Article Text

Cost comparison of predictive genetic testing versus conventional clinical screening for familial adenomatous polyposis
Free

## Abstract

BACKGROUND Mutations of theAPC gene cause familial adenomatous polyposis (FAP), a hereditary colorectal cancer predisposition syndrome.

AIMS To conduct a cost comparison analysis of predictive genetic testing versus conventional clinical screening for individuals at risk of inheriting FAP, using the perspective of a third party payer.

METHODS All direct health care costs for both screening strategies were measured according to time and motion, and the expected costs evaluated using a decision analysis model.

## Discussion

We performed a detailed comparison of all direct health care costs for genetic or conventional clinical screening for FAP. The predictive genetic testing approach costs about one third to one thirteenth less than that of the conventional clinical strategy over a wide range of variables. Thus, on the basis of economic variables alone, molecular genetic testing was the method of choice. A significant finding of this study was that the genetic testing strategy saved substantial costs only if the sigmoidoscopic surveillance regimens forAPC mutation carriers remained the same as for conventional clinical screening. FAP is a paradigm for cancer prevention based on the known adenoma−carcinoma sequence which occurs over an average of 5–10 years. Prophylactic colectomy in affected individuals essentially eliminates risk of colon cancer, although individuals may still be at risk of rectal cancer depending on the specific prophylactic operation performed and subsequent screening of the remaining rectum, and for other extracolonic manifestations associated with FAP. Clinical screening regimens have been established to ensure that at risk offspring and siblings of FAP patients benefit from early diagnosis and treatment. Interestingly, several registries have now advocated annual flexible sigmoidoscopy for presymptomatic family members known to carry an APCmutation.25-27 The efficacy of increasing surveillance frequency from a biennial to annual time interval forAPC mutation carriers is not yet proved, especially in the absence of histological or clinical data to support such findings. Early studies by Morson (1974) found an average 5% malignancy rate for adenomas over a life span and showed that only a few adenomas in FAP ever become malignant.3 The minimal interval of five years for such a transition would suggest the lack of an accelerated evolutionary process, such as that indicated for colorectal adenomas associated with hereditary non-polyposis colorectal cancer (HNPCC).28

The decision analysis carried out in this study was conservative for several reasons. Firstly, if a germline APCmutation is not detected by HDA and/or PTT assay, molecular linkage analysis using intragenic and closely linked polymorphic DNA markers can achieve predictive carrier risk estimates with greater than 99% accuracy in informative families.5 ,29 ,30 For families with a suitable pedigree structure, the inclusion of linkage based testing would result in greater cost savings under the genetic route. Several different molecular diagnostic techniques can be used for predictive genetic testing of FAP.6 ,9 ,17 ,23 The choice of optimal technique(s) is largely dependent on the nature of mutations and the frequency of specific mutations. We chose PTT for mutation analysis as the majority of germline APCmutations are truncating in nature. Another assumption regarding the time span for conventional clinical screening is also conservative as at risk relatives continue to be examined after age 50 years, albeit at a low frequency.4 Given, however, that the costs for each subsequent procedure following the baseline endoscopy were discounted at a rate of 5% per year to their present values, extension of the screening time frame would not significantly affect our analytical result. Finally, the cost comparison analysis was done with the perspective of a third party payer, and therefore, only the costs directly related to the comparative strategies were considered. Inclusion of direct personal and indirect costs, such as lost productivity of patients and accompanying family members during each clinic visit for a sigmoidoscopic examination, would result in further cost savings under the genetic route.

What are the implications of such a cost analysis for screening members of FAP families? Apart from the lower cost, the genetic route is less invasive, needs to be performed only once, and can be carried out early in life, thereby significantly modifying the 50% inherent risk of FAP in at risk relatives.4 ,5 In individuals identified as high risk, surveillence regimens can also be initiated for extracolonic manifestations such as upper gastrointestinal polyps and cancer. Because the age of onset of FAP adenomas is variable, patient compliance with screening regimens remains an important factor for the optimal management of this disorder. On the other hand, a reduced genetic risk will relieve anxiety associated with frequent colonic examination5 ,31; clinicians can now focus on those asymptomatic patients identified as “high risk” by genetic testing, but yet for whom one cannot predict the clinical sequelae. More importantly, family members identified to be non-mutation carriers can be released from unnecessary clinical surveillance. From the analysis presented here, we conclude that substantial direct cost savings could result from the adoption of a genetic screening strategy for FAP, but only if the frequency of sigmoidoscopic screening is not increased for asymptomatic patients carrying the APCmutation. Given the limited health care resources available, not only to screen and treat but also to counsel affected FAP families, it would seem prudent to remain focused on a biennial screening regimen.

## Acknowledgments

The authors would like to thank Dr Alan Bernstein for his support and helpful suggestions throughout this project, and Dr Carol Swallow for critical reading of the manuscript. We are grateful to FAP patients and their families for participating in this study. This work was supported in part by funds from Canadian Genetic Diseases Network (HN, BG).

APC