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Abstract

Letrozole, an aromatase inhibitor, demonstrates consistent superiority over tamoxifen in various treatment settings, has the only significant survival advantage according to results from a Phase III randomized trial, and is the only aromatase inhibitor approved as an extended adjuvant therapy in the treatment of breast cancer. Initial adjuvant letrozole significantly prolongs disease-free survival, especially reducing the risk of distant metastasis, and offers a significant disease-free survival benefit to patients at an increased risk of relapse (node-positive and chemotherapy-treated patients) when compared with tamoxifen. These findings led to its recommendation as an initial adjuvant therapy in the latest St Gallen guidelines. Similar findings were reported when letrozole was administered after completion of 5 years of adjuvant tamoxifen. The benefit of letrozole also increases with the duration of treatment. Overcoming the development of resistance to endocrine therapy is under investigation. As a potent aromatase inhibitor, letrozole is the ideal drug for tailored combination treatment regimens of the future.

Keywords

adjuvant therapy aromatase inhibitor breast cancer combination therapy estrogen letrozole postmenopausal women recurrence risk tamoxifen

Improvements in breast cancer detection, screening, educational programs and patient care have appreciably prolonged breast cancer survival rates; however, the risk of recurrence remains high in women whose initial disease has been successfully treated. Although 5 years of tamoxifen therapy has been shown to significantly reduce the risk of recurrence in women with early breast cancer, recent data indicate that new third-generation aromatase inhibitors (AIs; i.e., anastrozole, exemestane and letrozole) may offer a superior reduction in recurrence risk.

In the 10 years following its launch in the UK in 1996, letrozole has been shown to be well tolerated and effective in a variety of breast cancer treatment settings [101]. Recent milestones in the development of letrozole, including its recent approval in the early adjuvant treatment of postmenopausal women with breast cancer in the USA, UK and throughout Europe, are shown in Box 1 [101]. Letrozole, as a more potent AI and the only AI with published consistent data across the entire breast cancer care continuum, may be the most effective treatment option currently available to post-menopausal women with endocrine-responsive breast cancer.

Mechanism of action

Endogenous estrogen induces tumor growth in the majority of women with hormone receptor-positive breast cancer by stimulating the estrogen receptor (ER), and treatments have focused on reducing the levels of estrogen in women with endocrine-responsive breast cancer. In postmenopausal women, precursor androgen biosynthesis occurs primarily in the adrenal gland and is later synthesized into estrogen in the muscle, and in adipose tissue via the action of the aromatase enzyme [1]. Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme and, thus, inhibits the synthesis of estrogen [2]. Letrozole reduces estrogen biosynthesis to undetectable levels in women [3], without affecting adrenal corticosteroid synthesis significantly, aldosterone synthesis or synthesis of thyroid hormones [2].

Pharmacokinetics

Letrozole is absorbed quickly after oral administration and absorption is not affected by food [2]. It has excellent systemic bioavailability (99.9%) and a large volume of distribution (1.90 l/kg) [2]. Steady-state plasma concentrations are usually achieved after 2–6 weeks of treatment [2].

Metabolism & excretion

The main route of elimination of letrozole is via metabolism to a pharmacologically inactive carbinol metabolite by both cytochrome P (CYP) 450 2A6 and CYP3A4 [2]; the drug and its metabolites are excreted primarily by the kidneys [2]. Letrozole has a slow total-body clearance (2.21 l/h) and a long elimination half-life (42 h) [2].

Box 1.

Letrozole: development milestones.

November 23, 1996: Launched for breast cancer therapy in the UK.

August 12, 2004: Registration of letrozole orally (PO) for the extended adjuvant treatment of early breast cancer in postmenopausal women who have completed tamoxifen therapy in Switzerland.

September 14, 2004: Launch of letrozole (PO) for the extended adjuvant treatment of early breast cancer in postmenopausal women who have completed tamoxifen therapy in the UK.

March 7, 2005: Registration of letrozole (PO) for the extended adjuvant treatment of early breast cancer in postmenopausal women who have completed tamoxifen therapy in Germany through the EU's mutual-recognition procedure.

June 30, 2005: Preregistration of letrozole (PO) for the adjuvant treatment of hormone receptor-positive early breast cancer in postmenopausal women in the USA and Europe.

December 8, 2005: Registered for the early adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer immediately after surgery in the UK.

December 28, 2005: Registered for the early adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer immediately after surgery in the USA.

March 22, 2006: Registered for the early adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer immediately after surgery in Germany.

March 2006: Registered in Europe for the early adjuvant setting through the mutual-recognition procedure.

March 22, 2006: Novartis initiates enrollment into the Femara Anastrozole Clinical Evaluation (FACE) trial, which directly compares adjuvant anastrozole with adjuvant letrozole in patients with node-positive disease.

Potency

In vitro noncellular models indicate an inhibitory concentration (IC)₅₀ of 1–13 nM for letrozole, a potency that is similar to that of the second-generation AI fadrozole, more than two orders of magnitude more potent than that of the earlier generation AI aminoglutethimide and 2–5-times more potent than anastrozole [4].

In the clinical arena, letrozole is a more potent inhibitor of aromatase activity than anastrozole [5] and exemestane [6] in postmenopausal women with metastatic breast cancer. In a randomized, crossover study of 12 postmenopausal women with ER-positive metastatic breast cancer, on-treatment levels of estrogen were detected in 11 out of 12 women receiving anastrozole 1 mg/day orally, but in none of the 12 women receiving letrozole 2.5 mg/day (orally; p = 0.0022) [5]. In a Phase I open-label, dose-range finding study in eight women with metastatic breast cancer, letrozole achieved more than 90% suppression of estrogen within 2 weeks [3]. More recently, findings from the Aliquot study (n = 54), comparing initial adjuvant letrozole with initial adjuvant anastrozole, found that a more complete inhibition of aromatase is achieved with letrozole than with anastrozole and letrozole resulted in a greater degree of suppression of estradiol, the most bioactive estrogen [7].

Neoadjuvant therapy with letrozole

The P024 trial investigated the efficacy of 4 months of neoadjuvant therapy with letrozole compared with tamoxifen in 324 women who were ineligible for breast-conserving surgery [8]. Letrozole demonstrated response rates superior to tamoxifen (60 vs 41%; p = 0.004), and more women receiving letrozole than tamoxifen underwent breast-conserving surgery (48 vs 36%, respectively; p = 0.036) [8]. Response rate differences between the two drugs were most marked in tumors positive for epidermal growth factor receptor (HER) 1 and/or HER2 and ER (88 vs 21%; p = 0.0004); however it is important to note that the numbers of patients in these cohorts were small [8]. Letrozole was also found to inhibit tumor proliferation more than tamoxifen, independent of HER1/2 expression status [9]. In addition, letrozole significantly reduced proliferation to a greater extent than anastrozole and is the only AI to significantly reduce proliferation in tumors with low levels of ER [10]. This is an important finding, since it has been suggested that a greater suppression in proliferation would lead to a greater long-term survival in the adjuvant setting [11]. Finally, a study investigating the optimal duration of neoadjuvant therapy found that the optimum duration of neoadjuvant letrozole may be greater than 3–4 months, and treatment for 6 months or beyond (up to 12 months) will increase the number of patients with a complete clinical response and the number of patients whose disease is downstaged [12].

Initial & sequential adjuvant letrozole therapy

The Breast International Group (BIG) 1–98 trial is currently the largest adjuvant trial underway. It is an ongoing, independent study, conducted by the International Breast Cancer Study Group, involving 8028 women with hormone receptor-positive disease comparing adjuvant therapy in four arms: 5 years of tamoxifen or letrozole as initial therapy; 2 years of tamoxifen followed by 3 years of letrozole; or 2 years of letrozole followed by 3 years of tamoxifen [13]. In the first results from the BIG 1–98 trial, the preplanned primary core analysis was designed to answer the first question of letrozole versus tamoxifen monotherapy, and also allowed patient data from the sequential arms up to the point of switch to be incorporated into the monotherapy comparison. It is also important to note that, at 25.8 months of follow-up, a large number of patients (1200) were followed for 5 years in the BIG 1–98 trial. Compared with tamoxifen, letrozole significantly reduced the risk of an event ending a period of disease-free survival (DFS) by 19% (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.70–0.93; p = 0.003) and the risk of distant metastasis – a well recognized predictor of breast cancer death – by 27% (HR: 0.73; 95% CI: 0.60–0.88; p = 0.001) at a median follow-up of 25.8 months [13]. This was a significant benefit, with an absolute increase in 5-year DFS of 2.6% with letrozole compared with tamoxifen (Figure 1). These are impressive results, as the trial included a large population of women who were at increased risk of recurrence; 41.3% of participants were node-positive and 25.3% had received prior chemotherapy [13]. More women receiving tamoxifen died in the trial (166 receiving letrozole vs 192 receiving tamoxifen), while those receiving letrozole experienced a 14% reduction in mortality (Table 1), which is not significant at this early stage of follow-up.

Table 1.

Incidence of efficacy end points.

Event number (%)	Letrozole (n = 4003)	Tamoxifen (n = 4007)
Primary end point
Disease-free survival event*	351 (8.8)	428 (10.7)
– Local recurrence	21 (0.5)	37 (0.9)
– Contralateral breast cancer	16 (0.4)	27 (0.7)
– Regional recurrence	13 (0.3)	12 (0.3)
Distant recurrence	177 (4.4)	232 (5.8)
– Soft tissue	11 (0.3)	19 (0.5)
– Bone	80 (2.0)	99 (2.5)
– Viscera	86 (2.1)	114 (2.8)
– Second, nonbreast cancer	69 (1.7)	82 (2.0)
– Death without prior cancer event	55 (1.4)	38 (0.9)
Secondary end points
Death from any cause	166 (4.1)	192 (4.8)
Systemic disease-free survival events (excluding local and contralateral breast events)	323 (8.1)	383 (9.6)

A disease-free survival event was defined as the first of any of the following events: any breast cancer recurrence; a new, invasive cancer in the contralateral breast; a second, nonbreast cancer; or death without a prior cancer event.

Reprinted with permission from [13].

Figure 1.

Kaplan–Meier estimates of disease-free survival.

Prospectively planned subgroup analyses also revealed a significant (29%) reduction in the risk of recurrence for patients with node-positive disease, and a significant risk reduction (30%) in patients who received chemotherapy [13]. When compared with tamoxifen, letrozole also demonstrated a significant improvement in DFS, irrespective of age (<65 or ≥65 years of age) and in all ER-positive patients, irrespective of their progesterone receptor (PgR) status, although the effect was more pronounced in patients with ER-positive and PgR-positive tumors (Figure 2) [13]. Importantly, the results of DFS reanalysis, according to centrally assessed ER and PgR status by immunohistochemistry, have been presented [14]; this is the first such assessment of PgR status ever conducted in an adjuvant AI trial. Cost–effectiveness studies based on the first analysis of published BIG 1–98 trial results also demonstrated that letrozole as initial adjuvant therapy in hormone receptor-positive postmenopausal women with early breast cancer is cost-effective from both a British [15] and American perspective [16]. Data from the sequential arms of the trial will be available in late 2007 or early 2008 and will address the question of monotherapy versus sequential therapy.

Figure 2.

Results of primary, secondary and additional end points from the Breast International Group 1–98 trial.

Letrozole was generally well tolerated in the adjuvant setting but was associated with an increased risk of bone fractures [13]. Fracture occurred significantly more often in women receiving letrozole than in those receiving tamoxifen (5.7 vs 4.0%, respectively; p < 0.001) [13]. At 24 months, nonfasting serum cholesterol levels remained stable from baseline in the letrozole arm and decreased by a median of 14.1% in the tamoxifen arm [13]. The overall incidence of cardiovascular events (which includes stroke, thromboembolic events and cardiac events) of grade 3, 4 or 5 was similar with letrozole and tamoxifen (3.7 and 4.2%, respectively), although more women receiving letrozole had grade 3–5 cardiac events, which specifically includes cardiac failure and ischemic cardiac disease (2.1 vs 1.1%, respectively; p < 0.001) [13]. It is important to note that the numbers are small, and also that differences in cardiac events have been recorded with all AIs when they are compared with tamoxifen, a drug with known cardi-oprotective effects. Notably, letrozole was associated with significantly fewer thromboembolic events than tamoxifen (1.5 vs 3.5%; p < 0.001) [13].

Extended adjuvant therapy with letrozole

Many women who complete standard tamoxifen therapy may want to further reduce their risk of recurrence. Mammary 17 (MA.17) was a randomized, double-blind, placebo-controlled trial conducted by the National Cancer Institute of Canada Clinical Trials Group, comparing extended adjuvant therapy with letrozole versus placebo in 5187 women who had completed 5 years of adjuvant tamoxifen therapy [17]. Results of MA.17 demonstrated that extended adjuvant letrozole therapy offers women additional protection against recurrence. At a median follow-up of 2.5 years, progressive improvement was noted with letrozole, compared with placebo, after each year of treatment. The 4-year DFS rates in women receiving letrozole and placebo were 94.4 and 89.8%, respectively (i.e., absolute reduction was 4.6% in the letrozole group) [17]. In all women, letrozole significantly reduced the overall risk of recurrence by 42% (HR: 0.58; 95% CI: 0.45–0.76; p < 0.001) and developing distant metastasis by 40% (HR: 0.60; 95% CI: 0.43–0.84; p < 0.002) compared with placebo [17]. Compared with placebo, letrozole significantly improved overall survival in node-positive women by 39% (HR: 0.61; 95% CI: 0.38–0.98; p = 0.04), the only significant survival benefit observed to date in early breast cancer with an AI in a Phase III double-blind, randomized trial [17,18]. An unplanned analysis of 4653 women from MA.17 also demonstrated that letrozole appeared to be most effective in those with the most hormone-dependent (ER-positive/PgR-positive) tumors, even offering a survival advantage in this large patient population [19,20]. In addition, letrozole reduced the incidence of new contralateral breast cancer compared with placebo [17].

Interestingly, as mammographic density in healthy women is associated with breast cancer risk, the influence of letrozole on mammographic density was studied in a subset of women enrolled in the MA.17 trial. This pilot study of 105 women demonstrated that women who transitioned from tamoxifen to letrozole experienced greater decreases in mammographic density than those who transitioned from tamoxifen to placebo [21]. In a separate analysis of these MA.17 data, conducted to evaluate the relationship between the duration of letrozole therapy in the extended adjuvant setting and hazard for disease recurrence, the benefits of letrozole over placebo treatment increased as the duration of treatment increased. There was a significant reduction in the HR (letrozole/placebo) for DFS from 0.52 at 12 months to 0.19 at 48 months, indicating that the longer the exposure to letrozole, the greater the benefit [22]. Finally, recent data also demonstrate that women from the placebo arm of the trial who elected to switch to letrozole experienced an improvement in all outcomes (DFS, distant DFS and overall survival) compared with those who elected to have no treatment at the time of the trial unblinding, demonstrating that letrozole has efficacy even when administered after a prolonged period off tamoxifen [23].

The overall discontinuation rate owing to adverse events was similar in the two treatment arms (5 vs 4% in women receiving letrozole and placebo, respectively; p = 0.02) [18]. The incidence of cardiovascular events did not differ between the letrozole and placebo arms (5.8 and 5.6%, respectively; p = 0.76) [17]. Hot flashes, arthritis, arthralgia and myalgia were more common in the letrozole arm, whereas vaginal bleeding was more common in the placebo arm [17]. Hypercholesterolemia occurred with similar frequency in the two treatment arms (16% in both; p = 0.79), a finding that was further confirmed by the results of a substudy evaluating changes in serum lipid parameters in 347 women from MA.17 (see Table 2 for adverse events reported by women in the MA.17 trial) [24].

Table 2.

Acute toxicities reported by patients in MA.17*.

Toxicity	Letrozole (n=2572)					Placebo (n=2577)					p-value‡

	Grade 1	Grade 2	Grade 3	Grade 4	Total (n) (%)	Grade 1	Grade 2	Grade 3	Grade 4	Total (n) (%)
Edema	470	96	5		571(22)	428	110	3	1	542(21)	0.31
Hypertension	54	21	55		130(5)	48	13	68		139(5)	0.94
Hot flashes/flushes	823	661	2		1486(58)	782	601			1383(54)	0.003
Fatigue	801	183	14	1	999(39)	795	195	7	1	998(39)	0.95
Sweating	551	231			782(30)	543	217			760(29)	0.48
Anorexia	115	26	1		142(6)	87	19	3	1	110(4)	0.039
Constipation	297	60	6		363(14)	313	66	3		382(15)	0.48
Diarrhea	125	29	14		168(7)	140	26	10		176(7)	0.69
Nausea	267	35	6		308(12)	267	38	9		314(12)	0.83
Vaginal bleeding	121	22	2		145(6)	141	50	3	2	196(8)	0.005
Infection without neutropenia	34	63	27		124(5)	35	62	13	2	112(4)	0.42
Arthritis	110	46	10	1	167(6)	92	41	4		137(5)	0.07
Hypercholesterolemia	379	37	2		418(16)	357	48	6		411(16)	0.79
Dizziness	386	59	13		458(18)	383	51	6	1	441(17)	0.53
Insomnia	119	45	2		166(6)	103	30	2		135(5)	0.06
Depression	85	42	14	2	143(6)	74	49	7	1	131(5)	0.45
Headache	546	138	22		706(27)	519	140	25	1	685(27)	0.49
Anthralgia	381	245	25		651(25)	338	172	22		532(21)	0.001
Myalgia	241	121	18		380(15)	211	88	11		310(12)	0.004
Bone pain	81	46	13	1	141(5)	92	44	12	1	149(6)	0.67
Dyspnea		143	14	4	161(6)		142	18	3	163(6)	0.95
Alopecia	114	12			126(5)	84	5			89(3)	0.01
Vaginal dryness	75	72			147(6)	60	69			129(5)	0.26

Only toxicities that affected more than 5% of subjects or that differed by more than 1% between arms are shown. Toxicities were graded according to Common Toxicity Criteria Version 2.0. Empty cells indicate that the toxicity was not observed.

‡

p values are from Fisher's exact test.

Reprinted with permission from [17].

More women in the letrozole arm than the placebo arm experienced new-onset osteoporosis (8.1 vs 6.0%; p = 0.003), although the difference in the incidence of bone fracture between treatment arms was not statistically significant (5.3 vs 4.6%; p = 0.25) [17]. Results of a bone substudy in 226 women from MA.17 demonstrated that, after 5 years of adjuvant tamoxifen, subsequent letrozole therapy causes a modest increase in bone resorption and reduction in bone mineral density (BMD) in the spine (−5.35 vs −0.7, respectively; p = 0.008) and hip (−3.60 vs −0.71, respectively; p = 0.044) compared with placebo [25]. These substudy results confirmed that the AIs have a modest and predictable effect on BMD.

In a quality-of-life (QoL) substudy of 3612 women from MA.17, the largest QoL analysis from any third-generation AI to date, no significant differences were observed between the letrozole and placebo groups in the mean change in scores from baseline on the Short Form 36-item Health Survey physical and mental component summary scores at any of the time points tested [26]. A recent analysis again reports that extended adjuvant letrozole therapy in postmenopausal women improves efficacy and does not reduce QoL relative to placebo, regardless of age (<65 vs ≥65 years of age), in MA.17 participants [27].

Zometa–Femara Adjuvant Synergy Trial

Bone loss is a common consequence of increasing age in healthy women and may be exacerbated by adjuvant AI therapy in those with breast cancer [28]. The randomized, multicenter, open-label Zometa–Femara Adjuvant Synergy Trials (Z-FAST, USA; ZO-FAST, Europe) are investigating whether the negative effects of AIs on BMD can be prevented or reduced with the concomitant use of bisphosphonate [29 –31]. Z-FAST is evaluating the safety and efficacy of the potent bisphosphonate zoledronic acid (ZA) in 602 postmenopausal women with early breast cancer undergoing adjuvant letrozole therapy in the USA and Canada. In the Z-FAST trial, postmenopausal women with Stage I–IIIa ER-positive and/or PgR-positive breast cancer starting letrozole (2.5 mg/day for 5 years) were randomized to receive upfront ZA versus delayed ZA (4 mg intravenous infusion every 6 months). ZO-FAST has enrolled 1057 women at 112 centers in 28 countries outside of North America [30].

In Z-FAST, 1-year results indicate that T scores were significantly higher at 12 months in women receiving upfront ZA than in those receiving delayed ZA, thus demonstrating that bisphosphonate treatment can prevent bone loss effectively in this patient population [29]. Therefore, when appropriately managed, the risk of bone loss becomes minimal and does not justify withholding an AI for the adjuvant treatment of postmenopausal women with both endocrine-responsive breast cancer and osteopenia. In ZO-FAST, ZA significantly inhibited bone loss in women who were recently postmenopausal, either due to chemotherapy or a luteinizing hormone-releasing hormone agonist [31].

Combination therapy with letrozole to reduce resistance to endocrine therapy

Over time, breast cancer cells may have the ability to activate ER signaling through alternate pathways, thereby allowing cells to escape the antipro-liferative effect of AI therapy (Figure 3) [32]. However, alternate pathways activated during resistance to estrogen deprivation serve as new therapeutic targets [33]. Signal transduction inhibitors (STIs) may be effective in delaying or preventing the development of endocrine therapy resistance and treating already-resistant tumors [32]. The use of combination therapy with letrozole and other STIs – now being investigated preclinically and clinically – may effectively overcome endocrine therapy resistance (Box 2) [34 –39]. Notably, the results from several clinical trials investigating the safety and efficacy of combining letrozole with an STI (i.e., everolimus, temsirolimus, lapatinib, bevacizumab and trastuzumab) are demonstrating promise. Thus, letrozole is the most extensively studied AI, not only by itself, but also in combination with new agents. The collective results of these and several other trials already in progress will help to define the optimal use of letrozole as an alternative to tamoxifen in a variety of treatment settings and may even support its use over a much longer period of time than is presently recommended for tamoxifen.

Figure 3.

Signal transduction pathways and estrogen receptor signaling in endocrine-resistant breast cancer.

Box 2.

Preclinical and clinical studies of latrozzole combined with signal transductin inhibitors.

A preclinical study evaluating AEE788 (a combined inhibitor of the epidermal growth factor receptor [HER1/2] and vascular endothelial growth factor [VEGF] receptor tyrosine kinases) in combination with letrozole, demonstrated enhanced growth inhibition of hormone-dependent human breast cancer cells, compared with letrozole alone, suggesting that the HER1/2 status of the tumor may influence such inhibition [34].

A preclinical model of the treatment of endocrine-resistant breast tumors finds that using the specific mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) combined with tamoxifen or letrozole may enhance antitumor activity in endocrine-resistant disease [35].

Phase Ib and II trials are studying the safety and pharmacokinetics of RAD001 in combination with letrozole in patients with breast cancer [102].

A Phase II randomized, blinded trial of tipifarnib combined with letrozole is being conducted in postmenopausal women with advanced ER-positive breast cancer who had progressed after antiestrogen therapy [36].

A Phase II trial of letrozole plus the HER1/2 inhibitor OSI-774 (erlotinib) is being conducted in postmenopausal women with hormone-sensitive metastatic breast cancer [103].

A Phase III randomized, placebo-controlled trial of letrozole plus the dual HER1/2 tyrosine kinase inhibitor lapatinib in women with locally advanced/metastatic breast cancer is underway; biological studies will also be undertaken in this trial to predict which patients may be most likely to benefit from combined endocrine/signal transduction inhibitor therapy [32].

A feasibility trial evaluating letrozole combined with the anti-VEGF antibody bevacizumab suggests that the combination was well tolerated in 1 5 women with hormone receptor-positive metastatic breast cancer [37].

A study of 32 women with ER-negative and/or PgR-negative and HER2-positive metastatic breast cancer found that combination therapy with letrozole and the HER2 antibody, trastuzumab, was well tolerated and durable responses were observed in approximately 25% of study participants [38].

A Phase IV trial of letrozole plus trastuzumab in women with metastatic breast cancer is in progress [104].

Letrozole & microarray studies

Microarray analysis is a useful tool for finding biomarkers and unique gene expression profiles. In the future, gene microarray analyses may more accurately identify patients who are at high risk of relapse or resistance to endocrine therapy than the currently available methods, and may even serve as an alternative to clinical guidelines. At present, several studies hope to identify the subgroups of women with breast cancer who would most likely benefit from adjuvant letrozole therapy (Box 3) [39 –41].

Conclusion

The presumption that all third-generation AIs have similar efficacy may not be valid and, in fact, available data already indicate that this is not the case. In the metastatic setting, the suppression of estrone and estrone sulfate was found to be significantly better with letrozole than anastrozole (p = 0.019 and 0.0037, respectively) [5], and an open-label, randomized trial of second-line endocrine therapy in 713 women with advanced breast cancer found that women receiving letrozole had significantly higher overall response rates than those receiving anastrozole (19.1 vs 12.3%; p = 0.013) [42]. Results of a preoperative study on the effects of letrozole and anastrozole in 206 postmenopausal women with ER-positive breast cancer showed that both drugs significantly reduced proliferation and ER and PgR expression; however, only letrozole showed a significant effect in women with lower ER-expressing tumors [10].

Published data indicate that letrozole is well tolerated, effective and approved throughout the breast cancer continuum. Letrozole is well tolerated as an adjuvant therapy, and postmarketing experiences show that cases of blurred vision and increased hepatic enzyme are rare, having been reported by less than 1% of recipients since market introduction [2]. Letrozole is the only AI approved as an extended adjuvant therapy that offers a greater than 40% reduction in recurrence risk and has demonstrated an overall survival advantage in women with node-positive disease [17]. Neoadjuvant letrozole therapy has shown efficacy over tamoxifen [43], and the first results from the BIG 1–98 trial show that letrozole, as an initial adjuvant therapy, is superior to tamoxifen at reducing the risk of relapse, particularly at distant sites.

To many, the results from the BIG 1–98 and the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trials show similar 5-year DFS rates in women receiving letrozole in BIG 1–98 and those receiving anastrozole in ATAC. However, it is important to note that these trials did not use the same definition of DFS; the definition was more inclusive of events in BIG 1–98 when compared with that of ATAC. In the BIG 1–98 trial (but not in ATAC), DFS included the appearance of a secondary nonbreast cancer. Therefore, comparing the 19% reduction of recurrence risk observed with letrozole (HR: 0.81; p = 0.003) at a median follow-up of 25.8 months [13] to the 13% reduction seen with anastrozole in all women (HR: 0.87; 95% CI: 0.78–0.97; p = 0.01) and 17% in those with hormone receptor-positive disease (HR: 0.83; 95% CI: 0.73–0.94; p = 0.005) at a median follow-up of 68 months [44] is not an appropriate comparison.

Box 3.

Microarray studies.

Differences in gene pattern expression detected by microarray analysis in biopsies performed before and after 10–14 days of neoadjuvant letrozole treatment may elucidate the mechanisms of tumor response and resistance [39].

Molecular characterization of estrogen receptor-positive breast cancer before and during treatment with letrozole and anastrozole showed differences in gene expression patterns between the two treatments; in vivo estrogen-responsive genes could serve as candidate biomarkers for benefit from aromatase inhibitor therapy [40].

Microarray analysis of the tumor xenografts from animals treated with tamoxifen or letrozole, and retained at various points during the development of hormone resistance, revealed that chromatin-remodeling genes were overexpressed in acquired tamoxifen and letrozole resistance [41].

Executive summary

Reducing the risk of relapse

In the adjuvant setting, results of the Breast International Group (BIG) 1–98 trial indicate that letrozole is superior to tamoxifen in reducing the risk of relapse, especially at distant sites, and shows a disease-free survival (DFS) benefit in women at increased risk of breast cancer recurrence (i.e., those with node-positive and/or chemotherapy-treated disease).

The results from the sequential arms of BIG 1–98 will provide additional information on which strategy is better (i.e., initial vs sequential), but until then, women at increased risk of relapse may be better treated by starting therapy with letrozole than switching to it at a later date.

More than half of breast cancer recurrence and death occur 5 years posttamoxifen; therefore, there is a need for extended adjuvant therapy.

Refining treatment

The MA.17 trial is the only Phase III, randomized adjuvant aromatase inhibitor (AI) trial to demonstrate a survival advantage with an AI in early breast cancer to date.

Letrozole is currently the only AI approved in the extended adjuvant treatment setting, and its benefit should be discussed with all women currently completing tamoxifen therapy.

Studies show that the longer the exposure to extended adjuvant letrozole, the greater the benefit for at least up to 4 years.

Prescribing letrozole to women who have had a prolonged period off tamoxifen may also offer a significant reduction in recurrence risk and risk of developing distant metastases, and prolong survival.

The 2005 St Gallen guidelines now recommend to include letrozole as an initial adjuvant therapy as well as an extended adjuvant therapy.

Letrozole as the ideal combination partner will be an integral part of future tailored regimens for the treatment of breast cancer.

For women at increased risk of early recurrence who are better treated with an AI upfront, the results of the Femara Anastrozole Clinical Evaluation (FACE) trial will further refine treatment paradigms by identifying which AI is superior for this specific population.

Moreover, the effect of the drugs on subgroups differed markedly. In BIG 1–98, the 5-year DFS risk reduction with letrozole versus tamoxifen in patients who were node-positive or had prior chemotherapy was 29% (p < 0.001) and 30% (p = 0.01), respectively [13], whereas no significant benefit in time to recurrence in these subgroups was observed with anastrozole versus tamoxifen in ATAC [44]. Women who have a positive nodal status and low ER positivity face an earlier and higher risk of relapse [45], and thus should be treated with upfront AI therapy. Distant metastases, a well-recognized predictor of breast cancer death, were also more frequent in node-positive patients [46]. Notably, letrozole is the only AI to have shown a consistently significant benefit in these patients at increased risk of relapse, and the only AI to demonstrate a significant reduction in the risk of developing distant metastasis in patients with hormone receptor-positive breast cancer when administered as an initial adjuvant therapy [13]. Thus, in these women with more aggressive disease, the most appropriate initial therapy would probably be letrozole rather than anastrozole.

Future perspective

In the next 3–5 years, data from several key studies should clarify some of the issues regarding the use of letrozole. Results of the analysis addressing the question of monotherapy versus sequential therapy are expected in late 2007 and should aid in resolving the issue of optimal timing and sequencing of letrozole- and/or tamoxifen-based adjuvant therapies. Additional long-term safety data on letrozole will also become available. Rerandomization of women enrolled in MA.17 will continue to evaluate the long-term side effects of letrozole in the extended adjuvant setting and the feasibility of extending letrozole treatment for up to 10 years as a way of preventing breast cancer recurrence after 5 years of adjuvant therapy [17]. The Letrozole, Exemestane and Anastrozole Pharmacodynamics (LEAP) trial will directly compare safety parameters between the AIs in healthy postmenopausal women and will help clarify the real impact of AIs on serum lipids [47]. Initial results suggest that there are no significant differences in effects on total cholesterol, low-density lipoprotein:high-density lipoprotein ratios and triglyceride levels between anastrozole and letrozole or anastrozole and exemestane [47]. Finally, following the BIG 1–98 results showing a significant superiority in patients with node-positive disease, the Femara Anastrozole Clinical Evaluation (FACE) trial, a head-to-head comparison trial of letrozole versus anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor-positive and node-positive breast cancer, has been initiated and is now enrolling patients [48]. The FACE trial is a Phase IIIb open-label, randomized, multicenter study that will include 4000 postmenopausal patients from up to 250 international sites and will determine which AI is more beneficial in patients at increased risk of relapse [48,105].

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

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36.

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50.

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Letrozole: A Well-Tolerated and Effective Treatment for Breast Cancer

Abstract

Keywords

Mechanism of action

Pharmacokinetics

Metabolism & excretion

Potency

Neoadjuvant therapy with letrozole

Initial & sequential adjuvant letrozole therapy

Extended adjuvant therapy with letrozole

Zometa–Femara Adjuvant Synergy Trial

Combination therapy with letrozole to reduce resistance to endocrine therapy

Letrozole & microarray studies

Conclusion

Future perspective

References