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  3. New Hope, Old Fears Bonnie Krull, 54, had already had enough breast-caner scares for one lifetime, with a few to spare for r

New Hope, Old Fears Bonnie Krull, 54, had already had enough breast-caner scares for one lifetime, with a few to spare for r

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问题                         New Hope, Old Fears
    Bonnie Krull, 54, had already had enough breast-caner scares for one lifetime, with a few to spare for reincarnations (再生). Her great-aunt, aunt, mother and sister all developed the disease. A few years ago Krull herself, a telecom manager in Los Angeles and a mother of two grown sons, was being prepped for surgery for what her doctor concluded was a malignancy (恶性肿瘤) in her left breast. As she underwent a final mammogram so the surgeon could pinpoint where to cut, and with the Ⅳ already dripping, the radiologist suddenly muttered that the lump had vanished. Heartened for the clinical trial of tamoxifen, a drug that preliminary data suggested might prevent breast cancer. Last week federal health officials announced at a press conference results that convinced Krull, who by chance was in the group receiving tamoxifen rather than a placebo, that her luck was holding. Among the 13,388 high-risk women in the trial, tamoxifen reduced the incidence of breast cancer a full 45 percent. "I really believe that tamoxifen saved me," says Krull, "and that I am going to be the one who breaks the link in the family chain of cancer."
    Normally circumspect scientists were no less euphoric (愉快的). "For the first time we have demonstrated that one can alter the incidence of breast cancer," says Dr. Norman Wolmark, chairman of the National Surgical Adjuvant Breast and Bowel Project at Allegheny University of the Health Sciences, which ran the tamoxifen trial, and not just by tinkering at the margins. The 45 percent lower incidence Of invasive breast cancer among women receiving tamoxifen--85 cases compared to 154--was so stark that, in a controversial decision, the researchers ended the study 14 months ahead of schedule.
    The results were not all positive, though. The women on tamoxifen, who took two 10-milligram pills each day, also had 33 cases of endometrial cancer versus 14 in the placebo group, 17 cases of pulmonary embolism (potentially fatal blood clots in the lung) compared with six among the women on a placebo and 30 cases of dangerous lung clots in major veins compared with 19 in the placebo group. Tamoxifen, clearly, is not the silver bullet that will kill breast cancer. "This is not primarily about tamoxifen," says oneologist Nikolay Dimitrov of Michigan State University. "This is a proof of the concept that prevention works. Now we can look for new chemopreventives without the side effects of tamoxifen." Other such drugs are in the pipeline. Researchers hope to begin a clinical trial on one, raloxifene, as early as this fall. Made by Eli Lilly and Co., raloxifene serendipitously turned out to lower the incidence of breast cancer among women on whom it was being tested against osteoporosis.
    Until the perfect preventive comes along, should women at high risk for breast cancer ask their doctors for tamoxifen? (Because tamoxifen has been used for more than 20 years as a breast cancer treatment, doctors can prescribe it for such "off-label" uses as prevention, but government approval of such a use is at least six months away.) Many worried women are considering it. Karen Recht, a gift-shop manager in Wheeling, W. Va. , was in the tamoxifen trial. As chance would have it, she received the placebo. Recht, 57, volunteered because she wanted to help "the two little girls my sister (who died of breast caner at 45) left behind. I never dreamed I would benefit. But now I’m very tempted to try tamoxifen. I feel like it will give me five more years in which I won’t get breast cancer."
    The results announced last week apply just to high-risk women, the only kind participating in the study. For women at low risk for breast cancer, there is no evidence that the benefits of tamoxifen outweigh the dangers. "High risk" was defined as having the same chance of getting breast cancer as a 60-year-old American woman: a 1.7 percent chance of getting the disease within five years. Besides age, other risk factors include having a mother, daughter or sister with breast caneer; having a first child after age 30; having had breast biopsies, especially if the tissue turned out to be precancerous, and having the noninvasive breast cancer called lobular carcinoma in situ. Some 29 million American women meet this definition of high risk, including 3 million between 35 and 59. "But we need to be very cautious," says Dr. Patricia Ganz of UCLA’s Jonsson Comprehensive Cancer Center. "Tamoxifen might not be appropriate even for every highrisk women."
    That’s because a 45 percent reduction in the incidence of breast cancer is huge, but it is not 100 percent. Why did 85 women on tamoxifen still get breast cancer (and, in three cases, die of it)? One clue comes from the biochemistry of the compound. First synthesized in 1961 by chemist Dora Richardson, for Zeneca Pharmaceuticals, tamoxifen is an anti-estrogen (雌激素). It binds to receptors on the nuclei of breast cells. Receptors are like loading docks, specially shaped molecules on which estrogen circulating in the blood parks before getting transported right into the nucleus. There, estrogen turns on a suite of genes, including those for cell proliferation. But tamoxifen hogs the estrogen receptors. That leaves no spots for estrogen itself to dock and hence turn on the proliferation genes. Not all breast cancers have estrogen receptors, however. "In postmenopausal women, about 75 to 80 percent of the cancers are estrogen dependent," says UCLA’s Ganz. "But in younger women it’s only about 35 or 40 percent." Women whose cancers are not estrogen-sensitive are usually not prescribed tamoxifen as chemotherapy. "One reason tamoxifen did not prevent breast cancer in every woman might be that these women had estrogen-receptor-negative cells," suggests V. Craig Jordan of Northwestern University’s Lurie Cancer Center, who in 1973 first discovered that tamoxifen can prevent cancer in lab animals. One research priority is to figure out what determines whether a woman develops cancer cells with or without estrogen receptors.
    Another question is whether tamoxifen can help women who carry mutations in the BRCA1 or BRCA2 genes. When the tamoxifen trial began in April 1992, geneticists had not yet discovered these so-called "breast-cancer genes," which (with other hypothesized genes) account for some 7 percent of all cases of the disease. But DNA samples were taken from every woman in the trial. It should therefore be possible to go back and, by matching the BRCA status of each woman to how she fared on tamoxifen, figure out whether tamoxifen can prevent cancer in these highest-risk women. On paper, it might. "Estrogen turns on a whole host of genes inside the breast cell," says Dr. Brian Henderson of the Norris Comprehensive Cancer Center at the University of Southern California, "possibly including BRCA1. If we can dam up the effects of estrogen upstream by blocking them with tamoxifen or some other compound, you will never suffer from BRCA1."
    It is not clear whether tamoxifen helps younger or older women more. As UCLA’s Ganz points out, older women are more likely to have estrogen-sensitive cells whose proliferation tamoxifen can quash. So tamoxifen might be expected to be more effective for them. In the trial, tamoxifen indeed provided slightly more benefit to women over the age of 50: it prevented 17 cases of invasive breast cancer, out of the 33 cases expected without the drug. Among those 35 to 49, it prevented 14 cases out of the 31 expected. But the older women were also at greater risk for such serious side effects as endometrial cancer and blood clots in the lungs and veins. Tamoxifen had no effect on endometrial cancer or blood clots in younger women.
As UCLA’s Ganz points out, older women ______.
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答案are more likely to have estrogen-sensitive cells whose proliferation tamoxifen can quash
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