AMC Cancer Prevention & Control Program Scientific Achievements, 2006-2007

The 10 papers below are illustrative of the breadth of cancer prevention and control research being conducted at UCCC, reflecting epidemiologic research on cancer risk factors (breast cancer), research on cancer screening (lung and colorectal cancer), and chemoprevention studies (prostate and colorectal cancer). In addition, two recent publications illustrate the involvement of program members in expert panels to formulate practice guidelines (cancer survivorship) and recommendations for future research (colorectal cancer).

Change in body size and the risk of colorectal adenomas

Sedjo RL, Byers T (PC), Levin TR, Haffner SM, Saad MF, Tooze JA, D'Agostino RB Jr. Cancer Epidemiol Biomarkers Prev 16(3):526-531, 2007.

Adiposity has been recognized as a risk factor for colorectal adenoma, but the influence of weight gain, adipose tissue distribution, and possible differences between ethnic/racial and gender groups remains unclear. The aim of this prospective study was to examine the association between adiposity and weight change and colorectal adenoma risk.

Over approximately 10-year period, anthropometric measures and other risk factors were measured at three time points in the multicenter multiethnic Insulin Resistance Atherosclerosis Study cohort. Colonoscopies were then conducted on 600 cohort participants regardless of symptoms whose mean age at colonoscopy was 64 years. Obesity was found to be positively associated with risk of colorectal adenomas at the time of colonoscopy [adjusted odds ratio (OR(adj)), 2.16; 95% confidence interval (95% CI), 1.13-4.14] and was stronger in women (OR(adj), 4.42; 95% CI, 1.53-12.78) than in men (OR(adj), 1.26; 95% CI, 0.52-3.07). The risk of adenomas increased among participants who gained weight compared with those who maintained weight over the approximately 5 years (OR(adj), 2.30; 95% CI, 1.25-4.22) and approximately 10 years (OR(adj), 2.12; 95% CI, 1.25-3.62).

These associations were similar for both advanced and nonadvanced adenomas, and suggest a positive association between obesity, weight gain and colorectal adenoma risk. Given that stronger associations were observed when obesity was measured at the time of colonoscopy, the investigator concluded that obesity may be a promoting factor in the growth of colorectal adenomas.

Effect of a mailed brochure on appointment-keeping for screening colonoscopy: a randomized trial.

Denberg TD (PC), Coombes JM, Byers TE (PC), Marcus AC (PC), Feinberg LE, Steiner JF (PC), Ahnen DJ (PC). Ann Intern Med 145(12):895-900, 2006.

Even when primary care physicians have face-to-face discussions with patients before referring them for screening colonoscopy, patient nonadherence can be substantial. When making such referrals, primary care physicians often lack sufficient time to educate patients and address their potential misconceptions and fears about this procedure. To address this challenge, the investigators in this study tested whether an informational brochure sent to patients' home addresses after referral for screening colonoscopy would increase patient completion of the procedure.

The study was conducted as a randomized trial within 2 general internal medicine practices affiliated with the University of Colorado Health Sciences Center. Patients (n = 781) were 50 years of age or older and referred by their primary care physicians for screening colonoscopy. Patients were randomly assigned to receive usual care (control group) versus usual care plus an informational brochure (intervention group). The brochure was mailed within 10 days of referral for screening colonoscopy; it mentioned the name of the patient's primary care physician and encouraged patients to schedule a procedure. It also described colorectal cancer and polyps and the similar lifetime risks for colorectal cancer for men and women, colonoscopy and risk for perforation, the nature of bowel preparation for the procedure, and alternative screening tests.

The results from this trial revealed that the overall adherence rate was 11.7 percentage points (95% CI, 5.1 to 18.4 percentage points) greater in the intervention group than in the control group (70.7% vs. 59.0%). Older patients were more adherent than younger patients. Patients with low-income insurance plans, such as Medicaid, were less adherent despite being sent a brochure. Based on these findings, it was concluded that an inexpensive mailed brochure is an effective way to increase patient adherence to primary care physician referral for screening colonoscopy.

Sputum cytologic atypia predicts incident lung cancer: Assessments of latency and histologic specificity.

Byers T (PC), Wolf H, Franklin WA (TOP), Broderick S, Merrick D (TOP), Shroyer K (HRM), Hirsch FR (TOP,DT), Zeng C, Barón AE (DT). Cancer Epidemiol Biomark Prev, in press, 2007.

As new radiologic imaging methods are being developed for lung cancer detection, it seems timely to consider whether biomarkers in the sputum might complement imaging as a modality to assist in early lung cancer diagnosis. In particular, cytologic atypia of exfoliated cells has been shown to be associated with both prevalent and incident lung cancer. 

In this paper, the investigators report on the latency between sputum cytologic changes and lung cancer incidence in a sample of 174 incident lung cancers. Sputum samples were collected at baseline and periodically thereafter in a cohort of smokers and former smokers with chronic obstructive lung disease. Risk for incident lung cancer increased among those with cytologic atypia graded as moderate or worse (adjusted HR=2.37; 1.68 to 3.34). The association between sputum atypia and lung cancer incidence was greatest for those sputum samples collected 5 months or less before the diagnosis of lung cancer (OR=10.32; 5.34 to 19.97). The association was substantially stronger for squamous cell lung cancers (HR=5.13; 2.89 to 9.10) than for adenocarcinomas (HR=1.85; 0.94 to 3.65).

Given these findings, the authors conclude that cytologic atypia is a marker for increased lung cancer risk, and that cytologic changes seem to arise from late events that are most apparent for cancers arising in the central respiratory airways. The investigators also note that whether cytologic atypia might complement radiologic imaging in a combined approach to lung cancer early detection will require additional evaluation of these two methods used in combination with one another.

Five-year colon surveillance after screening colonoscopy.

Lieberman DA, Weiss DG, Harford WV, Ahnen DJ (CB), Provenzale D, Sontag SJ, Schnell TG, Chejfec G, Campbell DR, Kidao J, Bond JH, Nelson DB, Triadafilopoulos G, Ramirez FC, Collins JF, Johnston TK, McQuaid KR, Garewal H, Sampliner RE, Esquivel R, Robertson D. Gastroenterology, in press, 2007.

Outcomes of colon surveillance after colorectal cancer screening with colonoscopy are uncertain. We conducted a prospective study to measure incidence of advanced neoplasia in patients within 5.5 years of screening colonoscopy. Three thousand one hundred twenty-one asymptomatic subjects, age 50 to 75 years, had screening colonoscopy between 1994 and 1997 in the Department of Veterans Affairs. One thousand one hundred seventy-one subjects with neoplasia and 501 neoplasia-free controls were assigned to colonoscopic surveillance over 5 years. Cohorts were defined by baseline findings. Relative risks for advanced neoplasia within 5.5 years were calculated. Advanced neoplasia was defined as tubular adenoma greater than >/=10 mm, adenoma with villous histology, adenoma with high-grade dysplasia, or invasive cancer.

Eight hundred ninety-five (76.4%) patients with neoplasia and 298 subjects (59.5%) without neoplasia at baseline had colonoscopy within 5.5 years; 2.4% of patients with no neoplasia had interval advanced neoplasia. The relative risk in patients with baseline neoplasia was 1.92 (95% CI: 0.83-4.42) with 1 or 2 tubular adenomas <10 mm, 5.01 (95% CI: 2.10-11.96) with 3 or more tubular adenomas <10 mm, 6.40 (95% CI: 2.74-14.94) with tubular adenoma >/=10 mm, 6.05 (95% CI: 2.48-14.71) for villous adenoma, and 6.87 (95% CI: 2.61-18.07) for adenoma with high-grade dysplasia.

The authors concluded from this study that there is a strong association between results of baseline screening colonoscopy and rate of serious incident lesions during 5.5 years of surveillance. The investigators also note that patients who have cancer detected at baseline colonoscopy need intensive follow-up after curative resection to establish that all important lesions were discovered at baseline, that they were completely removed, and that they do not develop new important pathology in a short interval. Importantly, the investigators conclude that it is very likely that important lesions were missed or completely removed by experts with extensive colonoscopic experience, and that these data support the new guidelines that recommend repeat colonoscopies within 1 year if cancer is detected at baseline, even if a complete examination was performed at the time of resection. In contrast, the investigators note that patients with 1 or 2 tubular adenomas less than 10 mm represent a low-risk group compared with other patients with colon neoplasia, and that no benefit for early surveillance before 5 years was found for this group.

Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.

Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ (PC), Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T (PC), Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER.  JAMA 297(21):2351-2359, 2007.

Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine. To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas, a double-blind, placebo-controlled, 2-factor, randomized trial was conducted at 9 clinical centers. Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma. Participants were randomly assigned to receive 1 mg/d of folic acid (n = 516) or placebo (n = 505), and were separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of 2 colonoscopic surveillance cycles (the first interval was at 3 years and the second at 3 or 5 years later).

The primary outcome measure was occurrence of at least 1 colorectal adenoma. Secondary outcomes were the occurrence of advanced lesions (> or =25% villous features, high-grade dysplasia, size > or =1 cm, or invasive cancer) and adenoma multiplicity (0, 1-2, or > or =3 adenomas).

During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n = 221) and 42.4% for placebo (n = 206) (unadjusted risk ratio [RR], 1.04; 95% confidence interval [CI], 0.90-1.20; P = .58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n = 57) and 8.6% for placebo (n = 42) (unadjusted RR, 1.32; 95% CI, 0.90-1.92; P = .15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n = 127) and 37.2% for placebo (n = 113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P = .23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n = 35) and 6.9% for placebo (n = 21) (unadjusted RR, 1.67; 95% CI, 1.00-2.80; P = .05).

Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation. Based on these results, the investigators concluded that folic acid at 1 mg/d does not appear to reduce colorectal adenoma risk. In addition, the authors conclude that additional research is needed to investigate the possibility that folic acid supplementation might actually increase the risk of colorectal neoplasia.

Serum selenium and risk of prostate cancer-a nested case-control study

Peters U, Foster CB, Chatterjee N, Schatzkin A, Reding D, Andriole GL, Crawford ED (HRM,PC), Sturup S, Chanock SJ, Hayes RB.  Am J Clin Nutr 85(1):209-217, 2007.

Selenium is a potential chemopreventive agent against prostate cancer, whose chemoprotective effects are possibly mediated through the antioxidative properties of selenoenzymes. Several but not all case-control studies have reported an inverse relationship between serum selenium and prostate cancer risk, and few studies have examined the interaction between serum selenium and other antioxidative agents and oxidative stressors such as vitamin E and smoking.

In this nested case-control study, the investigators examined such interactions within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Serum selenium in prospectively collected samples was compared between 724 incident prostate cancer case subjects and 879 control subjects, frequency-matched for age, time since initial screen, and year of blood draw. The men were followed for up to 8 years.

Overall, serum selenium was not associated with prostate cancer risk (P for trend = 0.70); however, higher serum selenium was associated with lower risks in men reporting a high (more than the median: 28.0 IU/d) vitamin E intake [odds ratio (OR) for the highest compared with the lowest quartile of selenium: 0.58; 95% CI: 0.37, 0.91; P for trend = 0.05; P for interaction = 0.01] and in multivitamin users (OR for highest compared with the lowest quartile of selenium: 0.61; 95% CI: 0.36, 1.04; P for trend = 0.06; P for interaction = 0.05). Among smokers, high serum selenium concentrations were related to reduced prostate cancer risk (OR for the highest compared with the lowest quartile of selenium: 0.65; 95% CI: 0.44, 0.97; P for trend = 0.09; P for interaction = 0.007).

Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial

Lucia MS (HRM), Epstein JI, Goodman PJ, Darke AK, Reuter VE, Civantos F, Tangen CM, Parnes HL, Lippman SM, La Rosa FG (HRM), Kattan MW, Crawford ED (HRM,PC), Ford LG, Coltman CA Jr, Thompson IM. J Natl Cancer Inst 99(18):1375-1383, 2007.

The Prostate Cancer Prevention Trial (PCPT) reported a decreased incidence of prostate cancer overall but an increase in the incidence of high-grade prostate cancer with finasteride compared with placebo. This latter finding subsequently raised concerns about the safety of finasteride for prostate cancer prevention. For example, it has been proposed that finasteride might induce or increase the risk of high-grade disease through changes in intraprostatic androgen and/or estrogen signaling. However, finasteride also reduces prostate volume and can increase the sensitivity of DRE and PSA in detecting cancer, both of which could improve the detection of high-grade tumors in the finasteride treatment arm.

In this study, the investigators examined whether the increased high-grade prostate cancer associated with finasteride in the PCPT was due to finasteride's potential effects on tumor morphology or prostate size. Prostate biopsies with Gleason score 8-10 (n = 90, finasteride; n = 52, placebo) were examined histologically for hormonal effects, and those with Gleason score 7-10 (n = 282, finasteride; n = 244, placebo) were examined for pathologic surrogates of disease extent. Prostate volumes were measured at biopsy.

Samples from radical prostatectomies (n = 222, finasteride; n = 306, placebo) were examined for tumor grade and extent, and, where possible, grades at biopsy and prostatectomy were compared between the groups. Degenerative hormonal changes in high-grade biopsies were found to be equivalent between the finasteride and placebo groups, but prostate volumes were lower in the finasteride group (median = 25.1 versus 34.4 cm3, P<.001). Pathologic surrogates for tumor extent were lower with finasteride than with placebo, including mean percentage of positive cores (34% versus 38%, P = .016), mean tumor linear extent (greatest [4.4 versus 4.8 mm, P = .19] and aggregate [7.6 versus 9.2 mm, P = .13]), bilaterality (22.8% versus 30.6%, P = .046), and perineural invasion (14.2% versus 20.3%, P = .07).

Among patients who had prostatectomy, the finasteride-associated increase in high-grade disease (Gleason score > or = 7) at biopsy (42.7% finasteride versus 25.4% placebo, P<.001) was diminished at prostatectomy (46.4% finasteride versus 38.6% placebo, P = .10). Biopsy identified a greater proportion of patients with high-grade disease present at prostatectomy in the finasteride group than in the placebo group (69.7% versus 50.5%, P = .01). The rate of upgrading (from low-grade cancer at biopsy to high-grade cancer at prostatectomy) and pathologic stage at prostatectomy were similar in both groups.

Given these findings, the investigators concluded that the effects of finasteride on prostate volume and selective inhibition of low-grade cancer, rather than effects on tumor morphology, may have contributed to the increase in high-grade cancers with finasteride in the PCPT. Although induction of high-grade cancer cannot be excluded, the investigators note that the results suggest high-grade cancer was detected earlier and was less extensive in the finasteride group than in the placebo group.

Ornithine decarboxylase polymorphism modification of response to aspirin treatment for colorectal adenoma prevention.

Barry EL, Baron JA, Bhat S, Grau MV, Burke CA, Sandler RS, Ahnen DJ (PC), Haile RW, O'Brien TG.  J Natl Cancer Inst 98(20):1494-1500, 2006.

Previous research suggests that the G315A single-nucleotide polymorphism in the ornithine decarboxylase (ODC) gene may be a genetic marker for risk of colorectal neoplasia and may also modify the association of aspirin use with risk. Both of these hypotheses were tested among participants in the Aspirin/Folate Polyp Prevention Study who were randomly assigned to placebo or to aspirin treatment (81 or 325 mg daily) and followed for 3 years for the occurrence of new adenomas.

Genomic DNA from 973 subjects was analyzed for ODC genotype. Of the 973 subjects, 54% were homozygous wild-type (GG), 7% were homozygous variant (AA), and 39% were heterozygous individuals. At 3 years follow-up, the absolute risk of any adenoma was 45% and the risk of an advanced lesion was 10%. Overall, no association was found between ODC genotype and the occurrence of new adenomas, but genotype did modify the effect of aspirin on adenoma risk.

Although aspirin treatment had no protective effect among subjects with a GG genotype, among subjects with at least one A allele, it was associated with statistically significant reduced risks of any adenoma (RR = 0.77, 95% CI = 0.63 to 0.95; P = .02, P(interaction) = .04) and of advanced lesions (RR = 0.51, 95% CI = 0.29 to 0.90; P = .02, P(interaction) = .02). Among subjects with at least one A allele, 40.8% who took aspirin versus 52.9% who took placebo developed adenomas; 7.1% versus 14.0% developed advanced lesions. Based on these findings, the investigators concluded that ODC genotype may indeed modify the response to aspirin treatment for colorectal adenoma prevention.

Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices.

Doyle C, Kushi LH, Byers T (PC), Courneya KS, Demark-Wahnefried W, Grant B, McTiernan A, Rock CL, Thompson C, Gansler T, Andrews KS. CA Cancer J Clin 56(6):323-353, 2006.

Cancer survivors are often highly motivated to seek information about food choices, physical activity, and dietary supplement use to improve their treatment outcomes, quality of life, and survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer.

The report discusses nutrition and physical activity issues during the phases of cancer treatment and recovery, living after recovery from treatment, and living with advanced cancer. In addition, nutrition and physical activity issues such as body weight, food choices, and food safety are discussed, as well as issues related to specific cancer sites. Finally, common questions about diet, physical activity, and cancer survivorship are addressed.

This report provides the most authoritative compilation of behavioral guidelines in cancer survivorship to date, and is now available and widely disseminated for use by health care providers nationwide.

Priorities in colorectal cancer research: recommendations from the Gastrointestinal Scientific Leadership Council of the Coalition of Cancer Cooperative Groups

O'Dwyer PJ, Eckhardt SG (DT), Haller DG, Tepper J, Ahnen D (PC), Hamilton S, Benson AB III, Rothenberg M, Petrelli N, Lenz HJ, Diasio R, DuBois R, Sargent D, Sloan J, Johnson CD, Comis RL, O'Connell MJ. J Clin Oncol 25(16):2313-2321, 2007.

The Coalition of Cancer Cooperative Groups convened a multidisciplinary panel, the Scientific Leadership Council in GI cancer, to discuss and advise on the priorities and opportunities to advance current and future approaches into the clinical arena to impact most rapidly the morbidity and mortality from this disease. The Council's recommendations for research priorities, as summarized in this report, involved community and academic oncologists, patient advocacy groups, and other stakeholders including the pharmaceutical industry and governmental agencies.

Among the key findings and recommendations highlighted in this report are the following: 

1. The greatest immediate opportunity for reducing the burden of colorectal cancer is in the area of prevention and screening; 
2. Increasing the proportion of the population covered using currently available modalities and developing less invasive and more effective screening methods should therefore be given high priority; 
3. Additional research is needed to identify molecular markers that would target high risk populations most likely to benefit from chemopreventive approaches; 
4. Targeted therapies based on colorectal cancer biology at the molecular level are most promising for improving medical and surgical management of colorectal cancer, and developing individualized therapy based on host and tumor characteristics; 
5. The implementation of biology-directed laboratory investigations, both in association with ongoing clinical trials and as a separate developmental strategy for targeted therapies, should be expanded to facilitate the development of individualized therapies; and 6) The current portfolio of cooperative group clinical trials is addressing many of these concerns and thus rapid accrual into these trials needs to occur.