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  • Confronted With Cancer

    How to Cope With Cancer

    Edwin M. Knights Jr., M.D.

    Is there cancer in your family’s medical pedigree? And if so, how are you going to find it? From death certificates? Obituaries? Perhaps they will help, but death certificates were established as public health documents, not for the enlightenment of genealogists, so don’t get your hopes too high! It may take some real detective work, but it’s certainly worth the try. So let’s get out your family pedigree chart and see how we succeed. Let’s begin with the most recent generations.

    We know that cancer is a problem today in all the developed countries around the world. Thanks to the National Health Institute (NIH) and the American Cancer Society (ACS) we can study the statistics, see the trends, and decide where to focus our efforts. If you know of any cancers in the youngest generation, enter them now. If there was a cancer death, be sure to record the date, of course, but also keep a record of any “incidental” cancer cases -- those which might have contributed to death or just be an incidental finding. As one out of every four deaths in the United States is from cancer, the odds are pretty strong that it won’t be long before you’ve noted some cases. If you do, be sure to note the estimated date of ONSET, or at least when it was first suspected or diagnosed.

    Your best source of information will probably be from any living relatives. It’s a good idea to make a checklist, at least of the most common malignant diseases, or how they might present, such as a lump in the breast, rectal bleeding, a productive cough or perhaps urinary tract problems. And don’t forget skin lesions, which are often obvious but might be overlooked, and any disease which might have necessitated numerous blood transfusions. The list may refresh someone’s memory about a relative’s symptoms. Be sure to inquire whether the relative smoked or drank and, of course, their geographical locations and their occupations.

    What should you look for? In males, 55% of invasive cancer cases are of the prostate, lungs, and the colo-rectal areas. Prostate cancer accounts for 30% of new cancer cases in men. The three most common cancers in women are breast, lung, and colorectal cancer. These figures, however, do not include some other extremely common tumors: carcinoma in situ (non-invasive cancer) of the uterine cervix and over a million basal and squamous cell carcinomas of the skin. It’s also important to remember that a family history of breast or ovarian cancer is just as important on the paternal as on the maternal side.

    Lung cancer has been the leading cause of cancer deaths in women since 1987, when it surpassed breast cancer. If you are a male, your lifetime probability of developing cancer is 43 percent. In men under age 40, leukemia is the most common fatal cancer; in older males it is cancer of the lung and bronchus, followed by colorectal cancer.

    It may surprise you to learn that in children, cancer is the second leading cause of death between ages 1-14 in the U.S., with accidents causing the most fatalities. The diseases affecting children are much different than those in adults; lymphocytic and other leukemias are the most common, followed by tumors of the nervous system, lymphomas, soft-tissue lesions and tumors of the kidneys.

    Cancer in a Changing World
    The figures you read about adult cancer can be very misleading, however, because cancer statistics change with each generation, reflecting longevity, occupations, life styles, local environments, and even susceptibility to other illness. Let’s start with longevity. We take it for granted that most persons will live to age 70 or above today, with females having a little edge over the males. But let’s look back a bit and see how long your ancestors could have expected to live: (Ref. Table 1)



    Table 1.

    Years of Life Expectancy, U.S.A.

    Year
    All Races
    White
    Black
      Male Female Male Female Male Female
    1850     38.3 40.5    
    1900 46.3 48.3 46.6 48.7 32.5 33.5
    1950 65.6 71.1 66.5 72.7 59.1 62.9

    *

    The 1850 figures are for Massachusetts only. 99% of the measured population was white and the remaining 1% includes all other races.


    Pretty remarkable, isn’t it?. Back in 1900, most people weren’t living long enough to develop most of the cancers. And that’s still the case in many of the undeveloped nations. When Project HOPE visited Indonesia in 1961, about the only cancers were oral cancer from chewing betel nuts and choriocarcinoma, which a very rare uterine tumor. Twenty-five years later, people were still dying of malaria but cancer was beginning to appear, because their average life span had lengthened. The same thing happened earlier in the United States. Nutrition and public health improved and the longevity increased remarkably, except around 1918, when the deadly epidemic of influenza took its toll.

    Cancer arrived hand-in-hand with the industrial revolution. Although we are interested in the genetic aspects, we should never underestimate the influence of environment. Cancers have inscribed their own documentation of human history. (Ref. Table 2)


    Table 2.

    Occupational, Recreational, and Nutritional Diseases

    Occupation Disease Predisposition
    Chimney sweeps Scrotal cancer
    Uranium mine workers Lung cancer from radioactive dust
    Tailors analine Bladder cancer from analine dyes
    Leather tanners Testicular cancer
    Watch makers Cancer from licking the radioactive brushes used to paint radium on luminous dials
    Clay pipe smokers Lip cancer
    Sailors and farmers Skin cancers from over-exposure to the sun, cataracts
    Diet of salted and smoked food Gastric cancer
    Chewing betel nuts Oral cancer
    Mustard gas Lung cancer and DNA damage
    Nickel miners and smelters Carcinoma of the larynx
    Dry cleaners Perchloroethylene lung cancer
    Asbestos workers who smoked Bronchial cancer and mesotheliomas
    Vinyl chloride workers Liver cancer
    Marine electricians Asbestos-related lung cancer



    All you had to do was smoke while you were working to increase your chances of dying from lung cancer -- or bladder cancer. This is by no means a complete list of carcinogens, but perhaps it suggests there is genetic influence, as well.

    So far, it appears that creating a medical genogram for cancer isn’t likely to be too productive except for looking at the last couple of generations, when cancer became more popular. We aren’t likely to discover many inheritance patterns for malignant diseases by climbing up our family tree. But there’s an important way a pedigree study can be of significant value to current and future generations of your family. If you have not already done so, you can verify your ethnicity. “Oh, I know my ethnic background,” you insist.

    Perhaps you do, because folks weren’t too mobile back when to travel you either had to walk or ride a horse or mule. Early New Englanders tended to marry whomever they encountered in the next haystack But if you start counting, it may make you wonder a bit. Four grandparents, but eight great-grandparents, and then your forebears really begin to multiply: 16, 32, 64, 128, 256.... probability of a multi-ethnic pedigree is high. Are you sure they’re all accounted for?


    Importance of Ethnicity to Cancer Genetics
    When we examine various types of cancer in the United States, predispostion based upon ethnicity various considerably from one disease to another, but unfortunately for African Americans, they have the highest incidence and mortality rates for cancer. Theincidence rate is fully 60% higher than in Hispanics and Asian/Pacific Islanders and double that for American Indians. The overall cancer mortality rate for African Americans is 33% higher than in Asian/Pacific Islanders, American Indians and Hispanics. But there are exceptions, as breast and lung cancer death rates are higher in whites than in African Americans. And certain cancers are more common in Ashkenazi Jews.

    These figures and those for other cancers need very careful interpretation, of course, because there are numerous non-genetic factors which contribute greatly to the discrepancies. Major considerations include poverty, unavailability of health care for both screening and treatment, language barriers, occupatins, diet and many more.

    Cancer Management
    Because cancer management, which involves prevention, screening and treatment, requires such a large proportion of the effort and funding spent on health care in the industrialized world, our knowledge of cancer genetics has grown rapidly. All this research has begun to educate us about mutations predisposing us to cancer, the various types of heritability, preventive strategies, the importance of early diagnosis and the use of the most appropriate therapy. Most of our knowledge is linked to specific tumors and does not necessary apply to other types of cancer. Much of the published work relates to the “common” cancers which attract the most funding for research.

    Genetic Predisposition to Cancer
    Summaries of our progress in understanding the genetic basis of cancer have been published by Hyon Ju Kim and by M. Tevfik Dorak. Both refer to the “two hit” concept of Dr. Albert Knudson, in which a dominantly inherited susceptibility to cancer consists of the first hit, which is a germ line mutation, but requires a second hit to somatic cells. According to this hypothesis, sporadic cancer also requires two hits, but both would be to somatic cells, so that a person carrying hereditary germ line mutations would only require one more hit and thus be at risk to develop a specific type of cancer.

    In most cancers, the mode of inheritance is complex, and cancer has been described as being a multigenic, multifactorial, and multistep phenomenon. To this I would add one more description, multiconfusion. Multigenic refers to the variety of genes involved -- oncogenes, tumor suppressor genes and MHC genes. Multifactorial describes various factors that are involved with cancer development; these include chemicals, hormones, viruses, diet, radiation, etc. The multisteps in development of a cancer would be transformation and promotion leading to overt cancer. Multiconfusion is, of course, one of the end results.

    Many tumors just appear in a sporadic fashion, with no apparent inherited genetic abnormalities. In about 5-10% of cancers there are mutations involving the germ line and the cancer is familial in nature.

    Long before the Human Genome Project, physicians knew that our immune system had an important influence on our susceptibility to cancer. When there are immune deficiencies, there is increased cancer risk, especially for lymphoid tumors. They had also identified tumor-specific T-lymphocytes which could kill cells, or were cytotoxic (CTL), and tumor-infiltrating lymphocytes (TIL). When tumor suppressor genes (MHC genes) become impaired, or there is “loss of MHC expression,” cancer can develop. Scientists had proposed the immune surveillance theory, in which malignant changes can take place in normal cells but the immune system removes these cells from the system.

    Dominant Genetic Imbalances in Cancer
    Cancers occur when cell division goes wild. The controls that usually control cell reproduction, such as growth factors, cell surface receptors, enzymes, proteins, signaling molecules, growth inhibiting factors, and others, no longer function in an orderly manner. There are over 50 genes in the human genome, proto-oncogenes, which are very similar to cancer-producing retroviruses, or viral oncogenes. And they are inherited in a dominant manner. What makes these proto-oncogenes go bezerk and act like oncogenes?

    A number of events can cause trigger this behavior and turn them into what we might call psychogenes. The mechanisms are all complex, but just listing them shows the diversity of the causes of cancer. (Table 3)


    Table 3

    Diverse Cellular Mechanisms Causing Cancer
    1. Amplification -- takes place in breast cancer, neuroblastomas
    2. Insertional mutagenesis -- as caused by a virus in Burkitt’s lymphoma.
    3. Chromosomal translocations -- genes moving around on their chromosomes
    4. Mutations in genetic codings -- changes genetic activity, described as missense, nonsense or frameshift types.
    5. Demethylation or hypomethylation -- occurs in chronic lymphoid leukemia.
    6. Cyclins, genes involved in the control of cell cycling, can become oncogenes when they have mutated
    7. Loss or inactivation of tumor suppressors

    Tumor Suppressor Genes
    These are genes, inherited in a recessive manner, which usually act like anti-oncogenes. As they are paired, you would expect that both copies of tumor suppressor genes (TSGs) would have to be non-functional for oncogensis to occur. Unfortunately, it doesn’t work that way. It’s more like Animal Farm, where “all pigs are equal but some are more equal than others.” The mutated anti-oncogenes are so strong they overwhelm the normal allele and result in serious diseases.

    Just having a bad gene does not always insure the development of recognizable disease. Environmental factors may be needed to promote the appearance of symptoms. Geneticists also refer to another feature which is known as penetrance. This is defined as the proportion of persons having a specific genetic alteration who actually exhibit the associated trait. High penetrance occurs in polyposis-associated colon cancer (nearly 100%) but lower penetrance in breast cancer developing in women having the BRCA1 mutation, where it it occurs in about 60% of women by age 60.

    Gatekeepers and Caretakers
    In recent years the genetic instigation and control of cancer has been attributed to gatekeeper and caretaker genes, a concept which has broad clinical and therapeutic implicaations. At first, most cancer susceptibility genes were thought to be tumor suppressor genes which directly controlled cell proliferation. Later it was found that other genes indirectly predispose a person to cancer.

    Gatekeeper genes are those which directly regulate tumor cell growth or death. Caretaker genes promote tumors indirectly by causing aberrations in gatekeeper and other genes. Of course the mechanisms are quite complicated, but it is important to identify just which genes are involved in order to understand the cause, prognosis and eventually the selection of treatment in a specific case. Genetic identification of a person with a risk of cancer or perhaps early onset of cancer is aimed at improving the quality of life. It’s not just in selection of therapy, but enabling the patient to make better choices concerning family planning, retirement or possible hospitalization. The risk assessment includes family history, environmental factors, psychological effects, possible hospitalization and economic concerns as well as the genetic testing, and genetic counseling is definitely indicated.

    How Valid is the Testing?
    All of the evidence being used to make the diagnosis of cancer should be evaluated in several ways. This applies, of course, to every laboratory procedure, even if genetic testing is not performed or perhaps, under the circumstances, not even considered.No test is perfect and errors do occur; some positive or suspicious results with “screening” procedures need to be followed up with other, more specific approaches. The National Cancer Institute recommends that genetic tests be evaluated for analytic validity, clinical validity, and clinicl utility.

    Analytic validity refers to the technical accuracy and reliablity of a test, which would include the methodology, lab techniques and how specimens were obtained and handled. Some methods are more sensitive than others but sometimes they are more prone to error, e.g., they are not so specific. In genetic testing, it may be necessary to find a particular set of mutations by means of sequencing tests in which the sensitivity and specificity depends upon methodology, the proportion of the gene tested and the nature of the aberrations present in the gene.

    The clinical validity tells you how valuable the test will be for predicting the outcome in the patient. What is the likelihood that cancer will develop if a test were “positive”? This may involve weighing the test results along with the influence of environment or personal behavior. And as we have seen, even ethnicity may play a role, along with linkage studies and the presence or absence of a family history of the disease.

    Finally, the clinical utility is the consideration of just how much can be accomplished to modify the cancer or cure the patient based upon the results of testing. Depending upon when testing was done, the strategies include screening to detect early or precancerous lesions, surgical or other intervention to reduce the risk, or measures just to improve the quality of life.

    New Hope from New Uses
    Other important uses of genetic testing that are just evolving but offer new hope. As well as being of predictive value, the data obtained is used to select therapy, possibly aiming the treatment towards the specific genetic aberration rather than the broad “shot-gun” approach that was previously required, making it more efficient and far less stressful to the patient. Or in some cases it will make it possible to to select best choice from the available types of treatment.

    Tumor angiogenesis is also of prime interest, because cancers depend on the development of a blood supply for growth, invasion and metastasis throughout the body. Scientists are seeking ways to prevent tumors from growing by inhibiting their ability to stimulate vascularization of surrounding tissues.

    Microarray analysis is now being used to study tumors and predict how they will behave. Recognizable patterns, known as gene expression profiles, have been found to correlate with a number of primary or metastatic tumors, including those arising in the breast, colon, lung, ovary, prostate and metastatic prostatic tissue. Marker genes may prove useful both for prognosis and treatment purposes.

    GENETIC COUNSELING
    We’ve referred so much to the importance of genetic counseling, perhaps we should provide you with its definition, as published by the American Society of Human Genetics:

    “A communication process which deals with the human problems associated with the occurrence or risk of occurrence of a genetic disorder in a family. The process involves an attempt by one or more appropriately trained persons to help the individual or family to: 1) comprehend the medical facts, including the diagnosis, probable course of the disorder, and the available management; 2) appreciate the way that heredity contributes to the disorder and to the risk of recurrence in specific relatives; 3) understand the alternatives for dealing with the risk of recurrence; 4) choose a course of action which seems to them appropriate in view of their risk, their family goals, and their ethical and religious standards and act in accordance with that decision; and 5) make the best possible adjustment to the disorder in an affected family member.”

    IF YOU FIND YOU ARE AT RISK
    If you feel you might have inherited genes putting you at risk for cancer, you should first consult your physician and/or a genetic counselor.

    If a living close relative has a known type of cancer, he or she should have genetic counseling so the genetic pattern can be recorded for the benefit of other family members and future generations. Also, it would be advisable to bank some DNA from this person for future studies when needed. But even if a relative doesn’t have one of the high-risk genetic variants, if there is a strong family history of cancer, the risk is still statistically high in close relatives and careful surveillance is important. It is almost certain that all the genes associated with any cancer have not yet been found.

    Of course, we have only provided an introduction to cancer genetics. This is because the literature is voluminous and ever-changing, with valuable new information arriving all of the time. The following malignant diseases have received the lion’s share of the research efforts: bladder, breast, cervix, colorectal, endometrial, esophageal, kidney, liver, lung & bronchus, lymphomas, melanoma, ovarian, pancreatic, prostate and stomach. We have include pertinent references on these subjects. Web sites exist for all of these, and because of the massive amount of research, they require continual updating. The reader will undoubtedly find that time and effort spent researching family medical history will be most productive by revealing cancer risks and probabilities for the entire family and enabling the planning of appropriate strategies.



    BLADDER CANCER
    Cancer of the urinary bladder is most common in industrialized countries; rates in Asia and South America are only 30 percent of those in the United States. Mortality rates are 2-3 times higher in men than in women. There is a definite risk to people working with chemicals known as arylamines, and cigarette smoking increase the risk for bladder cancer by 2-5 times. The disease primarily affects older individuals. The highest rates are in white male and female non-Hispanics, but no specific genetic links have been reported to date.

    BREAST CANCER
    Breast cancer is far more prevalent in females, and for this reason, most of the scientific literature and research is based upon diagnosing and treating women. But it also can occur in males, often with aggressive behavior and very serious consequences. Also, it would be more correct to speak of breast “cancers” in women, because there are different varieties and their clinical courses can very dissimilar. Breast cancers are second only to non-melanoma skin cancers in women, with an estimated 211,240 new cases predicted for 2005.

    They will also cause 40,410 female deaths and 470 male deaths in the US (Amer. Cancer Soc.). A woman’s risk of developing breast cancer conferred by a first-degree relative is 2.1. The younger the relative was when diagnosed, the higher the risk to her first degree relative, especially if it occurred before age 50. The number of affected relatives and the closeness of biological family relationship are also significant in determining the risk. Linkage analysis studies of families have proved there is an autosomal dominant type of breast cancer that occurs in 5-10 percent of cases. Some highly penetrant genes are present in cancer-prone families.

    NON-GENETIC FACTORS
    As is true with many cancers, the breast lesions result from a combination of genetic and so-called “environmental” factors, and in this case, some of the environmental factors play very significant roles. At particular risk are women with a history of pre-menopausal breast cancer in the mother or a sister, a previous personal history of breast cancer or benign poliferative breast disease. Very likely under genetic influence are the high risks for cancer present in women having an early onset of menstruation (especially if before age 12) or those experiencing a late menopause (age 55 or older). Prolonged use of birth control pills and failure to deliver a baby by age 30 seem to be related, and post-menopausal use of estrogens may increase risk slightly. Other possible related causes, still being studied, are obesity and high alcohol consumption.

    GENETIC FINDINGS
    Much of the research on breast cancer has focused on mutations either in the BRCA1 or BRCA2 genes. The BRCA1 gene is on chromosome 17, the BRCA2 gene on chromosome 13. There are a couple of hundred variant alleles for BRCA2, and twice as many for BRCA1, but only some of them are related to breast cancer. Inheritance of any of these cancer-susceptiblity genes confers a lifetime risk of breast cancer of 50 to 85 percent, plus a significant risk of ovarian cancer.

    Although the BRCA1 and BRCA2 mutations contribute to but a small percentage of all the cases of breast cancer, about 10 percent of breast cancer in women under age 40 and 75 percent of familial cases occur in women carrying these mutations. For this reason, some women having these genes have undergone bilateral prophylactic mastectomies. This difficult decision is controversial, because of the personal effects of the surgery, the fact that all carriers do not develop breast cancer and that it is possible to treat breast cancer successfully if detected early. It appears that a better argument has been made for prophylactic bilateral salpingo-oophorectomy in these patients (see discussion of ovarian cancer).

    High-risk variants are more common in certain populations. They are found in 2.5 percent of Ashkenazi Jews and cause over a quarter of the breast cancers before age 40 in that ethnic group. In the general population, though, these high-risk variants areuncommon, being found in less than 0.5 percent and being associated with 5 to 10 percent of all breast cancer. The ATM gene on chromosome 11 is also under suspicion and being studied.

    The characteristics of the breast cancer differ in these two types of mutations. In the BRCA1 cases, the tumors are “high grade” with many mitoses (indicating active cell division). The tumors have smooth margins and are infiltrated with lymphoytes. BRCA2 tumors can also be “high grade,” and don’t tend to form tubules. There are also special stains and tests that help distinguish the two, but now it is also possible to use high-density microarray technology.

    Dr. N. Rahmen, at the Institute of Cancer Research in Surrey, United Kingdom, recently reported that the checkpoint kinase gene, CHEK2, is also associated with a high risk of breast cancer in both females and males. This gene acts in the same pathways as BRCA1 and BRCA2. Also, a new methodology has been used to detect the BRCA1 and BRCA2 mutations. It is allele-specific gene expression (AGE) analysis and it uses decay in the cells’ own RNA surveillance mechanism to pick out carriers of these mutations.

    USING GENES FOR PROGNOSIS
    Of particular interest are studies being done to recognize the degree of risk presented by a breast tumor so that the most appropriate treatment can be used to control the disease. Traditional methods have been the uses of “frozen sections” of a tumor during surgery so that the pathologist can grade the tumor, and similar microscopic examinations of slides containing sections of suspicious regional lymph nodes. These provide valuable information to the surgeon which helps in making decisions about the extent of surgery necessary. The preserved tissues are later evaluated much more thoroughly in a systematic manner before deciding upon the need for chemotherapy or hormonal therapy. These adjuvant treatment methods reduce the risk of distant metastases by about one-third, but a high percentage of patients receiving this treatment would have survived without it.

    Investigators in The Netherlands used DNA microarray analysis on breast tumors of 117 young patients and state they have come up with a gene expression profile that can be used to predict the behavior of the cancer.

    The investigators used genes regulating cell duplication, invasion, metastasis and small blood vessel formation to indentify patients with poor prognosis and who would benefit most from the adjuvant treatment with hormonal or chemotherapy. Finnish researchers have also reported finding another means of identifying breast tumors having poor prognosis -- they found elevated cyclooxygenase-2 (Cox-2) increases associated with poor survival. So far we could find no reported break-throughs which might lead to gene-specific tailored methods of therapy, but keep looking, because it isn’t because nobody’s looking for one!

    Because so many of breast cancer patients develop tumor resistance to current treatments, scientists are searching for new gene-targeted therapies that are both tumor-specific and well tolerated by the patient. Herceptin is one of the new agents which can be combined with other methods and seems particularly effective in patients with human epidermal-growth-factor receptor (HER2) gene amplification or high overexpression of HER2. Pathologists can detect HER2 protein in samples of breast tissue so that Herceptin can be used in appropriate cases. Other similar agents will eventually improve survival rates and the quality of life of cancer patients.

    FINDING IF YOU ARE AT RISK
    If you have worries about having inherited genes that might put you at risk for cancer, you should first consult your physician and/or a genetic counselor. If someone in the family has breast cancer, she should have genetic testing so that her genetic pattern is recorded. Also, it would be advisable to bank some DNA for future studies when needed. But even if a relative doesn’t have one or more of the high-risk variants of the BRCA1 or BRCA2 genes, if there is a strong family history of cancer, the risk is still statistically high in close relatives and careful surveillance is important. It is very probable that all of the genes associated with breast cancer have not yet been found.

    CERVICAL CANCER
    Thanks to Dr.George Papanicolaou, most cancers of the uterine cervix are now discovered in a very early stage in the United States, before they have become invasive. Risk factors for cervical cancer include early sexual activity, multiple sexual partners,cigarette smoking and infection with human papilloma virus 16.

    There are strong ethnic patterns which suggest a genetic susceptibility, but more research is needed in this area. The highest incidence is in Vietnamese women (43/100,000), and the lowest in Japanese women (5.8/100,000).

    Incidence rates exceeding 15/100,000 are found in Alaska Native, Korean and Hispanic women in the United States.

    COLORECTAL CANCER
    colon and the rectum, which comprise the lower portion of the gastrointestinal tract, are host to a variety of tumors which add up to the fourth most common cancers and are second in causing cancer deaths in the United States. There are marked ethnic differences in susceptibility. The highest ethnic rates in males in the U.S. are in the Alaskan Native population, followed in decreasing order by Japanese, African-Americans and whites, Chinese, Hawaiians and Hispanics, Filipinos, Koreans and Vietnamese. In females colo-rectal cancer is also most common in Alaskan Natives, followed by African-Americans, Japanese, whites, Chinese, Hawaiians, Vietnamese, Hispanics, Koreans and Filipinos. In each ethnic group the incidence rates for men is higher than that for women, but the ratio is highest among Japanese and Filipinos. Colon cancer is generally more common than rectal cancer in all of the ethnic groups, with about 95,000 cases of colon cancer diagnosed annually in comparison with 35,000 cases of rectal cancer. Colorectal cancer begins to appear after age 40 and peaks between ages 60 and 75, causing about 55,000 deaths each year. There are even statistics showing the incidence of colon cancer by ZIP code in parts of New York State. (www.health.state.ny.us/nysdoh)

    ENVIRONMENTAL EFFECTS
    Environmental effects are very important in the development of colo-rectal cancer and they no doubt are reflected to a great extent in the variable ethnicity. Diets high in animal fat and sugar have been implicated, plus a sedentary life style, alcoholic intake and the use of tobacco. For a long time it was believed that high-fiber diets protected against the development of colonic cancer, but this has been questioned. There is evidence that diets high in calcium vitamin D plus leafy vegetables such as Brussel sprouts, broccoli, cabbage and turnip greens reduce the risk of colonic cancer. Three inflammatory diseases predispose to the develop of cancer -- ulcerative colitis, Crohn’s disease and chronic diverticulitis of the colon.

    MULTIPLE POLYPOSIS OF COLON
    A hereditary condition which almost invariably leads to colo-rectal cancer by age 40 is familial adenomatosis polyposis, which also goes under the names of adenomatous polyposis of the colon, multiple polyposis coli, or familial multiple polyposis. And if that doesn’t make it confusing enough, there are at least nine disorder subdivisions, including Gardner syndrome and Turcot syndrome. The APC gene, located on chromosome 5, is atypical in these neoplasms. Familial adenomatous polyposis is inherited as an autosomal dominant trait.

    GENES CONTRIBUTING TO SUSCEPTIBILITY
    FAP genes Mutations in these genes result in the FAP syndrome, in which hundreds or even thousands of polyps develop in the mucosal linings of the colon and rectum. Each one has the potential of becoming malignant, and by age 40, cancer develops in nearly every case. This process is associated with the previously mentioned APC gene.

    HNPCC genes Four of the HNPCC genes cause the HNPCC syndrome, which occurs in various forms and can include cancers in the breast, ovaries, small bowel, stomach and uterus. They are hMSH2 on chromosome 2, hMLH1 on chromosome 3, hPMS1 on chromosome 2 and hPMS2 on chromosome 7. Persons with HNPCC often develop colon cancer before age 50 and may have a family history of colorectal cancer.

    Other genes Ninety percent of colorectal cancer is caused by other genes, some of which have combined effects but which are weaker than those of the FAP and HNPCC genes. Some of these genes are involved with the inflammatory bowel diseases which can later be associated with cancer. There are ethnic predispositions for these diseases, as they are most common among whites and especially persons with Ashkenazi Jewish heritage. In 1997, researchers at Johns Hopkins reported the APCI1307K mutation on the same gene that carries FAP; this mutation is not a direct cause of colon cancer but makes the gene susceptible to other changes which do cause the cancer. According to their findings, the types of colorectal cancer in Ashkenazi Jews occur as follows:


    Table 4

    Colorectal Cancer in Ashkenazi Jews


    Cancer Types Percentages
    Sporadic (not hereditary) 50-85%
    Familial 10-30%
    APCI1307K 10%
    Hereditary Non-Polyposis Colorectal Cancer 4-5%
    Familial Adenomatous Polyposis >1%



    DEALING WITH COLORECTAL CANCER
    The American Cancer Society and the American Gastroenterological Association have made recommendations for colon cancer screening. These are only guidelines and you should consult your physician about what screening program is most suitable for you.(Ref. Table 5)


    Table 5

    Colorectal Cancer Screening Programs



    Persons 50 years or older; no known risks factor for colorectal cancer

    Fecal occult blood screening every year

    AND

    Flexible sigmoidoscopy every 5 years

    OR

    Double contrast barium enema every 5-10 years

    or

    Colonoscopy every 10 years

    Persons with Close Relatives who have had Colorectal Cancer or Polyps

    Same as above but starting by age 40

    Persons with History of Adenomatous Polyps

    Colonoscopy 3 years after removal of a polyp, unless shorter interval is recommended. The interval would be based upon the type, size and number of polyps found. (Note: For a benign polyp to become malignant usually takes 10 years.)

    Persons with History of Colorectal Cancer

    Colonic surgery for colorectal cancer should have a colonoscopy within 1 year after surgery. If this is normal, is should be repeated again in 3 years; if normal, repeat every 5 years thereafter.

    Comments: The annual occult blood screening test, in which 3 stool samples are submitted, is the most cost-efficient method of screening. Colonoscopy is by far the best of the above methods for finding colorectal polyps or early cancer. Sigmoidoscopy can only examine the distal, or lower portion of the colon, and cannot locate polyps or other lesions farther up in the colon. Colonoscopy has been found statistically better than barium enemas for finding colonic cancer. Because sigmoidoscopy can be done without general anesthesia, it is much more readily available and far less expensive, making it the choice of most insurance programs. These options should be discussed with your own physician.

    TREATMENT AND SURVIVAL: GENETIC AIDS
    The primary treatment of colorectal cancer is surgical, depending upon the site, the degree of local invasion and the spread to regional lymph nodes or other parts of the body. These factors are expressed in stages, e.g., Duke’s stage A, B or C. Adjuvant chemotherapy improves survival among patients with Duke’s Stage C (also known as stage III) and is sometimes considered for patients with Duke’s Stage B (or stage II). Investigators at a number of medical schools have now identified genetic and molecular alterations which can be used to predict survival after chemotherapy. This information should aid in the development and use of more effective means of supplementing the surgical procedures.

    ENDOMETRIAL CANCER
    The ethnic occurrence of endometrial cancer in the U.S. has a pattern similar to that of breast cancer, with the highest age-adjusted incidence in Hawaiians, Whites, Japanese and Afican Americans. Lowest rates are in Korean, Vietnamese and American Indian women. Obesity is a risk factor. The postmenopausal use of exogenous estrogens is also a risk factor, but the risk is considerably reduced when they are taken with progesterone.

    ESOPHAGEAL CANCER
    Cancer of the esophagus is more common in Asia, Africa and Latin American than in the United States. It is primarily a disease of men, and it occurs in different forms. Most cancers of the esophagus were once of the squamous cell variety (similar to the cells of your skin). Recently there has been an increase of a glandular cell type, called adenocarcinomas, especially involving Caucasian males. The squamous type has its highest incidence in African Americans (15/100,000) and the lowest rate in Filipinos (2.9/100,000). Rates are also low in Chinese and Japanese men.

    Environmental factors include smoking tobacco and heavy alcohol consumption, plus possible nutritional deficiencies in developing countries. There is no convincing evidence of genetic predisposition.

    KIDNEY CANCER
    Kidneys are complex organs and have the capability of developing various types of benign and malignant tumors. Children can develop a Wilm’s tumor, also known as nephroblastoma, embryoma or adenomyosarcoma. It is a mixture of stromal cells, spindle cells and epithelial cells. The most common pediatric tumor of kidneys, it makes up 5-6 percent of pediatric cancer in the U.S., affecting 8.1 million white children. It can be unilateral or bilateral.

    Wilm’s tumor can be accompanied by a number of other inherited syndromes. It is sometimes linked to paternal exposure to lead or hydrocarbons. However, its genetic basis is well documented. The WT-1 gene involves chromosome 11p1310 exons, 4mRNA’s and 1 protein, apparently a classic tumor suppressor. The genes targeted are unknown, but the predisposition is inherited as a dominant negative oncogene. Other Wilm’s genes include WT-2 gene and Familial WT. About 85 percent of cases can be cured, although this is a high incidence of secondary tumors in irradiated areas.

    Adult renal cancer includes that from renal cells in the body of the kidney and from the lining cells of the renal pelvis, which funnels the urine into the bladder via the ureter. Men are affected about twice as often as women. The highest rates are in American Indian men in New Mexico. Rates in Afican Americans, Hispanics and Caucasians range from 10-13/100,000 for men and about 6,100,000 in women. Lowest rates are found in Asian populations. The only established risk is from cigarette smoking.

    A research team found a genetic link to clear cell carcinoma of the kidney in 1994; this variety causes about 85 percent of the adult renal cancer, amounting to about 23,500 cases per year. The mutant is a tumor suppressor gene located on the short arm of chromosome 3. The protein produced by this gene normally restrains growth. Both copies of this gene have to be damaged (two-hit model) for cancer to develop. This same gene plays a major role in an inherited cancer syndrome, von Hippel-Lindau disease. Persons with this disease can develop multiple tumors, including cancers of the kidney, eye, brain, spinal cord and adrenal glands.

    LIVER CANCER
    Cancers of the liver and intrahepatic bile ducts are most common in regions of Africa and Asia, accounting for only 1.5 percent of cancer cases in the United States. Because they are not diagnosed early, the five-year survival rates are less than 10 percent. The highest incidence rate is in Vietnamese men (41.8 per 100,000), and their are high rates in Chinese and other Asian-American populations. There is association with viral B hepatitis.

    LUNG AND BRONCHUS CANCER
    Lung cancer (which includes cancer arising in the bronchial tree) is the second most common cancer among men and women in the United States and the leading cause of death. Ethnic rates vary widely, from a high of 117/100,000 in African American males to a low of 14/100,000 in American Indian males. Rates for male Vietnamese, Caucasians, Alaska natives and Hawaiians are high, from 71-89/100,000. Among women, the highest rate is 51/100,000 in Alaska Natives, the low 15 /100,000 in Japanese. Smoking puts all groups at significant risk, and is blamed for 90 of all lung cancers. Asbestos exposure is another known cause, as is radon exposure.

    Genetic research is being done on lung cancers -- researchers are finding the genetic patterns are likely to be complex. There are four common types of lung cancer: squamous cell, adenocarcinoma, large cell and small cell. Even with adenocarcinomas, tumors which appear histologically similar respond quite differently to treatment. Dr. David Botstein and researchers at Stanford University have been using RNA from samples of normal lungs and lung tumors to identify suspicious genes. They were able to identify 3 subtypes of adenocarcinomas in which the patients had differing survival patterns and are continuing the studies in the hope of finding ways of targeting lung cancers with the most appropriate treatment. At the Medical College of Wisconsin, Dr. Steven Ahrendt and his colleagues are using bronchial washings to collect cancer cells for DNA studies. They report finding numerous different mutations in these cells, but more studies will be needed to obtain data that would aid in making an early diagnosis for a specific type of cancer.

    Polymorphisms in the p53 gene, found in nearly 30 percent of African Americans in an Anderson Cancer Center study reported by D. I. Amos, were associated with an increased risk for lung cancer. The mechanisms for how these polymorphisms work are still under investigation.

    Bronchial epithelium undergoes a number of changes when it becomes malignant. Most obvious are the abnormalities in the epithelial cells, which become dysplastic, with irregular shapes and enlarged, deeply staining nuclei. These cells begin to proliferate at an abnormally rapid rate. There is also atypical proliferation of tiny vascular channels, known as angiogenesis, and there are significant changes in proteins on the cell surfaces. One family of proteins, the epidermal growth factor receptors (EGFR), become “overexpressed” in nearly all squamous cell carcinomas and in most of the large cell and adenocarcinomas. Only the small cell tumors fail to express EGFR.

    Overexpression of EGFR is a consistent finding in the bronchial lining cells of high-risk smokers. Research is currently being conducted to see how EGFR information might contribute to chemoprevention or targeted lung cancer treatment.

    LYMPHOMAS
    Lymphomas are generally divided into Hodgkin’s and non-Hodgkin’s types; the more common non-Hodgkin’s lymphoma (NHL) will be discussed here, but its worth noting that together these lymphomas are the fifth most common type of cancer diagnosed in the U.S.A. The risk of developing NHL is increased by:

      Exposure to human T-lymphotrophic virus type I
      Exposure to Epstein-Barr (EBV) virus
      Infection of the gastrointestinal tract with Helicobacter pylori
      Infection with human immunodeficiency virus (HIV)
      Malarial infection
    Persons with weakened immune systems are susceptible to NHL. It is most common in non-Hispanic white males and the rate is particularly high in some Jewish populations in whom there is genetic predisposition for the disease.

    Genetic research on lymphomas is moving ahead, as researchers monitor changes in gene expression profiles associated with the multiple varieties, including Burkitt’s lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large cell lymphoma and B-cell lymphoma. Translocations have been found which disrupt normal gene sequencing and result in activation of oncogenes.

    MELANOMA
    Skin cancers, especially those of basal cell and squamous cell type, cause an estimated 40 percent of all cancers in the United States, but most fatalities from skin cancer are caused by malignant melanomas.


    Table 6.

    Melanoma in the United States

    (Ref.: American Cancer Society)

    2005 Estimates

    New Cases 59,600
    Deaths per year 7,800
    Survival Rate, localized lesion 91%
    “ “, regional spread 60%
    “ “, distant spread 14%


    Melanoma is a common cancer in young adults, particularly affecting whites with fair skin who have blond or red hair and who sunburn and freckle readily. The world’s highest incidence is in Australia. Melanomas are rare in African Americans and Asians and often occur in locations unexposed to the sun, such as nail beds or the soles of the feet. Persons suffering from xeroderma pigmentosum, a group of diseases in which the patients are especially susceptible to ultraviolet radiation, are greatly at risk to develop skin lesions, especially melanoma.

    Although most skin cancers are associated with the total cumulative exposure to ultraviolet radiation, melanomas do not usually appear in those areas, but are associated with intense intermittent exposure. Basal cell and squamous cell carcinomas are found on the face, backs of hands and forearms, where there may have been almost daily exposure to the sun. Melanomas occur most often on the backs of men and lower legs of women.

    A family history of melanoma can mean significant risk for the disease, the more relatives with melanoma, the higher the risk. About 8-12 percent of malignant melanomas occur in persons with a familial predisposition. Loci on chromosomes 1p and 9p are said by Goldstein and Tucker at the National Cancer Institute to be implicated with susceptibility for melanomas. Other investigators describe two genes in which an inherited mutation can contribute to the development of melanoma. One is CDKN2A, located on the short (p) arm of chromosome 9 at 9p21. It codes for proteins which help control cell growth and division. Mutations of this gene have been found in 20-40 percent of families with 3 or more affected first-degree relatives. A second gene, CDK4, is located on the long (q) arm of chromosome 12. A report from deCODE Genetics states that mutation in the p16 gene which encodes for a protein may be responsible for melanoma in some families. And BRCA2 germline mutations were found by the Breast Cancer Consortium to be related to increased occurrence of melanomas.

    Myriad Genetics announced a predictive test for malignant melanomas in late 2001. This test is based upon mutations in the p16 gene, which occur in melanoma but have also been reported in many other malignant diseases, such as leukemia, breast, bone, brain and ovarian cancers. Just how specific these mutations are for melanomas is not clear. Together with careful family history and clinical evaluation, the test could be of value, but interpretation and medical management will be complex should be carefully supervised and professionally guided.

    Therapy of melanomas is a challenging matter. In early staged disease, surgical procedures can potentially cure up to 90 percent of cases. Where there are metastases to regional lymph nodes or distant parts of the body, survival rates are difficult to predict and dependent upon many variable factors. Available treatments include chemotherapy, biologic therapy, tumor-infiltrating lymphocytes, lymphokine-activated cells, interferon, and various combinations. A number of immunotherapeutic methods are currently being evaluated at the Moffitt Cancer Center in Tampa, Florida.

    OVARIAN CANCER
    Ovarian cancer rates fifth in frequency among women in the United States. It is difficult to diagnose, so far impossible to prevent. The mortality rate is highest among white women, followed by Hawaiian women and African American women. There is an inverse ratio between parity and ovarian cancer. The lifetime risk for developing ovarian cancer is about 1/70, and the greatest single risk factor is a family history of the disease. The odds ratio for a woman with a single first-degree relative with ovarian cancer is stated to be 3.1, and it is 4.6 for a woman with 2 or 3 relatives with ovarian cancer. Prolonged use of oral contraceptives has been found to be protective against ovarian cancer.

    Hereditary ovarian cancer is transmitted via BRCA1 or BRCA2 mutations in an autosomal dominant pattern. Inheritance of either of these mutants confers a lifetime risk of ovarian cancer of 50 to 85 percent. 94 percent of BRCA-1 ovarian cancers are of the serous cell type, as compared with 60 percent of sporadic ovarian carcinomas. There are also mutations of p53 and PTEN which can produce syndromes which include ovarian cancer and it is also associated with a basal cell nevus (Gorlin syndrome), with multiple endocrine neoplasia type 1 (MEN1) and with hereditary nonpolyposis colon cancer (HNPCC). The autosomal dominant inheritance produce a vertical transmission pattern in a genogram, with a 50 percent risk of inheritance from a carrier parent.

    The reports by N. D. Kauff et al. and T. R. Rebbeck et al. on the results of bilateral salpingo-oophorectomieson women with BRCA1 or BRCA2 mutations are quite convincing evidence of the effectiveness of this method of preventing the development of ovarian carcinoma, or at least excising it while it is in its early stages Ovarian cancer is much harder to diagnose and often has spread by the time there is surgical intervention. Also, prophylactic oophorectomy reduces the risk of breast cancer by about half in carriers of BRCA mutations. Genetic counseling is definitely indicated, but both reports support the practice of recommending prophylactic oophorectomy after the completion of childbearing for women carrying a mutant BRCA gene. There are other smaller studies in which other investigators reached similar conclusions.

    PANCREATIC CANCER
    Cancer of the pancreas accounts for 2 percent of cancers each year, but because it can rarely diagnosed early, causes 5 percent of cancer deaths. The most common variety is adenocarcinoma, which arises from pancreatic ducts, but because symptoms don’t appear until late, the disease is usually far advanced when the diagnosis is confirmed. Other types of pancreatic cancer, arising from the insulin-producing islet cells or the enzyme-producing acinar cells, are quite rare.

    Pancreatic cancer usually occurs after age 55, with the mean age at time of diagnosis of 63 years, more often affects males, and is more common in African Americans than whites. Cigarette smoking seems to increase the risk; other possible risk factors include a folate-deficient diet, diabetes and exposure to carcinogens.

    About 10 percent of patients have a first-degree relative with the disease. At risk are persons with familial atypical multiple mole melanoma (FAMMM) syndrome, persons carring the BRCA2 mutant gene, and those having hereditary non-polyposis colon cancer (HNPCC). Of these, the most common are the cases associated with BRCA2 mutations (5-10 percent of pancreatic adenocarcinomas). These cases do not appear any earlier in life than those of sporadic origin, suggesting that the mutations have a low penetrance and that other factors, such as environmental causes, are also involved in the development of cancer.

    PROSTATE CANCER
    Prostate cancer is the second most common cancer diagnosed in the United States, with over 100,000 cases reported annually. However, these figures are very misleading, because just as many cases are NOT diagnosed. Small islands of malignant cells can be found within the prostate gland in 50 percent of men over age 70 and in nearly every man who lives 10-20 years longer. These lesions generally remain localized over many years. They do not enlarge the prostate and most go unnoticed unless a prostate-specific-antigen (PSA) test is performed. The introduction of PSA testing in 1987 was followed by a huge increase in the reported incidence of prostate cancer in the United States. As of 2001, the lifetime risk of a diagnosis of prostate cancer had risen to around 16 percent, but the lifetime risk of death from prostate cancer was only 3.4 percent.

    PSA-DYNIA
    PSA testing can be credited with finding many prostate cancers in younger men which could be followed up with needle biopsies of the gland. Hot debates raged over the ideal number and pattern for the biopsies, but with the usual six samples, at least 10 percent of the tumors are missed. In the successful cases, the pathologist can evaluate the histologic patterns and estimate the aggressiveness of the lesion. The PSA test could also be very misleading, owing to false negative or false positive results. False positive results can result from (among other things) prior surgical procedures, acute prostatitis, urinary retention and digital rectal examination immediately prior to the PSA testing. Artificial “normal” ranges were proposed for various age groups, but over-reliance upon this test resulted in chronic states of anxiety in many patients, a false sense of well-being in others, and enormous expenditures of time and money seeking to explain the results. The amount of “surgical overkill” that followed has never been documented. Measurements of free PSA or PSA complexes seem to be helpful because elevated circulating free PSA is associated with benign hyperplasia rather than malignancy. Dr. Arul Chinnaiyan and colleagues at the University of Michigan identified 2 genetic markers in 2001, hepsin and pim-1, which may prove useful in improving PSA specificity and possibly become therapeutic targets. The American College of Physicians, and other professional organizations, do not recommend routine use of the PSA test in men age 70 or over, but suggest making decisions on an individual basis after discussion of the pros and cons with the patient.

    Environmental factors involved with prostate cancer include diets high in saturated fat. Male hormones are related also, but more studies are needed to determine their specific effects. Some foods, e.g., tomatoes, and some vitamins and minerals are possibly protective, but evidence is inconclusive.

    PROSTATE CANCER GENETICS
    The role of genetics in prostate cancer seems to be dominant in about 10 percent of the cases; those cases are the ones appearing at a younger age and are likely to be more aggressive and deadly. Some of the recognized genes contributing to susceptibility are listed in Table ___, but they are not all equally involved and there are undoubtedly more! Others which seem directly involved in the malignant transformation of cells include MXI1 gene on chromosome 10, KAI1 gene on chromosome 11 and the PTEN gene on chromosome 10.


    Table 7.

    Genes Increasing Susceptibility to Cancer of the Prostate


    Gene Chromosome Comment
    HPC1 1 Believed to account for 9% of prostate cancer.
    Not precisely identified as yet.
    HPC2 1 Similar to HPC1, but at a different locus.
    Its existence is also questioned.
    HPCX X Accounts for 1/6 of hereditary prostate cancer*
    androgen X Associated with aggressive prostatic receptor cancer
    ELAC2 ? Estimated to affect 2-5% of cancer cases
    PCBC 1 (?) Associated with brain cancer



    *Explains why a man is at higher risk if a brother has prostatic cancer than if his father has the disease. As in the case of a number of other cancers, the epidermal growth-factor receptor (EGFR) tyrosine kinase family in tumor cells is being targeted by monoclonal antibodies in clinical trials in patients with prostatic cancer. Antibodies are combined with cellular toxins directed against EGFR. Phase 1 trials are said to show “encouraging results.”

    STOMACH CANCER
    Stomach, or gastric cancer is second in frequency only to lung cancer around the world, but incidence rates and mortality have declined in the United States and western Europe for several decades. Rates are high in Japan, China and eastern Asia, Latin America and eastern Europe. There are also high mortality rates in these areas.

    Many factors seem to contribute to gastric cancer, with strong correlation between the tumors and the consumption of salted, smoked and pickled foods. Better methods for preserving and storing foods are credited with reducing the incidence. Studies are under way to determine if beta-carotene, Vitamin C, is protective. It is known that H. pylori bacteria, causing chronic gastritis, are also associated with cancer, so anti-bacterial treatment is also being investigated. Cigarette smoking has also be implicated.

    GENETIC LINKS
    The Chinese are investigating possible genetic influence in areas of their country where gastric carcinoma appears to be familial. There are also families in other parts of the world in which familial diffuse gastric cancer is transmitted by autsomal dominant inheritance and appears at a young age. Guilford, Hopkins and associates found germ-line mutations in the E-cadherin (CDH1) gene in several of these families in 1998. Three out of every four carriers of this gene developed aggressive gastric cancer, leading other investigators to consider the wisdom of prophylactic gastrectomies. Five persons at risk who were studied by Huntsman et al. underwent this surgery and all had microscopic evidence of gastric cancer in the mucosal linings of their stomachs. The authors recommend genetic counseling for young persons with similar family histories of diffuse gastric cancer. Microscopic examination of cell blocks and smears prepared from aspirated gastric fluid removed during a gastroscopy can sometimes be useful in establishing a diagnosis, as biopsies might miss the small multifocal lesions.

    HELPING WITH DECISIONS
    We have already mentioned the importance of consulting your family physician and the need for genetic counseling, but there are many important decisions to be made after the diagnosis of cancer is confirmed, especially when it comes to the selection of treatments. The primary care physician has other resources available to aid you in making these choices, including oncologists, who specialize in cancer, and health care professionals engaged in clinical research.

    The explosion of genetic knowledge has resulted in many new possiblities for specific treatment of cancer and other diseases, as laboratory research reveals specific details about the mechanisms and molecular pathways involved.

    It becomes apparent that by blocking a certain pathway or modifying the role of a key gene, a disease process may be attacked in ways that were never before possible. In order to turn these concepts into realities, it is essential to run carefullymonitored clinical trials. But how is a patient to know which clinical trials are applicable and learn about the possibilities of participation? There is so much going on that it is difficult for even the most conscientious primary care physician to be aware of all the current options.

    There are three phases for all trials for treatment. Phase I determines the safest and best way to deliver the proposed new treatment. Phase II is an evaluation of how effective it works; e.g., in cancer, it would see how well it performed with various specific types. Phase III compares the new method against the best ones currently in use. Other studies involve ways to prevent cancers or manage symptoms and side effects.

    An organization has been established to serve the public through education, training and professional support related to cancer clinical trials. It is the Coalition of National Cancer Cooperative Groups, 1818 Market Street, Suite 1100, Philadelphia PA 19103. Their website is: www.cancertrialshelp.org rom this coalition of over 8,000 oncology professionals it should be possible to learn about government-approved trials being conducted by oncologists and related industries.

    There are also Patient Advocacy Group Members, some of which are shown below. If your specific interest is not included, we suggest you search the internet under the name of the disease.


    Alliance for Lung Cancer Advocacy, Support and Education www.alcase.org
    Colon Cancer Alliance www.ccaliance.org
    Colorectal Cancer Network www.colorectal-cancer.net
    The Leukemia and Lymphoma Society 1-800-850-9132
    National Alliance of Breast Cancer Organizations ww.nabco.org
    National Melanoma Foundation www.nationalmelanoma.org
    National Ovarian Cancer Coalition www.ovarian.org
    National Prostate Cancer Coalition www.pcacoalition
    North American Brain Tumor Coalition www.nabraintumor.org
    Ovarian Cancer National Alliance www.ovariancancer.org
    Pancreatic Cancer Action Network www.pancan.org
    Susan G. Komen Breast Cancer Foundation www.breastcancerinfo.com

    Other resources are supported by sponsored by various pharmaceutical and genomics companies:

    Amgen Trials Resource Center
    www.AmgenTrials.com
    Amgen: 1-866-572-6346

    Cancer Clinical Trials Hotline
    Aventic Pharmaceuticals: 1-800-RxTrial

    Cancer Survival Toolbox
    www.cansearch.org/programs/toolbox.html

    Clinical Trials Resource Center
    www.nccra.org

    Pharmacia Corp., Pfizer, National Colorectal Cancer Research Alliance
    1-800-724-4100

    Cycle of Hope
    www.cycleofhope.org
    Bristol-Myers-Squibb Co.: 1-800-717-HOPE

    Novartis Oncology Clinical Trials Information
    Novartis: 1-800-340-6843

    Strength for Caring
    www.StrengthforCaring.com
    Ortho Biotech Products, L.P.: 1-888-ICARE80

    Lilly
    1-877-CT-Lilly
    www.lillytrials.com


    The National Cancer Institute has booklets, brochures, etc. for patients, health professionals and the public on cancer, including various types, coping with cancer, diagnostic testing and clinical trials for methods of treatment. http//cancer.gov/publications

    Cancer Information Service: 1-800-4-CANCER
    National Cancer Institute
    31 Center Drive MSC 2580
    Bethesda MD 20892-2580


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