The British public health community was thrown into a tumult last month by widespread media reports that a new Swedish study raised serious doubt about the effectiveness of mammography screening.
"Breast Screening `Doesn't Prevent Deaths' " announced a front page headline March 11 in the London tabloid Daily Mail, and other media outlets joined the chorus, though less sensationally.
In fact, the study was roundly and internationally criticized for severe design flaws, and United Kingdom and Swedish officials rushed to reassure women that mammograms can save lives. But the debate over the value of screening points to a crucial question in cancer epidemiology: Can the benefits of early detection and treatment advances be demonstrated by links to declines in breast cancer mortality? And to what extent can these benefits be measured separately?
In several countries, breast cancer mortality rates have been falling steadily during the past decade. The U.S. rate declined about 5% from 1991 to 1995. And the Office for National Statistics in London reports declines nearly every year since 1989, for an overall 15% drop through 1997.
Experts interviewed generally agree on a few points: First, it is extremely difficult to disentangle the effects of screening, treatment advances, and population changes in risk factors. Second, despite that difficulty, improvements in treatment must be responsible for part of the recent downturn in mortality. And third, the mortality benefit from mammography screening, if there is one, should become increasingly evident with the availability of figures for the late 1990s. (Treatment advances for breast cancer and screening both came into wide use around the same time, in the 1980s. But new treatments can have a relatively rapid effect on mortality, while the effects of screening take longer to become evident.)
"We need another 5 years of observation of both incidence and mortality to be able to understand better what's going on," said Paola Pisani, Ph.D., of the International Agency for Research on Cancer in Lyon, France.
Anthony Miller, M.D., acting chief of IARC's chemoprevention unit, agreed. Miller, who was formerly at the University of Toronto and continues to direct the Canadian national breast screening study, noted that the recent declines in Europe particularly the U.K. and in the United States and Canada are "almost certainly due to treatment changes that occurred at the beginning of the 1980s," but it will be 5 to 10 years before a major impact of screening could be expected to emerge.
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Lennarth Nystrom of the University of Umea, Sweden, said that while most Swedish counties began screening by 1989, the program was not fully active in those areas until about 1991, and the entire national program was not in place until 1997. Given that time frame, "there's no way that we would be able at this time to see whether there is a decline or not. It's too early we have to wait a couple of years."
Weak Science
As for the article that spurred debate in the U.K. press, "the study should never have been published," Nystrom said. "The methods they used were not scientific, and it would never pass an international review." The article in fact was turned down by more prominent journals before being published in the Swedish scientific journal Läkartidningen.
Regarding Sweden, Miller concurs that it is premature to declare breast screening a failure. "I'd be amazed if we didn't see something in Sweden within the next 5 years, given the sort of compliance they're getting. But until we get data up to the end of the century, I don't think we'll be in a position to say yes or no [benefit] from screening."
Susan Moss, Ph.D., of the Institute for Cancer Research in Sutton, England, believes screening is probably already contributing to the mortality decline seen there, though she agreed it is a challenge to demonstrate that statistically. "Because mortality clearly started to fall in the U.K before you'd expect to see an effect of screening, a lot of people then said none of it must be due to screening."
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Virginia Ernster, Ph.D., of the University of California, San Francisco, described a similar phenomenon in the United States, which she speculated may help explain why mortality rates among women under 50 years old began falling in the 1970s, when rates were still rising among older women.
"There's been a vastly increased level of comfort with talking about breast cancerwomen's comfort with their own breasts, and with presenting concerns earlier on," she said. "There's been a huge increase in societal awareness and advocacy for breast cancer that has piqued all women's attention. That would tend to make women come in earlier, and make their physicians pay more attention to their concerns, rather than write off a young woman as unlikely to have breast cancer." Rates began to decline earlier among younger than older women in Canada and England as well, she noted.
In the U.K., Beral is planning to look at mortality by age, to see whether rates in the screened group (women aged 50 to 64) are declining more sharply than others. Moss and colleagues are working to estimate the levels of reduction that would be expected at different points in time based on the number of women who have been screened. They also plan studies linking screening records with death records to assess the impact on mortality at the individual level, and to compare mortality in different areas of Britain where screening began at different times. From these studies they hope to develop quantitative estimates for each factor driving the mortality decline.
Slippery Slope
Robert Tarone, Ph.D., of the National Cancer Institute, warned that attempting to partition effects in this way is a slippery business. "The problem, whenever we try to find out what's driving changes in the trends, is that we have very good information on the cancer rates themselves," he said, "but we don't have good information on how rapidly, for example, tamoxifen actually penetrated medical practice. So we don't know where in time to look for a change due to tamoxifen. We have slightly better information on when mammography picked up, but even that is sometimes indirect; for example, surveys of the number of mammography machines." Moss acknowledged these concerns and said the effects of assumptions in her studies would need to be tested.
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Added Pisani, "One must not forget that screening by itself is not effective. What is effective is a screening program, which includes appropriate treatment of the identified cases."
Another complication, Miller pointed out, is that the effects of treatment and screening may not be statistically independent either. Randomized trial results suggest that modern treatment advances can cut mortality by about 15%, and that screening may reduce it by 30% in women over age 50. But combining the two may yield less than the sum of these parts. To take the extreme example, if available treatment could cure all cases of breast cancer, no matter the stage, then early detection would not further reduce mortality.
No one knows whether, or how much, improved treatment has outpaced the value of early detection in this way, Miller said, but because some screening trials predated the treatment advances, the benefits may be less than originally estimated. "The only clue we have about this is our 1992 results in 50- to 59-year old women in the Canadian screening trial," he said. Although a third more cancers were found early in the mammography group, their breast cancer mortality after 7 years was similar to the control group's. Updated results will be published later this year.
Unknown Risks
Besides treatment and screening, the third element in the equation is the population level of breast cancer risk a largely unknown quantity that affects both incidence and mortality rates. As with the interventions, reliable data are lacking on changes in potential risk or protective factors, such as diet, obesity, and physical activity particularly retrospective data on women's exposure to these factors decades ago, when their breast cancer risks were largely being formed.
One exception is information related to childbearing. Vital statistics report how many children women gave birth to on average and how many women are childless at a given age. Internationally, breast cancer mortality rates reveal characteristic ups and downs that correlate with these reproductive variables over the years, even before treatment or screening advances could have had much effect.
Analyses by birth cohort show largely similar patterns in Britain, Canada, and the United States: increasing risk of breast cancer death for women born from the end of the 19th century to the mid-1920s, then declining risk for women born successively later. The reason seems to be that women whose prime childbearing years coincided with the Great Depression in the 1930s and the Second World War in the 1940s were more likely to be childless or to have fewer children. The postwar baby boom turned that around, with the result that breast cancer risk declined.
"I think the underlying risk factors are working in general to bring the rates down as well," Beral said. "The women now in the age groups that get the most breast cancer are in the cohort that started having children early," roughly, the parents responsible for the baby boom.
The women of the next generation the boomers themselves are beginning to reach the age of breast cancer risk. These women were more likely to delay childbearing, reversing the pattern, so their breast cancer rates would be expected to be high. "But it's not happening and that is puzzling," Beral said.
"The baby boomers depart from what had previously been a close relationship between childbearing trends and breast cancer risk," added Tarone. "It's one of the biggest mysteries in terms of cancer trends that I've ever seen. It's really hard to come up with any risk factor that would indicate breast cancer risk should be going down. Baby boomers are taller than their parents, they were the first generation to have oral contraceptives available all their lives." Obesity a protective factor in young women is increasing, he said, but is unlikely to be important enough to explain the puzzle.
Tarone's next step in probing breast cancer mortality will be a transatlantic collaboration with David Forman, Ph.D., at the University of Leeds, England.
"I think if there is any hope at all" of teasing out the strands of the mortality trends, "it's going to come through international comparisons, where you have a slightly greater chance of differentiating the effects," he explained, "because different countries adopted chemotherapy or screening to a greater extent, and also maybe adopted it at different times." To understand the baby boomer anomaly, he and Forman plan to look deeper into the past, at patterns among British women born as far back as the mid-19th century. There is evidence to suggest, as Brian MacMahon, M.D., Ph.D., at the Harvard School of Public Health, Boston, noted in the 1950s, as one steps back in time, reproductive factors appear to lose their grip.
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