Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. Herein we review general mechanisms of drug resistance, including multidrug resistance by P-glycoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions. Important anticancer agents specific to breast cancer are described. Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2002, 209,995 new cases of breast cancer were registered, and 42,913 patients died of it. In 5 years, the annual prevalence of breast cancer will reach 968,731 cases in the United States. World wide, the problem is just as significant, as breast cancer is the most frequent cancer after nonmelanoma skin cancer, with more than 1 million new cases in 2002 and an expected annual prevalence of more than 4.4 million in 5 years. Breast cancer treatment currently requires the joint efforts of a multidisciplinary team. The alternatives for treatment are constantly expanding. With the use of new effective chemotherapy, hormone therapy, and biological agents and with information regarding more effective ways to integrate systemic therapy, surgery, and radiation therapy, elaborating an appropriate treatment plan is becoming more complex. Developing such a plan should be based on knowledge of the benefits and potential acute and late toxic effects of each of the therapy regimens. Despite advances in early detection and understanding of the molecular bases of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have recurrent disease, which is metastatic in most cases. The rates of local and systemic recurrence vary within different series, but in general, distant recurrences are dominant, strengthening the hypothesis that breast cancer is a systemic disease from presentation. On the other hand, local recurrence may signal a posterior systemic relapse in a considerable number of patients within 2 to 5 years after completion of treatment. To offer better treatment with increased efficacy and low toxicity, selecting therapies based on the patient and the clinical and molecular characteristics of the tumor is necessary. Consideration of these factors should be incorporated in clinical practice after appropriate validation studies are performed to avoid confounding results, making them true prognostic and predictive factors. A prognostic factor is a measurable clinical or biological characteristic associated with a disease-free or overall survival period in the absence of adjuvant therapy, whereas a predictive factor is any measurable characteristic associated with a response or lack of a response to a specific treatment. The main prognostic factors associated with breast cancer are the number of lymph nodes involved, tumor size, histological grade, and hormone receptor status, the first two of which are the basis for the AJCC staging system. The sixth edition of the American Joint Committee on Cancer staging system allows better prediction of prognosis by stage. However, after determining the stage, histological grade, and hormone receptor status, the tumor can behave in an unexpected manner, and the prognosis can vary. Other prognostic and predictive factors have been studied in an effort to explain this phenomenon, some of which are more relevant than others: HER-2/neu gene amplification and protein expression, expression of other members of the epithelial growth factor receptor family, S phase fraction, DNA ploidy, p53 gene mutations, cyclin E, p27 dysregulation, the presence of tumor cells in the circulation or bone marrow, and perineural and lymphovascular space invasion. Systemic treatment of breast cancer includes the use of cytotoxic, hormonal, and immunotherapeutic agents. All of these agents are used in the adjuvant, neoadjuvant, and metastatic setting. Adjuvant systemic therapy is used in patients after they undergo primary surgical resection of their breast tumor and axillary nodes and who have a significant risk of systemic recurrence. Multiple studies have demonstrated that adjuvant therapy for early-stage breast cancer produces a 23% or greater improvement in disease-free survival and a 15% or greater increase in overall survival rates. Recommendations for the use of adjuvant therapy are based on the individual patient's risk and the balance between absolute benefit and toxicity. Anthracycline-based regimens are preferred, and the addition of taxanes increases the survival rate in patients with lymph node-positive disease. Adjuvant hormone therapy accounts for almost two thirds of the benefit of adjuvant therapy overall in patients with hormone-receptor-positive breast cancer. Tamoxifen is considered the standard of care in premenopausal patients. In comparison, the aromatase inhibitor anastrozole has been proven to be superior to tamoxifen in postmenopausal patients with early-stage breast cancer. The adjuvant use of monoclonal antibodies and targeted therapies other than hormone therapy is being studied. Interestingly, some patients have an early recurrence even though they have a tumor with good prognostic features and at a favorable stage. These recurrences have been explained by the existence of certain cellular characteristics at the molecular level that make the tumor cells resistant to therapy. Selection of resistant cell clones of micrometastatic disease has also been proposed as an explanation for these events. Neoadjuvant systemic therapy, which is the standard of care for patients with locally advanced and inflammatory breast cancer, is becoming more popular. It reduces the tumor volume, thus increasing the possibility of breast conservation, and at the same time allows identification of in vivo tumor sensitivity to different agents. The pathological response to neoadj uvant systemic therapy in the breast and lymph nodes correlates with patient survival. Use of this treatment modality produces survival rates identical to those obtained with the standard adjuvant approach. The rates of pathological complete response (pCR) to neoadjuvant systemic therapy vary according to the regimen used, ranging from 6% to 15% with anthracycline-based regimens to almost 30% with the addition of a noncross-resistant agent such as a taxane. In one study, the addition of neoadjuvant trastuzumab in patients with HER-2-positive breast tumors increased the pCR rate to 65%. Primary hormone therapy has also been used in the neoadjuvant systemic setting. Although the pCR rates with this therapy are low, it significantly increases breast conservation. Currently, neoadjuvant systemic therapy is an important tool in not only assessing tumor response to an agent but also studying the mechanisms of action of the agent and its effects at the cellular level. However, no tumor response is observed in some cases despite the use of appropriate therapy. The tumor continues growing during treatment in such cases, a phenomenon called primary resistance to therapy. The use of palliative systemic therapy for metastatic breast cancer is challenging. Five percent of newly diagnosed cases of breast cancer are metastatic, and 30% of treated patients have a systemic recurrence. Once metastatic disease develops, the possibility of a cure is very limited or practically nonexistent. In this heterogeneous group of patients, the 5-year survival rate is 20%, and the median survival duration varies from 12 to 24 months. In this setting, breast cancer has multiple clinical presentations, and the therapy for it should be chosen according to the patient's tumor characteristics, previous treatment, and performance status with the goal of improving survival without compromising quality of life. Treatment resistance is most commonly seen in such patients. They initially may have a response to different agents, but the responses are not sustained, and, in general, the rates of response to subsequent agents are lower. Table 1 summarizes metastatic breast cancer response rates to single-agent systemic therapy.
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PMID:Overview of resistance to systemic therapy in patients with breast cancer. 1799 29

Neoadjuvant therapy improves patient outcomes substantially by increasing the rate of breast-conserving surgery. Following primary surgery, women with hormone-sensitive early breast cancer remain at risk for loco-regional and systemic recurrence. The most common relapse event, distant metastases, is associated with the poorest outcomes. As a neoadjuvant therapy, anastrozole, letrozole, and exemestane have been investigated in phase 3 studies and have shown efficacy in this setting. All three aromatase inhibitors (AIs) significantly improved the rate of breast-conserving surgery. As initial adjuvant therapy, the third-generation AIs anastrozole and letrozole more effectively reduce recurrence risk compared with tamoxifen following surgery, especially in the first 2 years, when the risk is greatest. Tamoxifen, once the standard initial therapy, is associated with improved disease-free survival but may be more effective at reducing loco-regional recurrence than distant metastases. Initial adjuvant letrozole therapy has also shown a pronounced reduction in the risk of distant metastases early on in the course of therapy. If AIs are not used upfront, sequential use of exemestane or anastrozole following tamoxifen provides greater protection against relapse than continuing on tamoxifen. Side effects associated with estrogen deprivation of AIs are less serious than those of tamoxifen and are easily managed. Various molecular markers are under study as surrogates to predict response to neoadjuvant therapy, which may in turn predict responsiveness to adjuvant therapy. Surgeons treating breast cancer patients and prescribing endocrine therapy should be aware of all treatment strategies, including neoadjuvant and adjuvant hormonal therapy, and inform their patients of the benefits and the potential side effects. Early and long-term-risk reduction with AI treatment should be discussed with patients, as should the management of common AI-associated adverse events.
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PMID:Safely promoting breast-conserving surgery and preventing early relapses with an aromatase inhibitor. 1817 77

Ductal carcinoma in situ (DCIS) is commonly diagnosed today, mainly due to widespread use of screening mammography. Despite a better understanding of its biological behavior, many issues regarding its optimal management remain controversial. The biological behavior of DCIS has been associated with distinct molecular and histological features (such as expression of COX2, Ki67, c-erbB2, p53 mutation, presence or absence of comedonecrosis, nuclear grade, hormone receptor status, etc.). Recent advances in the diagnosis of DCIS include using magnetic resonance imaging, and the use of stereotactic-guided directional vacuum-assisted biopsy (DVAB). Ductoscopy and ductal lavage have a limited role in the management of DCIS. Surgical treatment of DCIS includes simple local excision to various forms of wider excision (segmental resection or quadrantectomy), or even mastectomy (either simple or skin-sparing). Radiotherapy following breast-conserving surgery significantly reduces local recurrence rates. Axillary lymph node dissection is not required for the management of DCIS; however, during the last decade, sentinel lymph node biopsy is increasingly used to exclude the presence of axillary metastases (when invasive disease is present within the DCIS). This approach has many advantages (including the avoidance of a second surgery if invasive disease is diagnosed within the DCIS) and should be considered when there is an increased probability for the presence of invasive breast cancer within the DCIS. The role of other minimally invasive methods (such as the "therapeutic" application of the DVAB technique, radiofrequency ablation, laser therapy, cryotherapy and brachytherapy) in the management of small DCIS remains unproven. Tamoxifen should be considered in the management of selected patients with DCIS, such as patients with hormone receptor positive DCIS, young patients, and patients without risk factors for potential side effects. Additionally, and controversial, there is evidence that aromatase inhibitors may be better than tamoxifen in the management of DCIS.
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PMID:Recent advances and current controversies in the management of DCIS of the breast. 1849 Jan 11

Women are at considerable risk of recurrence in the first few years following initial treatment for early breast cancer. To reduce the risk of recurrence, including distant metastases, those with hormone-sensitive breast cancer receive adjuvant endocrine treatment. Lymph node metastases are a predictor of high risk of early recurrence and distant metastases; however, a significant number of women with node-negative disease will also develop distant metastases. This is of concern, because the development of distant metastases is associated with a high risk of breast cancer death. Studies in postmenopausal women showed that an aromatase inhibitor (AI) as initial, upfront treatment reduces early recurrence, including distant metastases, compared with tamoxifen. The three available AIs (letrozole, anastrozole, and exemestane) are approved for adjuvant use. Upfront letrozole or anastrozole improved time to distant metastasis in patients included in the Breast International Group 1-98 and Arimidex, Tamoxifen, Alone or in Combination trials, respectively. Of note, the beneficial effects of letrozole on distant disease were already observed in the first report at 2 years of follow-up and confirmed in the updated results with 50 months of follow-up. Here, we discuss the available data for all AIs and strategies to be taken into account for patient management, with a special focus on the effects of available options on early recurrences and metastasis risk.
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PMID:Start strong or switch? Adjuvant endocrine strategies for postmenopausal women with hormone-sensitive breast cancer. 1853 26

After local therapy, women with early breast cancer remain at risk of recurrence for an extended period. For women with hormone-receptor-positive (HR+) disease, the risk of relapse peaks in the first 2-3 years after surgery. Distant metastases, which are associated with a high risk of death from breast cancer, account for the majority of relapses, both early and late. Preventing distant metastases is therefore a primary aim of systemic adjuvant treatment. Tamoxifen was the mainstay of endocrine adjuvant treatment for HR+ disease, but despite its proven benefits, a significant proportion of patients will relapse while on tamoxifen therapy. The third-generation aromatase inhibitors (AIs)--letrozole, anastrozole, and exemestane--have recently replaced tamoxifen as the recommended adjuvant endocrine therapy, on the basis of greater efficacy and better tolerability. However, the optimal use of AIs in the adjuvant setting requires further investigation, including identification of the best treatment strategy. Although a switching strategy does reduce relapses, only upfront AI therapy can address the early peak of distant recurrences that occur despite tamoxifen. Similarly, only upfront AI therapy can avoid the life-threatening side effects that occur in the early years of tamoxifen therapy. Available evidence supports a hypothesis that upfront adjuvant AI therapy is the most appropriate treatment strategy for postmenopausal patients with HR+ disease. Definitive evidence awaits results from ongoing randomized trials.
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PMID:Optimizing aromatase inhibitor integration into initial treatment strategies in postmenopausal women with hormone-receptor-positive early breast cancer. 1910 92

The CXCL12 chemokine binds to the CXCR4 receptor and contributes to survival, proliferation, and migration of malignant cells. Recent reports indicate that breast cancer cells lacking expression of CXCL12 but exhibiting CXCR4 can metastasize to target organs that secrete CXCL12. We observed that Tamoxifen (Tam), similarly to 5-dAzaC, results in significantly increased levels of CXCL12 transcript and protein in MCF-7 breast cancer cells. Bisulfite sequencing suggests that Tam, similarly to 5-dAzaC, may increase CXCL12 expression via reduction in methylation of cytosine in the cytosine-guanosine (CpG) dinucleotide island of the CXCL12 promoter of MCF-7 cells. Our results, together with findings of other researches, may suggest that Tam epigenetically activates CXCL12 expression in breast cancer cells and can make these cells less susceptible to attraction by exogenous CXCL12 to metastasis sites.
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PMID:Tamoxifen epigenetically modulates CXCL12 expression in MCF-7 breast cancer cells. 1974 59

Despite recent advances in hormonal therapy for breast cancer, tamoxifen remains a major therapeutic option, with indications ranging from primary prevention to metastatic disease. Understanding the variation in response to tamoxifen may significantly improve our ability to personalize cancer care and maximize therapeutic efficacy. One area of particular interest is the impact of cytochrome P450 CYP2D6 genetic polymorphisms on tamoxifen metabolism. Tamoxifen is considered a prodrug, whose efficacy may be dependent on active metabolites, including endoxifen. Patients with reduced CYP2D6 enzymatic activity tend to have lower endoxifen levels, but clinical relevance of reduced endoxifen levels remains to be determined. Several small to moderately sized retrospective studies have suggested an intriguing association between poor metabolizer status and increased disease recurrence. However, these data are limited by sample size and methodologic challenges, including the inability to adjust for major prognostic and confounding factors. Several subsequent studies have failed to find an association or found improved outcomes among reduced CYP2D6 metabolizers. Therefore, current findings are conflicting and should be considered preliminary. Nevertheless, the CYP2D6 test is commercially available, making clinical use possible even as evidence in this area is still evolving. More definitive clinical research is needed before routine CYP2D6 testing can be recommended and considered standard of care. Anticipated data from retrospective analysis of large adjuvant randomized trials of tamoxifen should help address the clinical utility of CYP2D6 testing.
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PMID:CYP2D6 testing in breast cancer: ready for prime time? 2012 Aug 36

To undertake a systematic review of three first-line treatments (letrozole, anastrozole and exemestane) for hormone sensitive advanced or metastatic breast cancer (MBC) in post-menopausal women. We searched six databases from inception up to January 2009 for relevant trials regardless of language or publication status. Randomised controlled clinical trials assessing the safety and efficacy of first-line AIs for post-menopausal women with hormone receptor-positive (HR+, i.e. ER+ and/or PgR+) with or without ErbB2 (HER2)-positive MBC, who have not received prior therapy for advanced or metastatic disease were included. Where meta-analysis using direct or indirect comparisons was considered unsuitable for some or all of the data, we employed a narrative synthesis method. Four studies (25 papers) met the inclusion criteria. From the available evidence, it was possible to directly compare the three AIs with tamoxifen. In addition, by using a network meta-analysis it was possible to compare the three AIs with each other. Based on direct evidence, letrozole seemed to be significantly better than tamoxifen in terms of time-to-progression (TTP) (HR = 0.70 (95% CI: 0.60, 0.82)), objective response rate (RR = 0.65 (95% CI: 0.52, 0.82)) and quality-adjusted time without symptoms or toxicity (Q-Twist difference = 1.5; P < 0.001). Exemestane seemed significantly superior to tamoxifen in terms of objective response rate (RR = 0.68 (95% CI: 0.53, 0.89)). Anastrozole seemed significantly superior to tamoxifen in terms of TTP in one trial (HR = 1.42 (95% CI: 1.15, NR)), but not in the other (HR = 1.01 (95% CI: 0.87, NR)). In terms of adverse events, no significant differences were found between letrozole and tamoxifen. Tamoxifen was associated with significantly more serious adverse events in comparison with exemestane (OR = 0.61 (95% CI: 0.38, 0.97)); while exemestane was associated with significantly more arthralgia in comparison with tamoxifen (OR = 2.33 (95% CI: 1.07, 5.11)). Anastrozole was associated with significantly more total adverse events (OR = 1.04 (95% CI: 1.00, 1.09)) and hot flushes (OR = 1.39 (95% CI: 1.03, 1.89)) in comparison with tamoxifen in one trial; however, the other trial showed no significant differences in adverse events between anastrozole and tamoxifen. The indirect comparison of AIs with each other in women with post-menopausal, hormone sensitive advanced or MBC showed that letrozole and exemestane were better in terms of objective response rate than anastrozole; while the more clinically relevant outcomes overall survival (OS) and progression-free survival (PFS) showed no significant differences between AIs. OS and PFS showed no significant differences between AIs and hence based on these results a class effect for all AIs is possible. However, these results are based on indirect comparisons and a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with appropriate caution. Head-to-head comparisons between letrozole, anastrozole and exemestane in the first-line MBC setting are warranted.
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PMID:Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer. 2053 42

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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