Breast cancer hormonal therapy

Indications for image-guided percutaneous bone biopsy are bone metastases and primary bone tumors. The biopsy is performed to verify that a suspicious bone lesion is indeed a metastasis, or in order to detect the primary tumor. In patients with breast cancer, hormone sensitivity of a metastatic bone lesion can be important for adequate therapy. In suspected primary bone tumors. 

The measurement of ER has become a standard assay in the clinical management of breast cancer. The presence of ERa identifies those breast cancer patients with a lower risk of relapse and better clinical outcome. Receptor status also provides a guideline for those tumors that may be responsive to hormonal intervention. But only about half of ER-positive patients respond to hormonal therapies. Of those who respond initially, most will eventually develop an estrogen unresponsive disease following a period of treatment even though ERa is often still present. Mutant receptors and constitutively active r eceptors as well as hormone-independent activation of the ERa are discussed. The involvement of ER 3 isoforms is under investigation. 

There is much interest in the possible hormonal effects of phytoestrogens in both men and women. The majority of studies conducted in women have examined the ability of phytoestrogens to alleviate menopausal symptoms. Whilst hormone replacement therapy is recommended for women experiencing menopausal symptoms, there remains some uncertainty as to whether HRT can increase the risk of breast cancer. As a result of these concerns, investigations into natural alternatives such as phytoestrogens have received considerable attention. 

CD Since the publication of the Women s Health Initiative study, there has been an increase in the use of non-hormonal therapies for the management of menopausal symptoms. Particularly for women with CHD and breast cancer risk factors, non-hormonal therapies may offer an alternative to assist with symptom management. A wide range of therapies, both prescription and herbal, have been studied with varying degrees of success. In choosing a particular therapy, it is important to match patient symptoms with a therapy that is not only effective but also safe. 

Adjuvant endocrine therapy reduces the rates of relapse and death in patients with hormone-receptor-positive early breast cancer tumors. Adjuvant chemotherapy reduces the rates of relapse and death in all patients with early-stage breast cancer. 

Initial therapy of metastatic breast cancer in women with hormone-receptor-positive tumors should consist of hormonal therapy. 

Long-term use of hormone-replacement therapy and concurrent use of progestins appear to contribute to breast cancer risk.7 The use of postmenopausal estrogen-replacement therapy in women with a history of breast cancer generally is considered contraindicated. However, most experts believe that the safety and benefits of low-dose oral contraceptives currently outweigh the potential risks and that changes in the prescribing practice for the use of oral contraceptives are not warranted. Oral contraceptives are known to reduce the risk of ovarian cancer by about 40% and the risk of endometrial cancer by about 60%. 

An NIH Consensus Development Conference Statement22 advises that adjuvant hormonal therapy should be recommended to women whose tumors contain hormone-receptor protein regardless of age, menopausal status, involvement of axillary lymph nodes, or tumor size. They also support a benefit of adjuvant chemotherapy for most women with lymph node metastases or with primary breast cancers larger than 1 cm in diameter (both node-negative and node-positive).22... 

The use of preoperative systemic therapy is gaining favor in both early-stage and locally advanced breast cancers. This approach to therapy, referred to as neoadjuvant or primary systemic therapy, most often consists of chemotherapy but in special circumstances also may include hormonal therapy (e.g., in inoperable patients with significant comorbidities). The advantages of preoperative systemic therapy include... 

Hormonal therapies that have been studied in the treatment of primary or early breast cancer include antiestrogens, oophorectomy, ovarian irradiation, luteinizing hormone-releasing hormone (LHRH) agonists, and aromatase inhibitors. 

In postmenopausal women, recently reported evidence supporting the use of aromatase inhibitors in the adjuvant setting is intriguing and may usurp the role of tamoxifen. Three different approaches to therapy have been undertaken with these new agents (1) direct comparison with tamoxifen for adjuvant hormonal therapy, (2) sequential use after 5 years of adjuvant tamoxifen therapy, and (3) sequential use after 2 to 3 years of adjuvant tamoxifen. Based on results of several studies, it has been concluded that therapy for postmenopausal women with ER-positive breast cancer should include an aromatase inhibitor.27,47 It is still unclear if the aromatase inhibitor should be used instead of tamoxifen or sequentially after receiving tamoxifen for 2 to 5 years.27 Concerns surrounding loss of bone density, changes in blood lipids, and cardiac and vascular disease require further study.27... 

Tamoxifen can be used in both premenopausal and postmenopausal women with metastatic breast cancer who have tumors that are hormone-receptor-positive. The toxicities of tamoxifen are described in the section on adjuvant endocrine therapy. The only additional toxicity that one might expect to find in the setting of metastatic breast cancer (specifically bone metastases) is a tumor flare or hypercalcemia, which occurs in approximately 5% of patients following the initiation of any SERM therapy and is not an indication to discontinue SERM therapy. It is generally accepted that this is a positive indication that the patient will respond to endocrine therapy. 

Fulvestrant is a new agent approved for the second-line therapy of postmenopausal metastatic breast cancer patients who have tumors that are hormone-receptor-positive. Studies examining the role of fulvestrant in the treatment of metastatic breast cancer have compared this agent with anastrozole. Given anas-trozole s mechanism of action, only postmenopausal women were eligible for these trials. There is no biologic reason why fulvestrant should not produce similar outcomes in premenopausal... 

Cytotoxic chemotherapy is eventually required in most patients with metastatic breast cancer. Patients with hormone-receptor-negative tumors require chemotherapy as initial therapy of symptomatic metastases. Patients who respond initially to hormonal manipulations eventually cease to respond and go on to require chemotherapy. The median duration of response is 5 to 12 months, but some patients will have an excellent response to an initial course of chemotherapy and may live 5 to 10 years or longer without evidence of disease. In general, median survival of patients after treatment with commonly used drug combinations for metastatic breast cancer is 14 to 33 months. The median time to response has ranged from 2 to 3 months in most studies, but this period depends in large part on the site of measurable disease. The median time to appearance of response is between 3 and 6 weeks in patients whose disease is primarily in the skin and lymph nodes, 6 to 9 weeks in patients with metastatic lung involvement, 15 weeks in patients with hepatic involvement, and nearly 18 weeks in patients with bone involvement. Thus it is often the case that an immediate response to therapy is not... 

Early breast cancer is resected completely with curative intent, and adjuvant chemotherapy and hormonal therapy are initiated to prevent recurrence. During adjuvant chemotherapy, laboratory values to monitor chemotherapy toxicity are obtained prior to each cycle of chemotherapy. After completion of adjuvant therapy, patients are monitored every 3 months for the first few years after diagnosis, with intervals between exams extended as time from diagnosis lengthens. 

Metastatic breast cancer is not curable, and therapy is intended to palliate symptoms. In most cases, hormonal therapy is the mainstay. While on therapy, patients are monitored monthly for signs of disease progression or metastasis to common sites, such as the bones, brain, or liver. 

Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer Status report 2004. J Clin Oncol 2005 23 619-629. 

CA 15-3 serum tumor marker is intended to detect disease recurrence in stage II and stage III breast cancer patients. It has been reported that CA 15-3, together with other suitable markers, is preferred in measuring the effect of applied hormonal therapy or chemotherapy in metastatic disease. Studies have indicated that CA 15-3 assay values are frequently elevated in patients with breast cancer. These... 

Low-dose hormone therapy (conjugated equine estrogen 0.45 mg and medroxyprogesterone acetate 1.5 mg/day) has demonstrated equivalent symptom relief and bone density preservation without an increase in endometrial hyperplasia. Whether such lower doses will be safer (cause less venous thromboembolism and breast cancer) remains to be seen. 

Alternatives to estrogen for hot flushes are shown in Table 31-6. Progesterone alone may be an option in women with a history of breast cancer or venous thrombosis, but side effects limit their use. For women with contraindications to hormone therapy, selective serotonin reuptake inhibitors and venlafaxine are considered by some to be first-line therapy, but efficacy of venlafaxine beyond 12 weeks has not been shown. 

The Million Women Study reported that current use of hormone therapy increased breast cancer risk and breast cancer mortality. Increased incidence was observed for estrogen only, estrogen plus progestogen, and for tibolone. 

In a reanalysis of 51 studies, less than 5 years of therapy with combined estrogen and progestogen was associated with a 15% increase in risk for breast cancer, and the risk increased with greater duration of treatment. Five years after discontinuation of hormone replacement therapy, the risk of breast cancer was no longer increased. 

With estrogen-based therapy, there should be yearly breast exams, monthly breast self-examinations, and periodic mammograms. Women on hormonal therapy should undergo annual monitoring, including pelvic examination, blood pressure checks, and routine endometrial cancer surveillance. 

---