By Beverly A. Caley & Faith Reidenbach

Michelle Head, a 36-year-old mother of three in Evansville, Indiana, was diagnosed with breast cancer in May 2000. She had a lumpectomy followed by adjuvant chemotherapy, drug treatment that is added to surgery and/or radiation for breast cancer to increase the chance of curing the disease or preventing its recurrence by attacking silent deposits of tumor that escaped from the breast via the lymph system or bloodstream. In Head’s case, the cancer recurred in her chest wall and lungs, despite adjuvant therapy. Yet for now, “I feel wonderful,” she says.

I really feel good and it is hard to believe I have cancer,” says Marion Stratakos, a 56-year-old living with stage IV breast cancer in Clover, South Carolina. Breast cancer is classified as stage IV if it has metastasized (spread outside the breast it first appeared in) or comes back after the original cancer was removed, sometimes despite additional treatment given to prevent recurrence.
Stratakos’ breast cancer was discovered in January 2001, and it has since spread to her spine, pelvis, and, most recently, to the skin at the back of her skull. But even so, “I have no pain,” she reports.

Currently, there is wide variation in the prognosis for people with metastatic breast cancer (MBC). But the experiences of Stratakos and Head are common enough that Gabriel Hortobagyi, MD, chair of breast medical oncology at M. D. Anderson Cancer Center in Houston, urges patients to think of themselves as living with a chronic illness.

“There is a small subset of patients with stage IV metastatic breast cancer who can benefit enormously from treatment, some of whom might actually be cured,” he explains. He and others use the term “personal cure,” meaning that an individual who is disease-free after treatment can be considered cured if she dies of some other cause without recurrence of the breast cancer. Dr. Hortobagyi says he has “a couple dozen” patients who are in complete remission more than 20 years after developing MBC.

In contrast, Larry Norton, MD, head of solid tumor oncology at Memorial Sloan-Kettering Cancer Center in New York, strongly dislikes the concept of converting breast cancer to a chronic disease. “I think that is a defeatist position,” he says. “We should be talking about eradicating the disease.”

One of the things these oncologists do agree on is that knowledge about MBC is evolving rapidly. “What I used to hold as the absolute truth 10 years ago has changed,” Dr. Hortobagyi stresses, “because of new discoveries and additional knowledge about how breast cancer behaves.”

Dr. Norton predicts that emerging treatments will have “such a dramatic impact on breast cancer in the next 10 years that it’s going to be a short decade.”
the hormonal approach

“Breast cancer is not a disease, it is a group of diseases,” Dr. Hortobagyi emphasizes. In one subgroup of breast cancer, tumors depend on the hormones estrogen and/or progesterone for their growth. Cells in such tumors have hormone receptors, which can be thought of as “docking sites” where estrogen or progesterone attaches to the cell. These tumors often respond to drugs such as Nolvadex® (tamoxifen) or Fareston® (toremifene) that block the hormone receptors.

Tamoxifen, which has been used for treatment of MBC for more than 20 years, has remained in the breast cancer treatment arsenal for two reasons: 1) it is a very safe drug, with its most common side effects being menopausal-like symptoms such as hot flashes, and 2) it works.

Tamoxifen is very effective in controlling advanced disease for, on average, 12-18 months, but it may also be effective at preventing disease in women at high risk for breast cancer. Other more serious side effects include development of uterine cancers or blood clots, which occur in less than 1% of patients.
Dr. Hortobagyi explains that for patients with hormone receptor-positive breast cancer and no life-threatening disease, hormonal therapy is the first choice.
A newer class of hormone therapies known as aromatase inhibitors block the action of aromatase, an enzyme that helps the body produce estrogen. Only effective in women who are postmenopausal, this class of hormonal drugs includes Arimidex® (anastrozole), Femara® (letrozole), and Aromasin® (exemestane), which are all effective in controlling disease in postmenopausal patients whose disease has become resistant to tamoxifen. In recent studies, Femara and Arimidex have proven superior to tamoxifen in time to progression for postmenopausal patients with MBC.

Hormonal treatment of premenopausal patients is more complex, largely because the ovaries produce large amounts of estrogen. Shutting down ovarian function becomes an important goal of treatment and can be accomplished through surgical removal of the ovaries or by using drugs like Zoladex® (goserelin) and Lupron® (leuprolide), both of which reduce or stop estrogen production in the ovaries and may be used in combination with tamoxifen for maximum benefit.

According to Dr. Hortobagyi, patients whose tumors have hormone receptors often benefit from receiving several different antihormone therapies in sequence. “I have had patients who have had five, six, sometimes even seven different types of hormone treatments in some sequence,” he explains. “That means a number of years of disease control, and since these interventions are so well tolerated, they are associated with a very high quality of life.”
choosing Chemotherapy

Many patients with MBC will need chemotherapy to control their disease—some right after diagnosis and some after hormonal therapy options have been exhausted.

Dr. Hortobagyi says hormonal therapy is only useful for patients with tumors that express the estrogen receptor (ER). Eventually, breast cancer becomes resistant to hormonal therapy and chemotherapy is introduced.
Chemotherapy may be introduced earlier if disease progression becomes life threatening. Dr. Hortobagyi adds that patients with ER-negative breast cancer are treated with chemotherapy from the beginning.

Treatment for Metastatic Breast Cancer
There are many chemotherapy agents that are effective in controlling MBC.

Anthracyclines

Anthracyclines, a class of drugs that includes Adriamycin® (doxorubicin) and Ellence® (epirubicin), have been used for decades and are among the most effective breast cancer treatments, being the first agents shown to prolong the survival of patients with MBC. Generally, the anthracyclines are administered in combination with Cytoxan® (cyclophosphamide) or Cytoxan and 5-FU (fluorouracil). Side effects include nausea and vomiting, and patients taking these drugs also experience low blood counts that can lead to infections. Anthracyclines can also be associated with heart damage, and the risk of damage is higher in older patients and patients who have received radiation to the chest.

Because anthracyclines are so effective in controlling the disease, there are efforts to minimize side effects. Doxil® (doxorubicin) is a reformulation of Adriamycin that encloses the drug in a bubble of fat molecules that prevents Adriamycin from interacting with normal tissues, greatly reducing its side effects. A phase III trial comparing Doxil with Adriamycin showed no reduction in effectiveness with the new formulation, but tolerability was greatly increased.

Taxanes

Challenging these treatments are the taxanes Taxotere® (docetaxel) and Taxol® (paclitaxel), which are two of the most effective agents for MBC. To date, Taxotere is the only agent with proven superiority over Adriamycin. Approved by the Food and Drug Administration (FDA) for patients with MBC as well as locally advanced disease, Taxotere is also effective in patients whose disease has progressed on anthracycline-based treatment.

Taxol has been in use longer than Taxotere, a semisynthetic derivative of Taxol, largely because it was discovered first. A study by pharmacologists reported at the 2003 meeting of the American Society of Clinical Oncology (ASCO) showed models predicting that Taxotere may be significantly better than Taxol in controlling breast cancer, although in other tumor types the two were predicted to be equal.

A randomized study currently under way is directly comparing the two agents to determine which is the clinically superior taxane. The advantages of Taxotere over Taxol include the decreased tendency of nerve damage with Taxotere, and Taxol has been shown to increase heart damage when used in combination with Adriamycin, whereas Taxotere can be safely administered with Adriamycin. In fact, the combination of Taxotere and Adriamycin has recently been shown to be better at controlling breast cancer and causing regression than Adriamycin and Cytoxan.

Recently, a large trial showed that administering Xeloda® (capecitabine) in combination with Taxotere could further prolong the survival of MBC patients. Xeloda is an oral drug, and, unlike many chemotherapy drugs, does not generally cause low blood counts.

Herceptin

One of the major randomized trials for MBC patients reported in 2001 showed that by combining Taxol with Herceptin® (trastuzumab), a targeted monoclonal antibody, the effectiveness of Taxol was greatly increased and prolonged survival. Herceptin has been shown to be effective in the approximately 25% of patients whose disease shows an overabundance of a protein known as HER2 (human epidermal growth factor receptor), which causes cells to divide and grow abnormally.

This combination has been approved by the FDA for use in MBC patients and has spawned numerous clinical trials combining other chemotherapy agents with Herceptin. Laboratory experiments have shown Herceptin could improve the effectiveness of commonly used agents such as Taxotere, Navelbine® (vinorelbine), Paraplatin® (carboplatin), Platinol® (cisplatin), and Gemzar® (gemcitabine).

Data presented at the 2002 San Antonio Breast Cancer Symposium found that the combination of Taxol, Herceptin, and carboplatin was more effective than Taxol plus Herceptin and could prolong survival.

“Preliminary data suggest that both response rate and time to progression are favorably altered by the addition of carboplatin to the combination,” says Dr. Hortobagyi. “For patients with HER2-positive breast cancer who otherwise would be best treated with a simultaneous combination, this three-drug regimen is very appealing.”

Gemzar/Navelbine

For a patient who has already received treatment with anthracyclines and taxanes, many options remain, so-called salvage regimens that have demonstrated activity in breast cancer. Gemzar and Navelbine are two agents commonly used in salvage treatment based on their ability in clinical trials to control disease in MBC patients whose disease progressed on other treatments.

A recent study showed that Gemzar increases the effectiveness of Taxol, with more patients experiencing disease shrinkage. More than half of the patients in this study who were treated with Gemzar plus Taxol remained in remission for six months or longer.

Combination Versus Sequential

One of the current debates among doctors who treat MBC patients is whether combination treatments or single-agent treatments given sequentially are best. In general, combination treatments are more toxic because side effects of the drugs are experienced at the same time. However, some physicians argue that the combination regimens are more effective.

“In general, patients with extensive, symptomatic disease are best treated with simultaneous combinations,” says Dr. Hortobagyi. “Other situations that require obtaining a response as quickly as possible will also require a simultaneous combination. Asymptomatic patients without life-threatening disease are appropriately treated with sequential single-agent therapy.”

Different physicians have different biases as to who should receive combination treatments, but to date it has not been proven which approach is better. At this point it is more of a decision between the physician and patient. In Dr. Hortobagyi’s practice, “the selection of chemotherapy regimen is based on the efficacy and safety profile of each regimen, [the patient’s physical] condition, and the patient’s perception of benefit and preference for not having certain types of side effects.”

Managing Side Effects of Chemotherapy Treatment
Chemotherapy is a double-edged sword. Doctors strive to minimize the side effects of these treatments because the potential for benefit, in terms of disease control, symptom control, and improved quality of life, outweighs the complications.

New agents to manage side effects include those that control nausea and vomiting, agents that treat or prevent mouth sores, and growth factors, which help maintain blood counts and relieve anemia (see CURE, Spring 2003).
An additional method of controlling side effects is to change the way the drugs are administered. The major toxicity associated with both Taxotere and Taxol is low blood counts (a result of myelosuppression—the suppression of bone marrow activity), which can lead to infections. But research has shown that when lower doses of the drugs are administered on a weekly or biweekly basis, there is a lower incidence of myelosuppression. And effectiveness of the drugs appears to be the same as the standard administration once every three weeks.
Xeloda takes a different approach to reducing side effects. The tumor itself unwittingly converts Xeloda, which is relatively harmless in its native form, to a cytotoxic agent. Tumors do this because they contain high levels of a cellular protein that changes Xeloda to 5-FU. Normal cells have this protein but in lesser amounts.

Marion Stratakos at first dreaded the side effects of chemotherapy, but her doctor assured her that great progress has been made in controlling them. She reports that chemotherapy has not been as bad as she feared. “I don’t know when to expect I will have pain, but so far, so good.”

Experimental Approaches
There are a number of other strategies under investigation to further improve the outcome of patients with MBC.

An experimental monoclonal antibody, AvastinTM (bevacizumab), blocks vascular endothelial growth factor, one of the most important proteins involved in promoting blood vessel development. The formation of new blood vessels, called angiogenesis, is critical to tumor growth and metastasis.

Avastin was recently reported to be effective in advanced colorectal cancer patients, with an improvement in overall survival. In late 2002, a phase III study of Avastin in MBC patients failed to meet its primary endpoint of improved progression-free survival. However, the combination of Avastin and Xeloda resulted in doubling the number of patients who had at least a 50% shrinkage of their tumor. Studies using Avastin to treat MBC are ongoing.

Vaccines

Vaccines stimulate the immune system to fight a disease. Most people associate vaccines with prevention of infectious diseases like smallpox and influenza, but they can also be effective in preventing disease recurrence in cancer patients as well as increasing the body’s own defense system to fight the tumor.

An experimental vaccine for metastatic breast cancer, Theratope®, recently completed its final stage of clinical testing. Earlier studies suggested a survival benefit for breast cancer patients who received Theratope following cyclophosphamide-based chemotherapy. However, results of the recent phase III trial showed Theratope did not improve overall survival nor did it increase time to disease progression. Ongoing trials are evaluating the vaccine in patients who were not pretreated with chemotherapy.

Gene therapy

Gene therapy, which is still experimental, is based on the concept of correcting a genetic defect by supplying the patient with a healthy copy of the gene. A gene called p53, for instance, provides potent antitumor effects by regulating cell division. Mutations in p53 interfere with that helpful activity and are associated with more aggressive breast cancer and resistance to certain types of chemotherapy. At M. D. Anderson, a clinical trial is under way in which a p53 gene therapy drug, Advexin®, and standard chemotherapy are being given to patients with locally advanced breast cancer prior to surgery or radiation. The goal is to boost cure rates and overall patient survival by killing cancer cells directly and stopping tumor growth without harming healthy cells.

Sorting Out the Options
“Every patient with metastatic breast cancer has at least four, five, sometimes 15 different treatments available to them, depending on the characteristics of their tumor and their state of health,” Dr. Hortobagyi says. “Different people, reasonable people, may look at the same information and draw different conclusions.”

Michelle Head and Marion Stratakos each consulted several doctors and were presented with multiple treatment options. Stratakos learned to cope with the differences in opinion: “You get a little frustrated, but you just have to talk to a lot of people. The more information you can get, the easier it is to make a decision.”

She adds, “You have to find doctors that you trust.”

Dr. Norton, too, advises patients to find professionals they trust and to listen carefully to their advice. “Be a partner in the process, but your primary job is to find a mentor or small group of mentors that you have confidence in,” he says. “I quote the coaching phenomenon. I used to do a lot of sports where I was totally exhausted at the end of the contest, and that’s the worst possible time for the individual to know what is right to do. You have to listen to the coach, even when it may not seem logical at the moment. That is a very important part of doing well.

“There should not be blind trust,” Dr. Norton continues. “There should be informed trust. Don’t just listen to opinions, don’t just listen to reasoning based on opinion, don’t even listen to reasoning based on data. Look for the actual data; look for clinical trial results. That is the secret to finding a therapy that works.”

For some patients with MBC, participating in a clinical trial is the best treatment option. “Either you get access to a new treatment,” Dr. Abrams notes, “or if you have earlier-stage disease, you might be in a phase III trial where you get standard treatment or standard treatment plus a new drug.” For information on enrolling in a study, he recommends contacting the National Cancer Institute by calling 800-4-CANCER or visiting www.cancer.gov.

Dr. Hortobagyi observes, “Some patients would not consider participating in a clinical trial because they think, ‘Gee, these doctors are using me as a guinea pig.’ In reality, having access to a clinical trial expands your treatment options. The more treatment options you have, the greater your probability of benefiting from some of them. Even if your life is prolonged by only a year, during that year, many positive things can happen. New and valuable treatment may appear. Remember that all standard treatments were experimental at some point.”

Regardless of whether or not MBC is conceptualized as a chronic condition, the growing number of treatment options has given patients hope.

“Our goal is to keep buying me time,” Head says. “We take it a step at a time and treat it as we need to treat it. If I can keep doing this until I get my kids raised, that’ll be wonderful.”