Breast cancer: The search for the cure continues

May 2, 2003

According to the National Alliance of Breast Cancer Organizations (NABCO), breast cancer is the second most common cancer in American women (skin cancer is No.1).

 

Breast cancer: The search for the cure continues

According to the National Alliance of Breast Cancer Organizations (NABCO), breast cancer is the second most common cancer in American women (skin cancer is No. 1). The incidence of this disease has risen over the past 40 years. In 1960, one out of 14 women would develop breast cancer sometime during her life. Now, that figure is up to one out of nine. NABCO estimates that nearly 40,000 women will die of breast cancer this year.

While the number of breast cancer cases is increasing alarmingly, fewer women actually die from the disease now. Mark Levin, M.D., an oncologist in Monsey, N.Y., said that because breast cancer is detected earlier in more cases, fewer women now develop metastatic disease. He estimated about one-quarter of the women with breast cancer have the metastasized form. Since the 1960s, major advancements in chemotherapeutic drugs have also been made. Many more agents are available now, and more are on the way.

Chemotherapy today

Currently, anthracyclines, such as doxorubicin, and taxanes, such as docetaxel (Taxotere, Aventis), are at the forefront of therapy. Newer agents like capecitabine (Xeloda, Roche) and gemcitabine (Gemzar, Lilly) have also been found to be quite effective. Other drugs include alkylating agents, antimetabolites, and vinca alkaloids (see Table 1). All of these agents work in different ways, but the net result is inhibition of tumor cell reproduction.

 

Table 1
DRUGS CURRENTLY USED TO TREAT BREAST CANCER

Drug classGeneric name
Anthracyclinesdaunorubicin doxorubicin epirubicin
Taxanesdocetaxel paclitaxel
Alkylating agentsbusulfan carmustine cyclophosphamide melphalan thiotepa
Antimetabolitescapecitabine fluorouracil gemcitabine methotrexate
Aromatase inhibitorsanastrazole aromasin
Mitotic inhibitorsvinblastine vincristine vinorelbine
Hormonesgoserelin megestrol acetate tamoxifen testolactone
Anti-HER2 monoclonal antibodiestrastuzumab

 

Because estrogen plays a role in the development of breast cancer, several estrogen-regulating drugs have been developed as well. Aromatase inhibitors reduce circulating estrogen, as does goserelin (Zoladex, AstraZeneca), a gonadotropin inhibitor. Megestrol acetate is a progestin, and tamoxifen is an antiestrogen with some weak estrogenic activity.

In clinical studies and in practice, all the above agents have been proven effective in some, if not many, patients. None of these drugs, however, has turned out to be the magic bullet against breast cancer. So, the search continues.

Coming soon

Several new drugs are in development. Pemetrexed (Alimta, Lilly) is a new antimetabolite that has had 20% to 30% response rates in phase II trials. Liposomal annamycin (Antigenics) performed well in preclinical studies. Flavopiridol (Aventis) is the first of a group of cyclin-dependent kinase (CDK) inhibitors to hit clinical trials. Cilengitide (Merck) has been under investigation to increase the effectiveness of radiation therapy. It seems to have succeeded without increasing adverse reactions.

Entire new classes are also under investigation. Three farnesyl transferase inhibitors (FTIs) are currently in early studies. So far, none of them appears to be particularly effective for monotherapy. Investigators may evaluate them in combination with other agents. The most likely agents would be taxanes, as the FTIs worked synergistically with them during preclinical studies. Another class, the calmodulin antagonists, has inhibited tumor cell growth during trials.

Several new drugs are derived from natural sources. Ecteinascidin 743 (ET-743, PharmaMar) has been isolated from a Caribbean sea squirt, Ecteinascidia turbinata. PM-3 is a compound derived from Brazilian propolis, a plant substance bees use to make beeswax. The topoisomerase inhibitors are a trio of drugs that originated from the bark of a Chinese tree. Other compounds that target topoisomerase include the camptothecins and nitidine derivatives.

As for the hormonal group of drugs, new aromatase inhibitor letrozole (Femara, Novartis) is on the way. Droloxifene (Pfizer), idoxifene (GlaxoSmithKline), and toremifene (Fareston, Orion) are three new selective estrogen receptor modulators (SERMs) in development. Raloxifene (Evista, Lilly), a SERM already on the market, is being studied to see whether it has any antitumor activity.

A new addition to the hormonal group is a class called antiprogestins. These drugs are expected to work on certain tumors that grow in response to estrogen. Mifepristone (Mifeprex, Danco) is in this class. So far, it seems to work best when combined with antiestrogens or aromatase inhibitors.

Vaccines for breast cancer are also being tested. One currently nearing the end of a phase III clinical trial contains Sialyl Tn (Theratope, Biomira), a synthetic version of a cancer antigen. The idea is that by administering the antigen, the immune system will begin to recognize and act against cancer cells (usually, cancer cells manage to remain undetected by the immune system). While the final results of the study won't be available until later this year, preliminary results were not earth-shattering. This may be because the study is less than two years old. More dramatic results may be seen over the long term.

Researchers are also looking for ways to make current drugs more effective and less toxic. The idea is to target cancer cells rather than normal cells. Monoclonal antibodies, for example, trastuzumab (Herceptin, Genentech), have been used in this way. Formulated to thwart HER2, a cancer gene, the monoclonal antibodies attach to HER2 protein growth factor receptors on tumor cells to prevent growth response. Research indicates that using these agents as adjuvant therapies (following chemotherapy or radiation) may prevent metastases.

Another targeting technique under study is the attachment of sugars to drug molecules. Cancer cells recognize and absorb certain sugars, such as hyaluronic acid. When hyaluronic acid was attached to doxorubicin, cultured cancer cells absorbed it, according to one preclinical study. Once inside, the two molecules separated and the doxorubicin destroyed the tumor cells. Researchers are optimistic the technique will work in humans as well.

Putting it all together

While the potential for a new wonder drug is thrilling, it may be more practical to work with what is currently available. Some of the newer drugs, when combined with standbys, may prove to be quite effective. Indeed, investigation of combination therapies is fast and furious at the moment (see Table 2).

 

Table 2
DRUGS UNDER INVESTIGATION FOR USE IN BREAST CANCER

Drug classGeneric name
Topoisomerase inhibitorsirinotecan mitoxantrone piroxantrone
Antimetabolitespemetrexed
Selective estrogen receptor modulators (SERMs)droloxifene idoxifene raloxifene toremifene zindoxifene trioxifene
AntiestrogensICI-182780 EM-652 EM-800 TAT-59
Antiprogestinsmifepristone onapristone
Farnesyl transferase inhibitors (FTIs)tipifarnib lonafarnib BMS-214662
Aromatase inhibitorsanastrozole formestane exemestane letrozole vorozole
Monoclonal antibodiesedrocolomab
Novel agentscamptothecins PM-3 nitidine analogs Ecteinascidin 743 (ET-743) liposomal annamycin cilengitide
Calmodulin antagonistsvarious currently marketed drugs (such as trifluoperazine and clotrimazole) CGS9343B berbamine derivative-EBB W7
Cyclin-dependent kinase (CDK) inhibitorsflavopiridol

 

Clearly, the biggest concern is metastatic breast cancer. Once the cancer has spread, it is much more difficult to treat. There is no universally accepted standard of treatment for metastatic disease, said Levin. Multiple chemotherapeutic agents seem to be more effective than single-drug treatment.

Research is in a shake-out stage right now, Levin said. Phase I and II trials are being conducted to identify the most active combinations of drugs. The most promising therapies to emerge from the phase II trials will go on to phase III studies. There, they will be pitted against one another to see which ones are the most effective.

Levin has experimented with a combined therapy of old standbys and a newer drug: cyclophosphamide, doxorubicin, and gemcitabine. By the end of his study, 20% of the participants were in remission: Their tumors had disappeared. "It's not unheard of, but it is high," he said of the figure. All in all, 89% of the women in the study responded to treatment.

Another new combination chemotherapy was studied by Miguel A. Villalona, M.D., FACP. His team evaluated a dual therapy of capecitabine and paclitaxel. Capecitabine, an oral dosage form, is converted to 5-fluorouracil (5-FU) after ingestion. In preclinical studies, paclitaxel appears to catalyze the last step in this reaction. The team wanted to see whether giving the two drugs together resulted in synergistic or potentiated efficacy.

Nineteen women with metastatic breast cancer participated in the study. There was a 56% response rate after 101 courses of treatment. Two women went into remission. Villalona concluded that the treatment was effective enough to warrant further study, and noted that adverse reactions were within the acceptable range.

Villalona is associate professor of Medicine at Ohio State University's Arthur James Cancer Center & Richard J. Solove Research Institute. Since completing his study, he said other investigators have also evaluated capecitabine and paclitaxel. One team in Spain confirmed the high response rate in breast cancer patients.

"However, most of the attention has been placed on another combination," said Villalona, referring to capecitabine and docetaxel. "It demonstrated in the phase III setting advantages compared with docetaxel alone." Villalona and his team have studied this duo as well. "We performed a trial of weekly docetaxel [instead of every three weeks] with capecitabine with very encouraging results not only in breast cancer, but in other tumors as well."

Drugs as risk factors

When discussing drugs and breast cancer, those agents that may actually contribute to tumor formation should not be ignored. There has been quite a stir in the media about hormone replacement therapy (HRT) and its risks and benefits. Physicians, patients, and researchers have expressed concerns over HRT contributing to cancer. One study, published last year, concluded that HRT given to breast cancer survivors did not increase their risk for recurrence. However, many other studies have found a correlation between HRT and cancer.

The SERMs are a compromise. In theory, the SERMs should give the benefits of estrogen without the risks. They act as estrogen agonists in the bone and heart tissues, where their benefits are well documented. The SERMs take an antagonistic role in the uterus and breast tissues. They are not without adverse reactions, though. They may increase hot flashes and the risk for thrombosis. A less well-known risk seems to come from drugs to treat psychosis. Antipsychotic drugs that decrease dopamine (e.g., phenothiazines, olanzapine, risperidone) may increase the incidence of breast cancer by elevating prolactin. Dopamine antagonists were found to increase the risk of breast cancer by 15% in one recently published, retrospective study. The perceived risk increased with the doses of the antipsychotics.

While the exact cause of breast cancer hasn't been identified, diagnosis and treatment have improved dramatically. Many clinicians believe that with continued efforts, funding, and research, a cure is within reach.

Jillene Magill-Lewis, R.Ph.

The author is a writer based in Washington State.

 

Jillene Lewis. Breast cancer: The search for the cure continues. Drug Topics Women's Health Supplement;147:18s.