Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death in the United States. It is estimated that the lifetime risk of developing breast cancer is one in eight, with an even higher rate in those with established risk factors. In 2002, it is estimated that some 2.2 million women in the U.S. had breast cancer, of which 193,700 were newly diagnosed.
Breast cancer typically originates in the epithelial lining of the lactiferous ducts (milk ducts) of the breast and may either remain localized or spread to distant sites. Breast cancer that remains localized is highly amenable to treatment, whereas invasive and metastatic disease has generally poorer outcomes. Although breast cancer has been one of the primary beneficiaries of many of the recent advances in cancer therapy, currently mortality rates remain high and further advances are desperately needed.
The greatest advance in the management of breast cancer has come from improvement in early diagnosis, through routine mammography and breast exam. Annual mammography is currently indicated for all women over the age of 50, for certain high-risk women over the age of 40, and at an even earlier age for women with a strong family history.
In spite of the advances in early detection, some women are still diagnosed at a later stage. The cancer presents as a palpable mass either in the breast tissue or in the adjacent axillary lymph nodes. Other local manifestations of advanced breast cancer may include skin thickening and discoloration, nipple discharge, edema, and skin dimpling or overt skin retraction. Systemic manifestations may include weight loss, malaise and in the case of liver meatstases, GI distress.
Causes and Treatments for Breast Cancer
Breast cancer is thought to arise through the complex interaction of genetics, internal hormonal milieu, and external environment factors. Risk factors for the development of breast cancer include a positive family history in a first-degree relative, states of extended estrogen exposure (early menarche, late menopause, late age of first pregnancy, and hormone replacement therapy), and exposure to dietary fats and cigarette smoking.
Based on the size of the tumor, the involvement of lymph nodes and the presence of metastasis, breast cancers are classified into four stages (Table 1). More than 70% of breast cancers belong to stage I /II and only 13% of them belong to stage IV.
Table 1. Breast Cancer Classification With Representative Survival Data
|Stage||TNM||Five-year Survival||Percentage of patients|
(Source: Adapted from American Cancer Society Cancer Medicine)
Patients diagnosed at an earlier stage have a better prognosis than those diagnosed at a later stage. Other prognostic factors that affect the success of the medical intervention and the survival of patients include lymph nodes status, estrogen receptor status, Her2/neu receptor status and histological grade.
The standard of care for primary breast cancer is breast-conserving surgery, plus lymph node resection followed by regional radiotherapy. For patients with estrogen positive tumors, Nolvadex® (tamoxifen) has been the drug of choice and its use after surgery should be continued for five years. Chemotherapy is used mostly prior to surgery (neo-adjuvant) or after surgery as an adjuvant.
Currently, there are numerous hormonal agents indicated for use in both locally advanced and metastatic breast cancer. These agents include progestins (e.g. Megace®), SERMS (Nolvadex®), aromatase inhibitors (Arimidex®) and estrogen receptor antagonist (Faslodex®), with Nolvadex® also indicated for breast cancer prevention in high-risk women. These compounds work either by blocking estrogen synthesis or by inhibiting estrogen receptor binding.
In developed western countries, endometrial cancer is the most common malignant tumor of the female genital tract. It is estimated that nearly 530,000 women in the U.S. have endometrial cancer, and 38,300 new cases are diagnosed each year. The mortality of this disease is low (17%) and its cure rate depends on the stage of the disease. The cure rate varies from 75-90% in stage I, to 10% in stage IV. (Table 2)
Table 2. Survival rates of endometrial cancer
(Source: J. Cancer Clin Oncol 2000)
Treatments for Endometrial Cancer
The standard therapy for endometrial cancer is hysterectomy and bilateral salpingo-oophorectomy with appropriate staging. For patients with type I endometrial cancer or for patients who would like to preserve childbearing potential, hormonal therapy has been the traditional palliative therapy.
Type I endometrial cancers are those which express estrogen and progestin receptors (PR). These cancers are well-differentiated, low grade (G1, G2), with no or minimal myometrial invasion, and are diagnosed at an early stage. Furthermore, they are associated with hyperestrogenism and develop in young women with classical risk factors such as obesity, anovulation nullipartiy, hyperinsulinism or unopposed exogeneous estrogens. A large proportion of endometrial cancers belongs to this type and are good candidates for hormonal therapy. The response rate of these cancers to progestin therapy is about 50-70%.
Unfortunately, not all endometrial cancers belongs to the type I. Some 35 to 50% of all endometrial cancers belong to the second type, which are usually PR-negative and do not respond well to hormonal therapy. These cancers are not associated with a hyperestrogenic state and commonly develops in elderly women who do not have the classic risk factors for endometrial cancer. These patients are slim, physically fit and have never used estrogen replacement therapy. When diagnosed, their cancers tend to be of poorly differentiated, high grade, with deep infiltration of the myometrium, lymphatic spread or distant metastases. Cytotoxic chemotherapy is the treatment of choice for these patients.
While chemotherapy has a higher response rate (40-60%) than hormonal therapy (25-30%), median duration of response following hormonal therapy especially third-generation aromatase inhibitors is substantially longer (30 months for hormonal therapy vs. 12 months for chemotherapy). Furthermore, hormonal treatments are generally associated with fewer severe side effects than cytotoxic therapies.
The leading hormonal therapy for breast or endometrial cancer is tamoxifen. However, with the launch of aromatase inhibitors (Arimidex®, Femara® and Aromasin®) and the estrogen antagonist, Faslodex®, the use of tamoxifen products have been decreasing. With a better efficacy- and safety- profile, and convenient dosing schedule, use of new agents such as aromatase inhibitors and estrogen antagonist are expected to increase in the future. (Table 3)
|Table 3. Selected product comparison of the Breast/Endometrial category|
|1st, 2nd or 3rd line||2nd/3rd||2nd||1st||1st||2nd|
|Dosage||QID||Once weekly||OD||OD||Once per month|
|Additional Benefits||-Lower Cholesterol-Increase bone density-Cancer prevention|
*MPA – Medroxyprogesterone
**AI – Aromatase Inhibitors
***ER antagonist – Estrogen Receptor Antagonist
+++ – Strong
++ – Moderate
+ – Low
Progestins have been successfully used in the palliative treatment of disseminated breast and endometrial cancer for several decades. Currently, there are two types of progestin agents, megestrol acetate (Megace®) and medroxyprogesterone (Depo-Provera®).
In women with advanced or metastatic disease, progestin therapy provides a response rate of 10-20% and survival of less than 1 year. Response rates to progestins are unaffected by route of administration and dose intensification. High doses only increase the risk of toxicity without additional benefits. The recommended doses for progestin treatment are 160mg/day of megestrol acetate or 200-400mg/day of medroxyprogesterone.
For the most part, side effects associated with progestin therapy are mild. Patients who take progestin therapy may experience increased, appetite, weight gain, fluid retention, dyspnea and, in rare circumstances, thromoboembolic events.
Megace® (megestrol) is a synthetic oral progestin introduced by BMS in 1971. When the product was first launched, it was indicated as the first-line treatment for breast and endometrial cancer. Today, this product has been reserved as a second- or third-line antineoplastic agent for treating breast and endometrial cancer.
When compared with tamoxifen and aromatase inhibitors, megestrol is considered less efficacious and have slight glucocorticoid and mineralocorticoid activity. As a result, patients taking megestrol for a long time might experience weight gain. This side effect was lately used to treat cancer patients with anorexia and cachexia.
The recommended dosage for megestrol for treating breast and endometrial cancer is 40mg PO four times per day. It takes at least 2 months of therapy to determine the antineoplastic effectiveness of megestrol.
Depo-Provera® (medroxyprogesterone) is another synthetic progestin used to treat endometrial cancer. Even though medroxyprogesterone has two formulations, oral and injectable, only the latter (medroxyprogesterone 400mg/ml) is used for treating endomterial cancer. FDA approved the depot formulation in 1975.
Medroxyprogesterone has a similar efficacy and side effect profile as megestrol. The recommended dosage for depot medroxyprogesterone is 400mg to 1g IM, to be repeated at weekly intervals.
Besides being used as antineoplastic agent for endometrial cancer, medroxyprogesterone is also used for the treatment of amenorrhea, abnormal uterine bleeding, endometriosis secondary to hormonal imbalances, and endometrial and renal cell carcinomas.
Selective Estrogen Receptors Modulator (SERMs)
Nolvadex (tamoxifen) is the first selective estrogen receptors modulator, approved for the treatment of breast and endometrial cancer. SERMs have the effect of estrogens in some tissues, but act as estrogen antagonists in others (e.g. breast and the endometrium). Launched by AstraZeneca in 1977, Nolvadex® is the hormonal agent studied most extensively in the past two decade and has become the standard first-line hormonal therapy for breast and endometrial cancer with estrogen receptors.
Unlike progestin therapy, Novladex® does not cause weight gain and is less likely to cause thromboembolism. Furthermore, due to its estrogen agonist effect, Nolvadex® has the additional beneficial effect of lowering cholesterol, reducing incidence of myocardial infarctions and increasing bone mineral density. These effects are particularly beneficial among patients with specific risk factors such as obesity, hypercholesterolemia (resulting from estrogen depletion in post-menopausal women), hypertension diabetes, and risk of thromoboembolic events, for whom progestin therapy may be contraindicated.
In breast cancer patients, Nolvadex® has been shown to reduce the risk of breast cancer recurrence and death in women of all age groups. However, in patients with disseminated endometrial cancer, the response rates vary between 0% to 53%. Its effect is greater when it is given for 5 years rather than 1—3 years.
Besides being indicated for treating breast and endometrial cancer, Nolvadex® has also been approved in prevention of breast cancer in women who are at high risk for developing the disease. In clinical trials, Novladex® have been proven to reduce the risk of breast cancer by 30 to 50%. Side effects with tamoxifen include hot flashes, sweating, nausea, vomiting and vaginal discharge.
Recently, some investigators have suggested that Novladex® could augment progesterone receptor concentrations in endometrial cancer and, thus, may increase the degree and duration of response of tumors to progestin therapy. Unfortunately, this theory has not been confirmed with clinical trials when this paper is written.
It is important to note that patients previously treated with progestins or who are unresponsive to progestational agents will not respond to Novladex®. This effect is probably related to the loss of estrogen receptor expression during the course of progestin therapy. As a result, physicians will either use Novladex® first followed by progestins or use both of these products together. The recommended dose of Nolvadex® is 20-40mg twice a daily.
In 1997, AstraZeneca launched a second SERMS, Fareston® (toremifene) in order to revitalize its breast cancer franchise due to the lost of Novladex® patent.
Unfortunately, this launch was a failure to AstraZeneca. Even though Fareston® has a 5-fold higher antiestrogenic/estrogenic ratio than Nolvadex®, its clinical response is no better than that of Nolavdex®.68 With the existence of generic tamoxifene at a cheaper price and with similar efficacy, most physicians prefer to prescribe the generic tamoxifene rather than trying the new product, Fareston®.
Gonadotropin-releasing hormone (GnRH)
Gonadotropin-releasing hormone (GnRH) analogues have previously been used to treat advanced endometrial and breast cancer. These products down-regulate receptors in the pituitary and subsequently cause a fall in the gonadotropin levels and a decrease in estrogen levels. There are only two GnRH analogues in the market, goserelin (Zoladex®) and leuprorelin acetate (Viadur®).
Due the lack of responses in recent studies, these products is seldomly used in the treatment of breast or endometiral cancer. GnRH is now used mainly for the palliative treatment of advanced prostate cancer, and prostate hyperplasia.
Arimidex®, Femara®, Aromasin®
Arimidex® (anastrozole), Femara® (letrozole) and Aromasin® (exemestane) are highly selective non-steroidal competitive inhibitors of the aromatase system. In contrast to tamoxifen, aromatase inhibitors do not block estrogen activity; rather, they suppress the synthesis of estrogen by inhibiting the aromatase enzyme necessary for estrogen production, and thereby deprive the tumor of growth stimulation. Even though they have been shown to be effective in treating endometrial cancer, aromatase inhibitors have only been approved for treating metastatic and advanced breast cancer.
Among all the aromatase inhbitor, Arimidex®, is the first product indicated to treat metastatic breast cancer since 1995. Its use, however, have been limited due to its position as the second line agents for treating breast cancer patients.
However, with the recent approval as the first-line agents for treating locally advanced or metastatic breast cancer, we believe the use of Arimidex® will improve in the future.
When compared with Nolvadex®, aromatase inhibitors such as Arimidex® were shown to be more effective with fewer serious adverse effects. In one recent study, Arimidex® was found to have higher clinical benefit rate (57% for Arimidex® vs. 52% for Nolvadex®) and longer median time to disease progression (TTP) (10.7 months for Arimidex® vs. 6.4 months for Nolvadex®). The incidence of thromboembolism and vaginal bleeding is also significantly less with Arimidex® than with Nolvadex®.
In another study, Femara® was found to have a higher clinical benefit rate, longer TTP than Nolvadex®. Side effects associated with Femara® include hot flashes, nausea, and hair thinning.
Estrogen Receptor Antagonist
Estrogen receptor antagonist is the latest class of hormonal therapy introduced to this category. Represented by Faslodex® (fulvestrant), estrogen receptor antagonist works by down-regrading the estrogen receptor, as opposed to blocking it. Two clinical trials have demonstrated similar efficacy, response rates and TTP, of Faslodex® to Arimidex® in postmenopausal women with breast cancer.
Adverse effects – most commonly, gastrointestional disturbances, hot flashes, nausea, asthenia, headache, and sweating – were also similar for Faslodex® and Arimidex®.
Given its convenient once-monthly intramuscular dosing schedule (250mg once a month), favorable toxicity profile, and efficacy comparable to that of Arimidex®, the use of Faslodex® may quickly surpass that of Arimidex® and may become the next Nolvadex® in the very near future.
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