Aromatase inhibitors are promising therapies in the arsenal of drugs used to treat breast cancer.
As breast cancer treatment advances, the aromatase inhibitors are taking front-and-center stage as promising therapies. They appear to be at least as effective as, and possibly more tolerable than, tamoxifen (Nolvadex, AstraZeneca). For advanced disease, new chemotherapeutic strategies are being developed that may increase survival time.
What should pharmacists know about new breast cancer therapies? How should they counsel patients who are taking them? In several interviews with Drug Topics, pharmacists and oncologists discussed the advances in breast cancer treatment and outlined the pharmacist's role in assisting women being treated with new agents for breast cancer.
"Aromatase inhibitors have challenged the dogma of how we treat breast cancer," said Laura B. Michaud, Pharm.D, Ph.D., BCOP. "This drug class is the most exciting development in the field." Michaud is a clinical pharmacy specialist in breast oncology at the University of Texas M. D. Anderson Cancer Center in Houston, a participating center in the National Comprehensive Cancer Network (NCCN). These inhibitors prevent the enzyme aromatase from converting androgens to estrogens in postmenopausal women. These agents are, therefore, effective in hormone-sensitive breast cancers and are appropriate for use only in postmenopausal women.
The key agents in this drug class to date are anastrozole (Arimidex, AstraZeneca), letrozole (Femara, Novartis), and exemestane (Aromasin, Pharmacia). Anastrozole and letrozole are nonsteroidal aromatase inhibitors and have been associated with bone mineral density loss; exemestane is a steroidal aromatase inhibitor, so the investigators involved in its development hope that it is less toxic to bone than the nonsteroidal drugs in this class. Because aromatase inhibitors are typically given as oral agents to be taken daily for several years, community pharmacists are likely to fill the prescriptions of women on these therapies.
"For the past 20 years or so, the only endocrine therapy shown to be helpful for early breast cancer after primary local therapy has been tamoxifen," Michaud said. "Now we have new data that challenge tamoxifen's role, primarily in postmenopausal women. Things had remained the same for so long, and now all of a sudden, everything's different."
She cited several studies comparing different aromatase inhibitors with tamoxifen in different strategies: sequential therapy, first-line, and midpoint switching. The studies were, respectively: Anastrozole, Tamoxifen, and Combination (ATAC), which compared the two agents as first-line postoperative therapy; extended adjuvant therapy with letrozole (MA-17 trial), in which patients were treated with either letrozole or placebo after five years of tamoxifen; and the Intergroup Exemestane Study (IES), in which patients with early breast cancer were either switched to exemestane or continued on tamoxifen adjuvant therapy.
Because the trials had different designs and tested the new agents at different sequences in the course of postoperative therapy, they raised as many questions as they solved, Michaud said. "We don't really know the best way definitively to treat early, hormone-sensitive breast cancer," she said. "As clinical pharmacists, we don't know if one aromatase inhibitor is better than the others, whether tamoxifen should be used [first], or whether we should start with the aromatase inhibitor. The investigators in these three studies used three different scenarios and nobody knows which strategy is the best. Although new studies have begun, we don't have the answers and won't for years to come."
In the ATAC study, anastrozole appeared to fare better than tamoxifen, but the study had a fairly short follow-up compared with the database of 20 years of tamoxifen; also, the combination arm was stopped early because the two agents used separately as monotherapies seemed to be more effective than the combination. For now, one approach might be to use each drug as it was used in its respective study, Michaud said. "For a newly diagnosed patient and beginning adjuvant therapy, anastrozole is a very feasible option," she said. "For someone already on tamoxifen, switching to exemestane may be appropriate. For patients about to complete tamoxifen therapy, extended treatment with letrozole after tamoxifen may be suitable."
The hope and assumption is that aromatase inhibitors will be safer than tamoxifen, which carries an increased risk of endometrial cancer and thrombotic events. Although aromatase inhibitors bypass those risks, they are associated with the typical risks of estrogen deprivation, and the greatest concern is the risk of bone mineral density loss. "We don't know yet how these therapies impact bone density, cardiovascular health, and cognitive functions," said Michaud. "We are depriving postmenopausal women of estrogen, when they have very little to begin with."
Community pharmacists are in a strategic position to see these developments unfold, she added. "These are the people on the front line filling these prescriptions," she said. "Therefore, they need to have the data regarding tolerability and safety, so that they can communicate effectively with patients."
In addition to the aromatase inhibitors, several new chemotherapy strategies are being explored, said Rachel Wolfberg, Pharm.D. These include biologic treatment used in conjunction with cytotoxic agents, investigative chemotherapies, and dosing strategies. Wolfberg is the pharmacy practice coordinator of the Robert H. Lurie Comprehensive Cancer Center of Northwestern Medical Faculty Foundation in Chicago, which is affiliated with Northwestern University, also an NCCN center.
"In our center, we're studying a drug that was just approved for colon cancer, bevacizumab (Avastin, Genentech) as a treatment for advanced breast cancer," Wolfberg said. "This agent works by blocking vascular endothelial growth factor (VEGF), and therefore tumor growth, and works synergistically with chemotherapy and is therefore to be used with chemotherapy. In the near future, bevacizumab may be approved for breast cancer."
Another drug being investigated for breast cancer has the investigative designation of ABI-007. "This is a type of paclitaxel (Taxol, Bristol-Myers Squibb), but it doesn't use the cremophor medium, which causes so many reactions and requires special tubing," Wolfberg said. " Therefore, it can be infused over a shorter time than paclitaxel, and higher doses can be used with fewer side effects." Dose-dense chemotherapy is another approach being explored, she said. "The dose-dense strategy is being explored in node-positive patients," she said. One dose-dense approach employs a biweekly cycle instead of every three weeks, and consists of the combination of doxorubicin (Adriamycin, Pharmacia) and cyclophosphamide (Cytoxan,Bristol-Myers Squibb). The rationale is that the dose-dense approach allows less time for the cancer cells to recover between cycles. "The hope is that dose-dense therapy is associated with decreased recurrence rates." Because dose-dense chemotherapy is associated with an increased risk of neutropenia, patients receive granulocyte colony-stimulating factor (G-CSF) between cycles prophylactically, she said.
The medical oncologists interviewed agreed that the exciting developments are in the aromatase inhibitors and the new chemotherapy strategies. "The advances are in chemotherapy and in endocrine therapy," David A. Riseberg, M.D., said. "We know convincingly that postmenopausal women with hormone receptor-positive disease should get an aromatase inhibitor at some point in their treatment. Five years of tamoxifen and nothing else would be insufficient." Riseberg is a medical oncologist at Mercy Medical Center in Baltimore, Md.
Regarding chemotherapy advances, he cited the advent of trastuzumuab (Herceptin, Genentech), a biologic agent used in combination with chemotherapy, in women with HER2-positive disease. HER2 is a type of estrogen receptor. "[Trastuzumab] is continuing to show good results in metastatic disease, with improvements in survival," he said. "We're also looking at a role for [trastuzumab] in earlier-stage disease," Riseberg said. "For women with HER2-negative disease, there are biologic agents in development. The combination of capecitabine (Xeloda, Roche) and docetaxel (Taxotere, Aventis) shows a survival advantage." Like Wolfberg, he saw potential in the dose-dense chemotherapy strategy.
The advent of the aromatase inhibitor class constitutes a "revolution" in the treatment of breast cancer, according to Amy D. Tiersten, M.D. She is an associate professor of medicine in the oncology department at New York University Medical Center. "They [these agents] work by preventing estrogen precursors from being converted to estrogen in peripheral tissues. This drug class is really changing our approach in both the adjuvant and metastatic settings." Some physicians are also using aromatase inhibitors as preventive agents in women who are at high risk of developing breast cancer, she said.
She concurred that other exciting developments are in the pipeline and that many of these developments will help elucidate the role of biologic agents such as bevacizumab. An ongoing study is examining the efficacy of bevacizumab in combination with paclitaxel, Tiersten said.
Although aromatase inhibitors seem to interact with few other drugs, pharmacists will want to review the medications of patients on such treatments, Michaud said. "Drug-drug interactions from other prescription medications are particularly a concern with medications that are not prescribed by the oncologist," she said. "The selective estrogen receptor modifiers (SERMs) such as raloxifene HCl (Evista, Eli Lilly ) can be a problem."
Raloxifene HCl was approved for osteoporosis and is often used for people who cannot tolerate bisphosphonates. "A lot of primary care physicians mistakenly give it to women with breast cancer for bone health," Michaud said. "If a patient is on an aromatase inhibitor, treatment with a SERM could be detrimental. In ATAC we saw that the addition of tamoxifen to anastrozole negated anastrozole's benefits. This could be because the estrogen receptors are down-regulated or that the treatment may change how the estrogen receptor functions with an extremely low estrogen level in the body."
Pharmacists should particularly query breast cancer patients about their use of complementary and alternative medicines (CAMs), she added, noting that patients may not think of an herb or supplement as a treatment that could affect their breast cancer therapy, and that many breast cancer patients use these products. "Many supplements have estrogen-like activity, including the phytoestrogens, soy, herbs that can promote estrogen-like activity, and supplements that may either have estrogenic activity or alter estrogen activity in the body," Michaud said, noting that gingko and ginseng can affect estrogen activity. "The use of those agents is very controversial in breast cancer patients. Phytoestrogens are not thought to be as potent as mammalian estrogens, but they function like a SERM."
Michaud commented that she counsels women that such treatments have the potential to negate the effects of an aromatase inhibitor. "When a patient understands that she's taking something to deplete the estrogens and then taking something else to boost the estrogens, she typically understands why phytoestrogen products should be avoided," she said.
"Talk to the patient. Ask them, 'What else are you taking?' if you don't have their complete medication history," she said. "Ask about vitamins, minerals, herbs, in addition to prescription medications. You can also say, 'If you do have an interest in complementary and alternative therapies, ask us before you take them.'"
Wolfberg agreed and pointed out that over-the-counter (OTC) medications can fall off patients' radar, also. "Patients often don't realize that OTC medications and supplements can affect the levels of chemotherapies and other agents," she said. "Therefore sometimes you have to dig deeper, because the patient doesn't know what to disclose. If you ask 'Are you on a medication?' they'll say No, but if you ask about OTCs and supplements, they may be on as many as 20." Patients who are taking ibuprofen for arthritis need to know that the treatment can affect platelets, which are already being compromised by chemotherapy, she said.
Riseberg appealed to community pharmacists to help minimize the risk of drug-drug interactions in breast cancer patients. "Aromatase inhibitors in general don't seem to cause much trouble, but it's important to make sure that none of those [interactions] occur in general," he said. "I try to talk to women about them and get them not to take complementary and alternative therapies I don't know about, but depending on a woman's level of desperation, she may not cooperate. A lot of times we don't know what drug-drug interactions are possible with a given agent until problems develop." The pharmacist can be another trusted community resource who can ward off such problems, he said.
Tiersten also stressed that the neighborhood pharmacist is a valuable resource for these patients. "The filling of a breast cancer treatment prescription is yet another time to remind patients that complementary and alternative therapies can affect breast cancer treatment," she said.
Wolfberg added that the next few years would be exciting as new therapies emerge and are refined. "The research is unearthing so many new treatments," she said. "For so long we didn't have treatments that improved survival, but they're coming out now and more will follow. In the meantime, we need to listen to patients and find out what their treatment-related problems are and to stay educated regarding the guidelines for the new treatments."
Paula Moyer. Advances in breast cancer: New therapies emerge. Drug Topics May 2, 2004;148:11s.