Few things frighten a woman more than discovering a lump in one of her breasts. With good reason: breast cancer may transform a woman's breast into the vehicle of her death. It is twice as likely to be diagnosed in an American woman today as it was sixty years ago. And the treatment—surgery, usually followed by radiation and chemotherapy—is disfiguring, painful, and all too often unsuccessful.
I have been researching and treating this disease for more than thirty-five years, a period in which the public's awareness of breast cancer has risen enormously. The disease has brought into being an entire industry of research organizations, charitable agencies, commercial ventures, and advocacy groups. Every new statistic is trumpeted in the media, and every encouraging research finding, no matter how tenuous, is held up as a potential breakthrough.
One result of this visibility has been a rise in public sympathy for victims of breast cancer and a concomitant rise in funding for breast-cancer research. But the growth in awareness has had another, less desirable result: a flood of often contradictory information that has led to public confusion. Paradoxically, women are both too anxious about their chances of developing breast cancer and too hopeful about our current approaches to diagnosing and treating the disease. They believe that breast cancer is an epidemic and that it is being cured. Unfortunately, both these beliefs arise from flawed reasoning—not by women but by the medical profession.
Two groups in the health-care profession are involved in the fight against cancer—indeed, against any kind of disease. The first works principally on the front lines, helping patients understand the therapies available and offering insight, treatment, and reassurance whenever possible. The second works mostly at scientific institutions, performing the methodical, frustratingly slow tasks associated with epidemiology, clinical trials, and laboratory analysis. As researchers, the members of the second group are necessarily less concerned with the fate of specific patients than with understanding specific diseases and whether medicine is successfully combating them. To move forward, they must coldly distinguish between genuine advances and wishful thinking. I have spent my career as a member of the first group, although Ihave also spent years helping to conduct and analyze clinical trials. In what follows Ihave adopted the researcher's view of the big picture, while also summarizing the risks and benefits of the treatments now available to women with breast cancer—treatments the clinician in me still recommends and performs, though the researcher wonders how often they will be of meaningful help. Only by stepping back from the perspective of caring for individual patients can one hope to make clear what doctors mean (or should mean)when they use such broad words as "epidemic"and "cure."
Many of my patients have conflicting images of their breasts. On the one hand, breasts are symbols of beauty, sexuality, and nurturing; on the other, they are troublesome organs that are increasingly likely to threaten women's lives. In the United States the likelihood that a woman will be found to have breast cancer has slowly and inexorably mounted since the 1930s, when some systematic data collection began. The increase in diagnoses, already a cause for concern, accelerated in the 1980s, growing by a rate of four percent a year. This year, according to the American Cancer Society, some 184,300 women will discover that they have the disease; another 44,300 will die of it. Of the women in whom cancer is diagnosed, 9,200 will not yet be forty—nearly twice the number of women under forty who were found to have breast cancer in 1970. The disease is now the leading cause of death for American women aged forty to fifty-five, and causes women to lose more years of productive life than any other disease. Numbers like these are why breast cancer is often called an epidemic.
To our grandparents, this picture would have seemed amazing. At the turn of the century cancer of the breast was a relatively unusual disease. What happened? Why does the incidence of breast cancer seem so much higher today?
Some of the increase is more apparent than real. Because women today are less likely to die young in childbirth or of infectious disease, they live long enough to develop diseases of middle and old age, breast cancer among them. And the recent jump in the number of breast-cancer victims under fifty is almost wholly due to the concurrent jump in the number of women in that age group, caused by the Baby Boom. A third reason for the increase in diagnoses of breast cancer is the growing use of mammography, a technique that uses x-rays to examine the breast. With mammography doctors catch many cancer cases earlier than they otherwise would have—and some cases that would never have been caught at all. The technique surged in popularity in the 1980s, and accounts for much of the recent spurt in diagnoses. (Now that mammography is routine, the rate of increase in diagnoses has slowed.)
At the same time, most experts in medical statistics believe that these factors do not explain all of the rise. Even when greater longevity, the population bulge, and the introduction of mammography are taken into account, a real, underlying increase remains. Minus those three factors, the chance that a woman will be found to have breast cancer has been growing steadily for decades, at roughly one percent a year.
What lies behind this rise? Although there is not enough evidence to say with certainty, an increasing number of observers have come to believe that the emergence of breast cancer as a widespread health problem is tied to the extraordinary transformations in women's lives. Coupled with better nutrition, the expansion of opportunities for women, especially in the industrialized West, altered not only women's lives but also their bodies, and especially their cycles of reproductive hormones—apparently making them more susceptible to certain cancers.
For most of human history menarche, the age of first menstruation, usually occurred in the late teens. (This is one reason that previous generations saw less early-teenage pregnancy—fewer adolescents were physiologically capable of having babies.) Once fecund, women of past millennia quickly became pregnant with the first of perhaps half a dozen children, each of whom they breast-fed for an extended period—a practice that regularly stops the menstrual cycle. If they survived to their mid-thirties, they were aged in appearance and probably post-menopausal; their brutal living conditions usually did not permit them to live much longer. Late menarche, multiple pregnancies, long nursing times, early menopause—all these combined to make women of the past menstruate much less often than their modern counterparts. Many women in the past may have ovulated only twenty times in their entire lives.
This grim picture changed only recently. Not until modern times has a large percentage of humankind been able to obtain a continuous supply of nutritious food and potable water or been able to control infectious disease. The average age of menarche has fallen to twelve in Western industrialized nations. Meanwhile, the age of first marriage has risen. According to the U.S. Census Bureau, it now averages twenty-four for women in this country; many educated and affluent women do not marry until their thirties, partly because of the increased opportunities to have careers outside the home. Pregnancy, too, has become much less common, as lost working time drives up the cost of having babies. Marriages produce an average of two children, which women nurse briefly if at all. And menopause does not occur until age fifty or later. Women today are thus exposed to reproductive hormones over a much longer span than in the past. They may have 300 to 400 periods—fifteen to twenty times as many as their ancestors had, exposing their breasts to historically unprecedented numbers of estrogen-progesterone cycles.
Estrogen and progesterone, like aspirin, have such familiar-sounding names that people often don't realize how powerful their effects are. Among these effects is the multiplication of cells within the breast. With repeated menstrual cycles that are rarely interrupted by full-term pregnancy, the number of cells in some parts of the breast can increase by a factor of a hundred or even more. If only because of the simple increase in number, this constantly repeated cellular multiplication is believed to increase the likelihood of genetic accidents. Most cancers are believed to arise from such accidents, and so the strong suspicion is that repeated menstruation is a precursor to cancer of the breast.
If the improvements in women's lives have indirectly promoted breast cancer, then it is unhelpful to call the growth in its incidence an epidemic. In medical terms an epidemic is the sudden outbreak of a generally rare condition, such as the deadly spread of cholera in a city with contaminated water, and should be stopped by striking at its source—in this example the contaminated water. The "epidemic" of breast cancer, in contrast, may be an unwanted accompaniment to what most Americans view as social and material progress. If this suspicion is true, it is obviously unacceptable to eliminate the epidemic's cause.
Equally important, the increase in breast cancer does not resemble other epidemics. Although the likelihood that a woman will be found to have the disease has climbed, the likelihood that it will end her life has not. After adjustments for today's longer life-span and the population bulge associated with the Baby Boom, the proportion of women who are killed every year by breast cancer—24.7 to 27.6 per 100,000 —has remained little changed since the 1930s. Women face an ever-increasing risk of being discovered to have breast cancer, then—but not of dying from it. It is highly unusual, to say the least, for a nationwide epidemic of a fatal disease not to affect the death rate.
This odd and even paradoxical situation has sown much confusion and fear. Breast cancer is a major public-health concern; it kills 0.04 percent of all American women yearly. But it is important for women to recognize that other conditions, especially the various forms of cardiovascular disease and, for smokers, lung cancer, are much more likely to claim their lives. Unfortunately, the enormous publicity accorded the rise in breast-cancer incidence has obscured the fact that the disease is not the leading killer of women. Also, the publicity usually obscures the fact that the majority of women who die of the disease are elderly. In a survey conducted by three researchers at the Dartmouth Center for the Evaluative Clinical Sciences and published in May of last year in the Journal of the National Cancer Institute, the median estimate female Baby Boomers gave of their chance of dying of breast cancer within a decade was 10 percent. A substantial minority thought the risk was 30 percent or more. In fact, the likelihood that a woman in her forties will die of breast cancer in the next ten years of her life is on the order of 0.4 percent.
In my view, the medical profession, too, has lost perspective. If a woman's chances of dying of breast cancer are little changed despite a huge rise in the incidence of the disease, there are two possible explanations. First, we could be making progress. To go on from the current hypothesis: as women's changing hormonal environment slowly drove up the number of breast-cancer cases, our mastery of the disease could have grown at such a rate that, year after year, the increase in cures precisely canceled out the increase in incidence, leaving the overall death rate unaffected. When my colleagues claim that we are curing breast cancer, they are implicitly endorsing this view. And why not? When physicians treat more cases of a disease while observing the same number of deaths, that means a smaller percentage of their patients are dying.
The second possible explanation is that the change in women's hormonal environment is creating a surge in slow-growing, less-aggressive forms of breast cancer. Because this "new" breast cancer, if it is indeed responsible for the rise in diagnosed cases, is a much less dangerous disease than the breast cancer that was found before, in many cases it would not need treatment beyond excising the primary tumor. The rise in incidence would not be matched by a rise in breast-cancer mortality, because women would die first of other causes. The apparent good news about the decline in the proportion of fatal cases would in fact be masking the unchanged prevalence of the "old" breast cancer: a persistent public-health problem that is just as likely to kill women now as it was sixty years ago. I believe this is just what we are seeing.
Female breasts are one of the most variable parts of the human anatomy. Evolved from sweat glands, they are designed to provide milk for infants through a system of ducts and lobules. The ducts are small tubes that run several inches back from the nipple to the milk-producing lobules, which stick out from the ducts like clusters of tiny grapes. Both are enveloped by fat and connective tissue, which are contained within a sac of skin shaped roughly like a teardrop. The whole assembly changes dramatically in size, shape, and constitution during the menstrual cycle, pregnancy, breast-feeding, and menopause. Not only do breasts vary from woman to woman but each woman's breasts continue to change throughout her life.
At any given time a third to a half of all Western women have some kind of breast problem, although most are not particularly concerned about the symptoms—nor need they be. The symptoms frequently include swelling and aching before menstrual flow; women may feel their breasts engorge and grow tender. If their breasts become lumpier, however, this may be owing to cysts—fluid-filled balloon-like sacs within the breast. Or the lumps may be solid, nodular clumps of overgrown breast-duct cells, known generically to doctors as mammary dysplasia or , the most widely used term, fibrocystic disease. These conditions are benign—a term doctors use to mean "not cancerous." ("Benign" does not mean "not painful" or "not harmful." Many benign conditions should be treated.)
If much of the breast is palpably lumpy, as is often the case, the diagnosis is usually "benign." Matters are less clear when the problem is in a small area: "dominant mass" is the term used by most doctors for a swelling that stands out sharply. In such a case a biopsy is almost routinely recommended. Sometimes the biopsy involves nothing more than extracting a sample from the breast with a needle, but the surgeon may also remove the entire lump. Afterward, the tissue is examined in a laboratory. Most of the time the news is reassuring; two thirds to four fifths of all biopsies reveal that the abnormality is not malignant. (Women in their forties are more likely than older women to have negative biopsies, because mammograms of their naturally lumpier breasts are harder to interpret.)Yet the specter of breast cancer remains—many of these "benign" conditions are statistically linked with the disease.
Breast cancer is as diverse as the breast itself, appearing in many different guises. Some cancers seem to erupt out of ordinary breast tissue with an awesome virulence, spreading rapidly throughout the body. When viewed under a microscope, the cells in these cancers almost always bear no resemblance to ordinary duct or lobule cells—they have lost all the specialized characteristics that differentiate cells in the breast from cells in other parts of the body. "Poorly differentiated" malignancies, as pathologists refer to them, are usually bad news, no matter what we bring to bear therapeutically.
Fortunately, these poorly differentiated, clinically virulent cancers are relatively uncommon. Much more often—perhaps in half of all breast-cancer cases—pathologists see malignancies that still bear some of the characteristics of normal breast tissue. These "moderately differentiated" tumors have a wide range of outcomes, though the prognosis for the patient is generally more favorable. A substantial number of women with moderately differentiated tumors will survive for years after treatment—even decades. In most cases these tumors evolve more slowly than their poorly differentiated cousins, probably taking years to become detectable. "Well-differentiated" tumors, a less common form, are more indolent still. Indeed, pathologists sometimes have trouble ascertaining whether they are truly malignant; women have a good chance of surviving them.
In recent years doctors have increasingly encountered a fourth, somewhat different type of breast tumor: in situ cancer. Twenty years ago in situ tumors made up no more than one or two percent of all breast-cancer cases. Today the figure is 10 percent or more, a five- to ten-fold increase. In situ tumors are usually small—half an inch or less across—and confined to the ducts and lobules of the breast. When diagnosed, these tumors usually appear not to have invaded the connective tissue or spread elsewhere in the body; like well-differentiated tumors, in situ tumors are not likely to be fatal.
I must caution that breast-cancer characterization remains an inexact science. The categories themselves are fuzzy. Well-differentiated and in situ tumors can occasionally grow fast and develop into serious, even fatal, disease; some poorly differentiated tumors respond amazingly well to treatment. The uncertainty is partly due to a lack of absolute procedures for distinguishing among the three classifications. Often a tumor is classified as poorly differentiated by one pathologist and moderately differentiated by another. Neither doctor could be accused of making a mistake.
More important, the degree of differentiation does not by itself describe the malevolence of a tumor. It is important to know too if the tumor cells respond to estrogen and progesterone—that is, whether they retain the biochemical equipment to link up physically with molecules of these hormones. (Given the apparent role of hormones in promoting the disease, their significance in its outcome is unsurprising.) Up to two thirds of all breast tumors have enough sensitivity to reproductive hormones to be, in the jargon, estrogen- or progesterone-receptor-positive; such tumors tend to grow relatively slowly and can be treated by modifying a woman's hormonal environment, either with drugs or (rarely) by removing the ovaries. Estrogen- or progesterone-receptor-negative tumors generally have poorer outcomes.
Even when such complicating factors are considered, though, the tumor's degree of differentiation is a reasonably accurate approximation of its virulence. The less resemblance cancer cells bear to the tissue that spawned them, the worse the prognosis for the patient.
Notwithstanding the myriad forms in which breast cancer presents itself, researchers believe that at a fundamental level all breast cancers are similar. In their view, breast cancer, like other cancers, is the result of accidental changes in the genetic makeup of a cell—mutations. When the cell reproduces, it passes on its altered DNA. It begins to reproduce independently, regardless of the body's needs—the defining characteristic of cancer. Cells depend on nutrients and oxygen from the bloodstream. Under ordinary circumstances aberrant, independently growing cells would outpace the available blood supply by the time they had formed a blob of tissue one or two millimeters in diameter; they would then die from a lack of oxygen and food. Instead cancer cells—by means that remain frustratingly unclear—create their own network of blood vessels to secure necessary nutrients. Once this circulatory system is established, the nascent tumor can continue to grow at its own pace. Eventually a discrete mass of aberrant cells becomes identifiable, either as a denser area on a mammogram or as a lump detectable by touch.
As the cancer progresses, it can invade the surrounding tissue and spread throughout the body in the familiar and frightening process known as metastasis. Metastasis is almost always how breast cancer kills its victims. Left untreated, as it generally was in previous centuries, the original, or primary, tumor usually grows very large, sometimes to the size of a grapefruit. Eventually it begins to outstrip its self-generated blood supply; portions of the tumor die, leading to ulceration of the breast surface and eventual death from infection, hemorrhage, or both. Today this peril is avoided with relative ease by removing the tumor. The metastases are quite another problem. As it grows, the primary tumor sheds cancer cells into its self-generated network of blood vessels. Spreading through the body, these cells can lodge in almost any vital organ, creating a second tumor—or a third, or a fourth. Like the primary tumor, the new tumors create their own blood supply, each one siphoning off nutrients from the body to feed its expansion. When the metastases reach an appreciable aggregate size—a total tumor load of two pounds or so, scattered throughout the body—the struggle for life is usually over.
From an intellectual point of view, metastasis is an amazing phenomenon. If a surgeon inserted a microscopic clump of normal cells from a woman's breast into another organ, the body's defense systems would wipe out the misplaced normal cells almost instantly. Yet cancer cells that split off from the main tumor and lodge elsewhere in the body not only survive but can grow exuberantly. For this reason most doctors believe that the best method for stopping breast cancer is to detect it before it has spread. Find the problem while it is still small and isolated—that is the hope.
The best method for early clinical detection of breast cancer is mammography. The American Cancer Society advises women aged forty to forty-nine to have mammograms every one to two years, and women aged fifty and over to have them annually. Women with any potential cancer symptoms, such as suspicious lumpiness of the breast, should see their doctor immediately.
We have been trying to treat breast cancer aggressively for decades. Many physicians now believe that the long effort to detect and control this disease is meeting with success. I shall argue otherwise. Despite the hopes pinned on mammography, it has had little impact on women's health—indeed, it may have had none. And although we have taken some important steps forward in our treatment of breast cancer once it has been diagnosed—steps that can add years to a woman's life—we are still far from curing the disease.
Finding breast cancer as early as possible seems to be a great idea, like trying to diagnose high blood pressure before it damages the heart or the kidneys. And mammograms can occasionally detect tumors as small as an eighth of an inch across, whereas the lower limit for tumors diagnosable by palpation (examining the breast manually) is about half an inch across. Yet one would like to be sure that this difference actually translates into a higher likelihood that treatment will be successful. An official nationwide mammography program would be a huge commitment: 51.5 million American women are aged forty or above. And one must bear in mind the cost of needless medical procedures generated by the huge number of false-positive mammograms—two to four false positives for every true positive, according to some measures. (A false positive shows a mass or lump that proves after further testing not to be cancerous.)We continue to consider creating a national screening program, but I believe it has never been proved that such a program would, on balance, be beneficial—even if it served the secondary purpose of bringing into the health-care system women who otherwise could not afford it or would not see a doctor frequently.
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.