The patient experience The impact of improved treatments for the management of hormone-sensitive breast cancer extends beyond clinical responses . Thanks to appropriate literature and access to the internet , patient awareness of treatment options has grown and patients are now , in many cases , able to engage their oncologists in informed conversations regarding treatment and what to expect in terms of efficacy and safety . Indeed , patients realize that although there is no cure for metastatic disease , treatment can greatly reduce the risk of progression and in the adjuvant setting , where treatment is administered with a curative intent , current treatment options reduce the risk of relapse . The approval of letrozole throughout the breast cancer continuum has provided patients with many reassuring options . The improvement in outcome with letrozole is achieved without a detrimental effect on overall quality of life . Adverse events such as hot flushes , arthralgia , vaginal dryness , and potential osteoporosis are most significant from the patient 's perspective , and it is important that caregivers pay attention to patients experiencing these events , as they can impact compliance unless effectively explained and managed . The major benefits of letrozole are to improve prospects for long-term survivorship in the adjuvant setting and to delay progression and the need for chemotherapy in the metastatic setting . Introduction The diagnosis of breast cancer is a devastating blow for women and is associated with depression , anxiety , and a range of other psychological problems , such as self-blame and negative perception of body-image -LSB- 1 -- 5 -RSB- . Newly diagnosed metastatic breast cancer -LRB- MBC -RRB- is also associated with high levels of psychological morbidity , particularly for younger women -LSB- 6 -RSB- . Prevention of relapse is a long-term therapeutic imperative , but the impact of therapy on quality of life -LRB- QOL -RRB- also needs to be taken into consideration when planning treatment strategies . All therapeutic modalities for early breast cancer -LRB- mastectomy or lumpectomy , radiation , chemotherapy , antibody therapy and endocrine therapy -RRB- can have a significant impact on patients ' QOL both in the short-term and in the transition period from primary treatment to long-term survivorship -LSB- 7 -- 9 -RSB- . Receiving good quality information about prognosis , treatment options , side effects , and risks of breast cancer recurrence is , therefore , important for patients diagnosed with breast cancer -LSB- 10 -- 13 -RSB- . The third-generation aromatase inhibitor -LRB- AI -RRB- letrozole was introduced a decade ago , but at that time , a limited amount of information on breast cancer and its treatment was available to patients . Since then , the international oncology community has made major advances in its knowledge about breast cancer biology , the individualization of treatment options , and communication with patients . Greater understanding of genetics and breast cancer risk has improved approaches for counseling individuals about their susceptibility -LSB- 14 -RSB- . In women who develop breast cancer , the individualization of treatment is becoming more sophisticated through the use of biomarkers as prognostic and predictive factors . These include human epidermal growth factor receptor -LRB- HER -RRB- 2 -LSB- 15 , 16 -RSB- , urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 -LSB- 17 , 18 -RSB- , mRNA expression patterns -LSB- 19 , 20 -RSB- , and , more recently , genetic profiling techniques -LSB- 21 , 22 -RSB- . Individualizing treatment is also made easier by the ability to more accurately determine the patient 's risk factors and prognosis ; for example , by using the Adjuvant ! Online program -LSB- 23 -- 25 -RSB- . Recognizing breast cancer overtreatment has also contributed to tailoring treatment according to individual risk -LSB- 26 -- 30 -RSB- . Oncology teams have facilitated patient involvement in selecting the most appropriate therapy -LSB- 24 , 31 , 32 -RSB- and have improved the provision of patient information , support , and counseling -LSB- 33 , 34 -RSB- . At the same time , patients began to organize effectively and expand their access to knowledge of new drugs and treatment paradigms -LSB- 35 -- 37 -RSB- . Patients have learned to be informed so that they can have constructive dialogues with their doctors and feel they understand and contribute to treatment decisions -LSB- 38 -- 42 -RSB- . Patients who take an active role in the decision-making process perceive that they have a treatment choice , in contrast to those who prefer a shared or passive role -LSB- 43 -RSB- . They know they can not be told at any time during the course of their disease that they are or are not cured ; they recognize that breast cancer is a chronic illness . Patients are now empowered with hope and the knowledge that breast cancer can be managed . Moreover , increased survival rates have prompted greater interest in the QOL of breast cancer survivors -LSB- 44 -- 46 -RSB- . Better education and improved access to screening has resulted in fewer patients being diagnosed with advanced breast cancer at their first presentation , and consequently , mortality has decreased -LSB- 29 , 47 -- 49 -RSB- . In addition , more effective adjuvant therapy with third-generation AIs has significantly decreased the risk of recurrence as compared with the previous standard of care based on tamoxifen -LSB- 50 -- 53 -RSB- . However , there remains a long-term risk of breast cancer recurrence over time -LSB- 54 , 55 -RSB- . Hormone receptor-positive -LRB- HR + -RRB- breast cancer is particularly challenging because of the persistent risk of recurrence with this chronic `` smoldering '' disease . The Early Breast Cancer Trialists Collaborative Group meta-analysis showed that in untreated women with the same nodal status , the breast cancer death rate is greater for patients with estrogen receptor-negative -LRB- ER − -RRB- versus ER + tumors in the first 5 -- 6 years , but substantially lower for ER − versus ER + tumors over the next 10 years -LSB- 56 -RSB- . Similarly , Saphner reported that beyond 5 years , the risk of recurrence was higher for patients with HR + tumors than for those with HR − tumors -LRB- P = 0.00002 -RRB- -LSB- 54 -RSB- . Patients may experience stress after medical therapy is ended because they feel they have lost a safety net -LSB- 57 , 58 -RSB- . This fear is understandable and justifiable in view of the persistent risk of recurrence for HR + breast cancer . An analysis of the MA .17 trial of extended adjuvant therapy recently showed an increasing risk of disease recurrence over time in patients treated with placebo after discontinuing tamoxifen -LSB- 59 -RSB- . Not surprisingly , therefore , patients may be willing to receive long-term therapy -LRB- extended adjuvant -RRB- to prevent recurrence provided that the benefits outweigh the risks and QOL is maintained -LSB- 60 -RSB- . Patients will try to tolerate treatment-related adverse events if there is the prospect of achieving a `` cure , '' i.e. remaining free of relapse during their lifetime . Tamoxifen was the mainstay of breast cancer therapy , but its time-dependent efficacy and serious adverse events created a need for new therapies -LSB- 61 -- 63 -RSB- . The suppression of estrogen was shown to be greater and more selective with third-generation AIs than with first - and second-generation compounds -LSB- 64 -RSB- , and this has resulted in better clinical outcomes and improved tolerability -LSB- 65 -RSB- . This review examines the clinical use of the third-generation AI letrozole from the patient 's perspective and assesses how it has improved treatment outcomes across the breast cancer continuum , including advanced or MBC , extended and initial adjuvant therapy , and neoadjuvant therapy . Metastatic setting Endocrine therapy is the first-choice treatment for women with HR + breast cancer without acute life-threatening symptoms and should be administered for as long as possible before switching to cytotoxic regimens . Endocrine therapy is preferred to cytotoxic chemotherapy because of its more favorable safety profile -LSB- 66 -RSB- . Thus , extending the time to the initiation of chemotherapy is important with endocrine therapy , because a considerable proportion of patients who progress to chemotherapy will experience toxic side effects without gaining benefit -LSB- 67 -RSB- . The most common acute side effects of chemotherapy , such as leukopenia , alopecia , and nausea and vomiting , are significantly increased in women receiving combination regimens compared with single agents -LSB- 68 -RSB- . Chemotherapy can also adversely affect certain aspects of QOL , notably increasing fatigue -LSB- 69 -RSB- , and some regimens may be associated with severe or life-threatening complications such as cardiac failure -LSB- 70 -RSB- . A meta-analysis to review the evidence and determine whether chemotherapy or endocrine therapy has the most beneficial effect on treatment outcomes -LRB- survival , response rate , toxicity , and QOL -RRB- concluded that in women with HR + MBC , a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease -LSB- 71 -RSB- . Prior to the introduction of third-generation AIs , postmenopausal patients with hormone-responsive MBC had few endocrine therapy options other than tamoxifen -LSB- 62 -RSB- . Second-line endocrine agents were limited by safety concerns , including weight gain or the risk of thromboembolism with megestrol acetate -LSB- 72 , 73 -RSB- and cardiovascular toxicity with aminoglutethimide -LSB- 65 -RSB- . Randomized controlled trials demonstrated that letrozole is better tolerated and more effective than these second-line endocrine agents -LSB- 65 , 72 , 73 -RSB- . Furthermore , letrozole has also demonstrated superior early survival compared with tamoxifen as first-line therapy in postmenopausal patients with MBC -LSB- 74 -RSB- . Importantly , longer time to disease progression with letrozole versus tamoxifen was achieved without increased time with adverse events and resulted in more quality-adjusted survival for patients on letrozole -LSB- 75 -RSB- . Maintaining functional ability is an important goal for patients treated in this setting . A subanalysis by different sites of metastatic lesion and Karnofsky Performance Scores also showed the superiority of letrozole compared with tamoxifen in patients with nonvisceral metastases , with visceral metastases without liver involvement , and with liver metastases -LSB- 76 -RSB- . From the patient 's perspective , it is important to receive the most effective therapy first-line ; therefore , letrozole represents a more attractive option than tamoxifen for postmenopausal women . Pharmacologic and clinical differences exist between third-generation inhibitors and should be considered in the selection of the most appropriate endocrine therapy -LSB- 64 , 77 -RSB- . Data from a small randomized crossover trial in 72 postmenopausal women with HR + MBC showed that overall QOL was significantly better with letrozole than with anastrozole -LRB- P = 0.002 for mean total Functional Assessment of Cancer Treatment-endocrine symptoms -RRB- -LSB- 78 -RSB- . Furthermore , letrozole was significantly better tolerated overall than anastrozole . Less nausea , fewer hot flashes , and less abdominal discomfort resulted in almost twice as many patients preferring letrozole to anastrozole -LSB- 78 -RSB- . While letrozole is an appropriate first-line therapy for the majority of patients with hormone-responsive MBC , a small subset of patients with HR + HER2 + tumors have high-risk disease and are candidates for early treatment with chemotherapy plus the anti-HER2 monoclonal antibody trastuzumab -LSB- 79 -RSB- . A meta-analysis of 12 studies involving 2,379 patients with MBC demonstrated that HER2 + tumors are less responsive than HER2 − tumors to endocrine treatment -LRB- overall relative risk 1.42 ; 95 % confidence interval , 1.32 -- 1.52 ; P < 0.00001 -RRB- -LSB- 80 -RSB- . Evidence from preclinical models suggests that trastuzumab may overcome relative resistance to endocrine therapy -LSB- 81 -RSB- , providing the rationale for combining anti-HER2 and endocrine therapies in the clinical setting . Recently , the first published results of an AI in combination with an anti-HER2 antibody -LRB- i.e. trastuzumab -RRB- show that the combination demonstrated durable responses for at least 1 year in 25 % of patients -LSB- 82 -RSB- . Preliminary results from a phase 3 trial -LRB- TrAstuzumab in Dual HER2 ER-positive Metastatic breast cancer -RRB- demonstrated that the combination of trastuzumab with an AI -LRB- anastrozole -RRB- was more effective than anastrozole alone in postmenopausal patients with HR + HER2 + MBC -LSB- 83 -RSB- . Another phase 3 trial , which is enrolling more than 1,200 patients in this setting and has just finished recruitment , is investigating letrozole in combination with lapatinib , a dual inhibitor of HER2 and HER1 tyrosine kinases -LSB- 84 -RSB- . The strategy of combining letrozole with trastuzumab -LRB- as investigated in the evaluation of Letrozole combined with Trastuzumab trial -RRB- , or another HER2-directed therapy , may allow patients with HR + , HER2 + tumors to safely delay the initiation of cytotoxic chemotherapy . Adjuvant therapy Patients receiving adjuvant therapy expect their treatment to prevent breast cancer recurrence and offer the prospect of cure . However , even modest gains in survival are sufficient to make adjuvant endocrine treatment worthwhile for premenopausal women with early-stage breast cancer -LSB- 85 -RSB- . This benefit threshold also appears to apply to women with a higher risk of recurrence for whom adjuvant chemotherapy is indicated -LSB- 86 -RSB- . Adjuvant therapy should be tailored to suit the needs of individual patients based on their clinical risk factors , attitudes , and personal life circumstances -LSB- 25 -RSB- . However , it is important to recognize that individual preferences can not always be fully explained on the basis of treatment-related determinants and patient or clinical characteristics -LSB- 87 -RSB- . The Anastrozole versus Letrozole : Investigation into Quality of Life study compared the effects of anastrozole and letrozole on estrogen levels , QOL , lipids , and bone health -LSB- 88 -RSB- . A total of 185 postmenopausal women with invasive breast cancer were randomized to receive adjuvant therapy with either 12 weeks of letrozole followed by 12 weeks of anastrozole or vice versa . Of the patients who have completed the 12 weeks of treatment -LRB- n = 146 -RRB- , 50 -LRB- 34 % -RRB- had a preference for neither drug , 50 -LRB- 34 % -RRB- preferred anastrozole , and 46 -LRB- 32 % -RRB- preferred letrozole . Both estradiol -LRB- E2 -RRB- and estrone sulfate levels -LRB- E1S -RRB- were significantly lower on letrozole than on anastrozole -LRB- P < 0.000001 -RRB- . Thus , 2.5 mg of letrozole reduces circulating E2 and E1S levels to a significantly greater degree than 1 mg of anastrozole , with no significant difference in patient preference . The greater suppression of estradiol levels might translate into improved clinical efficacy , although further studies , such as the ongoing Femara Anastrozole Clinical Evaluation trial , are required to confirm these findings . Patients with HR + tumors need to consider the prospect of life-long adjuvant therapy in view of the persistent risk of disease recurrence -LSB- 54 , 56 , 89 -RSB- . Following the introduction of third-generation AIs , there is much greater choice in endocrine therapy . The challenge for physicians is to select the most appropriate strategy to suit individual patient circumstances . Letrozole first entered the adjuvant setting as a treatment option for patients completing 5 years of tamoxifen -LSB- 90 -RSB- and has demonstrated clinical superiority over tamoxifen as initial adjuvant therapy -LSB- 51 -RSB- and neoadjuvant therapy -LSB- 91 -RSB- . Neoadjuvant therapy Neoadjuvant endocrine therapy with letrozole is an attractive option for some postmenopausal patients with HR + early breast cancer -LSB- 92 -RSB- , including elderly patients who are unable or unwilling to undergo chemotherapy or surgery , and patients with locally advanced HR + tumors who wish to have breast-conserving surgery but are not suited for preoperative chemotherapy -LSB- 91 , 93 -RSB- . In a randomized controlled trial , letrozole demonstrated a superior overall objective response rate and rate of breast-conserving surgery compared with tamoxifen as neoadjuvant therapy -LSB- 91 -RSB- . Currently , letrozole is the only AI approved in the neoadjuvant setting -LRB- in the United Kingdom and 16 other countries worldwide -RRB- . It provides a reasonable therapeutic alternative to preoperative chemotherapy in postmenopausal women with HR + disease in clinical situations where the low toxicity of the regimen is considered an advantage , e.g. in women older than 70 years -LSB- 91 -RSB- . However , patients need to be aware that a longer course of therapy may be required to achieve an objective response than is the case with neoadjuvant chemotherapy -LSB- 94 -RSB- . In one study , neoadjuvant letrozole was safely given over 12 months to postmenopausal women with large operable or locally advanced HR + breast cancers -LSB- 94 -RSB- . A longer treatment course may suit some patients and give them more time to consider their options for surgery , radiotherapy , and chemotherapy . Neoadjuvant therapy with letrozole could be considered a sensitivity test of endocrine therapy that might be incorporated into strategies to individualize adjuvant treatment according to response -LSB- 95 -RSB- . This would provide reassurance to patients that they will be receiving an adjuvant endocrine therapy that has shown activity against their tumor . Objective assessment of the antitumor activity of neoadjuvant letrozole can be made on the basis of response rate and by analysis of predictive biomarkers . In one study , neoadjuvant letrozole was found to inhibit tumor proliferation -LRB- determined by the biomarker Ki67 -RRB- more effectively than tamoxifen -LSB- 95 -RSB- . Letrozole was effective independently of HER2 expression status , although the greatest difference between letrozole and tamoxifen was seen in tumors that were HR + and HER1/2 + . Recent evidence has suggested that HER2 + tumors can continue to proliferate despite neoadjuvant letrozole or tamoxifen treatment , which could imply therapeutic resistance that may manifest later in the clinical course of the disease -LSB- 96 -RSB- . Biomarker studies may also reveal differences between AIs . In a randomized comparative trial , letrozole and anastrozole significantly reduced proliferation in HR + , HER2 + or HER2 − tumors -LSB- 97 -RSB- . Decreased proliferation was seen at all Allred ER expression levels with both agents , but only letrozole showed a significant effect in the lower ER cases . In addition , more cases showed a reduction in progesterone receptor -LRB- PgR -RRB- expression following letrozole than anastrozole -LSB- 97 -RSB- . Another study showed evidence of a decrease in HER2 expression after neoadjuvant treatment with letrozole -LSB- 98 -RSB- . Although complex , biomarkers may become increasingly important from a patient 's perspective , because they can help to improve the individualization of treatment . Furthermore , biomarkers may be useful to predict the risk of resistance to endocrine therapy and the need to consider alternative approaches in the future , such as combination therapies or cytotoxic chemotherapy . Knowing what to expect next is important for patients . However , further work is necessary to validate the use of clinical markers and biomarkers in the neoadjuvant setting as surrogate end points for long-term outcomes -LSB- 96 -RSB- . Early adjuvant therapy Tamoxifen was the gold standard endocrine therapy for all women with HR + breast cancer until recent results from large randomized trials challenged this paradigm for postmenopausal women -LSB- 50 , 51 , 99 -RSB- . Oncologists and patients now face an important choice when selecting adjuvant endocrine treatment -LSB- 66 , 100 -RSB- , whether to start with the most potent endocrine therapy -LRB- an AI -RRB- upfront or to start with tamoxifen and switch to an AI inhibitor after 2 -- 5 years . The ongoing Breast International Group -LRB- BIG -RRB- 1-98 randomized trial is expected to provide more information on the benefits of switching to letrozole after 2 -- 3 years on tamoxifen and will clarify which is the optimal strategy . The final results are expected to be released in 2008 -LSB- 51 -RSB- , but until then , the most appropriate endocrine therapy will need to be selected on the basis of currently available evidence . The MA .17 trial has already demonstrated that letrozole treatment is beneficial after 5 years of adjuvant tamoxifen -LSB- 90 , 101 , 102 -RSB- . Patients will ideally wish to receive treatment that provides the greatest long-term efficacy with the lowest risk of adverse events . BIG 1-98 showed that letrozole was significantly more effective than tamoxifen as initial adjuvant endocrine therapy -LSB- 51 -RSB- . Moreover , tamoxifen is perceived to be more toxic than AIs , largely because of well-publicized `` scares '' about increased risk of uterine cancer and thrombosis -LSB- 61 , 103 -RSB- . These side effects and vaginal bleeding were reported for tamoxifen in BIG 1-98 , whereas letrozole was associated with more skeletal events . The overall rate of cardiovascular events was not significantly different between the groups . Letrozole was also shown to be extremely well-tolerated in comparison with placebo in the MA .17 trial -LSB- 90 , 101 -RSB- . With the exception of adverse events related to suppression of estrogen , there was no difference in adverse events -LRB- Table 1 -RRB- . Table 1Safety profile of letrozole in comparison with placebo -LRB- A -RRB- and tamoxifen -LRB- B -RRB- reported in postmenopausal women with early breast cancerPlacebo Acute toxicities reportedTotal number -LRB- % -RRB- , any grade101Letrozole -LRB- n = 2,572 -RRB- Placebo -LRB- n = 2,577 -RRB- Edema571 -LRB- 22 -RRB- 542 -LRB- 21 -RRB- Hypertension130 -LRB- 5 -RRB- 129 -LRB- 5 -RRB- Hot flushes1 ,486 -LRB- 58 -RRB- a1383 -LRB- 54 -RRB- Fatigue999 -LRB- 39 -RRB- 998 -LRB- 39 -RRB- Sweating782 -LRB- 30 -RRB- 760 -LRB- 29 -RRB- Anorexia142 -LRB- 6 -RRB- a110 -LRB- 4 -RRB- Constipation363 -LRB- 14 -RRB- 382 -LRB- 15 -RRB- Diarrhea168 -LRB- 7 -RRB- 176 -LRB- 7 -RRB- Nausea308 -LRB- 12 -RRB- 314 -LRB- 12 -RRB- Vaginal bleeding145 -LRB- 6 -RRB- 196 -LRB- 8 -RRB- aInfection without neutropenia124 -LRB- 5 -RRB- 112 -LRB- 4 -RRB- Arthritis167 -LRB- 6 -RRB- 137 -LRB- 5 -RRB- Hypercholesterolemia418 -LRB- 16 -RRB- 411 -LRB- 16 -RRB- Dizziness458 -LRB- 18 -RRB- 441 -LRB- 17 -RRB- Insomnia166 -LRB- 6 -RRB- 135 -LRB- 5 -RRB- Depression143 -LRB- 6 -RRB- 131 -LRB- 5 -RRB- Headache706 -LRB- 27 -RRB- 685 -LRB- 27 -RRB- Arthralgia651 -LRB- 25 -RRB- a532 -LRB- 21 -RRB- Myalgia380 -LRB- 15 -RRB- a310 -LRB- 12 -RRB- Bone pain141 -LRB- 5 -RRB- 149 -LRB- 6 -RRB- Dyspnea161 -LRB- 6 -RRB- 163 -LRB- 6 -RRB- Alopecia126 -LRB- 5 -RRB- a89 -LRB- 3 -RRB- Vaginal dryness147 -LRB- 6 -RRB- 129 -LRB- 5 -RRB- TamoxifenWorst grade adverse events recorded within first 28 daysTotal number -LRB- % -RRB- , any grade51Letrozole -LRB- n = 3,975 -RRB- Tamoxifen -LRB- n = 3,988 -RRB- CVA or TIA39 -LRB- 1.0 -RRB- 41 -LRB- 1.0 -RRB- Thromboembolic event61 -LRB- 1.5 -RRB- 140 -LRB- 3.5 -RRB- aCardiac event -LRB- IHD , CF -RRB- 162 -LRB- 4.1 -RRB- 153 -LRB- 3.8 -RRB- Other CV event19 -LRB- 0.5 -RRB- a8 -LRB- 0.2 -RRB- Vaginal bleeding132 -LRB- 3.3 -RRB- 263 -LRB- 6.6 -RRB- Hot flushes1332 -LRB- 33.5 -RRB- 1516 -LRB- 38.0 -RRB- aNight sweats554 -LRB- 13.9 -RRB- 647 -LRB- 16.2 -RRB- aFracture225 -LRB- 5.7 -RRB- a159 -LRB- 4.0 -RRB- Arthralgia806 -LRB- 20.3 -RRB- a491 -LRB- 12.3 -RRB- Myalgia254 -LRB- 6.4 -RRB- 243 -LRB- 6.1 -RRB- CV cardiovascular , CVA cerebrovascular accident , TIA transient ischemic attack , IHD ischemic heart disease , CF cardiac failureaSignificant difference Based on the results from the BIG 1-98 and the Anastrozole and Tamoxifen Alone or in Combination -LRB- ATAC -RRB- trial , which compared upfront AIs with tamoxifen , it is clear that all postmenopausal women with HR + breast cancer should be given the opportunity to receive adjuvant use of an AI , and this recommendation is now reflected in internationally recognized treatment guidelines -LSB- 66 , 100 , 104 , 105 -RSB- . Patients with HR + breast cancer considered eligible for adjuvant chemotherapy because of their increased risk for relapse should also be candidates for the most effective adjuvant endocrine strategy -LSB- 100 -RSB- . Of note , the BIG 1-98 trial showed that adjuvant letrozole provides significant disease-free survival -LRB- DFS -RRB- benefits for patients at increased risk of recurrence , specifically patients with node-positive tumors , large primary tumors -LRB- > 2 cm -RRB- , and recipients of chemotherapy and also demonstrated a significant reduction in the risk of distant recurrence , a well-known predictor of breast cancer death -LSB- 51 -RSB- . Additional analyses of data from BIG 1-98 to determine the predictive value of centrally tested ER , PgR , and HER2 status on the response to letrozole and tamoxifen indicate that there is no difference in subgroups by ER/PR or HER2 status regarding the superiority of upfront letrozole versus tamoxifen -LSB- 106 -RSB- . Low-risk patients with HR + breast cancer who do not receive adjuvant chemotherapy are also candidates for AIs -LSB- 104 -RSB- because of the persistent risk of relapse -LSB- 54 , 56 -RSB- . While it is known that tamoxifen loses effectiveness after 5 years -LSB- 62 , 63 -RSB- , the optimal duration of initial therapy with an AI remains to be determined -LSB- 107 -RSB- . The MA .17 randomized controlled trial of extended adjuvant endocrine therapy has already shown that letrozole treatment is beneficial after 5 years of tamoxifen in postmenopausal patients -LSB- 90 , 101 -RSB- , but there are no equivalent data on the use of tamoxifen after initial AI therapy in the adjuvant setting -LSB- 100 -RSB- . Furthermore , the efficacy of switching to another AI in patients who discontinue treatment with letrozole is not known . Therefore , patients starting upfront therapy with letrozole will need reassurance that according to present knowledge , treatment can be continued for up to 5 years , and other options will be available down the line . In addition , patients will require information about the potential long-term impact of AIs on bone and the cardiovascular system -LSB- 107 -RSB- . According to the current treatment guidelines -LSB- 66 , 100 , 104 , 105 -RSB- , patients already taking a course of adjuvant tamoxifen may wish to switch to anastrozole or exemestane , as these AIs have demonstrated efficacy in this setting -LSB- 52 , 108 , 109 -RSB- . Although recent data have shown that this sequential adjuvant strategy is associated with a survival advantage -LSB- 53 , 110 , 111 -RSB- , it is important to note that these data were obtained from a selected population comprising patients at randomization who were disease-free after 2 -- 3 years of tamoxifen . It is therefore not valid to make a direct comparison with an unselected population treated in trials of upfront AI therapy . The decision to switch endocrine therapy after 2 -- 3 years , i.e. for a sequential tamoxifen -- AI strategy , should be based on an individual 's risk for recurrence , risk for osteoporosis , and ability to tolerate tamoxifen . Importantly , BIG 1-98 is expected to provide more information on the benefits of switching to letrozole after 2 -- 3 years of tamoxifen , and will clarify whether upfront or sequential AI use is the optimal strategy . The final results will be released in 2008 -LSB- 51 -RSB- . Extended adjuvant -LRB- including late extended adjuvant -RRB- therapy Many patients fear breast cancer recurrence -LSB- 112 -RSB- and are reassured by the `` safety net '' of continuing medical treatment and monitoring -LSB- 9 -RSB- . The MA .17 trial showed that extended adjuvant therapy with letrozole gives patients the opportunity of retaining the safety net for at least 5 more years after adjuvant tamoxifen -LSB- 101 -RSB- , and these results led to its approval in this indication . Currently , letrozole is the only AI approved as an extended adjuvant therapy . The final analysis of MA .17 after a median follow-up of 30 months showed letrozole significantly improved DFS -LRB- 42 % reduction in risk vs. placebo -RRB- , distant DFS -LRB- 40 % reduction in risk vs. placebo -RRB- and , in node-positive patients , overall survival -LRB- 39 % reduction in risk vs. placebo -RRB- -LSB- 101 -RSB- . A recent cohort analysis of the MA .17 trial data suggested that the longer patients are exposed to letrozole , the greater the benefit , at least out to 48 months -LSB- 59 -RSB- . In addition , an extension to the MA .17 trial -LRB- MA .17 Re-randomization -RRB- is being conducted to determine the benefits of continuing letrozole for a further 5 years -LSB- 102 -RSB- . When a planned interim analysis of MA .17 revealed a significant advantage for letrozole , the trial was unblinded and patients on placebo were given the option to switch to letrozole -LSB- 90 -RSB- . In this non-randomized comparison , women from the placebo arm who elected to switch to letrozole also experienced an improvement in outcome when compared with those who elected to have no treatment -LSB- 102 -RSB- . Recurrence risk persists beyond the completion of adjuvant therapy , even in patients at low risk of recurrence . One study shows that with systemic adjuvant therapy , patients with node-negative breast cancer have a ≥ 25 % 10-year risk of relapse and a corresponding 10-year breast cancer death rate as high as ≥ 10 % , depending on tumor grade and size -LSB- 113 -RSB- . Thus , the proven efficacy of letrozole given after a tamoxifen-free period means that physicians need to discuss the option of restarting endocrine therapy with almost all patients . Physicians have to consider how best to address this topic with patients who are up to 2 -- 3 years out beyond their initial 5 years of tamoxifen , i.e. about 5 -- 8 years after their initial diagnosis . This will be a major communication challenge and create a dilemma for patients who may feel well and have put their breast cancer behind them . Safety and compliance issues The clinical benefits of AIs and tamoxifen are generally achieved without a major detrimental effect on overall QOL -LSB- 114 -RSB- . Data from the MA .17 trial , which is the only large adjuvant trial comparing AI therapy not with tamoxifen but with placebo , showed that overall QOL was maintained during extended therapy with letrozole , and only a minority of patients experienced substantial changes in QOL , which were compatible with a reduction in estrogen synthesis -LSB- 115 -RSB- . It is important to recognize that patients may attribute such changes to their treatment , whereas they could in fact be symptoms of menopause -LSB- 116 -RSB- . However , side effects do occur , which not only affect patient adherence to endocrine therapy -LSB- 117 -RSB- but can also lead to additional morbidity and even serious or life-threatening complications in a small minority of patients -LSB- 51 , 52 , 90 , 99 , 108 , 109 -RSB- . The main safety concerns with long-term estrogen deprivation include potential effects on bone health , cardiac health , lipid profile , cognitive functioning , and sexual health -LSB- 100 -RSB- . The MA .17 trial showed that letrozole is well-tolerated in comparison with placebo -LSB- 101 -RSB- , and BIG 1-98 showed that letrozole was better tolerated than tamoxifen -LSB- 51 -RSB- -LRB- Table 1 -RRB- . A recent patient-reported outcomes study in 104 tamoxifen-intolerant women found that switching to letrozole was associated with a significant reduction in hot flushes -LRB- P = 0.001 -RRB- and significant improvements in QOL -LRB- P = 0.001 -RRB- and mood -LRB- P = 0.04 -RRB- . Furthermore , when given the choice of continuing therapy , 66 % of women indicated that they preferred to remain on letrozole , while only 24 % preferred to go back to tamoxifen -LSB- 118 -RSB- . Despite an increase in newly diagnosed osteoporosis with AIs , no significant difference in clinical fracture rate was seen between letrozole and placebo -LSB- 101 -RSB- . A companion study to MA .17 showed that there was only a modest increase in bone resorption and reduction in bone mineral density -LRB- BMD -RRB- in the spine and hip with letrozole compared with placebo -LSB- 119 -RSB- . Consequently , patients should be made aware of the risk of osteoporosis and given advice on lifestyle measures -LRB- e.g. exercise , diet , vitamins -RRB- to reduce risk . A baseline BMD measurement should be obtained for all patients before starting therapy with an AI . BMD should then be measured annually , and patients at high risk of osteoporosis should be considered for prophylactic use of a bisphosphonate -LSB- 120 , 121 -RSB- . However , recent data from ATAC may be reassuring for patients facing upfront AI therapy , since they indicate that women with normal initial BMD did not develop osteoporosis during a 5-year AI treatment -LSB- 122 -RSB- . Letrozole has been associated with an increase in arthralgia compared with placebo or tamoxifen , and myalgia compared with placebo -LSB- 51 , 101 -RSB- . Arthralgia and joint pain can be bothersome and may lead to impaired mobility . Patients need to be advised that constant exercising of the joints will alleviate this adverse event and that use of nonsteroidal anti-inflammatory drugs over a certain period of time may be helpful . Moreover , these complaints seem to be most frequent in the beginning of AI therapy -LSB- 123 -RSB- . Another potential consequence of endocrine therapy is a detrimental effect on sexual health -LSB- 115 , 116 -RSB- . Vaginal dryness is a consequence of menopause and treatments that cause menopausal symptoms , and has an important bearing on sexual health and well-being of breast cancer survivors -LSB- 124 -RSB- . Vaginal dryness can be a significant problem that can interfere with the stability of relationships -LSB- 125 -RSB- , and patients need to receive counseling with regard to this issue -LSB- 126 -RSB- . It has been shown that clinical assessment and an active intervention program for menopausal symptom management in breast cancer survivors can lead to an improvement in sexual functioning -LSB- 127 -RSB- . A recent report demonstrated that the use of local estradiol therapy may cause elevation of serum estradiol and may therefore be contraindicated in postmenopausal women on AI therapy -LSB- 128 -RSB- . So far , such data do not exist for estradiol-containing compounds ; thus , local estradiol treatment may be indicated in individual cases . Androgen treatment may also improve sexual well-being in postmenopausal women -LSB- 129 -RSB- , yet the oncological safety of this approach has not been validated in patients receiving AI therapy . Of note , the incidence of vaginal dryness in the MA .17 trial was similar in the letrozole and placebo groups -LRB- Table 1 -RRB- -LSB- 101 -RSB- . Differential effects on lipid profiles and cardiac risk have been reported between tamoxifen and AIs -LSB- 51 , 130 , 131 -RSB- , but data from the Letrozole , Exemestane , and Anastrozole Pharmacodynamics trial , directly comparing the effects of anastrozole , letrozole , and exemestane on lipid profiles in healthy postmenopausal women , suggest that the steroidal and nonsteroidal inhibitors have a similar impact on lipid profiles -LSB- 132 -RSB- . On the basis of evidence from large randomized trials , when comparing letrozole with tamoxifen or placebo , it appears that letrozole does not have clinically relevant adverse effects on lipids or cardiac risk during long-term adjuvant therapy , although further assessment is warranted -LSB- 51 , 101 , 133 -RSB- . While letrozole is well-tolerated , and any side effects that do occur can be managed , it is essential that patients are motivated to stay on therapy . This can be a particular challenge in the extended adjuvant setting . Thus , as patients now face the prospect of receiving endocrine therapy for 10 years or more , it is important to consider the overall life-long benefits and risks from the individual 's perspective . A low burden of adverse events and maintenance of QOL is important in maintaining adherence to long-term treatment -LSB- 60 -RSB- . In the MA .17 trial , the rate of patients choosing to discontinue therapy during the first year was similar for letrozole -LRB- n = 256/2 ,575 -RRB- and placebo -LRB- n = 254/2 ,582 -RRB- -LSB- 90 -RSB- . Letrozole is ingested orally and can be safely and conveniently taken at home . Physician contact with oral endocrine therapy can be much less frequent than , for example , with orally active chemotherapy where regular blood tests , side-effect monitoring , and resulting dose modifications make frequent physician contact mandatory . Patients with breast cancer prefer oral cancer therapy providing that it does not compromise treatment efficacy -LSB- 134 -RSB- . Conclusions Patients with breast cancer face bewildering choices at a time when they are experiencing highly stressful circumstances . Moreover , many of these women are not well-informed and thus are not able to take part in treatment decisions . The Gathering Information on Adjuvant Endocrine therapy initiative decided to delineate women 's knowledge and experience of adjuvant endocrine therapy . Results thus far indicate that only 22 % of patients were fully or highly involved in the decision to start adjuvant endocrine therapy -LSB- 135 , 136 -RSB- . Many of the women who took part in the survey were not satisfied with the degree to which they were involved in treatment decision-making , and women 60 years or older had the lowest levels of involvement -LSB- 135 , 136 -RSB- . The results from this survey show that information provided to patients about adjuvant endocrine therapy is suboptimal and indicate the need for programs to raise patient awareness . The medical community has a responsibility to help patients understand their prospects for survival and make the right choices about treatment -LSB- 24 -RSB- . Doctor -- patient discussions and programs to raise patient awareness will increase patients ' knowledge about the individualization of treatment and may increase the number of women who take an active role in treatment decisions . Patients with hormone-responsive breast cancer should be offered the opportunity of receiving the most effective endocrine therapy . Clinical evidence suggests that postmenopausal women should receive an AI rather than tamoxifen as their first option if tumor characteristics and individual side-effect profiles support this choice . Letrozole has consistently demonstrated superiority over tamoxifen in the metastatic and adjuvant treatment settings -LSB- 51 , 74 , 91 , 101 -RSB- . As a result of its innovative clinical trial program -LSB- 51 , 74 , 101 -RSB- , letrozole is approved for use in postmenopausal women throughout the breast cancer care continuum -LSB- 137 -RSB- . From the patient 's perspective , the major benefits of letrozole are improving prospects for long-term survivorship -LRB- `` cure '' -RRB- in the adjuvant setting and delaying progression and the need for chemotherapy in the metastatic setting . Endocrine therapy is very effective , has a generally favorable safety profile , and adds to the efficacy of chemotherapy . However , a major challenge for both physicians and patients is ensuring compliance with long-term daily therapy . This may be a particular problem in the extended adjuvant setting , where the patient may face the prospect of life-long therapy . As patients no longer feel sick , it is understandable that they may forget to take a dose and gradually lose interest in continuing with the treatment . Letrozole is well-tolerated and , as with all AIs , the majority of adverse events are secondary to the suppression of estrogen . The most important adverse events from the patient 's perspective are the `` visible '' ones , such as hot flushes , vaginal dryness , and arthralgias . To achieve optimal compliance , patients need to feel that physicians are taking their adverse events seriously and taking appropriate steps to alleviate any problems . Physicians who treat very few breast cancer patients may not have sufficient experience with AIs to satisfactorily manage individuals who are experiencing these adverse events . Letrozole is likely to continue to play a major role in the management of breast cancer in all settings -LRB- see the paper in this supplement by Drs. Ellis and Ma , on Femara ® and the future -RRB- . Considering its efficacy and favorable side-effect profile , it is the logical choice for inclusion in new regimens , including combinations with novel agents . As the future unfolds , the management of breast cancer is set for further change , and it is essential that patients are informed and educated so that they can actively participate in treatment decisions and thus derive the most benefit from treatment advances .

O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B I O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O B I O O O O O O O O O O B I O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B I O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

adjuvant therapy
breast cancer
letrozole
neoadjuvant therapy
patient


The discovery and mechanism of action of letrozole Because estrogen contributes to the promotion and progression of breast cancer , a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis , the estrogen receptor , and intracellular signaling pathways . The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition . Modern third-generation aromatase inhibitors -LRB- AIs -RRB- effectively block the production of estrogen without exerting effects on other steroidogenic pathways . The discovery of letrozole -LRB- Femara ® -RRB- achieved the goal of discovering a highly potent and totally selective AI . Letrozole has greater potency than other AIs , including anastrozole , exemestane , formestane , and aminoglutethimide . Moreover , letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs . The potent anti-tumor effects of letrozole were demonstrated in several animal models . Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs . An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women . Introduction Studies have consistently shown that lifetime exposure to estrogens increases the risk of breast cancer -LSB- 1 -RSB- . The degree of risk is increased by persistently elevated blood concentrations of estrogen -LSB- 2 -RSB- ; clinical indicators of persistently elevated blood estrogen concentrations , for example , age at menarche , first live birth , menopause , alcohol consumption , and obesity -LSB- 3 -- 5 -RSB- ; and , although still controversial , exposure to exogenous estrogen , for example , some forms of hormone replacement therapy and oral contraceptives -LSB- 6 -- 12 -RSB- . The presence of some of these factors also increases the risk of breast cancer being estrogen receptor -LRB- ER -RRB- - positive -LSB- 13 -RSB- . Studies have shown that higher levels of endogenous estrogen and testosterone -LRB- which is converted to estrogen by aromatase -RRB- increases breast cancer risk , regardless of predicted breast cancer risk -LSB- 14 -- 16 -RSB- . These data indicate that estrogen is an important risk factor even in women considered at high risk of developing the disease , for example , those with a family history of breast cancer . Estrogen is thought to contribute to the initiation and contributes to the promotion and progression of breast cancer via two complementary mechanisms -LSB- 1 -RSB- , the carcinogenic effects of estrogen metabolites , notably hydroxyl metabolites -LSB- 3 , 17 , 18 -RSB- , and stimulation of ER signaling pathways , including those initiated by activation of epidermal growth factors , notably the mitogen-activated phosphoinositide 3 kinase pathway -LSB- 19 -- 30 -RSB- . Greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis -LRB- aromatase inhibitors -LSB- AIs -RSB- -RRB- -LSB- 31 -RSB- , the ER -LRB- selective ER modulators -LSB- SERMs -RSB- , pure antagonists -RRB- -LSB- 32 -RSB- , and intracellular signaling pathways -LRB- signal transduction inhibitors -RRB- -LSB- 33 -RSB- . Hormone receptor -LRB- HR -RRB- - positive tumors are defined as those with ER or progesterone receptor -LRB- PgR -RRB- expression detectable above a pre-set limit -LSB- 34 -RSB- . Patients whose ER or PgR expression is below this pre-set limit are considered HR -- . Approximately two thirds of breast cancer patients have HR + tumors -LSB- 13 -RSB- and are candidates for treatment strategies designed to counteract the growth effects of estrogen . This review describes the rational development of the potent AI letrozole , which has therapeutic utility in HR + tumors across the breast cancer continuum . Mechanism of action of aromatase inhibitors Aromatase Aromatase -LRB- cytochrome P-450 -LSB- CYP -RSB- 19 -RRB- catalyzes the rate-limiting step -LRB- conversion of steroidal C-19 androgens to C-18 estrogens -RRB- in estrogen biosynthesis -LSB- 35 -- 37 -RSB- . Aromatization is the final step in steroid biosynthesis -LRB- Fig. 1 -RRB- -LSB- 38 -RSB- ; and , therefore , aromatase is an attractive target for selective inhibition -LSB- 39 , 40 -RSB- . Aromatase is expressed primarily in the ovary and also in central and peripheral tissues , fat , muscle , liver , and breast -LSB- 41 , 42 -RSB- . With increasing age , as ovarian estrogen production declines -LSB- 43 -RSB- , the contribution of peripheral production of estrogens increases -LSB- 44 -RSB- , and in postmenopausal women , peripheral aromatization of androstenedione produced by the adrenal gland -LRB- Fig. 1 -RRB- -LSB- 38 -RSB- becomes the main source of endogenous estrogens -LSB- 45 -- 49 -RSB- . Of note , normal and malignant breast tissue contributes to the peripheral synthesis of estrogens -LSB- 14 , 50 -- 53 -RSB- . Thus , expression of aromatase in breast tumors may contribute significantly to the degree of cellular exposure to estrogens -LSB- 14 -RSB- ; therefore , it is important to target both intra-tumoral and peripheral aromatase -LSB- 31 -RSB- . Fig. 1Aromatization of androgens to estrogens in postmenopausal women . A androstenedione , E1 estrone , E1S estrone sulfate , E2 estradiol , T testosterone . Reprinted from -LSB- 38 -RSB- with permission from the Society of Endocrinology The presence of intracellular aromatase activity could explain why estrogen concentrations are 10 -- 20 times higher in peripheral tissue than blood in postmenopausal but not pre-menopausal women -LSB- 41 , 54 -- 58 -RSB- . Moreover , estrogen concentrations are higher in tumors than in surrounding non-malignant tissue -LSB- 41 , 54 -- 58 -RSB- . Recent research has increased understanding of how aromatase is regulated by tissue-specific promoters -LSB- 59 -RSB- and how genetic variation may affect the pathophysiology of estrogen-dependent disease -LSB- 60 -RSB- . Pharmacogenomics may become an increasingly important tool for individualizing hormonal therapy for patients with breast cancer . Aromatase inhibitors Modern third-generation AIs effectively block the production of estrogen without exerting effects on other steroidogenic pathways and have been heralded as a `` triumph of translational oncology '' -LSB- 61 -RSB- . The search for potent and selective inhibitors of aromatase started with the first-generation inhibitor aminoglutethimide -LSB- 62 -RSB- . However , aminoglutethimide lacked selectivity for aromatase -LSB- 63 -RSB- and inhibited biosynthesis of cortisol , aldosterone , and thyroid hormone -LSB- 64 -RSB- as well as aromatase ; moreover , aminoglutethimide was also found to induce hepatic enzymes -LRB- Fig. 2 -RRB- -LSB- 65 , 66 -RSB- . Second-generation AIs included the nonsteroidal inhibitor fadrozole and the steroidal inhibitor formestane -LRB- 4-hydroxyandrostenedione -RRB- . Fadrozole was superior to aminoglutethimide in terms of potency , selectivity , and safety -LSB- 67 -RSB- , but its selectivity was not complete and clinical trials suggested that it was no more effective than tamoxifen -LSB- 68 , 69 -RSB- . Fig. 2The development of aromatase inhibitors -LRB- AIs -RRB- has culminated in agents with high specificity and potency for aromatase . Spectrum of action of first - through third-generation AIs : The third-generation AIs act exclusively on the aromatase enzyme and do not appear to exert additional effects . Potency of AIs determined by degree of inhibition of total body aromatase : 4-OHA 4-hydroxyandrostenedione . Reprinted from -LSB- 66 -RSB- with permission from the Society of Endocrinology To improve on fadrozole , Novartis synthesized a series of new compounds . Structure-activity relationship studies were then performed to identify the most potent AI from a series of benzyl-azole derivatives of fadrozole -LSB- 70 -RSB- . The third-generation AI letrozole -LRB- Femara ® -RRB- was the result of this structure-activity approach to drug design and achieved the research goal of creating a highly potent and totally selective AI -LSB- 71 -RSB- . These compounds were also used to design pioneering molecular modeling techniques used to map the active site of aromatase -LSB- 70 , 72 -RSB- . Other third-generation AIs developed during this period were the nonsteroidal agents vorozole -LRB- since discontinued -RRB- and anastrozole -LSB- 73 -RSB- -LRB- Fig. 2 -RRB- -LSB- 66 -RSB- and the steroidal agent exemestane -LSB- 74 -RSB- . AIs have been classified as steroidal -LRB- type I ; for example , exemestane -RRB- or nonsteroidal -LRB- type II ; for example , letrozole and anastrozole -RRB- -LSB- 75 -RSB- . A comprehensive review of AIs focuses on the pharmacology and clinical development of letrozole -LSB- 76 -RSB- . Letrozole pharmacodynamics and pharmacokinetics Potency The chemical structure of letrozole -LRB- 4,4 ′ - -LSB- -LRB- 1H-1,2,4-triazol-1-yl -RRB- methylene -RSB- bis-benzonitrile -RRB- is compared with other AIs in Fig. 3 -LSB- 77 -RSB- . The nitrogen-containing structures like the imidazoles and the triazoles bind to the iron in the heme moiety of CYP-450 , whereas the cyanobenzyl moiety present in the nonsteroidal AIs such as letrozole partially mimics the steroid backbone of the enzyme 's natural substrate androstenedione . Furthermore , the triazole compound letrozole was found to be superior to other derivatives of fadrozole in terms of in vivo inhibition of aromatase -LSB- 70 -RSB- . Fig. 3Comparison of the molecular structures of aromatase inhibitors . Reprinted from -LSB- 77 -RSB- with permission from Elsevier Letrozole is a highly potent inhibitor of aromatase in vitro , in vivo in animals , and in humans . The relative potencies of letrozole , anastrozole , and fadrozole were determined in a variety of model cellular endocrine and tumor systems containing aromatase -LRB- hamster ovarian tissue fragments , adipose tissue fibroblasts from normal human breast , the MCF-7Ca human breast cancer cell line transfected with the human aromatase gene , and the JEG-3 human choriocarcinoma cell line -RRB- -LSB- 31 -RSB- . These studies showed that although letrozole and anastrozole are approximately equipotent in a cell-free aromatase system -LRB- human placental microsomes -RRB- , letrozole is 10 -- 30 times more potent than anastrozole in inhibiting intracellular aromatase in intact rodent cells , normal human adipose fibroblasts , and human cancer cell lines -LRB- Fig. 4 -RRB- -LSB- 31 -RSB- . In several other studies , letrozole has consistently demonstrated greater potency compared with anastrozole , exemestane , formestane , and aminoglutethimide -LRB- Table 1 -RRB- -LSB- 31 , 71 , 75 , 78 -- 82 -RSB- . Fig. 4Relative potencies with which letrozole , anastrozole , and fadrozole inhibit aromatase from non-cellular and intracellular sources . Reprinted from -LSB- 31 -RSB- with permission from ElsevierTable 1Inhibitory concentrations of letrozole , anastrozole , exemestane , fadrozole , 4-hydroxyandrostenedione and aminoglutethimide against the aromatase enzyme derived from various cellular and non-cellular sources . Reprinted from -LSB- 77 -RSB- with permission from ElsevierAromatase inhibitorIC50 values -LRB- nM -RRB- , -LRB- relative potency ; letrozole = 1 -RRB- Human placental microsomesParticulate fractions of human breast cancerRat ovarian microsomesMCF-7Ca cancer cellsJEG-3 cancer cellsCHO cellsHamster ovarian tissueHuman breastLetrozole2 -LRB- 1 -RRB- 0.8 -LRB- 1 -RRB- Anastrozole8 -LRB- 0.25 -RRB- 15 -LRB- 0.053 -RRB- Exemestane15 -LRB- 0.13 -RRB- 5 -LRB- 0.16 -RRB- 4-OHA30 -LRB- 0.07 -RRB- 30 -LRB- 0.027 -RRB- AG20 ,000 -LRB- 0.0001 -RRB- 10,000 -LRB- 0.0008 -RRB- Letrozole11 -LRB- 1 -RRB- 0.07 -LRB- 1 -RRB- 0.07 -LRB- 1 -RRB- 20 -LRB- 1 -RRB- 0.8 -LRB- 1 -RRB- Anastrozole23 -LRB- 0.48 -RRB- 0.82 -LRB- 0.085 -RRB- 0.99 -LRB- 0.071 -RRB- 600 -LRB- 0.033 -RRB- 14 -LRB- 0.057 -RRB- Fadrozole5 -LRB- 2.2 -RRB- 0.05 -LRB- 1.4 -RRB- 0.07 -LRB- 1.0 -RRB- 30 -LRB- 0.67 -RRB- 1 -LRB- 0.80 -RRB- 4-OHA62 -LRB- 0.18 -RRB- AG1900 -LRB- 0.0058 -RRB- Letrozole1 .02 -LRB- 1 -RRB- 0.35 -LRB- 1.0 -RRB- 0.45 -LRB- 1 -RRB- 0.14 -LRB- 1 -RRB- Anastrozole5 .35 -LRB- 0.19 -RRB- 3.62 -LRB- 0.097 -RRB- 5.66 -LRB- 0.080 -RRB- 17.17 -LRB- 0.0082 -RRB- 4-OHA0.59 -LRB- 0.59 -RRB- 1.6 -LRB- 0.28 -RRB- 0.72 -LRB- 0.19 -RRB- Letrozole7 -LRB- 1 -RRB- Anastrozole25 -LRB- 0.28 -RRB- Fadrozole7 -LRB- 1 -RRB- Letrozole1 .4 -LRB- 0 -RRB- Anastrozole27 -LRB- 0.052 -RRB- 4-OHA60 -LRB- 0.023 -RRB- AG5500 -LRB- 0.00025 -RRB- 4-OHA 4-hydroxyandrostenedione , AG aminoglutethimideValues quoted are IC50 values representing the concentration needed to achieve 50 % inhibition of aromatase activity . The relative potency of each inhibitor compared with letrozole is shown in parentheses The degree of aromatase inhibition can be determined in vivo by measuring uterine weight after treatment with a standard dose of androstenedione in immature female rats -LSB- 71 -RSB- . Using this assay , it was found that the in vivo potency of letrozole is more than four orders of magnitude greater than aminoglutethimide -LRB- 50 % effective dose -LSB- ED50 -RSB- , 1 -- 3 μg/kg vs. 30 mg/kg , respectively -RRB- -LSB- 71 -RSB- . It has also been shown that neoadjuvant letrozole profoundly inhibits in situ aromatase activity and reduces endogenous estrogens within the breast in postmenopausal women with large primary breast cancers -LSB- 75 -RSB- . In postmenopausal women , letrozole achieves significantly greater plasma estrogen suppression of estrogens and greater inhibition of in vivo aromatization than anastrozole -LSB- 83 -RSB- . In the study , levels of aromatase were detectable in 11 of 12 patients during treatment with anastrozole -LRB- mean percentage inhibition in the whole group , 97.3 % -RRB- but in none of the 12 patients during treatment with letrozole -LRB- > 99.1 % suppression in all patients ; Wilcoxon , P = 0.0022 , comparing the two drug regimens -RRB- . Suppression of estrone and estrone sulfate was found to be significantly greater during treatment with letrozole compared with anastrozole -LRB- P = 0.019 and 0.0037 , respectively -RRB- . Another study conducted in 54 postmenopausal women with invasive breast cancer showed that more complete inhibition of aromatase was achieved with 2.5 mg of letrozole than 1 mg of anastrozole , resulting in significantly greater suppression of estradiol -LRB- P < 0.0001 -RRB- , the most bioactive estrogen -LSB- 84 -RSB- . This recent study confirms previous observations showing that letrozole produces near complete inhibition of aromatase in peripheral tissues , associated with greater suppression of estrogen than achieved with other AIs -LSB- 78 , 85 -- 90 -RSB- . Selectivity Letrozole is highly selective for aromatase and unlike first - and second-generation AIs does not significantly affect cortisol , aldosterone , or thyroxine -LSB- 77 -RSB- . In vitro studies showed that letrozole was more than three orders of magnitude more selective than aminoglutethimide in its effects on progesterone and corticosterone production , and more than 300-fold more selective against aldosterone than fadrozole -LSB- 71 , 78 -RSB- . In vivo adrenocorticotrophic hormone -LRB- ACTH -RRB- stimulation tests in rats showed that letrozole had no significant effect on either aldosterone or corticosterone levels , even at a dose 1,000 times greater than that required for inhibition of aromatase -LSB- 71 -RSB- . The selectivity of letrozole has been demonstrated in clinical studies in postmenopausal women . These studies showed that letrozole has no effect on the plasma levels of 17α-OH progesterone , thyroid-stimulating hormone -LRB- TSH -RRB- , luteinizing hormone -LRB- LH -RRB- , follicle-stimulating hormone -LRB- FSH -RRB- , or androstenedione and does not affect normal urine electrolyte excretion or thyroid function -LSB- 86 , 91 -- 93 -RSB- . Of note , the vast majority of patients treated with letrozole have a normal response to synthetic ACTH -LSB- 86 -RSB- . Anti-tumor activity in vivo The potent anti-tumor effects of letrozole have been demonstrated in several animal models -LSB- 77 , 78 , 94 -RSB- . Letrozole induced complete regression of estrogen-dependent , 9,10-dimethylbenz-a-anthracene -LRB- DMBA -RRB- - induced mammary tumors in adult female rats -LSB- 95 -RSB- . The ED50 for letrozole was determined to be 10 -- 30 μg/kg/day . The use of MCF-7 cells transfected with human aromatase gene -LRB- MCF-7Ca -RRB- and implanted into athymic nude mice has proved to be an effective in vivo model for predicting clinical results with AIs -LSB- 61 , 96 , 97 -RSB- . Using this model , it has been shown that letrozole produces dose-dependent inhibition of tumor growth , resulting in complete inhibition at a daily dose of 10 μg/animal/day -LSB- 94 , 98 -RSB- . Comparative studies using the MCF-7Ca model have shown that letrozole is more effective at suppressing tumor growth than the pure anti-estrogen fulvestrant and the SERM tamoxifen -LSB- 99 -RSB- . While anastrozole was also better than fulvestrant and tamoxifen in suppressing tumor growth , only letrozole was shown to induce tumor regression -LSB- 99 -RSB- . Another study , also using the MCF-7Ca model , demonstrated that letrozole potently inhibits mammary tumor growth but does not have the estrogenic effects of tamoxifen , as measured by its uterotrophic effects -LSB- 100 -RSB- . The observation that tamoxifen has an agonist effect even when estrogen synthesis is inhibited by letrozole suggests that there may be a degree of antagonism between these compounds -LSB- 100 -RSB- . Interestingly , studies in the MCF-7Ca model showed that letrozole is more effective as monotherapy than when combined with tamoxifen -LSB- 80 , 101 -RSB- . In the study reported by Long et al. -LSB- 101 -RSB- tumor volume doubling times were 3 -- 4 weeks in controls , 16 weeks with tamoxifen alone , 18 weeks with tamoxifen plus letrozole , and 34 weeks with letrozole alone . First-line treatment with letrozole was shown to be significantly superior to treatment with tamoxifen alone or with the two drugs combined -LRB- at week 16 , both P < 0.001 -RRB- . Tumors that progressed during treatment with tamoxifen remained sensitive to second-line letrozole therapy , whereas tumors that progressed on letrozole did not respond to second-line treatment with tamoxifen or fulvestrant . In another series of experiments conducted by the same group using the MCF-7Ca model , letrozole was even effective as third-line therapy for a limited period when administered after treatment with tamoxifen and exemestane -LSB- 102 -RSB- . The studies showed that although exemestane was more effective than tamoxifen in controlling tumor growth , letrozole as first-line therapy was the most effective treatment overall , both in terms of the degree of tumor suppression and the length of effectiveness of treatment -LSB- 102 -RSB- . The potential of letrozole as a chemopreventive agent was investigated in an in vivo model using aromatase-transgenic female mice -LSB- 103 -RSB- . The model provided evidence to show that aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes that can be completely abrogated by treatment with letrozole . Carcinogenicity studies have also found that letrozole decreases the incidence of spontaneous mammary tumors and granular cell tumors in rats -LSB- 104 -RSB- . Pharmacokinetics of letrozole Clinical pharmacokinetic studies of letrozole have been conducted in healthy volunteers -LSB- 105 -- 107 -RSB- and in patients with breast cancer -LSB- 108 , 109 -RSB- . Following oral administration , letrozole is rapidly and completely absorbed -LRB- mean absolute bioavailability of 99.9 % -RRB- and extensively distributed to tissues . It has a large apparent volume of distribution at steady state -LRB- 1.87 l/kg -LSB- range , 1.47 -- 3.24 -RSB- -RRB- , and approximately 60 % is bound to plasma proteins , mainly to albumin -LRB- 55 % -RRB- . The terminal half-life -LRB- T1/2 -RRB- of letrozole is 42 h . The terminal T1/2 was observed to be longer and area under the curve -LRB- AUC -RRB- greater in patients with breast cancer than in healthy volunteers , possibly due to reduction in metabolic clearance -LSB- 109 -RSB- . The major route of elimination of letrozole is metabolism by CYP-450 isoenzymes -LRB- CYP 3A4 and CYP 2A6 -RRB- into an inactive carbinol metabolite . Systemic exposure to metabolites is , therefore , low . Steady-state concentrations of letrozole are reached after 2 -- 6 weeks and maintained for long periods with no evidence of drug accumulation . In marked contrast to the first-generation AI aminoglutethimide , no significant drug interactions have been reported for letrozole ; however , when combined with tamoxifen , letrozole plasma concentrations are reduced by between 35 % and 40 % -LSB- 110 -RSB- . Age does not have an effect on the pharmacokinetics of letrozole . Exposure to letrozole , measured by AUC , is increased in renally impaired subjects but remains in the range seen in subjects without impaired function . However , hepatic impairment can markedly increase the T1/2 of letrozole , and caution is required in such patients . Differences in pharmacokinetics , including uptake rates , elimination T1/2 , and metabolism and clearance exist between AIs and have been reviewed by Lønning et al. -LSB- 111 -RSB- . The clinical significance of such differences is not known . Clinical development of letrozole Letrozole entered clinical trials on the basis of its high potency and selectivity for aromatase , the demonstration of unsurpassed anti-tumor effects in models of human breast cancer , and the development of a convenient oral formulation . Daily doses of 0.1 -- 5 mg have been shown to suppress estradiol , estrone , and estrone sulfate plasma concentrations by 75 -- 95 % from baseline , while doses > 0.5 mg suppress estrogens to below limit of detection -LSB- 92 , 112 , 113 -RSB- . Based on pharmacokinetic and pharmacodynamic studies , the recommended dose of letrozole is one 2.5 mg tablet once daily . Preclinical models -LSB- 97 , 101 -RSB- successfully predicted that letrozole would be superior to tamoxifen , the previous gold standard in the treatment of breast cancer . An extensive program of clinical trials has been conducted with letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women . The first randomized controlled trials demonstrated consistent superiority for letrozole compared with megestrol acetate , aminoglutethimide , and tamoxifen in patients with advanced breast cancer -LSB- 114 -- 118 -RSB- . The clinical efficacy of letrozole in advanced breast cancer is described in a review by Dr. Mouridsen in this supplement . Preclinical MCF-7Ca models have also predicted that letrozole should be clinically more effective than other less potent third-generation AIs -LSB- 99 , 102 -RSB- . Letrozole -LRB- 2.5 mg/day -RRB- and anastrozole -LRB- 1 mg/day -RRB- were directly compared in a randomized , open-label phase IIIb/IV study involving 713 postmenopausal women with advanced breast cancer previously treated with an anti-estrogen -LSB- 119 -RSB- . While there was no difference between the treatment arms in the time to progression , letrozole produced a significantly higher overall response rate than anastrozole -LRB- 19.1 vs. 12.3 % , P = 0.013 -RRB- . Letrozole and anastrozole are currently being compared in a large randomized head-to-head trial in early breast cancer -LRB- ClinicalTrials.gov identifier NCT00248170 -RRB- -LSB- 120 -RSB- . A review by O'Shaughnessy in this supplement provides the rationale for this trial and a description of its design . The clinical benefits of letrozole in early breast cancer have already been demonstrated in landmark randomized clinical trials . MA .17 was the first trial to show improved clinical outcomes with extended adjuvant hormone therapy -LSB- 121 -RSB- . In this trial , letrozole given after initial adjuvant therapy with tamoxifen significantly improved disease-free survival compared with placebo -LSB- 121 , 122 -RSB- . Full details of this trial are provided in a review by Dr. Goss in this supplement . Subsequently , the Breast International Group 1-98 trial provided high-level evidence for the superiority of letrozole over tamoxifen as initial adjuvant therapy -LSB- 123 -RSB- . A detailed description of this ongoing trial , which will also help to define the optimal sequence for hormone therapies in hormone-responsive early breast cancer , is provided in a review by Dr. Thürlimann in this supplement . Letrozole has also demonstrated superior efficacy compared with tamoxifen when used as neoadjuvant therapy -LSB- 124 -RSB- . This treatment setting is particularly interesting in terms of drug development because the effects of hormone therapy on breast tumors can be detected early and may be predictive of long-term outcome -LSB- 125 -RSB- . Conclusions Letrozole is a highly potent and selective AI that inhibits the enzyme activity of intracellular aromatase at the major sites where it is found , resulting in almost complete suppression of whole body aromatization . By effectively blocking estrogen synthesis , letrozole inhibits the growth or induces the regression of hormone-responsive breast tumors in vivo . Estrogen is implicated as a major risk factor in the majority of breast cancers ; therefore , use of the most potent AI is a logical treatment strategy . Studies conducted using in vitro and in vivo models have demonstrated that letrozole is the most potent of the third-generation AIs . Preclinical data obtained from MCF-7Ca xenograft models suggest that the greater potency of letrozole compared with anastrozole and exemestane may translate into clinically meaningful differences in postmenopausal women with hormone-responsive breast cancer . These models accurately predicted that letrozole would be more effective than tamoxifen in the clinical setting . The superiority of letrozole over tamoxifen has been consistently demonstrated in advanced and early breast cancer -LSB- 118 , 123 -RSB- . Outstanding clinical questions , including what is the most effective AI and what is the optimal sequence for adjuvant hormonal therapy , will be answered by the results of ongoing trials involving letrozole . In conclusion , experimental data indicating that letrozole efficiently inhibits aromatase activity have been confirmed clinically , leading to approved indications across the spectrum of breast cancer . The broad range of indications for letrozole in unique clinical settings is reshaping the management of hormone-sensitive breast cancer .

O O O O O O O O O B O O O O O O O B I O O O O O O O O B O B I O O O O O O B O O O B O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O B O O O O O O O B O B O O B I O O O O O B I O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O

aromatase
breast cancer
estrogen
postmenopausal