Considerations in Colorectal Cancer Screening: Stool DNA Testing as a New Option
Audio Conference Dial-In Information
• To participate simply dial: 1-800-362-0595 • Ask the operator to connect you to the “Considerations in Colorectal Cancer Screening: Stool DNA Testing as a New Option” conference
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Colorectal Cancer (CRC) Screening
• Compelling rationale • Suitable tests • Favorable cost effectiveness …but 60% of Americans of screening age have never been screened for colorectal cancer So, we have a problem to fix
1999 Behavior Risk Factor Surveillance System [database]. Atlanta, GA: Centers for Disease Control and Prevention; 1999. 3
Colorectal Cancer: Epidemiology
Colorectal Cancer Is:
Prevalent: Deadly: Expensive: Treatable: 147,500 new cases will be diagnosed in the United States in 2003 57,100 annual deaths; 5-year mortality of 40% One of the most expensive cancers to treat 90% survival rate when detected early
American Cancer Society. Cancer Facts & Figures 2003. Atlanta, GA: American Cancer Society; 2003.
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Early Detection Saves Lives
5-Year Survival Rates for Patients With Colorectal Cancer
100 75 50 25 0 Stage II Stage I (Dukes A) (Dukes B) Early Diagnosis: 90% 70% 100 75 50 25 5% 0 Stage III Stage IV (Dukes C) (Dukes D) Late Diagnosis: 50%
37% of Patients
63% of Patients
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American Cancer Society. Cancer Facts & Figures 2003. Atlanta, GA: American Cancer Society; 2003.
Natural History: A Typical Case
10+ years
Normal
Adenoma
Carcinoma
A series of molecular changes transforms normal colonic epithelial cells into colorectal carcinoma through the intermediate step of an adenomatous polyp
~25% of the general population have polyps by age 50 years
Centers for Disease Control and Prevention. A Call to Action: Prevention and Early Detection of 6 Colorectal Cancer. Available at: http://www.cdc.gov/cancer/colorctl/calltoaction/slides/slide07.htm.
Goals of CRC Screening/Surveillance
• Reduce mortality – Detection of early-stage cancers, before the development of advanced life-threatening disease • Reduce incidence – Identification and eradication of premalignant adenomatous polyps
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Risk Factors for Colorectal Cancer
Average Risk
• Age ≥ 50 years; asymptomatic
High-Risk Cases: 25%
High Risk
• Personal history of CRC or adenomas • Family history of CRC or adenomas • Genetic syndromes
– Familial adenomatous polyposis (FAP) – Hereditary nonpolyposis CRC (HNPCC)
Average-Risk Cases: 75%
• Inflammatory bowel disease
American Cancer Society. Cancer Facts & Figures 2002. Atlanta, GA: American Cancer Society; 8 2002:20–27.
Factors to Consider When Choosing a Screening Strategy
• • • • • • Patient’s risk of colorectal cancer Test effectiveness Patient’s willingness to comply Adverse effects Implementation issues Cost effectiveness
Adapted from Pignone M et al. Ann Intern Med. 2002;137:132–141.
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Recommended CRC Screening Strategies: Average Risk (ACS, ACG, AGA Guidelines) Options Beginning at Age 50 Years
Annual fecal occult blood testing (FOBT) Flexible sigmoidoscopy (FS) every 5 years Annual FOBT plus FS every 5 years Double-contrast barium enema (DCBE) every 5 years • Colonoscopy every 10 years
Digital rectal examination is not an appropriate CRC screening method
Winawer S et al. Gastroenterology. 2003;124:544–560. 10
• • • •
Sensitivity and Specificity
Sensitivity Percentage of patients with disease who are detected by the test Specificity Percentage of disease-free patients who are correctly called “negative” by the test
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Fecal Occult Blood Testing
Pros • Evidence base is from randomized, controlled trials • Noninvasive • No bowel preparation required • Readily performed by primary care practitioners • Cost effectiveness established Cons • Limited effectiveness • Requires annual testing • Patient resistance to handling stool • Diet restrictions used in some practices • False positives
Rex DK. Rev Gastroenterol Disord. 2002;2(suppl 1):S2–S11.
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Flexible Sigmoidoscopy
Pros • Office-based procedure • More practitioners trained than for colonoscopy • More effective than FOBT • Does not require sedation • Preparation easier than for colonoscopy Cons • Patient discomfort • Less effective than colonoscopy • Preparation, expertise: limit insertion • Perforation risk (1:10,000)
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Double-Contrast Barium Enema
Pros • Full-colon evaluation Cons • Poor sensitivity vs endoscopy • Poor patient tolerance • No data; only SCBE study • Optimal screening interval unknown • Radiologist expertise declining • Same-day colonoscopy not possible
SCBE, single-contrast barium enema.
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Colonoscopy
Pros • Most accurate test for detection of polyps and cancers (sensitivity: ~90%–95%) • Diagnostic and therapeutic • Longest protective interval • Reduced CRC mortality (indirect evidence2) • Better patient satisfaction than with sigmoidoscopy Cons • Highest “relative risk” - Diagnostic perforation risk = 0.03%–0.61%1 - Therapeutic perforation risk = 0.07%–0.72%1 • Highest up-front cost • Compliance Issues - Patient limitation of activities (bowel preparation, medications, and time) • Detection Limitations - May miss interval cancers, flat lesions, and lesions obscured by suboptimal bowel preparation
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1. U.S. Preventive Task Force. Screening for Colorectal Cancer: Recommendations and Rationale. Rockville, MD: Agency for Healthcare Research and Quality; 2002. 2. Winawer SJ et al. N Engl J Med. 1993;329:1977–1981.
Novel Screening Strategies
• Virtual colonoscopy • Stool-based DNA testing
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Virtual Colonoscopy
Pros • Some studies show adequate sensitivity for polyps >1 cm • Low risk of perforation (1:25,000) • Same-day colonoscopy potential (to avoid back-toback bowel preparation) • Extracolonic findings possible Cons • Requires bowel preparation • Most expensive diagnosis-only strategy • High rate of false positives • Mixed results (vary by site) • Cost effectiveness not established • Acceptability results variable (less than colonoscopy)
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Stool-Based DNA Screening
Pros • “Total colon” examination • Noninvasive, safe • No bowel preparation • Convenient (single sample collected at home) Cons • Less effective than colonoscopy
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How Is the Best Screening Test Chosen?
• Physicians should discuss with eligible individuals the pros and cons of each screening test • Factors to be considered:
– – – – – – – – Age Actual risk of colorectal cancer Risk of screening tests Discomfort Safety Adherence Resources Health insurance coverage
• Most important for eligible individuals is to undergo some type of colorectal cancer screening test
Walsh HA, et al. JAMA.2003;289:1297-1302. 19
Strategies to Promote CRC Screening: Patient Preferences
Screening Strategy
FOBT
Leard et al
31%
Ling et al
43%
FS
13%
2%
FOBT + FS
NA
12%
DCBE
14%
3%
Colonoscopy
38%
40%
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Leard LE, et al. J Fam Pract. 1997;45:211–218. Ling BS, et al. J Gen Intern Med. 2001;16:822–830.
A Comparative Study of Patient Perceptions and Screening Preferences
Study Design: • Prospective survey with 2,388 subjects completing survey • Subjects were previously unscreened, asymptomatic average-risk subjects aged 50 years and older • Currently participating in multicenter comparison of Stool-based DNA (SBDNA) and Fecal Occult Blood Test (FOBT) • Subjects completed a 25-item questionnaire within 48 hours after undergoing a screening colonoscopy
– The colonoscopy served as a reference standard for SBDNA and FOBT test performance
• Respondents were asked to rate each of the 3 screening tests on a variety of features using a 5-point ordinal scale and select a preferred strategy
Schroy et al. Gastroenterology. 2003;124(4):A604 21
A Comparative Study of Patient Perceptions and Screening Preferences (cont.)
50 45 40 35 30 25 20 15 10 5 0 Stool DNA (P < .001) FOBT (P < .001) CS (P < .001) No Clear Preference
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Preference (%)
Schroy et al. Gastroenterology. 2003;124(4):A604
Why a Stool-Based DNA Assay?
• Colorectal cancer (CRC) results from an accumulation of mutations in genes that control cell growth and normal cell death • CRC associated DNA alterations are known • The existence of detectable CRC-associated DNA alterations in stool has been established by over 10 years of published data • DNA is stable in stool
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Genetic Model of Colorectal Cancer
Typically 10+ Years
BAT-26 (sporadic) p53
DNA Alteration:
APC
K-ras
Adapted from Fearon ER, Vogelstein B. Cell. 1990;61:759–767.
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Stool Assay for Altered DNA*
• 23 DNA markers assayed to identify: – 21 separate point mutations in the K-ras oncogene, and APC and p53 tumor suppressor genes (most common) – Shortened forms of BAT-26, commonly altered marker of microsatellite instability – DNA Integrity Assay (DIA ®), indicative of a disorder in the normal process of programmed cell death (apoptosis)
*Data on file, EXACT Sciences Corporation. 25
A “Multitarget” DNA Stool Assay
• A variety of DNA mutations and other DNA alterations are present in cancer cells • While a small number of genes are involved, no single DNA alteration is present in every CRC • By testing for multiple DNA alterations, high sensitivity is achieved
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Stool DNA Screening Process
Physician Sends Requisition to Lab Stool DNA Analysis Is Performed in Lab and Reported to Physician
Patient Collects Stool at Home
Lab Provides Collection and Shipping Materials to Patient
Patient Returns Specimen to Lab
Physician Communicates Results to Patient DNA Alteration Identified: perform interventional colonoscopy No DNA Alteration Identified: continue routine screening program 27
Completed Clinical Studies*:
Stool-Based DNA Screening
Presented/Published Ahlquist et al, 20001 Brand et al, 20022 Tagore et al, 20033 Syngal et al, 20034 Overall Reported Experience
*As of August 20, 2003
1. 2. 3. 4. Ahlquist DA, et al. Gastroenterology. 2000;119:1219–1227. Brand RE, et al. Gastroenterology. 2002;122(suppl):A479. Tagore KS, et al. Clin Colorectal Cancer. 2003;3:47-53. Syngal S, et al. Gastroenterology. 2003;124:4(suppl):A42.
Sensitivity 91% (20/22) 69% (11/16) 63% (33/52) 62% (40/65)
Specificity 93% (26/28) —
Sensitivity for Advanced Adenomas
82% (9/11) —
98% (111/113) 57% (16/28) — 27% (6/22)
67% (104/155) 97% (137/141) 51% (31/61)
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Ongoing Clinical Validation Studies:
Stool-Based DNA Screening Multicenter Clinical Study • Objective: direct comparison of stool DNA with FOBT for CRC detection • Screening colonoscopy as reference standard • More than 5000 average-risk patients • 40 sporadic cancers anticipated • Results expected by the end of 2003
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Data on file, EXACT Sciences Corporation.
Comparing Cost-Effectiveness of CRC Screening Strategies
• Cost effectiveness establishes relative value of a healthcare intervention • The US Preventive Services Task Force conducted a systematic review of cost-effectiveness studies • The conclusions of the review were:
– – – – CRC screening is cost effective compared with no screening CRC screening reduces death CRC screening can decrease the incidence of disease Data are insufficient to support a definitive determination of the most effective screening strategy
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Pignone M et al. Ann Intern Med. 2002;137:132–141.
Cost Effectiveness and Patient Compliance
• Recent abstracts presented at Digestive Disease Week (DDW), May 2003 – If patients are willing and able to have a colonoscopy, they should have one, BUT many nonadherent patients would benefit from stool DNA screening, and its cost effectiveness is very favorable compared with other prevention methods1 – In the noncompliant patient population (~50 million patients in the US), stool DNA screening is a very cost-effective CRC screening strategy2
et al. Gastroenterology. 2003:124(4) Suppl A603. 2Ness et al. Gastroenterology. 2003:124(4) Suppl A622.
1Song
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Proposed Screening Strategy: Average-Risk Patients
Beginning at Age 50 Years: • Annual (3-card) FOBT • FS every 5 years • Annual FOBT plus FS every 5 years • Colonoscopy every 10 years • Other alternatives
– Virtual colonoscopy every 5 to 10 years – Stool-based DNA testing every 3 to 5 years
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Patient Selection
Stool DNA Testing Is Intended for: • Asymptomatic patients who are at average risk for developing colorectal cancer • Asymptomatic patients who are at increased risk but are noncompliant with colonoscopy
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Summary
• Colorectal cancer can be prevented • Screening reduces CRC mortality • All persons aged 50 years or older should begin regular screening
– High-risk persons may need to begin screening earlier
• Several effective screening options are available; “not” screening is no longer an option • Stool DNA testing is a promising new option for CRC screening
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