Good News and Bad News About Breast Cancer

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.