Treatment & Testing
Hormonal Therapy
Estrogen is a female hormone that is produced by the ovaries and adrenal glands and is found in circulating blood. Many organs in the body are composed of cells that respond to or are regulated by exposure to estrogen. Cells in the breast, uterus and other female organs have estrogen receptors (small proteins within the cell) and when exposed to estrogen, are stimulated to grow. When cells that have estrogen receptors become cancerous, the growth of these cancer cells can be increased by exposure to estrogen. When a cancer is known to have estrogen receptors, it is referred to as estrogen receptor-positive (ER-positive).
The basis of hormonal therapy as a treatment for breast cancer is to block or prevent ER-positive cancer cells from being exposed to estrogen, ultimately removing the growth stimulus of the cancer. Nolvadex® (tamoxifen) has historically been a mainstay of hormonal therapy and its side effects and efficacy are well established. However, there are currently several newer hormonal agents that are now available to patients with ER-positive breast cancer that may prove superior to Nolvadex®. Long-term results and further studies will help establish the clinical efficacy of these agents.
How Does Hormonal Therapy Work?
There are several ways to diminish estrogen in the body. One effective approach that is commonly used in many countries is to remove the ovaries, which are the primary source of estrogen in the body. In addition, chemotherapy can play a role in hormonal treatment because it causes ovarian failure, preventing estrogen release from the ovaries in many patients. Another approach is to utilize drugs that can block estrogen without removing the ovaries. Currently, the two most common classes of drugs used for the hormonal treatment of breast cancer are selective estrogen receptor modulators and anti-aromatase agents.
Selective Estrogen Receptor Modulators (SERM): SERMs block the estrogen receptors of cancer cells, thereby preventing the growth stimulatory effects of estrogen. Blocking the effects of estrogen on the cell removes the growth stimulus of ER-positive cancer cells. Currently, Nolvadex® (tamoxifen) is the most common SERM used for the hormonal treatment of breast cancer. However, Nolvadex® is associated with side effects, including an increased risk of uterine cancer. In response to these side effects, a new class of SERMS has emerged which are believed to have positive effects on bones as well as anti-estrogen effects on breast cancer without increasing the risk of uterine cancer.
Anti-Aromatase Agents: Anti-aromatase agents are a class of hormonal agents that work by inhibiting the formation of estrogen in the body. Aromatase is the enzyme (protein) that initiates the process through which hormones in the body are converted to estrogen. Anti-aromatase agents work by inhibiting aromatase. By inhibiting aromatase, the conversion process that is responsible for creating the active form of estrogen is blocked. This reduces levels of the active form of estrogen in the body so cancer cells are depleted of necessary growth stimulant. This is in contrast to Nolvadex®, which blocks the growth stimulatory effects of estrogen by directly binding to estrogen receptors. Anti-aromatase agents are classified into two groups: aromatase inhibitors and aromatase inactivators. Aromatase inhibitors transiently bind to aromatase, whereas aromatase inactivators permanently bind to the enzyme. Currently, two aromatase inhibitors, Femara® and Arimidex® and an aromatase inactivator, Aromasin®, are approved for treatment of postmenopausal women with various stages of breast cancer.
There are still several unanswered questions surrounding the use of anti-aromatase agents and many clinical trials are currently ongoing to determine the clinical applications of this new type of hormonal therapy. Specific issues being evaluated in current clinical trials include direct comparisons of these hormonal agents, optimal duration of treatment with specific agents and combinations of hormonal therapy and anti-aromatase agents in the neoadjuvant and preventive setting.
What Does The Research Indicate?
Hormonal treatment is most beneficial for women with ER-positive breast cancer. When hormonal treatment is offered to women with early stage cancers, it is considered adjuvant treatment (treatment that occurs after primary treatment); however, when women with metastatic cancers receive hormonal treatment, it is simply considered part of their treatment regimen. Research indicates that hormonal treatment is appropriate for both early and late stage ER-positive breast cancers. Several clinical trials have been performed to evaluate Nolvadex® and other anti-estrogens in many different settings. In addition, clinical studies have been conducted to evaluate anti-aromatase agents in the metastatic setting. Future clinical trials are planned to evaluate anti-aromatase agents in early stage cancers and for prevention.
Nolvadex®
The results of several clinical studies indicate that adjuvant hormonal treatment with Nolvadex® alone can reduce the rate of cancer recurrence and improve the duration of survival in all women with ER-positive breast cancer, but not those with ER-negative breast cancer. Individuals with ER-negative breast cancer, however, are at high risk of developing a cancer in their other breast and may want to learn more about prevention of breast cancer using hormonal treatment.
Unfortunately, not all individuals have the estrogen receptor status of their cancer determined. Analysis of multiple clinical studies suggests that patients with an unknown estrogen receptor status also benefit from adjuvant hormonal treatment. However, the benefit may be minimal, as women under 50 with an unknown hormonal status treated with Nolvadex® have an annual reduction in the risk of cancer recurrence of 3% and women over 50 with an unknown hormonal status have an annual reduction of 16%. In comparison, the annual reduction in the risk of cancer recurrence in ER-positive patients under 50 is 19% and in ER-positive patients over 50 is 36%.
Carcinoma In Situ: A clinical study has been performed to determine whether the combination of lumpectomy, radiation therapy, and Nolvadex® is of greater benefit than lumpectomy and radiation therapy without Nolvadex® for treatment of ductal carcinoma in situ (DCIS). In this study, 1,804 women with DCIS were treated with either lumpectomy, radiation therapy and placebo or lumpectomy, radiation and Nolvadex® for 5 years. The average follow-up was 74 months. Only 8.2% of patients treated with Nolvadex® experienced cancer recurrence, compared to 13.4% of patients treated with placebo. The incidence of invasive breast cancer in women treated with Nolvadex® was 4.1% at 5 years, 2.1% in the same breast and 1.8% in the opposite breast and 0.2% at regional or distant sites. The researchers concluded that surgery, radiation therapy and Nolvadex® was more effective for prevention of breast cancer recurrence in patients with DCIS than surgery and radiotherapy. Patients interested in treatment with Nolvadex® may wish to discuss the risks and benefits of Nolvadex® treatment with their physician.
Early Stage Breast Cancer: Clinical studies have demonstrated that individuals with ER-positive breast cancer that involves the lymph nodes live longer and have a reduced rate of cancer recurrence when they are treated with both adjuvant chemotherapy and Nolvadex®. This additive effect is greatest in post-menopausal women where Nolvadex® added to chemotherapy further decreases the annual risk of breast cancer recurrence by approximately 28% compared to treatment with chemotherapy alone.
At least two well-designed clinical studies in women with node positive breast cancer have demonstrated that women treated with the combination of Nolvadex® and chemotherapy have improved survival compared to women treated with Nolvadex® alone. One study compared treatment with Nolvadex® alone to treatment with the combination of Nolvadex® and the chemotherapy drugs doxorubicin and cyclophosphamide (ACT). Three years from treatment, ACT improved survival from 85% to 93% compared to treatment with Nolvadex® alone. A second clinical study has demonstrated a decrease in breast cancer recurrence when chemotherapy is added to Nolvadex®. At 4 years from treatment, 79% of patients treated with chemotherapy and Nolvadex® survived without evidence of cancer recurrence, compared to only 72% of patients treated with Nolvadex® alone.
In 1997, the results of a clinical trial comparing chemotherapy with or without Nolvadex® confirmed that lymph node negative, estrogen receptor positive patients treated with Nolvadex® in addition to chemotherapy experienced similar benefit to that previously reported in node positive patients. In this clinical study, 90% of node negative patients treated with CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy and Nolvadex® were alive without cancer recurrence, compared to 84% of patients treated with Nolvadex® alone.
Adjuvant hormonal therapy with Nolvadex® can also prevent the development of new cancers in the contralateral (opposite) breast. In a large analysis of 37,000 women treated with adjuvant therapy, the use of Nolvadex® was associated with a proportional reduction of contralateral breast cancer of 47% for women with estrogen receptor positive and negative cancers. Women with estrogen receptor negative breast cancer may also wish to discuss with their physician the risks and benefits of Nolvadex® treatment for prevention of a second breast cancer. It is currently recommended that Nolvadex® be administered for 5 years.
Anti-Aromatase Agents
Anti-aromatase agents are a class of hormonal agents that work by inhibiting the formation of estrogen in the body. Estrogen is initially released in an inactive form and, through a series of biochemical conversions, the final, active form of estrogen is produced. Aromatase is the protein (enzyme) responsible for facilitating the initial conversion step of estrogen. Anti-aromatase agents work by inhibiting aromatase so that the final form of estrogen is never produced. This reduces the amount of the active form of estrogen in the body. It is important to mention that thus far, anti-aromatase agents only demonstrate improvements in postmenopausal women. These agents are being refined and evaluated in clinical trials to determine whether they will benefit other women as well.
Early-Stage Breast Cancer: Arimidex® and Femara® are approved for the initial treatment of postmenopausal women with ER-positive or unknown receptor status locally advanced or metastatic breast cancer. Several clinical studies have recently been conducted to evaluate these agents in earlier-stage breast cancer and to directly compare these agents to Nolvadex® in postmenopausal women with ER-positive breast cancer.
One of the most recent studies involving an anti-aromatase agent was the Arimidex®, Nolvadex® Alone or in Combination (ATAC) clinical trial. Over 9,000 post-menopausal women with ER-positive or unknown receptor status breast cancer received either Arimidex®, Nolvadex®, or both drugs as adjuvant therapy for five years. At an average of approximately 2.5 years following therapy, 317 out of 3,125 women receiving Arimidex® had a cancer relapse or death, compared to 379 out of 3,116 women receiving Nolvadex® and 383 out of 3,125 women receiving both agents. These data represented a 17% decreased risk of relapse in the group of patients receiving Arimidex® compared to those receiving Nolvadex®. There was no additional benefit for the combination of agents over Nolvadex® alone. Contralateral breast cancer was reduced by 58% in women receiving Arimidex® over Nolvadex®, with no significant benefit of the combination over Nolvadex® alone.
Metastatic Breast Cancer: Two large clinical trials directly comparing Arimidex® to Nolvadex® were conducted in over 1,000 post-menopausal women with ER-positive or ER status unknown, advanced breast cancer. An average of 18.2 months following treatment, the time to cancer progression was 8.5 months for patients receiving Arimidex®, compared to only 7 months for patients receiving Nolvadex®. In the subgroup of patients with ER-positive breast cancer, the time to cancer progression was 10.7 months for patients receiving Arimidex®, compared to only 6.4 months for patients receiving Nolvadex®. An anti-cancer response was achieved in 57.2% of patients receiving Arimidex® and 52% of patients receiving Nolvadex®. Both treatments were generally well tolerated; however, patients receiving Arimidex® reported fewer blood clotting events and less vaginal bleeding.
Another clinical trial was recently conducted to compare Femara® to Nolvadex® as initial hormonal therapy in postmenopausal patients with ER-positive, metastatic breast cancer. At an average of approximately 2.5 years following therapy, the time to cancer progression was 9.4 months in the patients treated with Femara®, compared to 6 months for patients treated with Nolvadex®. The clinical benefit (complete or partial disappearance of cancer or stabilization of cancer) was achieved in 51% of patients treated with Femara®, compared to 38% of patients treated with Nolvadex®. Patients were allowed to “cross-over”, or receive treatment with the other agent if their cancer progressed while being treated with the initial agent. Therefore, true values for overall survival could not be determined, as half of the patients crossed-over and received both agents during their time of treatment. However, patients who initially received Femara® still had a four-month survival over those who initially received Nolvadex®.
Aromasin® is currently approved for the treatment of ER-positive or receptor status unknown metastatic breast cancer in patients who have stopped responding to Nolvadex®. Several clinical trials have demonstrated an improved survival when Aromasin® was compared to Megace® for treatment in postmenopausal women with ER-positive or receptor unknown status advanced breast cancer who had stopped responding to Nolvadex®. Clinical trials have also indicated an improvement in response rates and survival when Aromasin® was compared to Nolvadex® as initial therapy in postmenopausal patients with metastatic, ER-positive breast cancer.
What are the Other Benefits of Hormonal Therapy?
Hormonal treatment may offer additional benefits beyond the treatment of cancer. Although Nolvadex® acts against the effects of estrogen in breast tissue, it may act like estrogen in the other body systems. Women who take Nolvadex® may benefit similarly to those taking post-menopausal estrogen replacement therapy. Nolvadex® may help to lower the blood cholesterol and reduce the rate of bone loss (osteoporosis). Two clinical studies have reported that women treated with Nolvadex® had a lower risk of cardiac disease than women not treated with Nolvadex®. In addition, raloxifene, another selective estrogen receptor modulator (SERM) may have positive effects on bones, as well as anti-estrogen effects on breast cancer.
What are the Side Effects of Hormonal Treatment?
Nolvadex®: Nolvadex® is associated with some side effects similar to symptoms of menopause, which include hot flashes, irregular menstrual periods and vaginal discharge or bleeding. Not all women will experience these symptoms. More serious side effects can also occur as a result of prolonged exposure to Nolvadex®. There is a small increase in the number of blood clots in individuals taking Nolvadex®. Individuals taking Nolvadex® have a slightly increased risk of developing cataracts. In addition, Nolvadex® appears to increase a woman’s risk of developing uterine cancer about 2-3 times that of the general population. This risk of uterine cancer is similar to that for women taking postmenopausal estrogen replacement therapy. Since the majority of uterine cancers will be detected at an early stage when they are highly curable, the overall benefit of anti-estrogen treatment in breast cancer patients probably outweighs the risk of uterine cancer. All women who have a uterus and are receiving anti-estrogen therapy should undergo regular gynecologic examinations.
Anti-Aromatase Agents: Thus far, anti-aromatase agents have been linked with very few side effects. Clinical studies show a slightly increased risk of leucopenia (low white blood cell count), thromboembolic events (blood clotting) and vaginal bleeding. These side effects occur less often with anti-aromatase agents than with Nolvadex®. There is a slight increase for fractures and arthralgias with the use of anti-aromatase agents. No link has been established between anti-aromatase agents and uterine cancer. In fact, initial studies show no indication of the uterine lining growing thicker with the use of anti-aromatase agents.
Can Hormonal Therapy Prevent Breast Cancer?
Breast cancer patients treated with Nolvadex® have a lower risk of developing a new breast cancer in their unaffected breast; therefore researchers have speculated that Nolvadex® might be able to prevent breast cancer.
Several clinical studies around the world have been ongoing to determine whether Nolvadex® can prevent the development of breast cancer in high-risk women. In May of 1998, the results of the National Cancer Institute clinical study evaluating Nolvadex® was presented. The primary objective of this clinical study was to determine whether Nolvadex® could decrease the number of breast cancers and thereby decrease the number of women dying from breast cancer. Other goals of the study were to determine whether Nolvadex® could also decrease the number of heart attacks and bone fractures, as well as to determine whether Nolvadex® has any detrimental side effects.
Women aged 35-59 at high risk of developing breast cancer and all women over the age of 60 years were eligible to participate in this clinical study. A total of 13,388 women were enrolled in the clinical study and the average duration of follow-up is 3.6 years. Half of the patients enrolled in this clinical study were treated with Nolvadex® for 5 years and half of the patients received placebo (no Nolvadex®). Eighty-five women treated with Nolvadex® have developed invasive breast cancer, compared to 154 women treated with placebo, representing a 45% reduction in the development of breast cancer. Women treated with Nolvadex® also experienced a significant reduction in hip fractures; however, no reduction in development of heart attacks has yet been observed.
Based on the results of this clinical study, the Food and Drug Administration concluded that Nolvadex® should be approved for reducing the risk of breast cancer in women at high risk of developing breast cancer. Additional follow-up and the results of other clinical studies will further clarify the role of Nolvadex® and other hormonal therapies in the prevention of breast cancer.
Results of another recent study were recently reported and indicated that Raloxifene, another selective estrogen receptor modulator (SERM), may prevent the development of breast cancer in patients with high levels of estrogen. Researchers conducted the multi-center trial to determine if Raloxifene is more effective at reducing the risk of breast cancer in women with high estradiol (an active form of estrogen) levels than in women with low estradiol levels. Estradiol levels were measured for 7,290 postmenopausal women aged 80 years or younger with osteoporosis. No participants had a history of breast cancer or previous estrogen use. Participants received either Raloxifene or a placebo (inactive substitute) for 4 years. In the placebo group, 3% of women with higher estradiol levels developed breast cancer. In the Raloxifene group, 0.8% of women with higher estradiol levels developed breast cancer. In both groups, about 0.6% of women with undetectable estradiol levels developed breast cancer.
These results are promising for the potential use of Raloxifene to reduce the risk of breast cancer for women with high estradiol levels, as well as for potentially reducing the unnecessary use of Raloxifene in women with undetectable estradiol levels. For women with high estradiol levels, the evidence suggested that treating patients with Raloxifene for 4 years would have avoided 47% of breast cancer cases. Future trials may further define the role of Raloxifene and other hormonal agents in reducing the risk of breast cancer for women with high levels of estradiol.
Strategies to Improve the use of Hormonal Treatment in Breast Cancer
Researchers continue to evaluate optimal methods for using hormonal therapy as treatment of primary breast cancer. Currently, there are several ongoing areas of clinical research evaluating hormonal therapies for the prevention and treatment of breast cancer in different stages. Active areas of investigation include, but are not limited to, the following:
Prevention of Breast Cancer: Evaluating the optimal duration of Nolvadex® and Raloxifene therapy required for the prevention of breast cancer is ongoing, as are clinical studies evaluating anti-aromatase agents.
Anti-Aromatase Agents: Anti-aromatase agents are being evaluated in different stages of breast cancer. In a recent multi-center clinical trial, over 120 post-menopausal women with ER-positive advanced breast cancer received either Nolvadex® or Aromasin® as initial therapy. Complete or partial responses to treatment were achieved in 41% of patients receiving Aromasin®, compared to only 13.6% of patients receiving Nolvadex®. The overall anti-cancer response rates were nearly 56% for patients receiving Aromasin®, compared with 42.4% of patients receiving Nolvadex®. The higher response rates achieved with Aromasin® are very encouraging and the last phase of clinical trials comparing Aromasin® to Nolvadex® as initial treatment for patients with advanced breast cancer is currently underway. Results from this trial will determine whether the encouraging response rates achieved with Aromasin® will translate into improved disease-free survival time and overall survival time.
Adjuvant Hormonal Therapy: Evaluation of anti-aromatase agents alone or in combination with Nolvadex® is ongoing to determine the optimal hormonal treatment regimens for women with ER-positive breast cancer in the adjuvant setting.
Neoadjuvant Hormonal Therapy: Neoadjuvant therapy is the delivery of treatment prior to surgery in order to shrink the cancer and facilitate more complete surgical removal of the cancer. Anti-aromatase agents are being evaluated in the neoadjuvant setting.
A multi-center international clinical trial was recently conducted in order to address several issues regarding neoadjuvant hormonal therapy in patients with advanced breast cancer. Researchers aimed to evaluate and compare the anti-aromatase agent Femara® to Nolvadex® in patients with differing characteristics, including estrogen and progesterone receptor status, ErbB-1 and ErbB-2 status in the neoadjuvant setting.
Regardless of ErbB1/ErbB2 status, the overall anti-cancer response rate for ER-positive patients was 60% for those patients treated with Femara®, compared to 40% for those treated with Nolvadex®. Nearly half of the patients treated with Femara® were able to undergo breast-conserving therapy following neoadjuvant treatment, compared with 36% of those treated with Nolvadex®. Patients who were ER-negative showed a poor response to both Femara® (19%) and Nolvadex® (11%).
New Hormonal Agents: Researchers are also evaluating novel hormonal agents for the treatment of breast cancer. Faslodex® (fulvestrant) is a new anti-estrogen agent that has recently been approved by the FDA. Faslodex® binds to estrogen receptors on the surface of cancer cells and achieves its anti-estrogen effects through two separate mechanisms. First, when Faslodex® binds to the receptors, estrogen is crowded out and no longer able to bind to these receptors. Second, Faslodex® degrades the estrogen receptors to which it is bound. Both of these mechanisms prevent cancer cells from accessing sufficient amounts of estrogen needed for growth and replication.
A recent clinical trial was performed directly comparing Faslodex® to Arimidex®. In this trial, 400 postmenopausal women had early or advanced breast cancer and all had a cancer recurrence following previous hormonal therapy. The results indicated that 42% of patients receiving Faslodex® achieved an anti-cancer response, compared with 36.1% of patients receiving Arimidex®. The average anti-cancer response for patients receiving Faslodex® was 19.3 months, compared to only 10.5 months for patients receiving Arimidex®. Side effects of Faslodex® were comparable to those of Arimidex®. Further evaluation of Faslodex® in clinical trials will define the role of this new agent for breast cancer.
