Tuesday afternoon sessions included: Symposium 1: Second Primary Cancers; Symposium 2: New Approaches to the Chemoprevention of Breast Cancer; Symposium : Prevention of Genitourinary Cancers; Symposium 4: Natural Products and Their Derivatives for Cancer Prevention; and Symposium 5: The Role of Prophylactic Surgery in Cancer Prevention. Ann attended Symposium 4. moderated by Michael B. Sporn. Mechanism-based Discovery of Cancer Chemopreventive Agents from Natural Products, presented by John M. Pezzuto, Purdue University, West Lafayette, IN. “Cancer chemoprevention is a process by which the phenomenon of carcinogenesis is inhibited by dietary components or pharmaceutical agents.” “Plant extracts are first evaluated with a panel of in vitro bioassays (designed to monitor inhibition of the initiation, promotion or progression stages of carcinogenesis), and active leads are then evaluated in a more complicated and time-consuming assay, which employs carcinogen-treated mouse mammary glands in culture. “ “Following this experimental design, approximately 3,000 plant materials have been evaluated and this resulted in over 15,000 bioassay results. Approximately 100 compounds have been discovered that are active in various in vitro test systems, and many of these are active in preventing the formation of carcinogen-induced preneoplastic lesions in mouse mammary organ culture. Further, thus far we have discovered several lead compounds that mediate considerable cancer chemopreventive activity in full-term tumorigenesis models. These leads are promising candidates for development as chemopreventive agents.” “The effect of delaying tumorigenesis beyond the lifespan of a normal human being is equivalent to curing cancer.” This type of ‘cure’ is available in our lifetime. Dr. Pezzuto mentioned working with the Brassica family (cruciferous vegetables), various flavones, antioxidants and Cox-2 inhibitors. Resveratrol (from non-edible legumes), also found in the skin of grapes and especially in red wine has over 200 papers on its many activities. It inhibits hyperplasia (pre-malignancy) There is also some evidence that tomatillos (used in salsa) have value, as does zapota as an active inhibitor of colon cancer (cell culture), and many other foods. “Mining the World’s Oceans for Medicinals” presented by Chris M. Ireland, University of Utah, Salt Lake City, UT. “…the oceans represent better than 95% of the biosphere. All but 2 of the 28 principal phyla in the animal kingdom are represented in aquatic environments…” “…conservative estimates are that there are over 1 million species represented in the world’s oceans.” Dr. Ireland reported on several substances that his group is looking at including several in Phase I or Phase II, even one in phase III trials. The names of these may not be spelled totally correctly but: Cryptophyein – Phase I trial Ecteinascidin 743 – Phase II Dolastatin 10 – Phase II Bryostatin 1 – Phase III Hemiaserlin – Phase I (not cytotoxic) Stylissa Massa, Leucetta chagosensis and namidine A. These products come mostly from ocean sponges and may inhibit signaling in the EGFR Pathway, causing cell arrest. Symposium 1 from the abstracts: “Pharmacogenetics and second cancers” presented by Mary V. Relling. “The risk of de novo and of second cancers is determined by the interaction of exposures and host susceptibility. The ability of the host to successfully avoid carcinogenesis from exposures in partly dependent upon the germline status of genes involved in elimination and detoxification of carcinogens or in repair responses.” “Because many effective anticancer regimens rely upon irradiation or treatment with genotoxic medications, cancer survivors are exposed to a greater carcinogenic challenge than the general population. Therefore it is plausible that germline polymorphisms may plan an even more prominent role in second cancers than they do in first cancers, as host defense mechanisms are more seriously challenged by chemo and radio-therapy exposures than by routine environmental and dietary exposures." "The timing and interactions among treatment elements, rather than more crude measures such as cumulative dosages, are likely to be important determinants of second cancers." "Molecular therapeutic approaches to lung cancer chemoprevention" presented by Fadlo R. Khuri,UT M.D. Anderson Cancer Center, Houston, TX "Most approaches focusing on lung cancer chemoprevention have used retinoidss, synthetic or natural vitamin A analogs, for the last two decades. The results so far are mixed at best." "In collaboration with other SPORE (Specialized Programs in Research Excellence) investigators, we have developed phase IIb trials utilizing two novel molecular, targeted agents, which have shown promise in the treatment of advanced disease in an attempt to reverse the premalignant lesions of the airways. These trials will be launched in patients who have previously been treated for smoking related cancers, but are at least one to three years out from last treatment of disease, and have at least a 30 pack-year smoking history, and finally, evidence of sputum atypia. (drugs are Zarnestra, a farnesyl transferase inhibitor or Iressa, a tyrosine kinase inhibitor and a placebo)." Symposium 3 had no abstracts in the handout. Symposium 5 from the abstract: "Prophylactic mastectomy to reduce breast cancer risk", presented by Lynn C. Hartman, Mayo Clinic, Rochester, MN. "One of the options for risk reduction in women at high risk for breast cancer is prophylactic mastectomy (PM). It is indeed a difficult paradox that in an era of increasing breast conservation for cancer, we still consider mastectomy for prevention. But one needs to consider the situation of high-risk women specifically. In many of these women, each cell possesses a germline alteration conveying a high likelihood of neoplastic transformation. Thus, interventions need to address all the tissues at risk. In this presentation w will examine questions of efficacy, psychosocial impact following PM and the commonality with which the procedure is used." Ann's NOTE: I am reminded of my aunt (by marriage) having bilateral prophylactic mastectomies for atypical hyperplasia (her mother died of breast cancer), at almost the same time I was diagnosed with Stage 1 invasive lobular carcinoma, and received a lumpectomy. My aunt was confused and did not make a fully informed choice, and has had several reconstructive surgery issues, but overall, is happy with her decision. At a recent meeting here in NYC, "Emerging Trends in Adjuvant Therapy of Breast Cancer", the doctors discussed PM as having different appeal to women whose mothers died of breast cancer. Indeed, these women were more likely to be offered PM as an option. I seem to recall though, that the gene alteration simply makes it more likely a woman will be diagnosed, NOT that she will die of the disease, nor 'get' the same type of breast cancer as her mother. I also think that 'high-risk' women ought to meet as groups and discuss their options and issues. "Prophylactic colectomy in colorectal cancer", presented by Patrick M. Lynch, UT M.D. Anderson Cancer Center, Houston, TX. "Because of the well-characterized colorectal adenoma to carcinom progression, population screening measures have been directed toward early detectin and removal of adenomas, thereby potentially preventing invasive cancers." "Given sufficiently high risk of cancer and the limitations in early detection/prevention strategies otherwise, prophylactic colectomy has come to be considered the treatment of choice for Familial Adenomatous Polyposis (FAP), chronic ulcerative colitis (CUC), and, to a much lesser extent, Hereditary Nonpolyposis Colorectal Cancer (HNPCC). In FAP, prophylactic colectomy is offered at or within several years of diagnosis of multiple adenomas. Ideally a patient's APC gene mutation carrier status will have been determined Risk-reducing surgery in the management of women at increased genetic risk of ovarian, fallopian tube, and endometrial cancer, presented by Mark H. Greene, Division of Cancer Epidemiology and Genetics, NCI, Rockville, MD. "...risks and benefits of the following surgical management strategies: Ovarian cancer: tubal ligation; risk-reducing oophorectomy; Fallopian tube cancer" risk-reducing salpingectomy; and Endometrial cancer: risk-reducing hysterectomy. "A series of observations over the past several years has provided a substantial body of evidence to suggest that the fallopian tube is one of the target organs for BRCA 1/2-related carcinogenesis. Thus it is clear that the risk-reducing surgical procedure applied to women who carry germline mutations in BRCA 1/2 must include the complete excision of the fallopian tubes in addition to the ovaries." "It has recently been suggested that the risk of endometrial cancer is particularly high among families in which germline mutations in MSH6 are the basis for HNPCC (see last abstract for definition) susceptibility. The available data do suggest that endometrial cancer is a relatively uncommon cause of death within HNPCC families." "Finally it is worth noting that a nationwide, prospective study of the natural history of the post-risk-reducing salpino-oophorectomy has recently been opened to patient accrual through a tri-partite collaboration between NCI' Clinical Genetics Branch, the Gynecological Oncology Group and the Cancer Genetics Network." (GOG0199) Prophylactic surgery and the multiple endocrine neoplasia syndromes, presented by Samuel A. Wells, Jr., Duke University School of Medicine, Durham, NC. "The Multiple Endocrine Neoplasia (MEN) Syndromes are inherited as auotsominal dominant traits and characterized by the manifestation of multicentric tumors in several endocrine organs. MEN 1 is characterized by the development of hyperparathyroidism, pituitary tumors and pancreatic tumors. Less commonly, adenomas of the thyroid and adrenal cortex occur." "The MEN 2a and 2b are characterized by the presence of calcitonin (CT) secreting medullary thyroid carcinoma (MTC) and pheochromocytomas. Virtually all patients with the MEN type 2 syndromes develop MTC, the most common cause of death in patients with these syndromes. The ret gene on chromosome 10 is mutated in patients with type 2 MEN syndromes." Sixty patients who received thyroidectomies have been followed for over five years. None of the patients whose postoperative CT level was elevated has developed clinical evidence of metastatic disease. From the NCI website, 6/03 Remember we are NOT Doctors and have NO medical training. 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