Advances in breast cancer therapy: More options now available

This year in America, more than 200,000 women will be diagnosed with breast cancer, and more than 40,000 will die of the disease. The good news is that in recent years there has been an explosion in lifesaving treatments for breast cancer, bringing hope and excitement for breast cancer patients. In the past, those patients diagnosed with breast cancer had only one or two options. Today, patients are presented with many successful treatments alternatives.

According to the American Cancer Society, the first step in treating breast cancer is to remove as much of the tumor as possible. This is usually followed by chemotherapy, radiation therapy, or hormones that are sometimes given alone or in combination. The size of the tumor, lymph node involvement, history of breast cancer, age, family history, and whether or not the tumor is estrogen-positive or negative will often determine what type of therapy the patient will receive. Many of these same factors will also determine whether or not chemotherapy is begun before surgery, to shrink the tumor; after surgery; or both before and after surgery.

"Some of the biggest advances in breast cancer treatment have been with hormonal therapy," said James Trovato, Pharm.D., BCOP, associate professor, University of Maryland School of Pharmacy, and clinical specialist, oncology, University of Maryland Greenebaum Cancer Center. He added that hormone therapy plays an important role as adjuvant therapy following surgery and chemotherapy or radiotherapy, as neoadjuvant therapy, and in treating metastatic disease.

After menopause, the ovaries stop making estrogen. However, the adrenal glands continue to produce a small amount of androstenedione that is converted to estrogen in fat cells. According to the National Cancer Institute, among 80% of postmenopausal women with breast cancer, the tumor is estrogen receptor (ER)-positive, and estrogen stimulates the receptors to trigger the growth of the cancer cells. If the woman is ER-positive, then she is treated with hormonal therapy.

For about 25 years, women with ER-positive tumors have been treated with tamoxifen. The drug works by blocking the effects of estrogen at receptor sites, which causes the cancer cells to stop growing and, in high-risk women, curbs the progression of the tumor. Tamoxifen has been found to reduce the risk of cancer recurrence by 47% at five years, with a reduction in mortality of 26%.

Though tamoxifen has been very effective in treating women with breast cancer, its side effects have limited its use. The drug can increase a woman's risk for stroke, blood clots, and uterine cancer. In addition, so much estrogen is depleted that some women experience intense menopausal symptoms, including hot flashes, vaginal dryness, mood swings, and a decreased sex drive. Tamoxifen can also cause menstrual irregularities in premenopausal women.

While tamoxifen is effective at blocking estrogen action on the breast, the search has been on to find hormonal therapy that carries fewer side effects than tamoxifen does and maybe even more effective. According to Trovato, "An alternative may lie in a new group of drugs called aromatase inhibitors." These drugs reduce almost the entire amount of estrogen made in the bodies of postmenopausal women. Since aromatase inhibitors cut off the estrogen supply, they tend to cause fewer side effects than tamoxifen, "especially stroke, blood clots, and uterine cancer," he said.

However, women taking aromatase inhibitors are at a higher risk for osteoporosis because they have less estrogen to protect bone density. The current trend is to use tamoxifen for three to five years and then use an aromatase inhibitor. However, anastrozole (Arimidex, AstraZeneca) is approved for initial adjuvant therapy in postmenopausal women with ER-positive tumors. Letrozole (Femara, Novartis) is approved for use in postmenopausal women after they have received five years of tamoxifen therapy.

Clinical trials have evaluated the use of aromatase inhibitors as neoadjuvant therapy in women with ER-positive tumors. In one clinical trial, letrozole was found to have a greater preoperative response than tamoxifen for neoadjuvant therapy. Nearly half of women with ER-positive tumors treated with letrozole were able to undergo breast-conserving therapy compared with only 35% of patients receiving tamoxifen. Patients who were ER-negative did not do as well on either drug (letrozole, 19%; tamoxifen, 11%).

As with adjuvant and neoadjuvant therapy, hormone therapy plays an important role in treating metastatic disease. Tamoxifen and the aromatase inhibitors continue to be used as first-line hormonal therapy for metastatic breast cancer in postmenopausal women with ER-positive tumors, according to treatment guidelines. Recently, aromatase inhibitors have become the preferred treatment for postmenopausal women with metastatic breast cancer. Aromatase inhibitors have been found to be beneficial in postmenopausal women who have disease progression with tamoxifen therapy.

"More good news regarding aromatase inhibitors is that a review of clinical trials has shown that letrozole and anastrozole have been associated with a longer time-to-disease progression and less toxicity than tamoxifen in women with advanced disease," said Trovato. Another important note is that aromatase inhibitors can be used sequentially. If the patient fails on one aromatase inhibitor, another can be tried with success. In one clinical trial, patients who developed resistance to letrozole or anastrozole responded to treatment with exemestane (Aromasin, Pfizer).

"Another drug to look at is the antiestrogen drug fulvestrant [Faslodex, AstraZeneca]," said Trovato. It is an estradiol analog that binds to estrogen receptors, accelerating the degradation process. It is different from tamoxifen in that it does not have the partial agonist properties of tamoxifen. It is also only available as an intramuscular dose form that is administered once a month. Several clinical trials found it to be as effective as anastrozole for the treatment of postmenopausal women with ER-positive metastatic breast cancer progressing on a prior endocrine therapy.

One clinical trial found fulvestrant to as effective as tamoxifen in the subgroup of patients with known hormone-responsive disease. According to Trovato, fulvestrant is currently being used as second-line therapy or for those who can't tolerate or do not want to take tamoxifen. He believes that "fulvestrant's true use will probably be reserved for patients with adherence issues or for those who can't take oral medications."

The treatment of women with breast cancer has made great strides over the past 30 years. Women are now faced with more options that can dramatically improve their response rate, time-to-disease progression, and survival rate. The development of the aromatase inhibitors and newer antiestrogen drugs has helped to increase survival rates and, in some instances, cure breast cancer in women. Ongoing research in how to best use hormonal therapy (i.e., sequential, combination, or both) will continue to help improve the chances of survival or even cure breast cancer in women.

THE AUTHOR is a clinical writer based in Virginia.