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To prove the value of mammography scientifically is more difficult than it might seem. In some studies investigators ask women to volunteer for screening, and then report the number of breast-cancer cases and the percentage of women who survive five years after diagnosis. This figure is compared with the percentage in the population at large. In these studies researchers often go to considerable trouble to eliminate potential sources of confusion. For example, they may try to match by age the women undergoing regular mammography with other women. Or they may match by race or socioeconomic class. No matter how hard researchers try, though, such studies remain susceptible to three of the most common sources of bias in medical research.

Mammography may find a tumor as early as two years before it could have been detected by palpation. Let us, however, consider a hypothetical case in which the cancer has already spread to other parts of the body by the time it is discovered, and the woman goes to her grave on exactly the same day she would have if the tumor had been discovered later. In that case the sole effect of early detection has been to stretch out the time in which the woman bears the knowledge of her condition. But that is not how the woman would appear statistically if she had happened to become part of a research study. Pushing back the date of first diagnosis would increase the interval between diagnosis and death, apparently lengthening her survival. Statisticians call this effect "lead-time bias." Although nothing has actually changed, a woman who would have died, say, three years after treatment now dies five to six years after treatment—manufacturing an apparent victory for medicine.

A second problem with measuring the benefits of mammography is known as "length bias." Women typically have mammograms every year or every other year. Any cancers that are found between mammograms will be detected by palpation—very possibly by the woman herself. Such tumors are likely to be fast-growing; indeed, their rapid onset often explains why they were not picked up by the previous mammogram. The more aggressive tumors tend not to be diagnosed mammographically, and thus the tumors that are discovered by mammograms are often less dangerous. Mammography will be made to look good in a study comparing the survival rate of women whose tumors were diagnosed by mammography with that of women whose tumors were diagnosed by palpation, because the tumors discovered by mammography tend to be those that grow relatively slowly and thus take longer to kill patients.

The third and most important problem is "selection bias." This occurs when researchers measure the effect of a treatment on a group of people without realizing that those people are different from the general population. The risks that selection bias will occur are high, because women who participate in medical experiments are often not like the general population. Researchers typically work in teaching hospitals and thus draw their subjects from the patients who frequent them. These people may be more affluent than most Americans, and thus more prone to diseases of affluence. Or they may be more worried about their health, and thus more likely to seek expert medical care. In either case, the results of a test on such a select group can be misleading.

Many researchers agree that lead-time, length, and selection biases may flaw the optimistic accounts of the efficacy of mammography that have appeared in the scientific press and the popular media. Nonetheless, they support the idea of routinely screening women. The principal reason is that benefits from mammography have been observed in a special kind of study known as a prospective randomized clinical trial. In such a trial researchers randomly divide large numbers of volunteers into two groups at the outset (prospectively): a control group, which receives ordinary medical care; and a test group, which receives the medication or procedure under scrutiny. After a given period of time the two groups are compared. Properly conducted, such trials avoid all three kinds of bias. Even prospective randomized clinical trials have their pitfalls, though, because doctors can't control the actions of their patients. Members of the test group may fail to take their medicine or to show up for their medical procedures, and members of the control group may seek out a drug or procedure they are not supposed to have. As hard as researchers may try to ascertain levels of compliance, misclassification of a certain number of participants is inevitable. In addition, the medical care provided at  research centers, which often conduct clinical trials, may not be representative of the care received by most people.

Nonetheless, by ensuring from the beginning that the test group and the control group are statistically similar and by tracking everyone in both groups, these trials can produce data that are as solid as medical research gets. And several big prospective randomized clinical trials have reported that women who regularly undergo mammography have, roughly speaking, 25 to 30 percent less chance of dying from breast cancer in the decade after initial screening than women who are not screened. Most breast-cancer specialists thus endorse mammography.

In fact the evidence from these trials is weaker than it sounds. In April of last year an article in Cancer summarized all eight of the major mammography trials that have been conducted to date. Six of the trials saw no significant decreases in breast-cancer mortality as a result of mammography. "Significant," an important term, means that statistical tests indicate that the effect is probably not due to chance. Also, the two significant clinical trials were the first ones completed. "Should the early trials be accepted as the gold standard and the later ones dismissed as somehow incompetent?" Charles J. Wright, of the University of British Columbia, and C. Barber Mueller, of McMaster University, asked in The Lancet last July. "Surely not, in view of the increasing rigour of trial design over the past 30 years and the vast improvement in quality of mammography." Indeed, the two earliest trials have serious potential shortcomings. Explaining these shortcomings involves delving still further into technical details; some readers may wish to skip the next section of this article entirely. The gist of my argument is that the benefits of frequent mammography as opposed to palpation performed during regular checkups and also by a woman herself are not well established; if they do exist, they are not as great as many women hope.


The more important historically of the two trials that showed significant benefits is known as the HIP trial, after the Health Insurance Plan of Greater New York, the health-maintenance organization from which the researchers gathered participants. A classic of medical research, the HIP trial enrolled 60,696 patients from 1963 to 1966 and followed them for as long as eighteen years. In 1988 two of its principal investigators, Sam Shapiro and Philip Strax, won the Charles F. Kettering Prize for outstanding cancer research, both because the trial was one of the earliest large-scale attempts to test a preventive health measure and because it showed that periodic mammography reduced breast-cancer mortality by 30 percent over a ten-year period.

Notwithstanding the accolades awarded to this pioneering effort, it suffered from methodological weaknesses. In clinical trials, as I have said, the subjects should be randomly distributed between the test group (in this case women who received annual mammograms and clinical breast examinations) and the control group (women who received ordinary medical care from their own doctors). Experimenters always fear that they may introduce bias by inadvertently including or excluding the wrong people. The HIP trial demonstrates why they worry.

In this experiment the researchers assigned women to the test and control groups alternately in order of enlisting, a process intended to produce groups of equal size and composition. After assigning a woman to the test group the researchers made two simple determinations: Was she pregnant? Had she had breast cancer?If the answer to either of these was yes, Shapiro and Strax made the woman ineligible for the test group. They did not, of course, want to x-ray pregnant women. Nor did they think it a good idea to include women with breast cancer, because administering mammograms to women who had already been treated for the disease would not be a proper test of mammography for the purposes of the study. The test group of 30,131 women thus wound up with 434 fewer subjects than the control group of 30,565 women.

Shapiro and Strax gave the women in the test group annual mammograms and breast examinations for as long as five years. They then counted up the number in each group who died of breast cancer within ten years and compared the two figures. Because 147 died in the test group and 193 died in the control group, Shapiro and Strax concluded that mammography was beneficial. But was it?The researchers themselves attributed the "higher proportion"of the benefit, at least in the first five years, to clinical breast examination—that is, palpation. In order to be certain that the remaining benefit was due to mammography, one would have to confirm that excluding from the test group the 434 women who either were pregnant or had had breast cancer did not skew the results.

The ages of the women in the HIP study ranged from forty to sixty-four. Because few women in this age range are pregnant, most of the subjects excluded from the test group were surely dropped for having had breast cancer. In order to guarantee that the test and control groups were identical, the investigators would also have had to identify and exclude all the women in the control group who had breast cancer when the experiment began, by asking the same two questions they had asked women assigned to the test group. But they did not do this—they simply filed the names of the women in the control group, without performing any initial evaluation. (This was not unusual for control groups of the time.) As the trial progressed, the team leaders later wrote, women in the control group who "were identified through other sources as having had breast cancer diagnosed before their entry dates . . . were dropped from the investigation."In other words, the researchers tracked them by looking for their names in medical records, insurance claims, and death records; if they found evidence that breast cancer had been diagnosed in a member of the control group prior to 1963, when the study began, the scientists retroactively dropped her from the study. This meant that the researchers sometimes had to ascertain the time of diagnosis by finding very old records in scattered hospitals or asking family members about events many years in the past.

For my own research I have attempted to document medical histories, and can report that it is no easy task. Records disappear; memories are faulty; people move. More than half the subjects in the HIP study left that health-maintenance organization within fifteen years. (In one trial I myself inadvertently transmitted incorrect data to its statistical administrators: I reported that a deceased patient was alive, because a busy doctor's office taking part in the trial was unaware of the death. When this omission was discovered, I asked the National Cancer Institute to examine the body of research data Ihad supervised, and I was cleared of any wrongdoing.) In my experience people typically underestimate the time that has elapsed since a trip to the hospital. Informed of the real date, they say, "That long ago? I can't believe that much time has gone by!" In those instances when Shapiro and Strax relied on the memories of patients and relatives, they almost certainly retained in the control group some cancer cases that had actually been diagnosed before the trial began—inadvertently stacking the deck in favor of mammography.

A few such slips would be enough to throw off the entire experiment. Indeed, if it turned out that Shapiro and Strax had ascribed a mistakenly late date of diagnosis to as few as twenty-five women in the control group, the failure to exclude them, too, would have changed the study's conclusions. Correcting for it would cause the benefit of mammography to lose statistical significance—the touchstone of medical research. Twenty-five errors is in this case not a big number; it is equivalent to about six percent of the 434 patients excluded from the test group. To be sure, the trial may have been error-free; although they had not initially excluded from the control group women who had had breast cancer, Shapiro and Strax wrote that "confidence is warranted" that by the trial's end they had identified prior breast-cancer cases equally well in both groups. Still, the vulnerability of the conclusions to such a small error is troubling.

No such methodological worries seem to afflict the second of the trials to show a statistically significant advantage from mammography: the Kopparberg study, named after the county in southern Sweden where it took place. Beginning in 1977 the Kopparberg trial offered mammography to a test group of 38,562 women and ordinary medical care to a control group of 18,478 women. At the same time, the researchers performed a second big trial in another Swedish county. The test group in Kopparberg experienced a statistically significant reduction in breast-cancer mortality of 40 percent; the mortality reduction in the test group in the other county was statistically insignificant.

Strangely, though, as the researchers acknowledged, the mortality from all causes in the two test groups was "identical" to that in the control groups. In 1988 the late Petr Skrabanek, of Trinity College, Dublin, pointed out in the British Medical  Journal, "Not a single life was 'saved' in a trial that included over 130,000 women" in both counties. The women who underwent mammography may have died less frequently of cancer, but the gain was offset by deaths from other causes, such as heart attack. Presumably the "extra" deaths reflect the workings of chance. But it is awkward to argue that a decrease in cancer deaths in the treatment groups is meaningful while claiming that an equally great increase in deaths from other causes is a fluke.

One of the most recent clinical trials discussed in the Cancer article took place in Canada, where a team of physicians gave annual mammograms to 44,925 women and ordinary medical care to 44,910 women. The researchers enrolled women in the trial from 1980 to 1985 and followed their progress for a minimum of seven years. The subjects were divided by age into two subgroups: those who were forty to forty-nine when they entered the trial, and those who were fifty to fifty-nine. In neither subgroup was there an overall difference in mortality from breast cancer between the treatment and control groups—mammography had no effect.

Mammography supporters immediately dismissed these negative results as obvious signs of faulty equipment, poor training, or flawed experimental technique. Typical was the reaction of Charles R. Smart, then the director of the Division of Cancer Prevention and Control at the National Cancer Institute. Without presenting any supporting evidence, Smart dismissed a preliminary report from the Canadian researchers by writing in the journal Cancer Prevention, in 1990, "The lack of a decrease in mortality [in older women] suggests problems in the quality of the mammography in this trial."

Others took the Canadian trial more seriously. In a series of steps that sowed confusion in many women, the National Cancer Institute and the American Cancer Society reviewed all the available evidence about mammography, especially for younger women. In October of 1993 the NCI reported that mammography provided no certain benefit to women under fifty but some benefit to their elders. The American Cancer Society continued to endorse routine mammography for all women over forty. The dispute sparked by the inability of the Canadian study to find any benefit from routine mammography became bitter and personal. Angry critiques poured into the journals, and the Canadian researchers defended themselves with equal vigor. Contradictory editorials abounded.

The attacks and counterattacks clearly demonstrated how hard it has been to prove unequivocally that mammography has a strong beneficial effect on women's lives. Trying to resolve the controversy, several research teams employed a technique called meta-analysis. Roughly speaking, meta-analysis involves adding together the data from many clinical trials to create a single pool of data big enough to eliminate much of the statistical uncertainty that plagues individual trials. It is accomplished by gathering all available studies and comparing them one at a time with the "null hypothesis"—in this case the hypothesis that mammography has no impact whatever on mortality from breast cancer. If the null hypothesis is true, the series of comparisons should randomly differ from zero; added together, the chance variations will cancel one another out. If the studies consistently find an impact, the comparisons will draw the total away from the null hypothesis and toward the actual effect. The great virtue of meta-analysis is that clear findings can emerge from a group of studies whose findings are scattered all over the map.

In January of last year a team led by Karla Kerlikowse, of the University of California at San Francisco, published in the Journal of the American Medical Association the results of a meta-analysis of the eight trials: mammography reduces the seven-to-nine-year mortality from breast cancer in women aged fifty to seventy-four by about 23 percent, but it has no impact on women in their forties. A second meta-analysis of mammography for women in their forties appeared three months later in Cancer (the summary referred to above; its authors included Charles R. Smart, now retired). Including somewhat more recent data from the same trials, with an average follow-up time of 10.4 years, the Cancer article concluded that mammography in fact lowered the rate of mortality from breast cancer in women aged forty to forty-nine by about 16 percent. Indeed, these researchers argued, the true benefit was likely to be greater than that. First, the technology of mammograms is constantly improving. Second, not all the women in the groups scheduled to receive mammograms actually showed up for their examinations. Finally, Smart and his associates presented an argument for eliminating from consideration the results of the Canadian trial, because it had what they regarded as worrisome problems. For instance, almost four times as many advanced cancers were diagnosed in the women who had mammograms as in the women in the control group—a disproportionately high number of very dangerous tumors, which in the critics' view makes the experiment unrepresentative. If data from the Canadian trial were discarded, the researchers calculated, mammography would lower the rate of mortality from breast cancer for women in their forties by 24 percent.

Do the meta-analyses settle the matter? Yes and no. Even if one accepts the highest values from these overviews for the risk reduction associated with mammography—23 percent for women over fifty, 24 percent for women in their forties—the figures do not mean what people think when they read headlines about them. The percentages refer to the relative risk reduction—a statistical measurement calculated by dividing the difference between the risks in the test and control groups by the risk in the test group. For example, if a clinical trial shows that a treatment cuts the risk of dying from a disease from 70 percent in the control group to 50 percent in the test group, the relative risk reduction is 70 minus 50, or 20, divided by 50, which works out to 40 percent. This percentage sounds large, and it is of great import to medical researchers. But it has little to do with the question of interest to individual women—the absolute difference in risk between those who are screened and those who are not. Using the example I just gave, that difference would be 20 percent—half the relative risk reduction. In other words, the figure from the meta-analysis is the answer to the question "Given that I have breast cancer, how much will I have cut my risk of dying if the tumor was detected mammographically?" It is not the answer to the question "If I am a typical woman, how much will I cut my risk of dying from breast cancer by having an annual mammogram?"

Unfortunately, in this case the absolute reduction is much smaller than the relative reduction. According to a rough calculation described by Russell Harris and Linda Leininger, of the University of North Carolina at Chapel Hill, in the Annals of Internal Medicine in April of last year, annual mammographic screening for 10,000 women aged fifty to seventy will extend the lives of only two to six of them each year. ("The many must be screened to benefit the few," Harris and Leininger remarked.) For younger women, they argued, the benefit is even more meager: annual screening of 10,000 women in their forties will extend the lives of just one or two a year. As Harris and Leininger observed, "the use of the term 'marginal' to describe this risk reduction seems justified."

Even this small benefit may be more apparent than real. Almost all breast-cancer experts agree that mammography, which can diagnose smaller tumors, picks up some slow-growing cases of cancer that might otherwise never be caught. If these tumors grow sufficiently slowly, they will rarely become dangerous in a patient's lifetime. Discovering them will thus manufacture an apparent excess of "cures." Because we will detect the same number of big, dangerous, fast-growing tumors, the "cures" of slow-growing cancers will appear statistically only a number of years after diagnosis. Even if mammography had no actual effect on mortality, it would still produce a small statistical increase in survival many years down the pike. In a clinical trial the test group, with its frequent examination by mammography, would have a greater number of less-dangerous cancers diagnosed within it than would the control group—a form of length bias that would lead predictably to the modest prophylactic effect observed in the meta-analyses.

Society should ensure that this effect is worth the cost of obtaining it, which includes both the direct cost of mammography itself and the indirect cost of biopsies, laboratory analyses, and the time women must take off from work for checkups. (The emotional costs of the huge number of false positives are substantial too, but cannot be reckoned by this kind of accounting.) Charles Wright and C. Barber Mueller calculated in their Lancet article what they called a "low" estimate for the cost of mammography: $1.2 million for each woman benefited. Two previous cost-benefit analyses, they noted, produced comparable figures.

Now contrast the cost of mammography with that of another widely used cancer-screening technique: the Pap smear for cervical cancer. Named after George Papanicolaou, the physician who developed it in the 1930s, the test is less expensive than mammography, simpler to perform, and far more reliable. Because the Pap smear can detect cervical cancer in its long latent stage, before the cancer invades surrounding tissue, the test is widely believed to reduce the mortality of invasive cervical cancer by 90 percent. According to a study published in 1990 in the Annals of Internal Medicine by David Eddy, of the Duke University Center for Health Policy Research and Education, screening 10,000 women with a Pap smear every three years from their twenties to their seventies would prevent about 200 of them from developing invasive cervical cancer; if each detected cervical cancer translated into an additional ten years of life, the cost to society would be approximately $150,000 per woman benefited. Eddy's calculation cannot be directly compared with that of Wright and Mueller, because it used a different methodology. Nonetheless, it is clear that Pap smears provide much more benefit than mammograms, at a small fraction of the cost.

Is mammography worth it? I would argue, with Wright and Mueller, that "the benefits of mass population screening, even in older women, are too small and the harm and cost generated too great to justify widespread implementation of screening mammography." In fact, the authors suggest that routine mammography should be recommended only for women at high risk of developing breast cancer, such as those whose mothers or sisters developed breast cancer early in life. There is little factual basis for this plausible-sounding suggestion, though.

A similar radical stance was adopted by Michael Baum, the research director of the British Institute of Cancer Research, who quit England's national breast-cancer-screening advisory board last September because nationwide mammography is "not worth doing." Having helped to set up the country's screening program, he was disturbed by claims about the effectiveness of mammography. The London Sunday Times quoted Baum as saying, "There is a political correctness about screening. I took pride in setting up the service, which is as efficient as it can be, but just because you are doing something efficiently, it doesn't mean it is worth doing."

Abandoning widespread mammography in the United States is probably not feasible. After years of effort invested in encouraging mammography, to reverse course would cause widespread confusion and anger. Alarmed by the contradictory recommendations of "experts," women would probably keep having mammograms, just to be safe—and in their shoes I might do the same. Moreover, many physicians believe that routine mammography encourages women to come in for regular checkups, and thus may play an important role in general preventive medicine.

On balance, then, I reluctantly support the status quo. When my patients come in for their mammograms, I do not try to dissuade them. But I tell them that the most optimistic interpretation of the available evidence suggests that routine mammography has only a marginal effect on a woman's chances of surviving breast cancer—and that it may have no effect at all.


Once a tumor has been found, whether by mammography or palpation, it must be treated. The basis for the contemporary approach dates back to the 1890s, when William Halsted, a professor of surgery at Johns Hopkins University, developed radical mastectomy—the technique for removing a breast, the underlying chest muscles, and the lymph nodes in the armpit. A giant in medical history, Halsted was held in such respect that surgeons after him took an uncommonly long time to admit that his ideas about cancer were off base. He believed that breast cancer oozed slowly through the lymphatic system of the body the way foul water from a brackish pond travels through ditches to other parts of the landscape. (The lymphatic system is the collection of ducts, lymph nodes, and other organs that drain the tissue fluid called lymph into the bloodstream.) To Halsted's way of thinking, breast cancer could be cured by carving a wide swath around the initial tumor and its draining sites, leaving clear margins of healthy tissue—a scorched-earth approach.

Seventy-five years later a number of North American researchers began questioning Halsted's ideas. Instead of seeping slowly throughout the body from its initial site, breast cancer seemed to hop from place to place as cells sloughed off by the main tumor mass floated through the bloodstream. If this was true, removing a woman's entire breast would often be pointless, because most of the tissue surrounding the tumor would be healthy. After this heretical notion provoked much controversy among cancer specialists, Bernard Fisher, of the University of Pittsburgh, put together a series of large clinical trials that were intended to resolve the dispute. These trials demonstrated that a much less drastic operation called a lumpectomy was appropriate in many cases; when combined with radiation therapy it provided a chance of survival indistinguishable from that provided by Halsted-style mastectomy. After the results were published, in the mid-1980s, surgical practices changed. Remarkably, though, they didn't change very fast. Even today only a third of the women who undergo breast surgery have lumpectomies, whereas at least two thirds probably could, in light of the size of their tumors. The rest have modified radical mastectomies, a somewhat less severe version of Halsted's operation.

In the same period researchers questioned another tacit assumption about breast cancer: that lumps in the breast appear suddenly and must be treated quickly. Instead we have come to think that most breast tumors take years to develop to detectable size; some need decades. In its initial stages the tumor would be visible under a microscope—if one could somehow scan the entire breast with such precision. Only after months or years, however, can the malignancy be detected on a mammogram or by palpation. Yet standard practice still involves a rush to operate after diagnosis. The patient wants to know the details of her condition right away, and surgical exploration is the only conclusive means of providing this information. But surgeons also operate partly in the name of "getting this thing out before it spreads." I cannot count the number of times I have seen a surgeon solemnly tell anxious family members in the hospital waiting room, "Well, we got it all." Although surgeons today target their work more carefully and humanely than they did in the past, they still ignore a crucial fact: we cannot know whether we "got it all." Although our treatments can eliminate the primary tumor (not a small consideration, given its potential danger), there is little evidence that we actually eradicate breast cancer in any more patients than we did decades ago.

As I said, switching when appropriate from mastectomy to lumpectomy leaves survival rates unaffected—the less-severe operation simply does the same job. And we have, in my view, less than compelling evidence that routine mammography benefits otherwise healthy women. Any improvement in our treatment of breast cancer must therefore come from radiation or chemotherapy, both of which are by now standard practice. After a lumpectomy, according to a meta-analysis published last November in the New England Journal of Medicine, radiation decreases the risk of recurrence in the breast region (local-regional recurrence, as it is known) to that associated with full mastectomy—five to 10 percent during the next ten years. Without radiation the risk is about 20 percent. But radiation has no known effect on distant metastases from breast cancer (nonlocal recurrence), which are the chief sources of danger. As a result, post-surgical radiation has no demonstrable effect on survival—a point seldom made clear to patients. Reducing local recurrence is a reasonable goal, because any tumor in the breast could be lethal. But it will not diminish the danger from metastases.

Nor should we think that the modest benefit from radiation has no price. Radiation therapy is rough on the body. It kills cells, inducing inflammation in the breast. Responding to the inflammation, cells called fibroblasts proliferate and lay down scar tissue. Fifteen to twenty-five years after radiation therapy tissues in the irradiated area often feel thick, hard, even wooden—a strange, unpleasant sensation. Meanwhile, the blast of radiation may have created genetic damage that will lead to other types of cancer. For instance, worrisome evidence suggests that radiation may promote lung cancer in the irradiated side of the body. The risk seems slight, but its mere possibility should remind physicians that radiation therapy is not without its price.

Chemotherapy is a more complex issue, with better-established benefits and fewer side effects than it had in the past. Chemotherapeutic compounds kill cancer cells; the hope is that they will destroy any metastases lurking in the body. Thirty years ago chemotherapy was a treatment of last resort, administered only to patients with extensive metastatic disease. I can recall flying overnight to the University of Wisconsin in 1959 to pick up some precious vials of 5-fluorouracil, one of the first, then-experimental chemotherapeutic treatments, for a woman whose cancer was overwhelming her liver. I was dismayed when the drug made her extremely sick, though I thought that it might have postponed her death a little. In the early 1970s researchers discovered that chemotherapy was also effective when several agents were administered right after surgery—as an adjuvant treatment, in the jargon. Today chemotherapy is usually given in the form of a pharmaceutical cocktail, one of the most common being cyclophosphamide (sold principally under the trade name Cytoxan), doxorubicin (Adriamycin), and the original 5-fluorouracil (sold under several names, but usually called 5-FU). Although we have discovered how to moderate the side effects of chemotherapy, it is still heavy going. Common complaints include fatigue, nausea, hair loss, mouth sores, diarrhea, and premature menopause.

Chemotherapy is more effective in younger, pre-menopausal women than in older, postmenopausal women. Many researchers believe that premenopausal women receive this extra benefit because the drugs chemically destroy the function of their ovaries, frequently stopping their monthly estrogen-progesterone cycles. The decline in hormone production affects the two out of three tumors that are estrogen- or progesterone-receptor-positive. Deprived of the chemical catalyst they need to grow, the metastases often shrink, lengthening the time until they become dangerous.

Before chemotherapy, doctors sought to create a similar effect by directly removing patients' ovaries. If the cancer recurred, they tried to amplify the effect by removing women's adrenal glands. These small, triangular organs sit atop the kidneys and secrete hormones, one of which is DHEA, a still-mysterious substance that is a favorite preoccupation of health faddists. Most women convert some of the DHEA into estrogen, thus producing small amounts of estrogen after menopause. Even cutting out the adrenal glands—a procedure involving major abdominal surgery—wasn't the final step. In their zeal to combat estrogen, doctors also injected women with testosterone or prescribed synthetic male hormones.

Although these treatments sometimes slowed the progress of breast cancer, their cumulative impact was horrific and even barbarous. After having the breast and underlying tissue on one side of her chest cut away and covered with a thin skin graft, a woman could be subjected to intense radiation tharapy, primitive forms of chemotherapy, the removal of her ovaries, and, eventually, the removal of her adrenal glands. If this failed, she might be injected with male hormones that made her skin oily, pimply, and hairy.

Things are better today. Surgery is often less severe; chemotherapy can be more tolerable; and, perhaps most important, there is a substitute for removing the adrenal glands and injecting women with testosterone. In the 1970s researchers discovered that the actions of estrogen and other hormones can be blocked chemically by drugs called hormone antagonists, of which the most noteworthy is tamoxifen, which is sold under the trade name Nolvadex. Circulating in the body, tamoxifen molecules prevent breast cells from linking up to estrogen or progesterone molecules by attaching themselves to the cells in their place, blocking the hormones completely. Because hormones can stimulate the growth of the majority of breast tumors that are estrogen- or progesterone-receptor-positive, the potential of tamoxifen for treating this type of cancer is clear. (Tumors that do not respond to hormones grow faster and are less treatable.) Tamoxifen can cause irregular periods or aggravate hot flashes; it also apparently increases the risk of uterine cancer. But it is a vast improvement over removing women's adrenal glands.

Many studies have shown that the unwanted side effects of chemotherapy and antihormonal therapy are offset by the benefits. A compelling example is the Early Breast Cancer Trialists' Collaborative Group, an Oxford-based meta-analysis of 133 randomized clinical trials around the world which examined the effects of chemotherapy and antihormonal tamoxifen therapy on 74,652 women with breast cancer. In the trials breast-cancer patients were usually given mastectomies or lumpectomies and then divided randomly into two groups: one that received some type of chemotherapy or antihormonal therapy (the test group) and one that did not (the control group). The Oxford group reported in 1992 that women who underwent either treatment after surgery had a 12 to 14 percent greater chance of surviving for ten years than those who did not.

Note, though, exactly how this good news was phrased. The improved survival prospect for women who underwent these treatments was in comparison with the prospect for breast-cancer patients who received no systemic therapy—a relative, rather than absolute, increase in survival. Without chemotherapy, a woman with breast cancer faces a 55 percent chance of dying within ten years, according to the Oxford team. Chemotherapy cuts the figure to 48.7 percent, an absolute difference of 6.3 percent. Similar figures appeared in the tamoxifen trials. After surgery 41.2 percent of the women receiving tamoxifen died within ten years, whereas 47.4 percent of the control group died—an absolute difference of 6.2 percent. The treatments, then, buy some time for some women, and this is a very good thing; any woman told that she has even a small chance of surviving longer with adjuvant treatment will likely choose it. Nevertheless, we should not be extolling these therapies as major breakthroughs.

"Wait a minute," some readers may be saying. "Are you being too quick to dismiss these results? Don't these decreases in risk mean that we are eliminating this disease in some people? It may be a small number, but aren't we curing a few more than we did in the past?" These questions are difficult to answer, not least because they involve coming up with a good definition of "cure." For instance, if a woman of sixty-five is treated for breast cancer and then dies five years later of a heart attack, was she "cured" of cancer? Her family, friends, and even her doctor might think so, because the disease never troubled her again. Indeed, a common clinical definition of "cure" is survival for five or ten years. Many researchers would be less quick to claim a cure, because the cancer might have been on its way to recurring when the heart attack intervened.

Acknowledging these complexities, statisticians evolved a precise definition for "cure" in the 1950s. A true cure of a lethal disease like breast cancer is achieved only when people with that disease face the same chance of death as others in the population of the same age and sex. Such true cures are possible with many diseases. Most pneumonia sufferers, for instance, after recovering with the aid of antibiotics have exactly the same prospects for survival as people who have never had pneumonia. Like pneumonia, some cancers, including cervical cancer, childhood leukemia, superficial melanomas, and Hodgkin's disease, can be truly cured.

Breast cancer, unfortunately, is not among this select group. As far as we know, a woman found to have invasive breast cancer is always at higher risk of dying prematurely than women without breast cancer. Even thirty years after her diagnosis she is up to sixteen times as likely to die of the disease as a woman in the general population. That is why responsible researchers in this field avoid the word "cure." Even as they report advances, they must acknowledge the reality: Postsurgical chemotherapy and antihormonal therapy do buy time—an important advance. The slowed progress of the disease can give a woman additional years of life and even allow her to die of other, less traumatic, causes. But breast cancer is every bit as incurable as it was in Halsted's day.


In 1935, 26.2 out of every 100,000 women died of breast cancer. That was a long time ago, of course, when life expectancy for women was sixty-four years. Americans now live longer, which means that diseases of the elderly are more common. Although breast cancer affects many young women, it is still principally a disease of middle and old age—the median age at diagnosis is sixty-four. Statisticians must adjust raw data about incidence and mortality to compensate for underlying demographic shifts. In 1992, the latest year for which figures are available, the adjusted rate of mortality was 26.2 women per 100,000—the same as in 1935. (The death rate rose a bit from 1986 to 1989 and declined by about the same amount from 1989 to 1992.) Since 1935 medicine has seen improvements in surgical technique and anesthesia, and the introduction of mammography, radiation therapy, and chemotherapy, along with an enormous jump in general medical knowledge. But all this progress has had no effect on the chances that an individual woman will die of breast cancer. To my way of thinking, the constancy of the death rate in the face of rising incidence and aggressive treatment is a strong hint that we need to approach the disease in another way.

When I discussed the evidence relating to mammography, radiation, and chemotherapy, I was in the realm of fact—although some colleagues may disagree with my interpretation. In what follows I am moving into unsteadier terrain. Of course, I believe that my view of breast cancer is correct, and much of it is shared by other specialists. But I will be satisfied if I can persuade readers that the mere existence of a coherent alternative explanation raises questions about the mainstream view.

As I have said, almost all cancer researchers think that the disease is triggered by an accidental change in the DNA of at least one cell. That cell divides, producing two cells, then four, then eight, and so on, with the volume of the tumor doubling in each successive generation. By the time the tumor has doubled twenty-three times, the original cancer cell has multiplied to more than eight million. At that point the tumor is about an eighth of an inch in diameter, just big enough to be detected (sometimes) by a mammogram.

Such a tumor is not very dangerous by itself; the danger lies in the metastases. The question is how soon the tumor metastasizes.

For almost thirty years John S. Spratt, a cancer surgeon now at the University of Louisville Department of Surgery, has been measuring the growth rates of breast tumors. In one of his most recent studies, performed in collaboration with researchers from Heidelberg, Germany, Spratt examined the progressive mammograms of 448 women who had tumors that turned out to have been visible in mammograms made before the tumors were diagnosed. (The women's doctors were not necessarily at fault for missing the tumors; in many cases mammographic imagery is ambiguous.) Comparing first, second, and even third mammograms provided evidence of how fast the tumors grew in the intervals. The median doubling time was 260 days, but the range was considerable: the fastest tumor doubled in ten days, the slowest in 7,051 days—that is, almost twenty years. These figures have striking implications.

Consider a woman who is unlucky enough to develop a single cancerous cell on her forty-third birthday. If the woman is especially unlucky, the cell has a fast doubling time of, say, thirty days. Twenty-three cell generations later the tumor might be visible on a mammogram; in another six or seven doublings it will be just big enough to feel. By then the woman will be forty-five. She will probably die before her fiftieth birthday. If, though, the woman develops a cancer with a slow doubling time of, say, 360 days, twenty-three doublings will take about twenty-three years, at which point the tumor might be seen with mammography. The tumor will be palpable in another six or seven years, meaning that without mammography it probably would not be detected until the woman was in her mid-seventies. By that age some people have already died of other causes.

I have simplified these calculations considerably. Spratt and his German colleagues found that breast cancers do not grow at a constant rate but instead slow down as time passes. Yet the principle holds that tumors that begin with fast doubling rates grow faster than tumors that begin with slow doubling rates at comparable stages of formation.

Close scrutiny of tumor doubling times could explain why the earlier diagnoses provided by mammography seem to provide so little prolonging of individual lives, despite the statistical appearance of benefit caused by earlier diagnosis. Although mammography is able to spot tumors as small as an eighth of an inch, which contain eight million cells, the average size at diagnosis with mammography is about 600 million cells. Such a tumor is only a bit more than a quarter of an inch across, but it has already doubled almost twenty-seven times and may have been in the body for decades. The average size of tumors detected by palpation is about 45 billion cells and about an inch and a quarter in diameter; these tumors have doubled an additional eight or nine times. To argue that earlier diagnosis provides an important benefit, one must believe that the tumor is considerably likelier to spread in those eight or nine later doublings than it was in the preceding twenty-seven.

There is no evidence that this is the case; indeed, the small amount of available data suggests that this view is wrong. With mammography we can see breast tumors earlier than we could before. But it is illogical to assume that our newfound ability to observe breast tumors between the twenty-seventh and thirty-fifth doublings means that they are especially likely to spread during this time or afterward and not before. If tumors are more likely to metastasize after rather than before mammography can detect them, the burden is on mammography advocates to demonstrate it. Meanwhile, I believe that the reasonable course is to assume that breast cancer can spread at any time in its development, and that metastasis has probably already occurred by the time we are able to detect the primary tumor. If this view is correct—and I should stress that studies to prove it have not yet been conducted—then it would explain why research has had such difficulty proving that mammography can save women's lives.

Similarly, examination of tumor doubling times could explain why chemotherapy boosts five- and ten-year survival rates but has little impact on the annual percentage of women who die of breast cancer—that is, why it helps women with the disease to live longer but leaves them just as likely to die of metastatic breast cancer in the end. My best guess is that adjuvant chemotherapy wipes out 95 to 99.9 percent of the residual cancer cells in a patient's body. (It doesn't get them all because the remaining tumor cells are innately resistant to chemotherapy.) Expressed as a percentage, the figures are impressive, but the actual impact is surprisingly slight. Suppose that a woman's tumor has metastasized and that the new tumor has grown to a million cells—a lot of cells, but not enough to be seen by the naked eye, or palpated, or spotted by any current imaging method (CAT scan, ultrasound, magnetic resonance imaging, and so on). If chemotherapy kills 99 percent of the cancer cells in a woman's body, this prophylactic treatment will reduce the metastasis from a million cells to 10,000. The remaining cells, which are resistant to chemotherapy, will keep on proliferating, more than likely at the same rate. In six and two thirds cell generations the tumor will have grown back to a million cells and the woman will be right back where she was before treatment began.

Cruelly, chemotherapy helps least those who need it most. If a woman's cancer has the short doubling time of thirty days, the six and two thirds doublings the tumor needs to recover from chemotherapy translate into about 200 days. Because chemotherapy is often administered monthly for six months, the gain is roughly equivalent to the length of treatment. Producing so much suffering, chemotherapy would in this case be a dubious exercise. If the woman's cancer has a doubling time of 360 days, however, she would gain 2,400 days, which is six and a half years. That sounds like a good payoff, but does she need it?If cancer were diagnosed in that woman at sixty-four (the median age of diagnosis), her slow-growing metastases would probably not become life-threatening for twenty to twenty-five years, when she would be in her late eighties. Because most people do not live that long, there would be little point in subjecting her to a round of chemotherapeutic treatment that would give her another seven years when she probably would die of something else in the meantime. If chemotherapy has little impact on a woman's chance of surviving either aggressive or indolent tumors, is it any wonder that it makes few inroads on mortality?

At the same time, chemotherapy should not be dismissed. The calculations above, for doubling times of thirty and 360 days, represent extremes; I used them to illustrate my point. A more representative example would apply Spratt's median doubling time of 260 days to my hypothetical forty-three-year-old woman. If, as before, the first cancer cell develops on her birthday, the resultant tumor could take eighteen to twenty years to show up on a mammogram. (Such calculations are necessarily inexact, because individual tumors do not always grow at the same rate.) The woman would then be in her early sixties—near the median age of diagnosis. With no treatment other than lumpectomy, she would be likely to die before the age of seventy-five. But if chemotherapy gave the woman the time it would take the tumor to double another six or seven times, the onset of life-threatening metastatic disease would be postponed until the woman was at least eighty; antihormonal therapy might buy an equivalent number of years. In real terms the achievement would probably be smaller, because people in their eighties are likely to die of heart disease or some other condition. Nonetheless, the woman would have gained five to ten years of life. This is a precious gift, one that she and her doctor can justly celebrate.

But consider the breast-cancer patients doctors most dread seeing—women in their thirties or forties. Such cases are relatively uncommon; breast cancer owes its status as the leading killer of women in this age group mostly to the even lower likelihood that they will be killed by anything else. Nonetheless, the individual tragedy of a disease that strikes down young, vibrant people makes it disproportionately urgent to treat them. Sadly, younger women in whom cancer is diagnosed are more likely than older women to have fast-growing tumors, because slow-growing tumors are usually still too small to detect. Given the probable doubling rates, these women will be lucky if we can give them an extra five years. Five years is, of course, much better than nothing—but much less than the thirty or forty years these women will lose. Anyone who treats younger breast-cancer patients knows that we will not have made major progress in the treatment of this disease until we can give women like these, with fast-growing cancers, thirty doubling times rather than six or seven.


In effect, mammography today provides our definition of breast cancer. Any tumor spotted on a mammogram is treated, almost reflexively, with surgery, radiation, and often chemotherapy and antihormonal drugs. Thinking about doubling times suggests the inadequacy of this approach. When doctors diagnosed breast cancer by palpation in annual exams, they found principally fast-growing tumors—ones whose average doubling time, according to the work of Spratt and other researchers, was about ninety days. Despite decades of work, medicine still is unable to treat this kind of cancer effectively. Today the spectrum of breast cancer is different. Perhaps because of the hormonal changes created by the changes in women's lives, physicians are increasingly likely to observe the "new" cancer described above, which is slower-growing and much less dangerous. These cancers, because they progress so much more slowly, have a radically different impact on women's lives. For that reason we should be more discriminating in how we treat them.

"New" may be a misnomer for this slow-growing breast cancer. Although its incidence has risen, I suspect that it has been with us for at least fifty years; we just weren't able to see it. In fact, I would not be surprised if someday we are all found to harbor somewhere in our bodies several small, slow-growing tumors that will never cause us any problems. (They are beaten to the punch by cardiovascular disease or faster-growing cancers.)

Among the most important varieties of the new breast cancer is the in situ tumor—the small, localized, almost nongrowing tumor that at the time of diagnosis has seemingly neither become invasive nor developed the capacity to metastasize. Prior to mammography, as noted earlier, in situ tumors accounted for only one to two percent of all breast-cancer diagnoses, whereas today in communities where people see doctors often and have lots of tests, in situ tumors account for at least 10 percent of all breast-cancer diagnoses. After lumpectomy and radiation, only one out of ten in situ malignancies recurs in the next five to eight years.

Most of my colleagues celebrate this as a triumph, because it appears that we are catching cancers earlier than ever and curing more of them. They may be right. But consider this—if one out of ten in situ cancers recurs after treatment, nine out of ten do not. If my view is correct, even without treatment many or most in situ cancers would never have grown big enough to be detected by palpation, let alone to pose a threat to life. They might even have become invasive and metastasized, but the metastases would also be too small to be detectable and would never be lethal—rendering the recurrence rate and thus the question of treatment ultimately unimportant to survival. As a result, mammography is only leading physicians to diagnose an ever-larger number of harmless tumors. Patients who otherwise would never have known they have cancer may needlessly suffer through the unique pain, anxiety, disfigurement, and expense associated with modern medicine and cancer. For all we know, the chief effect of mammography has been to disguise our inability to cure the old cancer, by burying it in cases of new cancer.


Because of the prevalence of in situ and other slow-growing breast cancers, women who receive a positive mammogram should not despair. Two thirds to four fifths of positive mammograms lead to biopsies that do not reveal cancer. Even if the biopsy indicates cancer, the patient should keep in mind that not all tumors are truly dangerous, and she should strive to learn what kind of tumor she has.

Although scientists are divided in their opinion of its accuracy, I believe that one of the most promising gauges of risk is the "S-phase fraction," which is a rough measure of a tumor's doubling time, derived from a technique known as flow cytometry. Technicians calculate this measure by chopping up a small amount of tumor tissue in a kind of specialized blender, staining the cell nuclei with a dye, and squirting the result one cell at a time through a very fine nozzle. The cells shoot through a thin laser beam, each nucleus casting a shadow as it crosses the light. Computers record the shadows with enough detail to discern the approximate percentage of cells in the sample that are dividing. From these data physicians can infer whether the cancer is aggressive (a doubling time kf sixty days or less), moderate (sixty-one to 150 days), indolent (151 to 300 days), or very indolent (more than 300 days). Because tumor growth rates may change over time, and metastases do not necessarily march in lockstep with the tumors that spawned them, the actual situation faced by patients is more complex than indicated by this summary. Nevertheless, Ibelieve that the broad principle holds:armed with information about a tumor's growth rate and the patient's age at diagnosis, doctors could often be more informative than they are now about what lies ahead for their patients.

If doctors could accurately gauge tumor growth rates, using any agreed-upon test, my strong hunch is that about a third of the tumors now detected would be found not to need treatment beyond removal of the tumor itself. Perhaps another quarter of women in whom breast cancer is diagnosed could gain considerable time—enough to take them safely into old age—with antihormonal therapy alone. The remainder could be helped by the combination of surgery, radiation, and chemotherapy, though not nearly as much as the providers of these treatments or their patients would hope. For this last group of women, I am very sorry to say, modern medicine has less to offer than newspaper headlines suggest. The outcome was dictated well before diagnosis—by the date the first cancer cells developed and by the rate at which they grew.

If, as I suspect, a woman's fate is set very early in the development of a tumor, it seems implausible that advances in detection will have an impact on the disease. One can always hope that science will develop a wonder drug that eradicates tumors completely, even when they can't be seen or felt. But for the present I think we should focus research on improving our ability to distinguish between women with breast cancer who can benefit from aggressive treatment and the larger number who will gain little from it no matter what we do.

The ultimate hope is preventing this awful disease, perhaps by modifying the contemporary hormonal environment that seems to promote it. Researchers at the University of Southern California have been examining ways to lower young women's exposure to reproductive hormones. Another approach is to use an anti-estrogen drug like tamoxifen preventively in postmenopausal women whose histories of breast problems indicate that they are at high risk of developing cancer; I am involved in a study that is examining this kind of treatment. The risks in changing the hormonal balance of millions of women are considerable, however, and it seems likely that any new preventive for breast cancer will have its own side effects.

Advances in this area will surely be slow, but they may be the only realistic hope for eventually lowering the death rate from breast cancer. Meanwhile, we should carefully consider whether we are misleading some women with messages of unwarranted hope at the same time that we are needlessly terrifying and hurting other women by diagnosing and treating a condition that will never pose a threat to their lives.