoprevention include difluoromethylornithine (DFMO), which irreversibly inhibits ornithine decar- boxylase and blocks cell proliferation. Ursodeoxy- cholic acid reduces the concentration of the second- ary bile acid deoxycholic acid in the colon and affects arachidonic acid metabolism [9–11]. 3-hydroxy-3- methylglutaryl Coenzyme A reductase inhibitors are usually used in the setting of lowering cholesterol but also have antioxidant anti-inflammatory properties and inhibit cell proliferation [12]. Preclinical work in mutant APC murine models have shown that sulin- dac in combination with EGFR inhibitor EKI-785 can decrease intestinal polyps [13]. Almost one-half the mice treated with the combination agents did not develop polyps. With the recent success of beva- cizumab, an antibody to the VEGF-receptor in metastatic colorectal cancer, and cetuximab, an anti- body to EGFR, further strategies will be applied to prevention.
The continued study of immunology, tumour biology and natural history through controlled trials focusing not only on efficacy endpoints but also on biological markers in tissue and serum will help develop detailed risk models. Chemopreventive agents appear thus far to have efficacy in several tumour types, and we hope to define their future role in treating and preventing other cancers in high-risk individuals.
Advances in delaying the development of colorec- tal carcinoma have been shown in patients with FAP with celecoxib treatment. Current and future trials using celecoxib alone or in combination with
chemotherapy and other biological therapies are tar- geting several cohorts including children with APC mutations, patients with FAP, HNPCC, prior colorec- tal adenoma, or prior history of sporadic adenomas [14]. The use of celecoxib in the prevention of polyps has resulted in continued efforts to define a high-risk population and to implement a chemopreventive agent in the treatment of cancer. With regard to aspirin use in the prevention of colon adenomas, two large randomised, placebo-controlled trials showed benefit. However, although the Aspirin/Folate Polyp Prevention Study and the Colorectal Adenoma Pre- vention Study reported positive results, a certain per- centage of patients receiving aspirin intervention still developed colon adenomas. This suggests that aspirin use cannot be a substitute for colon surveil- lance and that further studies are necessary for effec- tive colon cancer chemoprevention.
Surgical Prevention of Colorectal Cancer in FAP
Familial adenomatous polyposis coli (FAP) may not be considered a single disease entity with standard- ised guidelines for operative treatment. However, prophylactic colectomy after the manifestation of polyps but prior to the development of colorectal cancer remains the most effective prevention of col- orectal cancer in FAP. The optimal timing of prophy- lactic surgery remains a clinical decision taken inde- pendently of mutation analysis. In the case of the classic FAP phenotype, restorative proctocolectomy and ileal pouch-anal anastomosis might be the pro- cedure of choice. The development of reliable guide- lines for attenuated FAP variants requires further evidence from clinical studies on surgical strategy and the advantages of prophylactic surgery over reg- ular endoscopic screening with removal of polyps. A study by Winde et al. [15] has shown that low-dose rectal sulindac maintenance therapy is highly effec- tive in achieving complete adenoma reversion with- out relapse in 87% of patients after 33 months. Rectal FAP phenotype should be crucial in the surgical deci- sion. Colectomy with ileo-rectal anastomosis and regular chemoprevention might proceed to be a promising alternative to pouch procedures. Chemo- prevention with lower incidence of FAP-related tumours via dysplasia reversion might be possible in the future.
The Aftermath of Prophylactic Colectomy
A patient after a proctocolectomy is cleared from col- orectal cancer, but he is not entirely free from trou- bles. Duodenal adenomas might be the next problem,
moreover desmoids are also a recognised entity in FAP. The lifetime risk of developing duodenal cancer in familial adenomatous polyposis (FAP) is about 5%. When and to what extent surgical intervention should be undertaken to prevent death from invasive carcinoma is controversial [16]. Of 48 proctocolec- tomies with a mean follow-up of 74 months (range, 3–288 months), Tulchinsky et al. [17] reported the development of extra-colonic manifestations includ- ing desmoid tumours (in 12), duodenal adenomas (in 9), pouch adenomas (in 5), and rectal stump adeno- mas (in 3), in 38 patients. Two patients died (4%) because of desmoid tumour and malignant fibrous histiocytoma.
Aiming to prevent duodenal polyps, enteral ade- nomatous polyposis coli gene replacement therapy in mice has awakened interest [18]. Preclinical studies of gene transfer for the treatment of desmoid disease in familial adenomatous polyposis [19] is under study and seems an attractive alternative for the treatment of desmoids, but it is too early to under- stand if this will develop into a clinical application.
Conservative surgical treatments such as pan- creas-preserving total duodenectomy in familial ade- nomatous polyposis have been advocated, but sur- gery cannot be considered a future trend for a genetic disease.
New Screening Methods
Virtual colonoscopy, which is an electronic recon- struction of the colon from high-resolution abdomi- nal computed tomographic (CT) scans or magnetic resonance imaging (MRI) studies, holds promise as a colon-screening tool. Current technology has already resulted in reliable identification of colonic lesions as small as a few millimetres. Complete colon prepara- tion is still required, and the cost is not yet known.
Research is under way to assess the potential of doing virtual colon studies without any preparation. If this succeeds, screening may well become both cost- effective and convenient. The utility of capsule endoscopy small-bowel surveillance in patients with polyposis [20] might find an indication in selected cases of more advanced duodenal adenoma that can be related to the presence of small-bowel polyps.
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