UMLS:C0027627 - FACTA Search

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Query: UMLS:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer represents a major health problem, with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of an increasing incidence, breast cancer mortality has been declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. Better knowledge of breast cancer biology now allows the cosmetic, physical and psychological consequences of radical mastectomy to be spared in the majority of breast cancer patients. Use of the sentinel node technique is rapidly expanding and this will further reduce the extent and the consequences of surgery. Several clinico-pathological factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse. Nodal status, tumour size, tumour grade and age are accepted universally as important factors to define risk categories. Newer factors such as uPA/PAI-1, HERer2-neu, proliferative indices and gene expression profile are promising and will allow better discrimination between patients at different risk. Endocrine manipulation with tamoxifen, ovarian ablation or both is the preferred option in the case of endocrine-responsive tumours. Tamoxifen administered for 5 years is the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen, with a different safety profile. At present, anastrozole can be used in the adjuvant setting in cases of tamoxifen intolerance or toxicity. Chemotherapy is the treatment of choice for steroid receptor-negative tumours. Polychemotherapy is superior to single agents and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four of CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. The taxanes have been approved for adjuvant therapy in the USA, while European approval is pending. Combined endocrine-chemotherapy is the standard adjuvant treatment in high-risk patients with endocrine-responsive tumours. Endocrine manipulation is usually administered after completion of the chemotherapy programme. For HER2-neu overexpressing tumours, several rapidly accruing trials are exploring the potential additive effect of trastuzumab, a monoclonal antibody directed against the extramembrane portion of the HER2 receptor. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer, with increased rates of breast-conserving surgery. A proportion of patients achieve a pathological complete response and these patients have significantly better long-term outcomes. Twenty-five to forty percent of breast cancer patients develop distant metastases. At this stage the disease is incurable; however, treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In the case of hormone receptor positivity and in the absence of visceral, life-threatening disease, endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure anti-oestrogens and progestins. Aromatase inhibitors are the most active agents, but the choice and the sequence of endocrine therapies are also dictated by prior adjuvant treatment. Chemotherapy has to be preferred in cases of receptor-negative tumours, acquired resistance to hormones and aggressive visceral disease. Combination regimens are usually associated with higher response rates and sometimes survival prolongation, and this approach should be recommended in young patients with good performance status and visceral disease. On the other hand, single agents have a better tolerability profile and should be tand should be the treatment of choice when a careful balance between activity and tolerability is needed. For HER2-neu positive tumours, the combination of trastuzumab and chemotherapy is significantly superior to chemotherapy alone in terms of both response rates and survival. Other useful palliative treatments include bisphosphonates for the control of metastatic bone disease and radiotherapy for painful bone lesions or local relapses.
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PMID:The curability of breast cancer and the treatment of advanced disease. 1510 48

The clinical development of aromatase inhibitors in recent years represents a significant addition to our armamentarium for the treatment of postmenopausal patients with hormone receptor-positive breast cancer--both for metastatic disease and in the adjuvant setting. In patients with metastatic disease, third-generation aromatase inhibitors have shown significantly superior efficacy over tamoxifen as first-line hormone therapy. In the adjuvant setting, preliminary results with the use of aromatase inhibitors in ongoing large clinical trials indicate significant gains in disease-free survival rates and in the occurrence of contralateral breast cancer, either alone for 5 years or sequentially after tamoxifen for 2-3 or 5 years. While tamoxifen monotherapy continues to be standard adjuvant therapy for patients with low risk primary breast cancer, postmenopausal patients with higher risk hormone-positive primary breast cancer should also be offered an aromatase inhibitor. Aromatase inhibitors are also prescribed for patients with contraindications to tamoxifen. The optimal sequence and duration of aromatase inhibitor adjuvant therapy as well as its long-term impact on overall survival remain to be established. In general, aromatase inhibitors have a good toxicity profile. Long-term effects such as the risk of osteoporosis need to be better defined.
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PMID:The emerging role of the new aromatase inhibitors in the treatment of breast cancer. 1584 8

There are important surgical issues related to the use of the third generation aromatase inhibitors in both the neoadjuvant and adjuvant settings. Neoadjuvant hormone therapy is effective at downstaging tumours, particularly large tumours initially thought to be inoperable or requiring mastectomy. Randomised trials have shown that the newer aromatase inhibitors letrozole and anastrozole increase the numbers of women who are suitable for breast-conservation compared with tamoxifen, and that letrozole is superior to tamoxifen in terms of clinical response. Aromatase inhibitors are most effective in ER-rich tumours and are clinically and biologically effective in both HER2 positive and negative tumours, whereas HER2 positive tumours show a level of resistance to tamoxifen. In neoadjuvant studies comparing aromatase inhibitors with tamoxifen, the duration of use has been 3-4 months, by which time any response is usually evident but longer treatment periods produce continued shrinkage and response. The re-excision rate following breast conservation surgery after neoadjuvant hormone therapy is favourable compared with the rates following immediate wide local excision. Local recurrence rates are acceptable in patients undergoing neoadjuvant therapy and breast-conserving surgery providing post-operative radiotherapy is given. Adjuvant aromatase inhibitors, as well as having an effect on metastatic disease and survival, reduce local and regional recurrence.
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PMID:Surgical issues surrounding use of aromatase inhibitors. 1602 54

Significant progress has been made in the last 30 years in the adjuvant hormonal and chemo-therapeutic treatments of breast cancer. Currently, several cytotoxic agents are available for use including anthracyclines, taxanes, and cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and a new class of hormonal agents, aromatase inhibitors were introduced. A greater than 50% improvement in risk of relapse and 25% absolute overall survival advantage is presently realistic for many women with lymph node-positive breast cancer who receive adjuvant therapy. Aromatase inhibitors (AI) now constitute a superior alternative to tamoxifen as adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. Extended hormonal therapy with letrozole after completion of five-years of tamoxifen has been shown to improve survival and reduce late relapses. It has also been established that anthracycline containing combination chemotherapy is superior to CMF if the number of cycles is kept the same. Inclusion of a taxane in an anthracycline-based regimen has further improved efficacy. The schedule of administration of drugs, particularly of paclitaxel, also appears to have an impact on efficacy. On the other hand, increasing the dose of cyclophosphamide or anthracyclines above the standard dose do not appear to improve the efficacy of these regimens, whereas substandard dose are clearly inferior. Currently there are several highly effective adjuvant chemotherapy regimens, however there is no single best treatment, let alone a universally effective one. Tamoxifen was the first truly molecularly targeted agent to be used in the treatment of cancer though it took some time to understand that its benefits are restricted to hormone receptor-positive cancers only. Clinical experience shows that similar principals apply to adjuvant chemotherapy as well. Only a subset of patients with micro-metastatic disease benefit from cytotoxic therapy. A major current research effort is focused on the discovery of molecular markers that could predict who will benefit from what particular type of chemotherapy. In the near future, important clinical advances will come from the incorporation of trastuzumab into adjuvant chemotherapy regimens for patients with HER-2 amplified tumors. Results from several large randomized studies are expected shortly and will define the use of trastuzumab in this clinical setting.
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PMID:Adjuvant therapy for breast cancer. 1616 38

Expression of the estrogen-synthesizing genes aromatase, steroid sulfatase (STS) and 17beta-hydroxysteroid dehydrogenase type1 (17beta-HSD(1)) has been shown to be up-regulated in primary breast cancer tissue but their expression status in metastatic tumor tissue has yet to be determined. The mRNA expression levels of the three estrogen-synthesizing genes as well as of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and cyclooxygenase (COX)-2, all of which have been reported to up-regulate the estrogen-synthesizing genes, were determined by means of a real-time PCR assay in 100 primary breast cancer tissues and 15 soft tissue metastases. In addition, PCR-gel electrophoresis was used to determine the proportion (%) of promoter (l.4, l.3, Pll and l.7) usage of aromatase. Aromatase and STS mRNA levels were significantly (P=0.04 and P=0.03, respectively) higher in soft tissue metastases than in primary tumors, while 17beta-HSD(1) mRNA levels tended (P=0.09) to be higher. The proportions of the promoter usages were very similar for primary tumors and soft tissue metastases, and the mRNA levels of TNF-alpha, IL-6 and COX-2 were not significantly different. Levels of aromatase, STS and 17beta-HSD(1) mRNA are up-regulated in soft tissue metastases compared to those in primary tumors, suggesting that intra-tumoral estrogen synthesis may play a significant role in the growth stimulation of tumor cells in soft tissue metastases as in primary tumors. TNF-alpha, IL-6 and COX-2, on the other hand, are unlikely to be implicated in this up-regulation.
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PMID:Quantitative analysis of aromatase, sulfatase and 17beta-HSD(1) mRNA expression in soft tissue metastases of breast cancer. 1655 83

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.
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PMID:Aromatase inhibitors and bone loss. 1698 48

Hormone receptor-positive breast cancer is increasingly considered a chronic disease, as there remains an ongoing risk of local and distant relapse for years after diagnosis. While early recurrence risk peaks 2-3 years post diagnosis, the majority of breast cancer recurrences and deaths occur following 5 years of adjuvant tamoxifen. Aromatase inhibitors have achieved greater relative reductions in recurrence risk than tamoxifen alone and are now widely recommended as adjuvant therapy for postmenopausal women with hormone-sensitive breast cancer. Although both anastrozole and letrozole have demonstrated superior disease-free survival compared with tamoxifen, letrozole to date offers the greatest significant reduction in the risk of distant metastases in patients with hormone-sensitive breast cancer. Anastrozole and exemestane also reduce local and distant recurrence risk in the "switch setting" following 2-3 years of tamoxifen. Extended adjuvant letrozole, given after 5 years of tamoxifen, significantly reduces local and distant recurrence as well as mortality in patients with node-positive disease. Specialist nurses and nurse practitioners facilitate informed choice for breast cancer patients through explaining treatment options and side effects; they thus need an understanding of which treatment strategies reduce recurrence risk, especially the risk of distant metastases.
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PMID:The role of endocrine therapies in reducing risk of recurrence in postmenopausal women with hormone receptor-positive breast cancer. 1837 13

Aromatase inhibitors (AIs) are becoming more widely used than tamoxifen as adjuvant hormonal therapy for postmenopausal women (PMW) with early breast cancer (EBC). It is clear that these drugs offer important efficacy benefits over tamoxifen and differ from tamoxifen in their safety profile. The accepted strategies for adjuvant AI therapy include initial adjuvant treatment following surgery, switching and/or sequencing from prior tamoxifen, and extended adjuvant therapy following the full 5 years of tamoxifen treatment. Among the available AIs, letrozole has been evaluated in large, well-controlled, double-blind clinical trials in the initial adjuvant, extended adjuvant, and more recently, the sequential adjuvant settings. Letrozole is the most potent of the AIs and provides near complete suppression of plasma estrogens in PMW. Letrozole also significantly reduces the occurrence of early distant metastases, the most lethal type of recurrence event, which can lead to improved survival. Clinical comparisons of letrozole with both tamoxifen and placebo have also provided important long-term safety data on the use of AIs as adjuvant therapy in PMW with EBC. The weight of clinical evidence indicates that letrozole is a safe and effective option for adjuvant hormonal therapy across all three AI treatment settings.
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PMID:Long-term efficacy and safety of letrozole for the adjuvant treatment of early breast cancer in postmenopausal women: a review. 1977 14

The strategy of using estrogen suppression to treat breast cancer led to the development of aromatase inhibitors, including the third-generation nonsteroidal compounds anastrozole and letrozole, and the steroidal compound exemestane. Aromatase inhibitors potently inhibit aromatase activity and also suppress estrogen levels in plasma and tissue. In clinical studies in postmenopausal women with breast cancer, third-generation aromatase inhibitors were shown superior to tamoxifen for the treatment of metastatic disease. Studies of adjuvant therapy with aromatase inhibitors include (i) head-to-head studies of 5 years of the aromatase inhibitor versus 5 years of tamoxifen monotherapy; (ii) sequential therapy of 2-3 years of tamoxifen followed by an aromatase inhibitor (or the opposite sequence) versus 5 years of tamoxifen monotherapy; (iii) extended therapy with an aromatase inhibitor after 5 years of tamoxifen; and (iv) sequential therapy with an aromatase inhibitor versus aromatase inhibitor monotherapy. Recent results from the Arimidex, Tamoxifen, Alone or in Combination and Breast International Group 1-98 trials advocate using an aromatase inhibitor upfront. This article examines the clinical data with aromatase inhibitors, following a brief summary of their pharmacology.
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PMID:The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum. 2061 98

The primary goal of systemic adjuvant therapy for breast cancer is to control the risk of local and distant tumor recurrence and thus improve long-term survival. Tamoxifen has been the standard adjuvant endocrine therapy for pre- and postmenopausal women with hormone receptor-positive breast cancer. In estrogen receptor-positive disease, 5 years of tamoxifen reduces the annual breast cancer death rate by 34% irrespective of the use of chemotherapy, age, or other tumor characteristics. Aromatase inhibitors (AIs) can further improve disease-free survival, reducing distant metastases and, in some cases, extending overall survival. Anastrozole and letrozole are approved as upfront adjuvant treatment, anastrozole and exemestane are approved for use in switching strategies after 2-3 years of tamoxifen, and letrozole is approved as extended therapy following the completion of 5 years of standard adjuvant tamoxifen. Choosing the most appropriate adjuvant AI treatment strategy can be a challenge. Original publications and treatment guidelines can help physicians select the optimal adjuvant treatment for individual patients, according to their risk profile.
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PMID:Clinical practice decisions in endocrine therapy. 2065 3

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