Rethinking Breast Cancer

Nancy Ulene, 43, wasn’t particularly worried when a routine mammogram turned up something her radiologist thought was fishy. She had had a tumor seven years earlier that turned out to be benign. But this time was different. A biopsy confirmed that Ulene, the niece of former Today show medical expert Art Ulene, had ductal carcinoma in situ, or DCIS, a growth that is variously described as either an early-stage breast cancer or a precancerous lesion. “It was very confusing,” says Ulene, a color stylist for Walt Disney TV Animation. “I needed to know more.”

What she soon learned was that the kind of cancer she hada group of malignancies so tiny that they were rarely seen before the advent of mammograms powerful enough to spot themis at the heart of a raging debate in the cancer community. Doctors know what to do when they find tumors the size of marbles or plums. That’s what surgery, radiation and chemotherapy are for. But what do you do with cancers the size of pencil points? Do you treat them as you would a massive tumor? Do you leave them alone? Should you even be looking for them in the first place?

This year, according to the American Cancer Society, some 200,000 women (and 1,500 men) will learn that they have breast cancerup from a little more than 100,000 two decades ago. While the death rate from the disease has dropped modestly over the past decade, there is a growing sense of frustration among cancer experts. Part of the problem is DCIS. Thirty years ago, these miniature tumors, which usually don’t spread into the rest of the body, were diagnosed in some 6% of breast-cancer patients. Today the ratio is closer to 20%, largely because of advances in detection techniques. Yet the treatment of choice is still surgery followed by radiation. “We may be far overtreating our patients,” says Dr. Julie Gralow, an oncologist at the Fred Hutchinson Cancer Research Center in Seattle. “We’ve now got women being diagnosed with tumors that probably never would have been treated if we didn’t have mammography. They probably would have lived long, natural, healthy lives never knowing they had breast cancer.”

The long-simmering debate over the value of routine mammograms flared up again last month because of new questions about whether the test has been sufficiently proved to save lives (see box). But the mammography squabble masks a deeper problem: advances in screening and diagnostic technology have outpaced treatments, leaving cancer patients and their doctors struggling to make treatment choices neither are prepared to make.

That’s the bad news. The good news is that the situation is on the mend. Basic research into the molecular chemistry of cancer is well funded and advancing steadily, delivering better diagnoses and smarter drugs. Meanwhile, a series of dramatic improvements in the tools of treatment are moving into clinical trials, promising patients kinder, gentler ways to treat their cancers. Among the highlights:

Surgeons are developing several techniques that destroy tumors while sparing more breast tissuewithout reducing the chances of survival. (This can be particularly important for small-breasted women who don’t necessarily have a lot of tissue to spare in the first place.)

Doctors are experimenting with new ways to deliver lethal radiation that more closely targets the tumor and takes just a few days at mostcompared with the more usual six-week regimento finish the job.

Researchers who are trying to minimize the need for chemotherapy are finding that patients can avoid chemo altogether if just one or two cancer cells are discovered in a lymph nodeapparently these cells are not active enough to cause any further trouble.Most of these new approaches still need to be more fully tested before they can be widely adopted. Some of them will undoubtedly fail. The ultimate prize, which could be available within the next 10 to 15 years, would be a diagnostic test that determines which genes in a particular tumor have gone awry. As doctors are increasingly aware, it’s not just a tumor’s size but its underlying biology that determines how quickly it will grow. Genetic tests may one day accurately identify those tumors that are likely to spread and those that are not. The tests may also tell doctors to which drugs your particular tumor is most vulnerable.

Before peering any further into the future, however, it helps to know a little biology. Most breast cancers begin in the milk ducts, narrow passageways that radiate throughout the breast. A few cells, for reasons that are not completely understood, start accumulating genetic mistakes that cause them to grow abnormally. Eventually the cells develop into DCIS. The good thing about DCIS cells is that they haven’t spread beyond the milk duct. The bad thing is that they are malignant. “Some people call DCIS precancer, but it’s not precancer,” says Dr. Dennis Slamon, director of breast-cancer research at the UCLA School of Medicine. “It’s preinvasive. It’s cancer that hasn’t invaded outside the breast ducts.”

After a tumor starts to break out of its milk duct, it’s often still quite small. About the smallest tumor a mammogram can pick up is 0.5 cm to 1 cm in diameter. By contrast, the average cancers that are felt either by women or their physicians are around 2.5 cm. Even though mammograms still miss about 10% of all tumors, it’s their ability to spot smaller tumors, which are generally easier to treat, that keeps women coming back for their annual appointment.

Once the cancer puts down roots in the lymph nodes, the prognosis gets worse. The lymph nodes act as a kind of sewer system for many types of toxins and wastes. Tumors growing in the lymph nodes have a greater chance of breaking off and traveling to the bones, brain, lungs or other parts of the body, where they can seed new growths, called metastases. Here again, doctors used to think that any breast cancer that had spread to the lymph nodes must have been growing a long time. Now they realize that the fact the cancer has shown up in the lymph nodes may have more to do with how aggressive it was from the start than with how long it has been growing.

That’s what makes DCIS treatment so controversial. What if most of the tiny tumors that show up in high-resolution mammograms are the ones that grow the slowest or maybe even disappear of their own accord? It probably doesn’t matter too much how quickly you treat these slow-growing tumors; most women would survive. And if that’s the case, wouldn’t it make sense to leave those tumors alone until you could figure out whether they are going to grow? Some breast-cancer experts even speculate that more women may die with these tumors in their breast than because of them.

An intriguing study on invasive tumors, begun in 1988, provides some clues. The trial included about 1,200 women whose tumors were less than 2 cm across with no evidence of malignancy in their lymph nodes and whose cancer cells looked, under the microscope, as if they weren’t particularly dangerous. Although these women did not receive the “watchful waiting” approach pioneered in prostate-cancer patients, they weren’t treated as aggressively as they might have been. For five years after their tumors were surgically removed, doctors did nothing more unless there was a recurrence. Though 11% of the women did in fact develop a second cancer, their survival rate (and this is the key) was comparable to that of another group of women who had undergone chemotherapy (with or without the drug tamoxifen) at the time of their surgery.

No one is recommending a wholesale “cut and wait” approach for breast cancerparticularly on the basis of a single study. For one thing, waiting to see how aggressive a cancer truly is makes a lot more sense for men in their 80s than for women in their 40s.

The question about what to do with DCIS is also rife with extenuating factors. If DCIS never left the breast ducts, physicians could safely ignore it. No one knows for sure, but at least one study suggests that perhaps 40% of DCIS lesions will develop into invasive tumors that, if left untreated, could eventually prove fatal. That means that maybe 60% of DCIS cases never threaten a woman’s healthand therefore these growths do not need to be removed.

Before the routine use of mammograms, most cases of DCIS were discovered accidentally, often during other surgeries. Thanks to better screening, the absolute number of DCIS cases has jumped seven-fold in the U.S. over the past three decades. “At the moment, we don’t know which women diagnosed with DCIS might be able to get by with minimal treatment,” says Dr. Eric Winer, director of breast oncology at the Dana-Farber Cancer Institute in Boston. As a result, most doctors agree that it’s prudent to treat all DCIS cases as if they are dangerous. (In the past couple of years, however, some surgeons have started treating the tiniest, least aggressive DCIS lesions by excision alone, forgoing radiation, provided they can get wide, cancer-free margins around the tumor.) That’s not the only dilemma with DCIS. Radiologists don’t actually see a DCIS lesionthey see its footprint in the calcified remains of dead and dying cells. What makes mammography as much an art as a science is that these so-called microcalcifications are often just a normal part of breast anatomy. It’s the pattern of microcalcificationswhether new ones appear suddenly or line up in particular formations like soldiers in a rowthat suggests something more sinister.

For a variety of reasons, radiologists in the U.S. tend to err on the side of caution. That is, they identify lots of “abnormalities,” of which only 2% to 11% prove to be cancerouseither DCIS or an invasive tumor. Sometimes a second mammogram or an ultrasound provides the necessary reassurance. Other times, a biopsywhich entails the removal of some breast tissueis required to resolve any ambiguity. Here the odds of finding cancer rise to about 25%, which means that 75% of biopsies come back negative.

For years many women got an ugly scar along with their answer because most biopsies began with a wide surgical incision. Nowadays, more breast centers offer such minimally invasive biopsies as the Mammotome, which relies on careful positioning of the breast to remove the least amount of tissue. “We’re trying to reserve surgery for treatment, not diagnosis,” says Dr. Joshua Gross, chief of breast imaging at Beth Israel Medical Center in New York City. “So many women I see have scars all over their breasts. The scars aren’t from being treated. They’re from doctors finding out if a woman even needs to be treated.”

Thirty years ago, surgery meant mastectomyremoval of the entire breast. By the 1980s, studies had shown that for tumors that had not spread, only the portion immediately surrounding the cancerous growth needed to be cut awayprovided the operation was followed by radiation therapy to destroy any wayward cancer cells the surgeon may have missed. Today, as more women are being treated for ever smaller tumors, doctors are finding that even these so-called lumpectomies can be further refined.

The new minimalist approach begins with the first cut, which many surgeons now place near the nipple, under the arm or in the lower portion of the breast so that any scars are much less obvious. Because many small tumors are confined to the duct or its immediate vicinity, doctors have learned they don’t need to remove so much of the overlying fatty tissue as they used to. “Taking out too much fat was what led to the concavities and deformities we saw in the past,” says Dr. Alexander Swistel, director of the Weill Cornell Breast Center in New York City. The remaining tissue can then be rearranged to fill in the void.

Doctors have also developed a new technique for determining whether a cancer has spread to the lymph nodes. Instead of taking 15 to 20 lymph nodes from in and around the armpit for further examinationa procedure that can lead to problems with swelling and disability of the armthey are focusing on certain key spots called sentinel nodes. The surgical team injects a blue dye into the tissue from which it has just removed a tumor and traces its path through the lymph system. The first node or two that the dye reaches are presumably also the first nodes in which any cancer cells would take up residence. The sentinel nodes are removed and closely examined. If they are free of cancer, chances are all the other nodes are clear. Preliminary evidence suggests that this is indeed the case, though two randomized controlled trials of the technique are under way to make sure.

Eventually, women may be able to forgo surgery entirely. Doctors at the M.D. Anderson Cancer Center at the University of Texas in Houston and the Weill Cornell Center in New York City are experimenting with high-frequency radio waves that can literally cook tumors from the inside. Using ultrasound to guide them, doctors insert a multipronged probe into a tumor. The prongs open up like the spokes of an umbrella and melt malignant cells without burning surrounding breast tissue. So far, the procedure has been performed only on women who were planning to get a mastectomy or lumpectomy anyway. But early results have been encouraging enough that physicians hope to test it as a stand-alone procedure this year.

One of the drawbacks to minimally invasive surgery, in the eyes of many women, is that it is usually followed by radiation. Currently, doctors shoot high-powered beams across the affected breast five days a week for six or seven weeks. But it has become increasingly clear, particularly with smaller tumors, that if the cancer recurs, it usually does so in the original spot from which the tumor had been removed. By focusing radiation more precisely on the place where the original tumor occurred, says Dr. Silvia Formenti, chairwoman of radiation oncology at New York University School of Medicine, “we think we can make radiation better and easier for the patient.”

Taking a page from treatment manuals for prostate cancer, a few doctors have implanted tiny radioactive “seeds” in the breast to ensure that the maximum amount of radiation is delivered near the tumor site. They leave a small, balloon-tipped catheter in the breast after a lumpectomy. The balloon is filled from the outside with the radioactive material for five to 10 minutes twice a day. After five days, both catheter and contents are removed.Don’t have five days to spare? Doctors in the U.S. and Europe think they may be able to deliver all the radiation that’s needed while a woman is still on the operating table. In an experiment conducted on 15 women in England, physicians inserted a tiny coil into the cavity created by the removal of a tumor. The bottom of the coil was shielded in lead to protect the heart and lungs, while the breast tissue was stretched around the coil. As the surgical team left the room to avoid exposure, the device delivered a full course of radiation treatment at once. After 25 minutes, the coil was removed. In 18 months of follow-up, none of the breast cancers have recurred.

Unfortunately, some cancers do reappear, sometimes far from their original site. This is where chemotherapy can make a difference. Once again, it’s not always clear who will benefit most. A concrete example helps explain:

Many doctors would recommend chemotherapy to a woman whose tumor measures 2 cm across, even if it has shown no sign of spreading to the lymph nodes. Why? There is always the possibility that some cancer cells have already escaped to the rest of the body through the bloodstream.

How often does that happen? Statisticians estimate that 20 of every 100 women who get only mastectomy (or lumpectomy plus radiation) for a 2-cm tumor that has not spread to the lymph nodes would, all other things being equal, suffer a recurrence sometime in the next five to 10 years. Fourteen of those tumors would have come back regardless of whether any additional therapies had been tried. The remaining six would have been prevented by chemotherapy. “For a 6% improvement, that’s a lot of women who have to accept chemotherapy,” says Dr. Gralow at the Fred Hutchinson Cancer Research Center in Seattle. But there is no way to figure out in advance which six tumors actually needed to be treated.

That may change as scientists learn more about the genetic alterations that transform a normal cell into a malignant one. Last month a group of scientists from the U.S. and the Netherlands published a paper in the research journal Nature describing a molecular test they have developed that may predict, at the time of surgery, which cancers will be likely to metastasizeand therefore might benefit from chemotherapy. Using so-called DNA microarrays, the researchers analyzed some 25,000 genes from the breast cancers of 100 women. By winnowing the number of relevant markers to about 70 genes, they produced a DNA profile that correlated closely with the women’s actual outcomes. “There’s not much that stands in the way of this test being used clinically,” says Stephen Friend, one of the paper’s authors and a co-founder of the biotech firm Rosetta Inpharmatics. Clinical trials could begin, he believes, within the year.

Such a test might prove particularly helpful in determining what to do about the so-called micrometastases that pathologists are starting to discover in some women’s lymph nodes. Once again, better detection techniques have revealed minute clumps of cancer0.2 mm acrossthat are smaller than anyone had ever seen before.

Until recently, the presence of any cancer in a lymph node would be a clear signal that chemotherapy was required. But at the upcoming meeting of the American Society of Clinical Oncology in May, a group of cancer experts will recommend that these minute malignancies be left alone, as long as the original breast tumor is small. “We used to seek out and destroy every cell,” says Dr. Eva Singletary, a breast surgeon at the M.D. Anderson Center in Houston, who chairs the expert panel. “Now we try to target and control our treatment.”

Ideally, Singletary would like to be able to tailor each woman’s treatment to the characteristics of her particular tumor. Already scientists have identified a biological marker called the HER2 receptor, whose presence usually signifies a very aggressive cancer. For the past four years, a drug called Herceptin has been given to women with metastatic tumors that make a lot of the HER2 protein. Now trials are being conducted to see if Herceptin, which may have some deleterious effects on the heart, will nonetheless help other women with smaller tumors that haven’t yet spread.

Herceptin is only a beginning, says UCLA’s Slamon, who identified the HER2 receptor. There are bound to be other cancer proteins that pharmaceutical manufacturers can use as targets as they develop new, more selective drugs. “Using a combination of (these kinds of) therapies earlier in the disease could have a dramatic impact on outcomes,” Slamon says.

It might also lay to rest any debate over the benefits of mammography; in the final analysis, early detection is only as good as the treatments that follow. You want to know which women’s lives will be saved by surgery, radiation, chemotherapy or hormone treatment. Otherwise, you risk doing more harm than good.

That’s why it helps, when trying to sort through the current unsettled state of affairs in breast cancer, to take the long view. “There’s always a trend or an issue that everyone’s chasing after,” says Fran Visco, president of the National Breast Cancer Coalition. “I do think we’re at a place where we can begin asking some of those questions regarding targeted therapy. But I don’t think we’re going to get the answers next month or next year.”

In the meantime, women like Nancy Ulene who discover they have breast cancer have to decide what to do with their lives and their breasts based on information currently available. There are days when many women would probably agree with Ulene’s assessment that it’s all a “crapshoot” anyway. After much soul-searching, she finally opted for a partial mastectomy and tamoxifen. It may not happen today. It may not happen tomorrow. But eventually those decisions will start to get easier.

FOR MORE INFORMATION
The National Cancer Institute’s hot line at 1-800-4-CANCER can answer questions about cancer diagnosis and treatment and offer tips for preventing breast cancer. On the Web, visit www.cancer.gov