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Aromatase Inhibitors:
Tomorrow’s Treatment for Today’s Patient


Rebecca A. Hawkins, MSN, AOCN®
Oncology Nurse Practitioner
St. Mary’s Regional Cancer Center
Walla Walla, Washington
Deborah L. Toppmeyer, MD
Director, New Jersey Comprehensive Breast Care Center
Director, Cancer Risk Assessment and Counseling Program
The Cancer Institute of New Jersey
UMDNJ/Robert Wood Johnson University Hospital
New Brunswick, New Jersey

Pieces of the Puzzle: Prognostic Indicators for Breast Cancer  

Breast cancer is the leading cause of cancer death in women age 40 to 44 years, and the second leading cause of cancer death for women overall (Table 1). Indeed, 40,200 women were estimated to have died of breast cancer in the year 2001, said Rebecca A. Hawkins, MSN, AOCN®, breast cancer survivor and Oncology Nurse Practitioner, St. Mary’s Regional Cancer Center, Walla Walla, Washington. Although the numbers of women diagnosed are many, the breast cancer experience differs for each individual. According to Ms. Hawkins, “An increased understanding of the various histologic factors and prognostic indicators for breast cancer will help to guide oncology professionals in implementing treatment plans and patient education efforts more effectively.”

Types of Breast Cancer
Breast cancer is generally characterized as non-invasive or invasive disease. Non-invasive breast cancers, ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), are both considered precancerous or early cancerous tumors, limited to their site of origin. DCIS is contained in the duct, and has not yet spread further. LCIS is contained in the lobule, and has not yet spread further. While neither DCIS nor LCIS is usually life-threatening, both require prompt treatment. In addition, LCIS is considered a prognositic indicator, representing an 8% to 10% increased risk for developing future lobular or ductal carcinoma.

The most common invasive breast cancers are also called infiltrating. Adenocarcinoma is the most common histology of invasive disease. Infiltrating ductal breast cancer, which represents 70% to 80% of all invasive breast cancers, is a malignancy that has arisen in the duct, and has spread to the breast tissue and fat. This cancer generally presents as a solid mass, and is detected on mammogram. Infiltrating lobular cancer, comprising 5% to 10% of breast cancers, is a malignancy that has begun in the lobule and may spread to other parts of the body. This type of cancer is often first detected as a large lumpy area upon breast self-examination. Less common forms of invasive breast cancer include medullary, mucinous, tubular, and inflammatory breast cancer, papillary carcinomas, and Paget’s disease.

Indicators for Treatment and Prognosis
According to Ms. Hawkins, there are several disease factors that help in determining the aggressiveness of disease and in identifying an optimal treatment plan for each person with breast cancer.

The grade of cancer is defined as the histologic differentiation or similarity to normal breast tissue, with lower grade numbers indicating well differentiated tumors. Three factors—tubule formation, nuclear features, and mitotic index—are used to determine the grade, which in turns indicates how likely the cancer is to metastasize.

Tumor size is directly related to the risk of recurrence, with larger size indicating poorer prognosis. For example, a <1.0-cm tumor is associated with 91% 10-year recurrence-free survival, a 3.1- to 5.0-cm tumor only a 62%10-year recurrence-free survival (Rosen et al 1993).

Lymph node status is another important indicator of disease recurrence. “Indeed, women with histologically negative lymph nodes have a 70% to 80% probability of remaining disease free after treatment,” Ms. Hawkins said. However, 40% of women have positive lymph nodes at diagnosis, and the number of positive lymph nodes correlates with the incidence of treatment failure.

Hormone receptor status is an important factor in determining the appropriate treatment course and prognosis for persons with breast cancer (Table 2). Normal breast tissue has hormone receptors that respond to stimulation of estrogen and progesterone, and most breast cancer cells retain estrogen receptors. Low-grade tumors tend to be estrogen receptor (ER)- and progesterone receptor (PR)-positive, while postmenopausal women generally have ER-positive and premenopausal women ER-negative disease. Even though it remains controversial, said Ms. Hawkins, hormone receptor status may be used to help predict responsiveness to hormonal manipulation. Approximately 75% of women with ER- and PR-positive disease respond to hormonal therapy, while this is the case in only 5% to 10% of women with ER- and PR-negative disease. Finally, of those who respond to antiestrogen therapy for ER-positive disease, about 70% also have PR-positive disease.

DNA analysis is another method by which prognosis may be predicted. Flow cytometry may be used to determine cell proliferation activity throughout the S phase, wherein DNA replication occurs. The percent of cells in S phase and percent of cells proliferating in S phase are measured, and the final S phase value is read as high or low. DNA ploidy is determined by analysis of DNA content, with normal content referred to as diploid and abnormal content as aneuploid. According to Ms. Hawkins, ploidy status has particularly strong prognostic value in postmenopausal women.

Molecular and biochemical markers have been widely investigated in recent years. As a gene that carries out normal functions, called a proto-oncogene, becomes malignant, it is referred to as an oncogene. Some examples of oncogenes that are characterized by overexpression include Her2/neu, int2/ PRAD/hst, cytosolic tyrosine kinase, myc, VEGF, and bc12, while oncogenes characterized by mutation or underexpression include P53, Rb, and nm23. For example, the proto-oncogene Her2/neu encodes for a transmembrane protein that is the receptor for a peptide growth factor. An overamplification of this gene is associated with a decreased disease-free interval and overall survival. In contrast, P53 is normally a tumor suppressor gene. When working properly, it prevents overexpression or proliferation. “The loss of this function, however, allows increased tumor growth and is associated with aggressive tumor behavior,” said Ms. Hawkins. Finally, tumor markers such as CEA and CA 27-29 may be helpful for early prediction of recurrence or metastasis. However, Ms. Hawkins cautioned that patients should understand that these markers are only a small piece of the breast cancer puzzle.

Depending on the breast cancer type, stage, grade, and other disease and patient health factors, patients often receive treatment with surgery (eg, wide excision, lumpectomy, modified radical mastectomy, reconstruction), combined with chemotherapy and/or hormone therapy. Chemotherapy may be given in the neoadjuvant, adjuvant, and palliation settings. Hormone therapy may be given as prevention, such as in the case of tamoxifen, or in the adjuvant and palliation settings.

Challenges and Coping after Treatment
Many patients with breast cancer report that the time of real challenge begins after completion of therapy. Others may believe the ordeal is over, and yet the women feel that they have been forever changed. They face the challenge of re-entering their lives with feelings such as denial, fear, shock, anger, anxiety, loss of control, loneliness, and sheer panic. In addition, many women experience depression, overwhelming fatigue, alterations in cognition, alterations in sexuality, and menopausal symptoms. Many women’s family and work roles will have dramatically changed. “Fortunately, there are a number of strategies for coping that oncology nurses can offer these patients,” said Ms. Hawkins. First, these women may be encouraged to utilize traditional support resources, such as support groups, counseling, relaxation techniques, and reliance on family, friends, and church groups. In addition, newer strategies including unconventional methods, such as yoga, naturopathic medicine, and exercise, may be helpful. Indeed, Ms. Hawkins’ institution participates in a retreat program for survivors of breast cancer, in which the women can experience a number of these methods. “After breast cancer diagnosis and treatment, women need to redefine what quality of life means to them. As oncology nurses, we have the opportunity to reach beyond the diagnosis and treatment phases for our patients, to make a difference in healing not only the body, but also the soul,” Ms. Hawkins concluded.

Table 1. Breast Cancer Facts
• Breast cancer is the most common cancer in women
• Breast cancer is the leading cause of death in women age 40 to 44 yrs
• Breast cancer is the second leading cause of cancer death, after lung cancer
• 70% of all breast cancers occur in women older than 50 yrs
• In 2001, an estimated 192,200 women were diagnosed with breast cancer
• In 2001, an estimated 40,200 deaths resulted from breast cancer

Table 2. Hormone Receptor Status

• Low-grade tumors tend to be ER- and PR-positive
• Postmenopausal women usually have ER-positive disease
• Premenopausal women usually have ER-negative disease
• Women with ER- and PR-negative disease respond to hormone therapy 5% to 10% of the time
• Women with ER- and PR-positive disease respond to hormone therapy 75% of the time
• In those who have ER-positive disease and respond to antiestrogen therapy, approximately 70% also have PR-positive disease


Aromatase Inhibitors in the Treatment of Breast Cancer

As the treatment of breast cancer has become more targeted, hormone therapy has re-emerged as a major weapon against this devastating disease, said Deborah L. Toppmeyer, MD, Director, New Jersey Comprehensive Breast Care Center, Director, Cancer Risk Assessment and Counseling Program, The Cancer Institute of New Jersey, UMDNJ/Robert Wood Johnson University Hospital, New Brunswick. According to Dr. Toppmeyer, the hormonal manipulation of breast cancer is a critical treatment option. In both the metastatic and adjuvant settings, the use of hormone therapies, including the aromatase inhibitors, may have a significant impact on overall survival for many patients with hormone-dependent breast cancer (Table 1).

Aromatase Inhibitors: Mechanism of Action
There are a number of mechanisms of action by which different hormone therapies work to fight breast cancer in women (Table 2). Premenopausal women derive most of their estrogen from the ovaries. However, postmenopausal women derive estrogen mainly from the action of the aromatase enzyme, which converts adrenal androgens to estrone and estradiol. Two types of agents work to target the aromatase enzyme, thereby suppressing estrogen biosynthesis in the peripheral tissues. New steroidal compounds, which serve to inactivate the aromatase enzyme, are currently under study. In addition, the aromatase inhibitors, which are nonsteroidal compounds, inhibit this enzyme. The newer aromatase inhibitors include letrozole and anastrozole. Because the aromatase enzyme is reconstituted every 24 hours, the aromatase inactivators are not likely to offer a significant benefit over the aromatase inhibitors. Both drug classes reduce peripheral estrogen levels by greater than 90%, Dr. Toppmeyer said. Therefore, these agents may be highly effective in targeting hormone-dependent breast cancer in postmenopausal women.

Letrozole, for example, is an aromatase inhibitor currently indicated for first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer, as well as for treatment of postmenopausal women who have advanced breast cancer with disease progression after anti-estrogen therapy. This agent has been shown to be highly potent and selective, both in vitro and in vivo. In addition, animal data have shown letrozole to prevent the appearance of spontaneous mammary tumors and to be as effective as oophorectomy in inducing estrogen deprivation.

Aromatase Inhibitors: Select Clinical Studies
In early studies, postmenopausal women with advanced breast cancer and disease progression after tamoxifen therapy received either megestrol acetate or letrozole. The results showed significantly longer time to progression, delayed disease progression, longer median duration of response, and increased response rates with letrozole.

This agent also demonstrated positive results in two prospective, double-blind, randomized, well controlled, multinational phase III studies. In study 025, Mouridsen and colleagues (2001) treated postmenopausal women with either letrozole 2.5 mg qd or tamoxifen 20 mg qd as first-line therapy for stage III B locally advanced or locoregional recurrent or metastatic breast cancer, until progression of disease. Crossover treatment was allowed if it was deemed appropriate. All patients had estrogen receptor (ER)- and/or progesterone receptor (PR)-positive or unknown disease. After a median follow-up time of 34 months, the results showed a significantly longer median time to progression and time to treatment failure as well as superior overall response rates and clinical benefit rates with letrozole. Importantly, the median time to chemotherapy was also significantly longer with letrozole than with tamoxifen (16 vs 9 mos), Dr. Toppmeyer commented. The median survival time was 34 months with letrozole, compared with 30 months with tamoxifen. However, Dr. Toppmeyer pointed out that this was likely due to the crossover design of the trial; a survival benefit was observed with letrozole at 12 and at 24 months. The most common side effects for both letrozole and tamoxifen were hot flushes (17%, 14%), nausea (7%, 6%), and alopecia/hair thinning (5%, 3%). Thromboembolic adverse events were low with both treatments (2%, 2%).

Study 024 was similar in design to study 025. However, in this trial, postmenopausal women who were ineligible for breast-conserving surgery and had ER- and PR-positive disease underwent preoperative treatment with either letrozole 2.5 mg qd or tamoxifen 20 mg qd for 4 months. At that time, patients underwent a mastectomy or breast-conserving surgery, with further therapy as determined by the investigator. This approach is desirable in some cases to reduce tumor volume and allow surgery, allow breast-conserving surgery specifically, or expose micrometastases and increase the chance of cure with adjuvant therapy, Dr. Toppmeyer explained.

These results showed superior results with letrozole in terms of clinical, ultrasound, and mammographic response rates. In addition, significantly more women receiving letrozole were able to undergo breast-conserving surgery than those receiving tamoxifen.

Finally, as part of the large, double-blind, randomized ATAC trial, Baum and colleagues treated postmenopausal women who had invasive breast cancer who had completed primary therapy with either 1) the aromatase inhibitor anastrozole 1 mg/day plus tamoxifen placebo; 2) anastrozole placebo plus tamoxifen 20 mg/day; or 3) anastrozole 1 mg/day plus tamoxifen 20 mg/day. After approximately 2.5 years of follow-up, preliminary data show that anastrozole achieved a significantly increased median disease-free survival time and decreased incidence of contralateral breast cancer, compared with tamoxifen. In terms of side effects, tamoxifen demonstrated fewer musculoskeletal complaints and fractures, while anastrozole showed a lower incidence of hot flashes, vaginal discharge, and serum-related effects.

In closing, Dr. Toppmeyer noted that, hormone therapies continue to play a major role in the treatment of hormone-dependent breast cancer. Current data suggest that aromatase inhibitors may be more effective than tamoxifen in the metastatic setting, and may also be useful in the neoadjuvant and adjuvant settings in treating women with breast cancer.

Table 1. Characteristics of Hormone-Dependent Breast Cancer
• Functional ER, PR
• Histologic differentiation
• Low S phase, diploid
• Long disease-free interval
• Metastasis to sites of more treatable disease
• Indolent clinical course
• More prevalent in older patients
• Responds to sequential hormone therapies

Table 2. Mechanisms of Action of Hormonal Therapies

Reduce estrogen levels
   • Ovarian ablation (premenopausal women)
   • Aromatase inhibitors/inactivators (postmenopausal women)
Partially block ER transcriptional activity
    • Tamoxifen, toremifene, raloxifene, idoxifene (mixed estrogen agonist/antagonist activity)
 Totally block ER transcriptional activity, induce ER degradation
   • ICI 182, 780, EM-800 (pure estrogen antagonists)
Mechanism unknown
    • High-dose progestins, estrogens, androgens


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