Identifying patterns in genes unlocks one more piece for cancer researchers.

By Alice McCarthy

“I’m happy to say that my treatment has been much easier than I expected‚” says Tammy Isaac of Bellaire‚ Texas. The 36-year-old mother of three children‚ all under age 5‚ is referring to her ongoing treatment for recurrent breast cancer.

Diagnosed initially in May 2001‚ Isaac underwent chemotherapy and radiation. Within six months the cancer had spread (metastasized) to two sites outside the breast. Isaac had her ovaries removed in an effort to decrease production of estrogen that may have been feeding the cancer. In November 2002‚ she began Xeloda® (capecitabine)‚ one of the newest drugs in the fight against advanced breast cancer.

“Looking at me you’d never know I’m still in treatment‚” she says. “I’m busy living an active life‚ and I feel fine.” Thanks to a plethora of new medications and treatment strategies‚ women with metastatic disease are now living much longer than similarly diagnosed women just 10 years ago. And Isaac attests that women can tolerate treatment better in the process. “I do everything I’ve always done‚” she says.

“The good news in advanced breast cancer therapy is that we have a broad array of therapies that can provide long periods of disease control in many women‚” says Charles Vogel‚ MD‚ medical director‚ Cancer Research Network‚ Plantation‚ Florida. Treatment revolves around using these drugs in combination or sequentially if the disease progresses on other treatments.

Broadly‚ two drug treatment approaches are used to treat advanced breast cancer—either hormonal therapy‚ cancer-killing (cytotoxic) chemotherapy‚ or a combination of both. With chemotherapy‚ the goal is to directly target breast cancer cells and kill them. With hormonal therapy‚ the idea is to interfere with the cancer cell’s hormonal interactions to slow or stop cancer cell growth and‚ potentially‚ shrink the tumor.

“We have figured out ways to minimize toxicity with these drugs so we get a lot of mileage now‚ even in women with metastatic breast cancer‚” says Dr. Vogel. “And that is just with the standard drugs we have now.”

Treatment Considerations
“Among the critical things we look at when making treatment decisions for women with advanced breast cancer are her age‚ menopausal status‚ overall health‚ and the tempo and sites of her disease‚” says William Gradishar‚ MD‚ co-director‚ Lynn Sage Breast Cancer Program‚ Northwestern University Medical School‚ Chicago‚ adding that it is also fundamental to consider key characteristics of the woman’s tumor since some types of breast cancer cells have receptors that bind the hormones estrogen and progesterone and direct the cancer cell to grow once they bind to these receptors. These are hormone-receptor-positive (HR+) cancers and generally grow more slowly. If the cancer cell lacks hormone receptor‚ it is a hormone-receptor-negative (HR-) tumor type.

Hormonal Treatments
For postmenopausal‚ HR+ women with metastatic disease‚ the first treatment of choice is usually a hormonal therapy that interferes with estrogen‚ either directly or indirectly‚ by making the estrogen receptor less functional (see table).

“We have the luxury of many hormonal choices‚” says Dr. Gradishar‚ “and they are used sequentially for as long as each one works. The idea is to delay chemotherapy and its potential side effects as long as possible.”

Since 1977‚ the traditional workhorse of breast cancer hormonal treatments has been Nolvadex® (tamoxifen)‚ which blocks estrogen from binding to its receptors. For advanced breast cancer‚ tamoxifen can be used as first-line therapy in both premenopausal and postmenopausal women with hormone-sensitive disease. For women with metastatic disease‚ tamoxifen produces some clinical benefit in about 35-40% of women. Common side effects are typical of menopause and include hot flashes and night sweats. Rarely‚ tamoxifen can also cause blood clots and uterine cancer.

Though consensus is still building‚ drugs called aromatase inhibitors (see sidebar)‚ including Arimidex® (anastrozole)‚ Aromasin® (exemestane)‚ and Femara® (letrozole)‚ are becoming the usual first-line hormone choices for treating postmenopausal women with advanced breast cancer. They work by reducing the amount of estrogen produced by a woman’s fat and muscle cells that would otherwise signal cancer cells to grow when they reach their target receptors. Trial data now show that Arimidex and Femara are as good—if not superior—to tamoxifen for treating postmenopausal women with metastatic disease. For example‚ compared with tamoxifen‚ these drugs may lengthen the time before chemotherapy is necessary and postpone the time before the cancer progresses. Typical side effects of aromatase inhibitors include hot flashes‚ and some women develop joint aches.

Faslodex: Newest Hormonal Option
Capturing the most attention recently in the breast cancer hormonal arena is Faslodex® (fulvestrant)‚ an injectable medication. The U.S. Food and Drug Administration (FDA) approved Faslodex in April 2002 for treatment of HR+ metastatic breast cancer in postmenopausal women with disease progression following previous anti-estrogen therapy.

“Faslodex gives us another much-needed option for a woman with breast cancer who has hormone-responsive disease‚” says Joyce A. O’Shaughnessy‚ MD‚ Baylor-Charles A. Sammons Cancer Center‚ Dallas‚ an investigator in the
Faslodex clinical trials.

“The beauty of Faslodex is that it binds to the estrogen receptor permanently‚ which leads to the destruction of that receptor‚” she explains. “This is a brand new way for a hormonal therapy to interfere with estrogen-stimulated breast cancer growth.” Common side effects with Faslodex include hot flashes and injection site reactions.

“The encouraging clinical story with Faslodex‚” explains Dr. O’Shaughnessy‚ “is that we know that close to half of all women whose disease progressed despite tamoxifen therapy will have some clinical benefit.” This is defined as either tumor shrinkage by 50% or remission with no growth for at least six months.

"And‚ we know Faslodex is at least equivalent‚ if not superior‚ to the aromatase inhibitors in patients who have failed tamoxifen‚” says Dr. Vogel. In one clinical trial comparing Faslodex with Arimidex‚ both drugs performed equally in terms of tumor shrinkage‚ “but the duration of that response was longer in Faslodex patients (19.3 months) than Arimidex (10.5 months)‚” says Dr. O’Shaughnessy.
“Based on what we know now‚ all these hormonal agents have activity and there is no critical evidence at present that you have to give them in any particular order‚” she says. “But most of us in the breast cancer world believe Faslodex is probably better than tamoxifen in treating postmenopausal metastatic breast cancer‚ and that Faslodex is as effective as Arimidex.”

Dr. Gradishar adds that premenopausal women take tamoxifen along with drugs such as Zoladex® (goserelin) to shut down the ovaries‚ which induces artificial menopause. For HR- women—or if disease progresses despite all other hormone treatment—the usual choice is chemotherapy either alone or with a targeted drug called Herceptin® (trastuzumab) if the tumor has been shown to have an overabundance of a protein called HER2‚ a human epidermal growth factor receptor.

Women who make too much HER2—about 25% of all breast cancers—have more aggressive disease. Herceptin‚ an antibody that binds to the HER2 receptor‚ reduces the cell’s ability to respond to growth signals. Available since 1998‚ it is being combined with hormonal treatment and chemotherapy in advanced breast cancer patients. On average‚ about 40% of women with HER2 overproduction respond to Herceptin therapy; 50-70% response when chemotherapy is added. Dr. O’Shaughnessy says she believes Herceptin has had a major impact on improving the overall survival of women with HER2-positive metastatic breast cancer.

“In fact‚ we have seen an encouraging rise in the overall survival of women with metastatic breast cancer over the past seven years due to the availability of several important new treatments‚” she explains.

Chemotherapy
While chemotherapy previously meant side effects such as hair loss and nausea‚ the newer chemotherapies are kinder‚ gentler‚ and even more effective at curing or controlling disease than in the past.

In the past‚ the most commonly used chemotherapy regimens for patients with both early-stage and advanced breast cancer were different combinations of drugs including Cytoxan® (cyclophosphamide)‚ methotrexate‚ Adriamycin® (doxorubicin)‚ Ellence® (epirubicin)‚ and 5-FU (fluorouracil). These drugs are given in combinations such as CMF‚ AC‚ or FAC. These drugs were the most active agents for the treatment of breast cancer until their supremacy was challenged in the late 1980s and 1990s by the arrival of two new agents known together as the taxanes but separately as Taxol® (paclitaxel) and Taxotere® (docetaxel).

First used in patients with advanced metastatic breast cancer‚ both Taxol and Taxotere were found to be effective in shrinking tumors. The taxanes were then added to existing combination regimens in patients who had early-stage disease in hopes of increasing the efficacy of combination chemotherapy and decreasing the numbers of women whose cancer recurred. Currently‚ with a broad array of new drugs with new mechanism of actions available‚ researchers are exploring how best to give the drugs‚ what combinations work best‚ and who should receive what combination.

Physicians are also putting a new spin on old drugs in a way that will minimize toxicity. Doxil® (doxorubicin) is a reformulation of Adriamycin that encloses the drug in a bubble of fat molecules (liposome) to protect normal tissues from exposure to the active ingredients of both Adriamycin and Doxil. With traditional Adriamycin‚ heart toxicity is a worrisome side effect and often limits the amount of medicine received‚ but the coating makes Doxil cardioprotective‚ explains Beth Overmoyer‚ MD‚ director‚ Breast Cancer Clinical Trials‚ Ireland Cancer Center‚ Cleveland.

In addition‚ unlike Adriamycin‚ Doxil doesn’t have an upper limit to the total amount of drug that can be safely given over a period of time‚ she says. This lessened exposure to normal tissues means Doxil is associated with less hair loss and nausea or vomiting than Adriamycin. And‚ a recent study from British researchers presented at the 2002 American Society of Clinical Oncology meeting suggests it works as well as Adriamycin with fewer side effects. Doxil is not yet approved for treatment of breast cancer in the United States‚ although it has received European approval for breast cancer treatment.

For women with metastatic disease‚ chemotherapy is able to control disease progression‚ relieve symptoms‚ afford a better quality of life‚ and in some cases‚ prolong life. Xeloda‚ which is converted into 5-FU in the body‚ is given in pill form‚ and‚ unlike the taxanes‚ does not cause hair loss.

When Rosalie Dodd‚ MD‚ was diagnosed with recurrent metastatic breast cancer in her bones and liver in September 1999‚ she was a practicing plastic surgeon in Bismark‚ North Dakota‚ where she also operated a small horse farm.
“I never planned to retire‚” Dr. Dodd‚ now 70‚ says today from her home in Astoria‚ Oregon‚ where she moved to be closer to her family while coping with what she calls a “chronic” disease of metastatic breast cancer.

For Dr. Dodd‚ Xeloda was the drug that made her life manageable‚ eliminating the bone pain almost immediately. While she has struggled with the swelling and cracking of her hands and feet—a side effect called hand/foot syndrome—it has not stopped her from long walks on the beach with her dog‚ digging for clams‚ and enjoying the ocean.

“It’s not what I thought I would be doing‚ but I have an active church community and like talking to the fishermen‚” she says. “But considering I was given six months to live‚ this is a good quality.”

In addition to the issues of prolonged life are those of quality of life‚ which means exploring the use of agents that are as tolerable as possible. Each patient is assessed as to the likelihood she will experience significant side effects from a particular treatment and to weigh that against the possible benefit from treatment. New regimens are constantly being evaluated and compared against the older to find which affords the greatest benefit with the fewest side effects.

The Newest Therapies
Some of the most eagerly anticipated new medicines are targeted agents—drugs that specifically interfere with a particular enzyme or growth pathway involved in cancer development and growth.
2C4 is only in phase I clinical trials‚ but‚ according to Dr. Vogel‚ everyone wants to get their hands on it. 2C4 acts like Herceptin but targets other molecules Herceptin does not. “The other exciting thing with 2C4 is that the tumor doesn’t have to be HER2 positive for it to work‚” says Dr. Vogel‚ explaining why it may have broader applicability than Herceptin.

“Targeted therapy will be the wave of the future‚ and it’s very different than standard chemotherapy‚ which does not distinguish between cancer cells and normal cells‚” says Anthony Tolcher‚ MD‚ associate director of clinical research‚ Institute for Drug Development‚ Cancer Therapy Research Center‚ San Antonio‚ Texas.

“We’re talking about identifying targets that are present in tumor cells‚ not normal cells‚ or on targets that the cancer cell has become dependent upon‚” adds Dennis J. Slamon‚ MD‚ PhD‚ director‚ Revlon/UCLA Women’s Cancer Research Program‚ Los Angeles.

Researchers agree the key to success with so-called targeted therapy involves understanding which people have the targets and will obtain the most clinical benefit followed by research with many different drug combinations to find the right fit.

“I’m very encouraged by the new targeted therapies even if they haven’t proved effective with certain chemotherapies in certain disease stages so far‚” says Dr. Overmoyer. Adds Dr. Slamon‚ “I believe what will win the battle will be when we’re able to specifically identify what’s broken and able to target that specifically.”

One drug‚ Zarnestra™ (tipifarnib)‚ targets proteins involved in signaling breast cancer cells to grow. Dr. Tolcher says nearly one in four women on this drug in a phase II clinical trial had some sort of clinical benefit.

Specifically‚ in 76 women with advanced breast cancer‚ Zarnestra‚ given in a tablet form‚ produced a partial reduction of the tumor among 10-14% of the women. In a different 9-15%‚ cancer did not progress for at least six months. The most common side effects were lowered blood cell levels.

“The key now is to find what it is about those women who responded so we can direct it only to those with that type of biomarker‚” Dr. Tolcher says. Zarnestra is being studied with a variety of other breast cancer agents‚ including Taxol and Herceptin.

Another approach involves angiogenesis inhibitors‚ which interfere with a tumor’s ability to grow supporting blood vessels. “I work a lot with combining angiogenesis inhibitors with chemotherapy agents‚” says Dr. Overmoyer‚ “and I believe some of them really do change the biology of the cancer.” The leading antiangiogenesis therapy in testing‚ Avastin™ (bevacizumab)‚ is in advanced phase III trials in combination with chemotherapy (see sidebar‚ page 37). Avastin targets an important protein molecule involved in new blood vessel formation‚ vascular endothelial growth factor (VEGF).

A category of endothelial growth factor inhibitors that includes TarcevaTM (erlotinib) and IressaTM (gefitinib) are now in phase II testing in breast and other cancers. They are oral drugs that target the epidermal growth factor (EGF) receptor‚ which is sometimes overproduced in cancer cells. Erbitux® (cetuximab or C225)‚ an intravenous monoclonal antibody therapy‚ also targets the EGF receptor and will soon begin phase II testing for breast cancer.

A new chemotherapy drug category‚ epothilones‚ includes cytotoxic drugs that kill cancer cells in a manner similar but not identical to the taxanes. “The beauty of epothilones is that they appear to be effective for treating women whose tumors have been growing through the taxanes‚” says Edith Perez‚ MD‚ director‚ Breast Cancer Program‚ Mayo Clinic‚ Jacksonville‚ Florida‚ a researcher involved in recent phase II epothilone clinical studies.

In these phase II studies with BMS-247550‚ one of three or four epothilones in clinical trials‚ 25-53% of treated women responded to the drug. “There is essentially no chemotherapy drug that can give you a response of 53% as a single agent in multi-institutional studies‚” says Dr. Perez. But she cautions the number of treated women in both studies was very small‚ and large phase III studies are planned to confirm these results. Side effects were similar to the taxanes‚ including neuropathy (pain in the extremities)‚ but changes in the dosing strategy reduced the problem.

In addition‚ a number of therapeutic vaccine strategies are in various stages of development for breast cancer. Vaccines‚ given to women who are at high risk for metastatic disease‚ are designed to cause the body’s own immune system to destroy the cancer. The Theratope® (STn-KLH) vaccine just completed a large phase III study in 1‚000 women with metastatic breast cancer.

“It was a well-done investigation‚” says Dr. Slamon. “Now we’re waiting for the final results to see if it has made an impact in terms of reducing recurrence and improving survival.” Results should be available in late 2003. Theratope has fast-track designation with the FDA for the treatment of metastatic breast cancer.

Tammy Isaac is grateful her therapy has not stopped her from caring for and enjoying her young family. “Every day I see news about breast cancer research and that helps me keep a positive outlook‚” she says. “My job is just to keep on with my everyday life‚ drive the kids to soccer‚ and be willing to fight forever.”