Wednesday, October 29, 2003 State-of-the-Science Forums 9-12 were held at 7:30 AM. Forum 9 “Cancer Prevention and Control Among Survivors” Forum 10: “Treatment and Prevention of Intraepithelial Neoplasia: An Important Target for Accelerated New Agents” Forum 11: “Alternative Medicines vs. Chemoprevention Forum 12: “Minorities and Medically Underserved: Ethnic Differences in Cancer Susceptibility” Julia H. Rowland, Dir, Office of Cancer Survivorship Research, NCI, Bethesda, MD from the abstract, “Behavioral research suggests that the diagnosis of cancer may represent a teachable moment for cancer control efforts. Survivors themselves, many of whom seek ways to alter risk for subsequent cancer morbidity and mortality, are propelling demand for attention to post-treatment health. Diet/nutrition, physical activity, stress management, and smoking behaviors are common targets for change in the wake of cancer.” Wendy Demark-Wahnefried from her abstract “Interventions for Cancer Survivors: Capitalizing on a Teachable Moment” “...if queried, the majority of cancer survivors indicate interest in programs that promote exercise and healthful dietary change.” All of the forums were of interest to the Project but Ann attended Forum 11. Walter Willett, Frederick John Stare Prof of Epid and Nutr, Depts of Nutr and Epid, Harvard Univ., Boston, MA presented snippets of negative results from studies. Ann’s NOTE: Several years ago at the San Antonio Breast Cancer Conference, he announced from the podium that vitamins were not effective and we needed to get on with pharmaceuticals. It was a stunning and amazingly inappropriate statement in our opinion. He discussed the evidence against the use of beta-carotene in lung cancer patients and current smokers. He actually stated that there was no real value for fruits and vegetables, which is a statement completely out of line with current research. See our section on Studies-Fruits, Vegetables, etc. He suggested that calcium might be a problem for those with metastatic cancer but then qualified it as possibly “from dairy products”, which is quite different than proof of calcium as a problem. He did show a series of studies”in both case-control and cohort studies, long term use of multiple vitamin supplements has been associated with lower risk of colon cancer.” (Giovanucci, 1998, Jacobe et al, 2003 Am J Epid, Schrauzer, 1977, Duffield-Lillico, 2003). John Potter, Sr VP & Dir, Div of Public Health Sciences, Fred Hutchinson Cancer Research Ctr, Prof of Epid, UWA, Seattle, WA, said that India had very low rates of cancer and that may be a factor of diet. He suggested our food pyramid inappropriately left off herbs and spices which were broadly used in Indian food. This cuisine also features the use of cloves, pepper, cinnamon, ginger, garlic and onions (see our section on Studies for much more on Herbs/Spices) There are many studies underway looking at curcumin (turmeric) which is a COX-2 inhibitor, as well as other herbs and spices. Dr. Potter stated that these (antioxidants) work in many different ways, such as modifying the detoxification enzyme, altering immune function, reducing inflammation, modifying the steroid hormone, as well as being antimicrobial. The following spices are antibiotic agents that help reduce Helicobacter pylori (the bacteria that leads to gastric cancers, ulcers, etc.):cloves, cinnamon, chili pepers, horseradish, curcumin, and garlic. Forum 12: William J. Blot, CEO, Int’l Epid Institute, Rockville, MD from the abstract: “The Southern Community Cohort Study (SCCS) is a prospective investigation begun in 2002 to enroll nearly 100,000 adults age 40-79, over two-thirds of whom would be African Americans, into a long-term followup to evaluate environmental and host determinants of cancer and assess reasons for the differences by racial and demographic indicators.” The differences referred to are the higher mortality among African Americans with cancer. “Causes of higher incidence are not clear and methods to improve early detection and increase survival are needed.” So far almost 17,000 people have been enrolled in this study. Plenary 4: “Diet, Obesity and Physical Activity: Strength of the Science Underlying These ‘Modifiable’ Causes of Cancer”, featured Arthur Schatzkin, Chief, Nutr Epid Branch, NCI, Bethesda, MD speaking on “Diet and Cancer” talked about environmental factors such as chemicals, radiation exposure, and infectious agents. He suggested that there have been exposure assessment errors in reporting diets in past studies and diet may variable affect cancer site, histology, and molecular profile. For correct information to be generated, one needs the right dietary factors, timing, no measurement error, a look at nutrition-gene interaction, etc. Ann’s NOTE: We would add that populations studied rarely achieve even the ‘Five a Day’ NCI suggests for women (not to mention the Nine a Day for men) referring to consumption of fruits and vegetables. And according to John Potter, as above, spices and herbs. “The genomics revolution may give us greater insight into diet and cancer links via 1) nutrition-gene interactions (leading to sharpening of relative risks) and 2)Mendelian randomization studies complementing traditional nutritional epidemiologic investigations.” Rachel Ballard-Barbash, Assoc Dir, Applied Research Program, NCI, Bethesda, MD. spoke on “Obesity and Cancer”. From the abstract: “At present, data provide convincing evidence of a positive association of overweight and obesity with cancers of the colon (among men), renal cell, postmenopausal breast cancer, endometrium, and probable evidence of a positive association with colon cancer (among women), adenocarcinoma of the esophagus, gastric cardia, and thyroid cancer (among women).” “Limited evidence does not suggest any consistent direct association between overweight and obesity and ovarian cancer.” “ The consistent inverse association between overweight and obesity and premenopausal breast cancer persists after adjustment for multiple potential confounding factors.” “Current challenges in this field include examining differences in risk associated with body mass index (BMI) by subgroup characteristics, such as exposure to hormone replacement therapy, and to tumor characteristics, such as genetic tumor markers or hormone receptor status of hormone dependent tumors.” Current areas for questions include: “Does the risk of BMI and cancer vary within different population groups, such as among African Americans and Asians? Does timing of increased body mass or weight gain, such as inter-utero, during puberty or pregnancy, or in mid-life have a differential effect on cancer risk for different cancers? Do hormonal or other growth factors, such as sex steroids, insulin-related growth factors, and leptin relate to cancer risk and explain the association of obesity with some cancers?” Leslie Bernstein, Prof and ALFAC, Inc. Chair in Cancer Research, Sr Assoc Dean for Faculty Affairs, Keck School of Med and the Norris Comprehensive Cancer Ctr, USC, Los Angeles, CA spoke on “Physical Activity and Cancer”. “It is now commonly accepted that physical activity reduces risk of colon cancer and breast cancer, whereas data for endometrial cancer are suggestive of a relationship and those for prostate cancer are still inconclusive. Other cancer sites have been studied in relation to physical activity, but the body of evidence is small and inconclusive”. Questions to be considered: “Can we measure physical activity with sufficient accuracy to detect relationships to cancer? What facets of activity should we measure? What time periods in life are most important to modify cancer risk and how do these vary by cancer type? What is the optimal level of physical activity needed to impact the risk of a particular cancer? How do we validate reports of activity earlier in life? What biologic mechanisms explain any observed relationships? Plenary 5: “Clinical Prevention Trials in the 21st Century” “The Future of Lung Cancer Chemoprevention Trials: Patient Selection, Drug Selection, and Intermediate Biomarkers”, was presented by Paul A. Bunn, Jr. Dir. U Colorado Cancer Ct, UCo, Denver, CO. From the abstract (excerpts): Lung cancer is the leading cause of cancer death in the U.S. and throughout the world. Active tobacco smoking causes 85-87% of the cases and passive tobacco exposure causes another 3-5% of cases. The risk of lung cancer is directly related to the number of cigarettes/day and the duration of smoking is frequently expressed in pack/years. Risk is much lower in smokers who stop at age 30 and somewhat lower in smokers who stop by age 50. Nonetheless, the risk of lung cancer remains increased above that in non-smokers for many decades. About 50% of lung cancers in the U.S. develop in former smokers. Because the etiology is known for the majority of cases, the potential benefits of prevention are huge. “The Development of Bowman-Birk Inhibitor and Difluoromethylornithe (DFMO) for Human Chemoprevention: Two Promising Odysseys across the Centuries”, presented by Frank Meyskens, Prof of Med & Bio Chem, Dir Chao Family Comprehensive Cancer Ctr, UC Irvine, Irvine, CA. From the abstract (excerpted): In the end, the compound(s) [chemopreventive agents], must be both efficacious and nearly free of toxicity to be broadly adopted, an expectation that is very hard to fill. Dr. Meyskens went on to discuss a variety of clinical trials and studies in colon, prostate, breast, cervix and non-melanoma skin cancer taking place around the U.S. using either DFMO or Bowman-Birk Inhibitor to halt premalignancies. Bowman-Birk Inhibitor is a soybean component. The final presentation in this plenary was entitled: “Colorectal Chemoprevention Trials: What Have We Learned? What’s Next?”, presented byJohn A. Baron, Prof of Med and of Community & Family Med, Dartmouth Med School, Hanover, NH. For a variety of reasons colon cancer is a good target for chemoprevention since “there are several attractive candidate preventive interventions” and the surrogate endpoint biomarker of adenomatous polyps. Thus we know more in this area than for other organs. “...prevention trials have shown that NSAIDs and calcium supplements can prevent colorectal neoplasia. For the future, Dr. Baron suggests configuring “study designs that can investigate effects late in carcinogenesis or those that have longer latency.” Mechanistic biomarkers to epidemiolgoical and experimental studies will be useful but “their interpretation is not always straightforward.” Symposia 8-10 were the final events of this meeting. 8. ”Molecular Prediction for Tumor Progression” First presentation was from Li Mao, Assoc Prof, Thoracic/Head & Neck Med Onc, UT MD Anderson Cancer Ctr, Houston, TX and offered the following: “The carcinogenic process in epithelial cancers is multistep and requires accumulation of multiple genetic and epigenetic alterations.” “It makes sense that multiple parameters should be considered in using biomarkers for either risk prediction or chemoprevention given the complexity of the cellular process.” Molecular Detection of High-Risk Oral Premalignant Lesions within a Longitudinal Study. Miriam Rosin, Wan L. Lam, Lewei Zhang, British Columbia Cancer Agency, Vancouver, BC, Canada. Improvements in conventional treatment of oral cancer have had little impact on survival over the last 3 decades. At diagnosis, the lesion is often wide-spread with abnormal cells often escaping clinical detection. Up to a third of patients are at risk of developing a second oral malignancy (SOM), which is defined as a recurrence of the tumor or the development of a second primary cancer. Prognosis is better for patients in which the disease is detected early. However, prediction of outcome for the earliest stages of this disease is challenging, relying on histopathological evaluation. Although histology is a good predictor for high-grade lesions [severe dysplasia and carcinoma in situ], it is less effective for assessing the progression risk of oral premalignant lesions (OPLs). In a retrospective study, we have reported that microsatellite analysis can be used to predict progression of oral leukoplakia (1). Loss of heterozygosity (LOH) of specific chromosomal loci can differentiate high risk mild/moderate dysplasias from morphologically indistinguishable non-progressors. These same patterns of allelic loss are predictive of the development of SOMs (2). Here we report preliminary data from an ongoing, NIDCR-funded prospective study in Vancouver. The eight year long Oral Cancer Prediction Longitudinal (OCPL) study will monitor 400 patients with high-risk oral lesions. Two hundred of these patients with cancer are at risk of recurrence, while the remaining 200 with low-grade dysplasia are at risk of progression. The main objective of the study is to validate the use of the aforementioned LOH risk patterns as predictors of malignant transformation. The OCPL study database collects clinical, pathological, demographic, and medical information for each patient, both historically and prospectively. This information will be used to develop a multi-faceted risk model for clinical application. Clinicopathological predictors of recurrence. One of our early objectives was to determine whether clinicopathological indices could assist a clinician in determining when and where to biopsy lesions in cancer patients. Treatment of the primary cancer often induces reactive white and red lesions that are not readily differentiated from (pre)-malignant changes, hence complicating the decision and location to biopsy. The situation is further complicated by the reluctance of clinicians to repeatedly biopsy such fragile sites, impeding the timely diagnosis of high-risk changes. We have collected and analyzed data on the first 107 patients with cancer. Twenty-three of these patients (21.5%) have developed SOM at the treated cancer site within an average of 35 months (we refer to them as the SOM group). Eighty-four patients did not develop SOM over 57.5 months (referred to as the non-SOM group). There was no significant difference between the two groups with respect to demographics, smoking habits and features of the primary oral cancer (TNM staging, grading and treatment). Clinicopathological parameters were evaluated one year after treatment. SOM association with leukoplakia at the former cancer site was found to be significant (81% in SOM vs. 51% in non-SOM; P = 0.02). However, neither clinical appearance (i.e., nonhomogeneous vs. homogeneous) nor histology were predictive of SOM development. Interestingly, a striking difference was observed in toluidine blue (TB) stain uptake by lesions in the SOM group. Fifty percent of leukoplakia in the SOM group were positive for this dye, compared to 17% of non-SOM lesions (P = 0.04), supporting the use of TB for identification of secondary lesions. Furthermore, the use of TB to identify primary high-risk OPLs was observed in a pilot study. Clinicopathological and molecular predictors of OPL progression. We have evaluated data from the first 45 patients with primary OPLs (a total of 66 lesions were examined). Data suggest that patterns of allelic loss may be different between TB-positive and TB-negative lesions. Also, TB staining may identify OPLs that have a greater risk of progression, since TB-positive lesions were more likely to have LOH (85% of TB-positive lesions, compared to 42% of TB-negative lesions; P = 0.0004). In addition, 57.5% of TB-positive cases exhibit a high-risk LOH profile compared to 11.5% of TB-negative cases ( P = 0.0002). 21% of TB-positive cases showed clinical progression compared to 0% of TB-negative lesions (P = 0.02). This positive association between TB staining and molecular risk was independent of clinical appearance of dysplasia. We have also begun to explore the value of fluorescent spectroscopy in managing primary OPLs in patients with no cancer history. We have examined 67 lesions with this approach. Preliminary data suggest an association between loss of autofluorescence and presence and degree of dysplasia (P = 0.01). An association was also observed between loss of autofluorescence and progression of the OPL to invasive cancer (although the latter is not statistically significant; P = 0.07). Exfoliated cells as a noninvasive source of tissue for molecular analysis. We have previously reported that the patterns of allelic loss observed in exfoliated cells, collected by brushing OPLs, closely resemble those observed in biopsies of the same region. We found that this approach can be applied to detect outgrowth of clones of altered cells after therapy and may also be of use in the follow-up of primary dysplasias. We have completed microsatellite analysis of exfoliated cells collected with a cytobrush from the site of previous cancer in 47 treated patients, collection occurring approximately 1 year from the end of treatment. Eleven (24%) of these patients later developed a SOM at the brushing site (mean time from end of treatment to SOM, 22.6 months). In comparison, the non-SOM group has been followed for 34.9 months without outcome (P < 0.0001). Ten microsatellite markers were used to evaluate LOH on 3 chromosome regions: 3p14, 9p21, and 17p13. LOH was significantly more frequent in SOM cases, with 9 of 10 (90%) samples having LOH on at least 1 region compared to 10 of 29 (34%) in non-SOM cases (P = 0.003). Of interest, the same LOH pattern was present in the initial tumor biopsies and in follow-up brushings for 6 of 9 (67%) SOM cases, compared to 3 of 31 (10%) non-SOM, (P = 0.001), supporting the involvement of residual cells at cancer sites with SOM. We have also explored whether exfoliated cells can support fluorescent in situ hybridization (FISH) using loci-specific BAC probes. Preliminary work with cancer patients suggests abnormal cells are detectable in tumor margins (10-15 mm from the cancer) and in some cases also in distant, contralateral, clinically normal mucosa. Genomics within a longitudinal study. The main spin-offs of the OCPL study are the creation of an infrastructure and the collection of material for analyzing new biomarkers. Microsatellite analysis has proven useful for allelotyping of specific loci, however its resolution is limited and therefore only a few of the alterations have been associated with progression. We are using a high density, whole genome bacterial artificial chromosome array, developed in Vancouver, to identify novel genetic alterations in OPLs that might be predictive of progression. With ~32,000 clones on the array providing resolution (80 kb) which is 13 times that of the current technology, the profile of the entire genome can be obtained in a single comparative genomic hybridization experiment. Conclusion. The utility of molecular markers as risk indicators is now widely accepted. One requirement before such markers can be used routinely to manage high-risk patients is their evaluation within prospective studies. Such work will be invaluable to the tailoring of intervention for individuals with OPLs. References. 1. Rosin, M.P., Cheng, X., Poh, C. et al. Clinical Cancer Res., 6, 357-62 (2000). 2. Rosin, M.P., Lam, W.L., Poh, C., et al. Cancer Res., 62: 6447-6450 (2002). 3. Rosin, M.P., Epstein, J.B., Berean, K., et al. Cancer Res., 57, 5258-60 (1997). Symposium 9 “Endogenous DNA Damage as a Target for Chemoprevention” featured a talk “New Biomarkers of Endogenous DNA Damage” presented by James A. Swenberg, Dir Ctr for Envi Health and Susceptibility, UNC, Chapel Hill, NC. From the abstract (excerpts): “DNA damage arises from many sources including chemicals and their metabolites, radiation and numerous metabolic processes including those that generate free radicals. The extent of total endogenous DNA damage in living cells and tissues is still being investigated, but appears to be in the range of several lesions per million nucleotides.” “Our laboratory has been developing several new assays for endogenous DNA damage.” “Several investigators have compared endogenous amounts of DNA damage following dietary interventions and antioxidants.” “In summary, it is critical that we better understand the sources of endogenous DNA damage, how lifestyle, drugs and diet can modulate its formation, what repair processes are involved, and what role endogenous DNA damage plays in mutagenesis and carcinogenesis. Symposium 10 “Vaccines: Strategies to Prevent Cancer” A presentation was given by Mary L. Disis, Assoc Prof, Div Oncol, UWA, Assoc Memb, Fred Hutchinson Cancer Ctr,, Seattle, WA. From the abstract (excerpts): “Cancer vaccines have theoretical appeal as chemopreventive agents. Vaccines have been very successful in the prevention of human infectious disease.” “The potential for the development of effective cancer vaccines has increased over the last few years due to the identification of hundreds of cancer antigens, development of highly quantitative assays for the assessment of the cancer specific immune response after vaccination, and targeting a patient populations with minimal disease burden or identifying those at high risk for the development Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.