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Extended Adjuvant Endocrine Therapy in Breast Cancer: Current Status and Future Directions
comprehensive review Extended Adjuvant Endocrine Therapy in Breast Cancer: Current Status and Future Directions Paul E. Goss,1,2 Hyman B. Muss,3 James N. Ingle,4 Timothy J. Whelan,5 Melinda Wu6 Abstract Women with hormone receptor–positive breast cancer have traditionally been treated with 5 years of adjuvant tamoxifen to reduce their risk of subsequent recurrent disease. Among those who experience subsequent disease recurrence, the majority do so after 5 years, suggesting that longer durations of endocrine therapy might be beneficial. Two options tested include longer tamoxifen and, in postmenopausal women, a switch to an aromatase inhibitor (AI). In the National Cancer Institute of Canada Cooperative Trials Group MA.17 trial, we tested the AI letrozole given to postmenopausal women for 5 years after tamoxifen as extended adjuvant therapy because of its efficacy in patients with advanced breast cancer in progression on previous tamoxifen. The first interim analysis (median, 2.4 patient years) showed substantial benefits from letrozole, and all patients were unblinded and offered the option of letrozole. Despite two thirds of the patients crossing over to letrozole, an intent-to-treat analysis at 54 months’ follow-up continued to demonstrate the strong beneficial effect of extended adjuvant letrozole. Furthermore, significant benefit was demonstrated among patients who had been randomized to placebo but elected to take letrozole after a prolonged washout from previous tamoxifen (late extended adjuvant therapy). A trial examining the merits of > 5 years of treatment with an AI, MA.17R, is ongoing, as are a number of other trials of duration of therapy. This article reviews results from MA.17 and the design of these trials of duration. Clinical Breast Cancer, Vol. 8, No. 5, 411-417, 2008; DOI: 10.3816/CBC.2008.n.049 Keywords: Anastrozole, Aromatase inhibitors, Hormone receptor, Letrozole, Tamoxifen
Introduction Tamoxifen had been considered the standard first-line adjuvant therapy in patients with estrogen receptor (ER)–positive breast cancer for the past 30 years.1-4 However, based on current data, its use beyond 5 years is of minimal, if any, additional benefit and substantially increases toxicity.5,6 Inhibiting estrogen synthesis with aromatase inhibitors (AIs) demonstrated superiority over 5 years of tamoxifen—in terms of reducing recurrence risk—in several clinical trial settings, including as an alternative to tamoxifen or in sequence with it.3,7-9 In the National Cancer Institute of Canada Cooperative 1Massachusetts
General Hospital Cancer Center Medical School Boston, MA 3University of Vermont, Burlington 4Division of Medical Oncology, Mayo Clinic, Rochester, MN 5McMaster University, Juravinski Cancer Centre, Hamilton 6University of Toronto Ontario 2Harvard
Submitted: Feb 28, 2008; Revised: Apr 18, 2008; Accepted: May 9, 2008 Address for correspondence: Paul E. Goss, MD, PhD, FRCPC, FRCP, Massachusetts General Hospital Cancer Center, 55 Fruit St, LH – 302, Boston, MA 02114 Fax: 617-643-0589; e-mail: [email protected]
Trials Group (NCIC-CTG) MA.17 trial, letrozole was given as extended adjuvant therapy to postmenopausal women after 5 years of tamoxifen. Improvement in disease-free survival (DFS) was demonstrated as well as a survival advantage in women with node-positive disease (P ≤ .001)10,11 and in all women with ER/progesterone receptor (PgR)–positive disease.12 This article reviews the benefits of extended adjuvant AI therapy in reducing the risk of late recurrences of breast cancer in postmenopausal women and discusses recent analyses of late extended adjuvant AI therapy, in which treatment was started years after patients completed 5 years of tamoxifen. Also, current trials evaluating the optimal duration of AI therapy and a trial confirming the value of late extended therapy after ≥ 1 year off any previous adjuvant endocrine therapy are reviewed.
Late Recurrence Risk and the Need for Extended Adjuvant Therapy The substantial risk of breast cancer recurrence ≤ 15 years after diagnosis and primary treatment is well established.2,13 Results from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that more than half of breast cancer recurrences and two thirds of breast cancer deaths occur beyond the initial 5 years of
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Clinical Breast Cancer October 2008 • 411
Extended Adjuvant Endocrine Therapy Table 1 MA.17 Updated Efficacy Analysis11,23 Outcome
Intent-to-Treat (All Patients)
Node-Positive
Hazard Ratio*
P Value
Hazard Ratio*
P Value
Disease-Free Survival
0.58
< .001
0.61
Not reported (95% CI, 0.45-0.84)
Distant Disease-Free Survival
0.60
.002
Not reported
.001
Overall Survival
0.82
.3
0.61
.04
.12
Not reported
Not reported
Contralateral Breast Cancer
0.63
*Letrozole †Placebo
versus placebo. followed by letrozole versus no treatment.
tamoxifen therapy.2 Notably, distant metastases are the most common type of late recurrences.14,15 Among 1086 patients from the British Columbia Breast Cancer Outcomes database, 159 patients (15%) developed a breast cancer event between 5 years and 10 years after initial presentation, 53% of whom had distant metastases.14 As expected, distant metastases were associated with a poorer prognosis. In a retrospective cohort study of 1616 patients with early breast cancer (stages I and II; mean age, 60 years) using data from a large integrated healthcare system at a median follow-up of 44.5 months, women with distant metastases showed the highest risk of death (hazard ratio [HR], 13.6; P < .001) compared with disease-free women, followed by patients with a locoregional recurrence (HR, 4.6; P < .001) and a contralateral recurrence (HR, 3.0; P < .01).15 Based on data from 10 adjuvant therapy breast cancer trials conducted by the Eastern Cooperative Oncology Group, the annual rate of recurrence in patients with ER-positive breast cancer is substantial in the later years, at 5.2% annually between years 5 and 8, and 4.6 annually between years 8 and 12, after surgery, and recurrence after year 4 is also higher than that of patients with ER-negative breast cancer.13 Among patients with ER-positive disease not receiving adjuvant therapy, breast cancer demonstrates a continuous recurrence rate ≥ 15 years.13,16 In another study of women with node-negative disease without lymphatic or vascular invasion at presentation, the risk of relapse was > 25%, and the risk of death was approximately 10% at 10 years.16 Most notably, these rates of recurrence and death at year 10 were consistently higher than at year 5, supporting evidence of a significant ongoing risk and the chronic nature of hormone receptor–positive early breast cancer. Even for lower-risk patients (ie, nodenegative, tumor grade I), 10-year outcomes regarding the incidence of late recurrence and death have been found to be substantial.17 The ongoing EBCTCG metaanalysis reports that in patients with ER-positive disease, 5 years of tamoxifen reduces recurrence and contralateral breast cancer by approximately 41% and breast cancer mortality by 34%.2 The EBCTCG established that among patients completing a full 5-year course of adjuvant tamoxifen, the risk of breast cancer relapse continues to increase during years 5 to 15 after surgery, without any indication of a plateau.2,18 Of note, this was confirmed at the 7-year follow-up assessment of the initial patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14
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trial. This study showed that > 5 years of tamoxifen is not associated with any further benefit and is associated with an increased risk of stroke, endometrial cancer, and pulmonary embolism.5 Similar results were observed in another study, which showed that the annual rate of relapse after 5 years of tamoxifen was similar in both the long-term and short-term tamoxifen groups, suggesting that there is no benefit in receiving tamoxifen for > 5 years.19 The first analysis of the ATLAS (Adjuvant Tamoxifen Longer Against Shorter) trial presented at the 2007 San Antonio Breast Cancer Symposium shows a small improvement with ongoing tamoxifen, but no safety information was provided.6 Of note, a substantially increased cumulative toxicity, especially for serious life-threatening events (ie, venous thromboembolism, endometrial cancer), has been reported in several trials investigating the use of tamoxifen for > 5 years.5,20 The ATTOM (Adjuvant Tamoxifen Treatment, Offer More) trial will provide additional evidence as to the potential efficacy of longer durations of tamoxifen. Currently, its use beyond 5 years is not recommended.5,21 At this time, the data remain insufficient to recommend tamoxifen for > 5 years, and extending treatment beyond 5 years with an AI represents a better option.
The Landmark MA.17 Trial The ongoing risk of breast cancer presents an argument for continuing antiendocrine treatment, particularly in women with hormone-responsive tumors, beyond the standard of 5 years of adjuvant tamoxifen.13 Because of the chronic nature of recurrence risk in hormone receptor–positive early breast cancer, the NCICCTG initiated a large, randomized, double-blind, placebo-controlled trial, MA.17. This trial was designed to test the effectiveness of 5 years of letrozole 2.5 mg daily orally in postmenopausal women with primary breast cancer who had completed 4-6 years of tamoxifen not > 3 months before randomization.10 Subjects (N = 5187) were stratified by their hormone receptor and lymph node status and whether they had received previous adjuvant chemotherapy. The primary endpoint was DFS, defined as the time from randomization to the time of recurrence of the primary disease (in the breast, chest wall, nodal, or metastatic sites) or development of contralateral new primary breast cancer. Secondary endpoints included overall survival (OS), defined as time to the death from any cause; quality of life (QOL); and long-term safety. A planned interim analysis was conducted when 171 recurrences (events) occurred.10 Analysis at 2.4 years (207 events) showed a highly significant improvement in the estimated 4-year DFS for patients treated with letrozole (93% with letrozole compared with 87% for placebo). Extended adjuvant letrozole offered a 43% reduction in recurrence risk (75 with letrozole vs. 132 with placebo; HR, 0.57; 95% CI, 0.43-0.75; P = .00008).10,22 Because of this strong treatment effect, early unblinding of the study was recommended by the data and safety monitoring committee.10 Based upon these impressive initial results from the MA.17 trial, extended adjuvant letrozole represents a new paradigm for breast cancer treatment. With letrozole, postmenopausal women with hormone receptor–positive disease now have the opportunity to effectively reduce their risk of late recurrence without the risk of the life-threatening side effects associated with tamoxifen.10 Updated trial findings at a median follow-up of 30 months revealed a continued significant
Paul E. Goss et al Table 2 MA.17 Updated Safety Analysis11 Side Effect
Letrozole (%)
Placebo (%)
P Value
Clinical Bone Fractures
5.3
4.6
.25
New Osteoporosis
8.1
6
.003
Hypercholesterolemia
16
16
.79
Cardiovascular Disease
5.8
5.6
.76
Hot Flashes
58
54
.003
Myalgia
15
12
.004
Arthralgia
25
21
< .001
Alopecia
5
3
.01
reduction in recurrence risk of 42% (P < .001) with letrozole, a significant 40% improvement in distant DFS (DDFS; P = .002), and a significant survival advantage in patients with node-positive disease (HR, 0.61; P = .04), supporting the initial decision to unblind the trial (Table 1).11,23 A more recent analysis supported the conclusion of the safety monitoring committee to unmask MA.17 early. This analysis showed support for the initial decision to release the interim analysis results and to allow patients on placebo to cross over to letrozole; patients who went on letrozole after placebo had a significantly lower risk of recurrence than patients who declined placebo (DFS: HR, 0.37, P < .0001; DDFS: HR, 0.38, P = .004; contralateral breast cancer: HR, 0.18, P < .0001).10,12,22 The benefits of extended adjuvant therapy were further confirmed in 2 trials, one using anastrozole and another using exemestane.24,25 In the NSABP B-33 trial, extended adjuvant exemestane versus placebo was investigated in patients who were disease-free after 5 years of tamoxifen.24 This trial was unblinded after enrollment of about half (N = 1598) of the planned 3000 patients after the results of NCICCTG MA.17 in 2003, which showed benefit from extended adjuvant letrozole after 5 years of tamoxifen. At the time of unblinding, the NSABP B-33 study found a significant improvement in 4-year relapsefree survival, which included local, regional, distant, and opposite breast recurrence, after 30 months (96% vs. 94%; P = .004) and, although not reaching statistical significance, a trend toward improvement in DFS, which additionally included second primary non–breast cancer and death (91% vs. 89%; P = .07) and in DDFS (HR, 0.69; P = .13).24 The Austrian Breast and Colorectal Cancer Study Group (ABCSG) compared anastrozole (n = 387) with placebo (n = 469) at 5 years of follow-up. Although this small, open-label trial (N = 856) displayed unbalanced treatment arms, significantly fewer patients in the anastrozole group experienced disease recurrence compared with patients in the placebo group (30 patients vs. 57 patients; HR, 0.62; 95% CI, 0.40-0.96; P = .0477).25 These trials, although not as robust as MA.17, lend further support to the use of AIs in the extended adjuvant setting, with letrozole remaining the only AI with this indication approved by regulatory authorities.
MA.17: Safety and Quality of Life Safety The AIs have a safety profile different from tamoxifen in that they are not associated with increased risk of serious life-threatening
Figure 1 MA.17R Re-randomization Recruitment Criteria and Protocol Stratify Previous Tamoxifen
N = 1800
Placebo
Yes or No Tamoxifen
Any Aromatase Inhibitor Letrozole
3-5 Years
5 Years
0-2 Years
5 Years
adverse events such as thromboembolism or uterine cancer.1,3,5,8,9 MA.17 was the only large, blinded trial of an AI wherein not only self-reported side effects but also their effect on QOL were evaluated against a placebo.10,11,26 Important to the interpretation of toxicity and QOL data from MA.17 is that patients were selected by virtue of having been able to complete 5 years of previous tamoxifen. Women most vulnerable to problems with endocrine therapy might therefore not be represented by the patients in this trial. With this proviso, letrozole was generally well tolerated, with overall toxicities as expected.11 The incidence of hot flashes (58% vs. 54%), myalgia (15% vs. 12%), arthralgia (25% vs. 21%), and alopecia (5% vs. 3%) occurred significantly more often in patients receiving letrozole. These adverse events were considered a result of patients’ depleted estrogen levels, and the majority of such side effects can be effectively managed.11 It is interesting to note that these side effects also were frequently experienced by patients receiving placebo, in whom the rate of arthralgia was also high. The incidence of new-onset clinical osteoporosis occurred in 8.1% of patients treated with letrozole compared with 6% of patients treated with placebo. Although there was a trend toward a numerical increase in clinical fractures in patients taking letrozole (5.3%) compared with placebo (4.6%), this difference was not statistically significant (Table 2).11 In patients treated with letrozole experiencing a fracture, median time from randomization to a fracture event was 1.06 years compared with 0.86 years for placebo-treated patients. The median time to any fracture occurrence for those receiving letrozole was 0.70 years versus 0.52 years for patients receiving placebo. To further define the effects of letrozole on skeletal health, a subset of 226 patients enrolled in MA.17 were monitored for bone mineral density (BMD) and bone turnover markers.27 Although at 12 months there was no statistically significant difference between the 2 groups, among patients remaining in the cohort at 24 months, there was a significantly greater decrease in total hip BMD among women taking letrozole (–3.6% vs. –0.71%; P = .044). Evaluation of the bone resorption marker urine N-telopeptide correlated with the BMD findings. Patients treated with letrozole had an increase in N-telopeptide at 6 months (P = .054), 12 months (P < .001), and 24 months (P = .016). However, more patients receiving placebo (10.6%) compared with letrozole (4.1%) were using bisphosphonates, which could have had a positive effect on their BMD. Another observation was that BMD scores were more likely to show a significant decrease in women who were osteopenic at the initiation of letrozole treatment than in patients with BMD within the normal range.
Clinical Breast Cancer October 2008 • 413
Extended Adjuvant Endocrine Therapy Figure 2 Schemata of Ongoing Clinical Trials Evaluating Duration of Aromatase Inhibitor Therapy NSABP B42 (N = 3840) Aromatase Inhibitor 5 Years Tamoxifen Aromatase 2-3 Years Inhibitor 2-3 Years
Tamoxifen Aromatase 2-3 Years Inhibitor 2-3 Years
Placebo (%)
P Value
Hot Flashes
22
17
.0002
Night Sweats
17
14
.047
Sweating
18
14
.003
Change in Sexual Desire
16
15
.36
Anastrozole 3 Years
Vaginal Dryness
22
19
.016
Avoidance of Intimacy
16
15
.5
Anastrozole 6 Years
Poor Memory
14
14
.73
Feeling Depressed
11
11
.96
Muscle and Joint Aches
43
39
.02
Difficulty Sleeping
29
26
.047
Weight Gain
21
22
.45
Letrozole 3-2 Years Tamoxifen 2-3 Years
Placebo 5 Years
Letrozole 5 Years
ABCSG16 SALSA (N = 3500) Aromatase Inhibitor 5 Years
Letrozole (%)
GIM4 LEAD (N = 4050)
Letrozole 5 Years
Dutch DATA (N = 1900)
Anastrozole 2 Years Tamoxifen 2-3 Years Anastrozole 5 Years
Table 3 Symptom Analysis: Percentage of Patients Being “Very Bothered” by a Specific Symptom26
Abbreviations: ABCSG = Austrian Breast and Colorectal Cancer Study Group; DATA = Different Durations of Adjuvant Anastrozole Therapy after 2 to 3 years of Tamoxifen; GIM = Gruppo Italiano Mammella; LEAD = Letrozole Adjuvant therapy Duration; NSABP = National Surgical Adjuvant Breast and Bowel Project; SALSA = Secondary Adjuvant Long-term Study with Arimidex
Symptom According to MENQOL
Abbreviation: MENQOL = Menopause Specific Quality of Life Adapted with permission from TJ Whelan et al. J Clin Oncol 2005; 23:6931-40.
The incidence of cardiovascular disease in patients enrolled in MA.17 was similar among patients in the 2 groups (5.8% letrozole vs. 5.6% placebo), as was the incidence of hypercholesterolemia (16% in both arms; Table 2).11 In the MA.17 lipid substudy, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, lipoprotein (a), and triglycerides were measured at baseline (N = 347), 6 months, 12 months, and yearly thereafter ≤ 36 months.28 The only differences between the 2 cohorts were marginally significant differences in the percentage changes in HDL cholesterol at 6 months (decreased HDL with letrozole vs. increased HDL with placebo; P = .049), in LDL cholesterol at 12 months (increased LDL with both letrozole and placebo; P = .033), and in triglycerides at 24 months (increased triglycerides with letrozole vs. decreased triglycerides with placebo; P = .036) but not at any other time points.28 These findings confirm that AI therapy with letrozole does not increase the risk of hypercholesterolemia, supporting previous findings that although AIs lack the potential cardioprotective effects of tamoxifen, they do not increase the overall risk of cardiovascular events.29 In this aging population treated with endocrine therapy, an increasing cardiovascular risk competes with recurrence as a cause of mortality, making women with cardiovascular disease more likely to die from causes not related to breast cancer.3,8,9,30 In fact, long-term followup of all survivors in the MA.17 trial demonstrated that non–breast cancer occurrences accounted for 72% of deaths among patients aged ≥ 70 years and 48% of deaths among patients aged < 70 years.31
The SF-36 evaluates 36 items, including general physical function, pain, general health, vitality, social functioning, and mental health. From this information, individual and global summary scores of physical and mental status are derived. The MENQOL assesses symptoms specifically related to menopause and estrogen depletion that might be affected by AIs.26,32,33 In the MA.17 QOL substudy, mental and physical summary scores on the SF-36 were similar between patients taking placebo and letrozole, although some small differences were noted in the bodily pain domain.26 On the MENQOL questionnaire, only the vasomotor domain showed a significant difference between groups, with 22% of the placebo group and 29% of the letrozole group reporting worsening in QOL related to vasomotor symptoms (P < .001). These symptoms improved over time for both patient groups. Together, the results demonstrated that, compared with placebo, letrozole did not have a detrimental effect on overall QOL after 36 months of treatment. Bothersome symptoms were noted by a minority of patients in the placebo and letrozole groups, and of these, only hot flashes (17% placebo vs. 22% letrozole; P = .0002) and sweating (14% placebo vs. 18% letrozole; P = .003) were significantly different between groups (Table 3).26 The incidences of night sweats, vaginal dryness, muscle and joint aches, difficulty sleeping, change in sexual desire, avoidance of intimacy, poor memory, feeling depressed, or weight gain did not differ significantly between treatment arms.
Additional MA.17 Analyses Quality of Life Analyses Although it is clear that adjuvant AI therapy results in substantial improvements in DFS and OS, the QOL associated with AI treatment is an important consideration for clinical decision-making. To address this issue, the MA.17 trial evaluated a group of healthy women free of recurrent cancer. Data were collected using 2 surveys: a general QOL instrument, the 36-Item Short-Form Health Survey (SF-36); and a symptom-specific instrument, the Menopause Specific Quality of Life (MENQOL) questionnaire.
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Several additional analyses of women enrolled in MA.17 have been conducted. A cohort analysis of all events up to the date of study unblinding by length of time on therapy showed that the HRs significantly decreased from 0.59 at 6 months to 0.19 at 48 months (P < .0001), corresponding with a 41%-81% reduction in recurrence risk over time.34 These significantly decreasing HRs achieved with letrozole for ≤ 48 months for the primary study endpoint of DFS suggest a greater benefit with letrozole the longer patients remain on therapy (Table 4).12,34-37 In this analysis, DDFS
Paul E. Goss et al Table 4 MA.17 Updated Sub-analysis Subanalysis Optimal Duration of Extended Adjuvant Letrozole34
Effect of Hormone Receptor Status35
Effect of Age36
Intent-to-Treat Analysis37
Post-Unblinding Analysis12
Number of Patients
5170 (n = 2360, node-positive)
5187 (n = 3809, ER/ PgR–positive tumors; n = 636, ER-positive/ PgR-negative tumors)
5169 (n = 2152, aged < 60 years; n = 1694, aged 60-69 years; n = 1323, aged > 70 years)
5187
2383
Median Follow-up
Key Findings*
Implications
6, 12, 24, 36, and 48 months were analyzed
DFS: significantly decreasing HRs with letrozole over time (P < .0001); DDFS: significantly decreasing HRs with letrozole over time (P = .0013); OS: significantly decreasing HRs with letrozole over time for patients with node-positive disease (P = .038)
At q 48 months, the longer the exposure to letrozole, the greater the benefit
30 Months
DFS: HR, 0.49 for ER/PgR–positive tumors; HR, 1.21 for ER-positive/PgR-negative tumors; significant treatment effect between ER/PgR–positive and ER-positive/ PgR-negative (P = .02); DDFS: HR, 0.53 for ER/PgR–positive tumors; no significant treatment effect (P = .06); OS: HR, 0.58 for ER/PgR–positive tumors; no significant treatment effect (P = .09)
Letrozole appears to have a greater benefit in tumors with a functional ER; PgR status should not be regarded as a reason for denying or prescribing adjuvant AI therapy for patients for whom it is indicated until this finding is confirmed
30 Months
4-Year DFS: significant benefit in subgroup of patients aged < 60 years (HR, 0.46; P = .0004); 4-year OS: significant benefit in subgroup of patients aged > 70 years with node-positive disease (P = .04); toxicities: no difference for letrozole vs. placebo in patients aged > 70 years; QOL at 36 months: similar for letrozole vs. placebo for patients aged > 70 years
For patients aged > 70 years in good health, letrozole has benefits similar to those in younger patients, without any significant increase in toxicity or decrease in QOL compared with placebo; older patients should also be considered for letrozole after 5 years of tamoxifen
4-Year DFS: HR, 0.68 (P = .0001); 4-year DDFS: HR, 0.80 (P = .089); 4-year OS: HR, 0.98 (P = .828); CBC annual rate: HR, 0.61 (P = .033)
Patients who were originally randomized to letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS, DDFS, and CBC despite 73% of placebo patients crossing over to letrozole after unblinding
DFS: HR, 0.37 (P < .0001); DDFS: HR, 0.38 (P = .004); OS: HR, 0.30 (P = .004); CBC: HR, 0.18 (P < .0001)
Patients can receive benefit from letrozole even if a period of time has elapsed since treatment with tamoxifen (a 5 years) and should be considered for late extended adjuvant therapy
64 Months
63.6 Months
*All hazard ratios are for letrozole versus placebo or placebo to letrozole versus placebo (for post-unblinding analysis). Abbreviations: AI = aromatase inhibitor; CBC = contralateral breast cancer; DDFS = distant disease-free survival; DFS = disease-free survival; ER = estrogen receptor; HR = hazard ratio; OS = overall survival; PgR = progesterone receptor; QOL = quality of life
showed a similar pattern of increasing superiority for letrozole over time, with the test for trend being highly significant (P < .0013). A retrospective analysis of the effect of hormone receptor status on clinical outcome with extended adjuvant letrozole was also performed. Letrozole demonstrated the greatest efficacy in women with ER/PgR–positive tumors (n = 3809), the most hormone-dependent subset.35 A significant survival benefit was also observed in this large patient population. Women in this group showed a 51% improvement in DFS compared with placebo. Those with ER-negative/ PgR-positive (n = 200) tumors also benefited, with a 44% reduction in events compared with placebo. By comparison, women (n = 636) with ER-positive/PgR-negative tumors did not appear to experience
a DFS benefit with letrozole. However, the following caveats should be considered: there were very few patients in this subgroup, the confidence interval in the ER-positive/PgR-negative subgroup for DFS was very wide (95% CI, 0.63-2.34), and the receptor levels were measured locally. Although the best outcomes were observed in the ER/PgR–positive patients, because receptor levels were measured locally rather than centrally and in light of the small number of patients in the other subgroups, the data require confirmation before PgR is incorporated into treatment decisions. The benefits of letrozole in postmenopausal women with earlystage breast cancer were independent of age.36 Benefits in DFS and DDFS were observed with letrozole in all age groups. In particular,
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Extended Adjuvant Endocrine Therapy among patients aged ≥ 70 years and in good health, the benefits of letrozole were similar to those observed in younger patients, without any increase in toxicity or decrease in QOL compared with placebo. A separate intent-to-treat (ITT) analysis, which assessed all outcomes (DFS, DDFS, OS, and contralateral breast cancer), was also performed. It did not take into account whether patients in the placebo group switched to letrozole at the unblinding of the data. This ITT analysis, which included all events before and after the unblinding, based on the original randomization of letrozole versus placebo, showed a significant benefit for women originally randomized to letrozole compared with patients initially receiving placebo at a median follow-up of 64 months.37 Furthermore, women originally randomized to letrozole within 3 months of completing tamoxifen did better than placebo patients even though 73% of placebo patients crossed over to letrozole after unblinding. This benefit was noted for DFS (P = .0002), DDFS (P = .041), and contralateral breast cancer (P = .037). An additional post-unblinding analysis also showed the benefit of late extended adjuvant letrozole. When MA.17 was unblinded in 2003, most patients who were receiving letrozole chose to continue their 5 years of planned therapy. Patients who had been receiving placebo were given the chance to switch to letrozole: about two thirds of patients treated with placebo (n = 1579) crossed over to letrozole, but 804 patients decided to be followed annually and not receive treatment.12,38,39 This analysis was performed after a median follow-up of 63.6 months in all patients who had a recurrence or died before unblinding or discontinued treatment because of any toxicity. The 2 groups studied also had different baseline characteristics, with the women electing to switch to letrozole at increased risk for disease recurrence (ie, younger age, node-positive disease, previous chemotherapy). The multivariate analysis was adjusted for all known risk factor imbalances. Efficacy results from the post-unblinding analysis showed that patients who received late extended adjuvant letrozole experienced a significant reduction in DFS (HR, 0.37; P < .0001), DDFS (HR, 0.38; P = .004), risk of contralateral breast cancer (HR, 0.18; P = .004), and an improvement in OS (HR, 0.30; P < .0001) despite a gap between the completion of tamoxifen and the initiation of letrozole. Safety analysis after unblinding was comparable to that observed in the main trial. In patients who received late extended adjuvant letrozole, there was an increased incidence of osteoporosis (self-reported; 5.3% vs. 1.6%) and fractures (5.2% vs. 3.1%) but no increase in the incidence of cardiovascular events (4.2% vs. 3.1%).12
Ongoing Trials of Extended Adjuvant Aromatase Inhibitor Therapy To determine whether adjuvant AI therapy for > 5 years is superior to AI therapy for 5 years, a randomized, placebo-controlled trial (MA.17R) is being conducted (Figure 1). This trial randomizes women completing 5 years of any AI (after any duration of previous tamoxifen or no previous tamoxifen) to 5 more years of letrozole or placebo. This trial includes women who completed 5 years of letrozole after 5 years of tamoxifen in the original MA.17 trial.29,40,41 Disease stratification includes receptor status (positive vs. unknown), lymph node status (negative, positive, unknown), previous adjuvant chemotherapy (yes or no), interval between last dose of AI and randomization (< 6 months, 6 months, 2 years), and duration of tamoxifen use (0 years, < 2 years,
416 • Clinical Breast Cancer
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2-4.5 years, > 4.5 years).41 Companion translational studies in this trial will examine whether common genetic single nucleotide polymorphisms for genes encoding proteins involved in the pharmacokinetic and/or pharmacodynamic pathways for letrozole contribute to a variation in toxicity and efficacy of letrozole in individual patients. In addition to the extension of MA.17, several other trials are under way to determine the optimal duration of AI therapy (Figure 2). The NSABP B-42 trial will examine specifically whether 10 years of endocrine therapy is superior to 5 years. Women who have completed 5 years of endocrine treatment with any AI, or 2-3 years of tamoxifen, followed by 2-3 years of AI, will be randomized to receive letrozole for an additional 5 years versus placebo.42 In a similar trial using anastrozole (ABCSG 16; SALSA [Secondary Adjuvant Long-term Study in Arimidex®]), > 1700 postmenopausal patients (of a total 3500) who have been free of breast cancer recurrence after approximately 5 years of any endocrine therapy have already been enrolled. Patients are randomized to receive 2 years or 5 years of extended adjuvant anastrozole. The primary outcome measure is DFS, and assessments of OS and fracture rates are planned.43,44 Two additional trials will evaluate letrozole use in patients treated with 2-3 years of tamoxifen after primary resection. In the LEAD (LEtrozole Adjuvant therapy Duration) study, patients will be randomized to receive shorter-term letrozole for 2-3 years or letrozole for 5 years.45 In a similar population, the Dutch DATA (Different Durations of Adjuvant Anastrozole Therapy after 2 to 3 years of Tamoxifen) trial will analyze differences between 3 years and 6 years of anastrozole in postmenopausal women with hormone-sensitive breast cancer.46 A primary endpoint of DFS has been established for both trials.
Conclusion In women with early-stage hormone receptor–positive breast cancer, the risk of disease recurrence is highest after 5 years, with the most common and serious late relapse event being distant metastases. This risk is observed in patients treated with tamoxifen and in untreated patients. The MA.17 trial has demonstrated that extended adjuvant letrozole allows patients to further reduce their risk of relapse following 5 years of tamoxifen. Extended adjuvant letrozole significantly reduced the risk of recurrence by 42% and distant metastases by 40%. These results from the MA.17 trial have led to the approval of letrozole as the only approved extended adjuvant therapy. All current guidelines support the use of letrozole as an extended adjuvant therapy,47,48 and results from the MA.17 cohort analysis show that the longer the use of letrozole, the greater the benefit (≥ 4 years).34 When considering extended adjuvant therapy after the completion of tamoxifen, clinicians and patients should consider the residual risk of recurrence and individual patient preferences.47 The MA.17 results clearly show that the benefit of extended adjuvant letrozole is observed irrespective of nodal status and that the option of extended adjuvant therapy should be discussed with all patients completing tamoxifen. MA.17 post-unblinding results show that women with hormonedependent breast cancer who were prescribed letrozole following a prolonged delay after completing tamoxifen also experienced a significant improvement in outcomes. Women who have not been given letrozole immediately after completing tamoxifen should be
Paul E. Goss et al considered candidates for late extended adjuvant therapy. Of note, AIs and tamoxifen are now appropriate choices for initial adjuvant therapy for postmenopausal women with hormone-sensitive breast cancer.48 For patients who have received initial adjuvant tamoxifen, extended adjuvant and late extended adjuvant letrozole therapy offers an opportunity for further protection against late relapses. The results of the MA.17R re-randomization trial and others, including NSABP B-42, will build upon current information and help determine the optimal duration of AI therapy for women with hormone receptor–positive breast cancer.
References 1. Duffy S, Jackson TL, Lansdown M, et al. The ATAC (‘Arimidex’, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: first results of the endometrial sub-protocol following 2 years of treatment. Hum Reprod 2006; 21:545-53. 2. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687-717. 3. Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005; 365:60-2. 4. Adjuvant therapy for breast cancer. NIH Consensus Statement 2000; 17:1-35. 5. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001; 93:684-90. 6. Peto R, Davies C, on behalf of the ATLAS Collaboration. ATLAS (Adjuvant Tamoxifen, Longer Against Shorter): international randomized trial of 10 versus 5 years of adjuvant tamoxifen among 11,500 women – preliminary results. Breast Cancer Res Treat 2007; 106(suppl 1):(Abstract 48). 7. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003; 21:2101-9. 8. Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer [published erratum appears in: N Engl J Med 2006; 354:2200]. N Engl J Med 2005; 353:2747-57. 9. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial [published erratum appears in: Lancet 2007; 369:906]. Lancet 2007; 369:559-70. 10. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349:1793-802. 11. Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005; 97:1262-71. 12. Goss PR, Ingle JN, Palmer MJ, et al. Updated analysis of NCIC CTG MA.17 (letrozole vs placebo to letrozole vs placebo) post unblinding. J Clin Oncol 2008. In press. 13. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996; 14:2738-46. 14. Kennecke HF, Olivotto IA, Speers C, et al. Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen. Ann Oncol 2007; 18:45-51. 15. Lamerato L, Havstad S, Ganhdi S, et al. Breast cancer recurrence and related mortality in US pts with early breast cancer. J Clin Oncol 2005; 23(16 suppl):62s (Abstract 738). 16. Chia SK, Speers CH, Bryce CJ, et al. Ten-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies. J Clin Oncol 2004; 22:1630-7. 17. Hortobagyi GN, Kau S-W, Buzdar AU, et al. What is the prognosis of patients with operable breast cancer (BC) five years after diagnosis? Proc Am Soc Clin Oncol 2004; 22(14 suppl):585 (Abstract 585). 18. Freedman GM, Anderson P, Li T, et al. Identifying breast cancer patients most likely to benefit from aromatase inhibitor therapy after adjuvant radiation and tamoxifen. Cancer 2006; 107:2552-8. 19. Delozier T, Spielmann M, Janvier M, et al. Optimal duration of adjuvant tamoxifen (TAM) in early breast cancer (EBC): ten year results of a randomized trial (TAM-01) of the FNCLCC Breast Group. Breast Cancer Res Treat 2005; 94(suppl 1):S10 (Abstract 14). 20. McDonald CC, Alexander FE, Whyte BW, et al. Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. BMJ 1995; 311:977-80. 21. Bryant J, Fisher B, Dignam J. Duration of adjuvant tamoxifen therapy. J Natl Cancer Inst Monogr 2001; 30:56-61. 22. Pater J, Tu D, Shepherd L, et al. Decision making in adjuvant trials in breast cancer: the
NCIC CTG MA.17 trial as an example. Breast Cancer Res Treat 2008; 108:265-9. 23. Kaufmann M, Rody A. Long-term risk of breast cancer recurrence: the need for extended adjuvant therapy. J Cancer Res Clin Oncol 2005; 131:487-94. 24. Mamounas E, Jeong JH, Wickerham DL, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of tamoxifen: intent-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol 2008; 26:1965-71. 25. Jakesz R, Greil R, Gnant M, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst 2007; 99:1845-53. 26. Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005; 23:6931-40. 27. Perez EA, Josse RG, Pritchard KI, et al. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol 2006; 24:3629-35. 28. Wasan KM, Goss PE, Pritchard PH, et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 2005; 16:707-15. 29. Goss P. Update on the MA.17 extended adjuvant trial. Best Pract Res Clin Endocrinol Metab 2006; 20(suppl 1):S5-S13. 30. Monnier A. Comparing AI cardiovascular safety data: trial comparators and outcomes. Ann Oncol 2006; 17(suppl 9):ix100 (Abstract 266P). 31. Chapman J, Meng D, Shepherd L, et al. Competing causes of death from a randomized trial of extended adjuvant endocrine therapy for breast cancer. J Natl Cancer Inst 2008; 100:252-60. 32. Abetz L, Barghout V, Thomas S, et al. Letrozole did not worsen quality of life relative to placebo in post-menopausal women with early breast cancer: results from the US subjects of the MA-17 study. Breast Cancer Res Treat 2005; 94(suppl 1):S97 (Abstract 2047). 33. Barghout V, Abetz L, Thomas S, et al. Impact of letrozole on quality of life in post-menopausal women with early breast cancer: does age matter? Breast Cancer Res Treat 2005; 94(suppl 1):S97 (Abstract 2040). 34. Ingle JN, Tu D, Pater JL, et al. Duration of letrozole treatment and outcomes in the placebo-controlled NCIC CTG MA.17 extended adjuvant therapy trial. Breast Cancer Res Treat 2006; 99:295-300. 35. Goss PE, Ingle JN, Martino S, et al. Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17. J Clin Oncol 2007; 25:2006-11. 36. Muss HB, Tu D, Ingle JN, et al. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol 2008; 26:1956-64. 37. Ingle JN, Tu D, Pater JL, et al. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17. Ann Oncol 2008; 19:877-82. 38. Goss PE, Ingle JN, Palmer MJ, et al. Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs. placebo) post unblinding. Breast Cancer Res Treat 2005; 94(suppl 1):S10 (Abstract 16). 39. Robert NJ, Goss PE, Ingle JN, et al. Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs. placebo) post unblinding. J Clin Oncol 2006; 24(18 suppl):15s (Abstract 550). 40. Pritchard KI, Goss PE, Shepherd L. The extended adjuvant NCIC CTG MA.17 trials: initial and rerandomization studies. Breast 2006; 15(1 suppl):S14-20. 41. ClinicalTrials.gov [Web site]. Letrozole after tamoxifen in treating women with breast cancer. Available at: http://www.clinicaltrials.gov/ct2/show/NCT0000314 0?term=00003140&rank=1. Accessed: February 5, 2008. 42. Mamounas EP, Lembersky B, Jeong JH, et al. NSABP B-42: a clinical trial to determine the efficacy of five years of letrozole compared with placebo in patients completing five years of hormonal therapy consisting of an aromatase inhibitor (AI) or tamoxifen followed by an AI in prolonging disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Clin Breast Cancer 2006; 7:416-21. 43. ABCSG. Annual meeting of the Austrian Breast and Colorectal Study Group (ABCSG). Breast Care 2007; 2:47-9. 44. ClinicalTrials.gov [Web site]. Secondary adjuvant long term study with Arimidex (SALSA). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00295620?ter m=00295620&rank=1. Accessed: February 5, 2008. 45. Oncotech.com [Web site]. Letrozole Adjuvant therapy Duration (LEAD) study: standard versus long treatment. A phase III trial in post-menopausal women with early breast cancer. Available at: http://www.oncotech.org/albero/progetti_gim4. asp. Accessed: February 5, 2008. 46. ClinicalTrials.gov [Web site]. Different durations of adjuvant anastrozole therapy after 2 to 3 years tamoxifen therapy in breast cancer (DATA). Available at: http:// www.clinicaltrials.gov/ct2/show/NCT00301457?term=00301457&rank=1. Accessed: February 5, 2008. 47. Goldhirsch A, Wood WC, Gelber RD, et al. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007 [published erratum appears in: Ann Oncol 2007; 18:1917]. Ann Oncol 2007; 18:1133-44. 48. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23:619-29.
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Introduction Tamoxifen had been considered the standard first-line adjuvant therapy in patients with estrogen receptor (ER)–positive breast cancer for the past 30 years.1-4 However, based on current data, its use beyond 5 years is of minimal, if any, additional benefit and substantially increases toxicity.5,6 Inhibiting estrogen synthesis with aromatase inhibitors (AIs) demonstrated superiority over 5 years of tamoxifen—in terms of reducing recurrence risk—in several clinical trial settings, including as an alternative to tamoxifen or in sequence with it.3,7-9 In the National Cancer Institute of Canada Cooperative 1Massachusetts
General Hospital Cancer Center Medical School Boston, MA 3University of Vermont, Burlington 4Division of Medical Oncology, Mayo Clinic, Rochester, MN 5McMaster University, Juravinski Cancer Centre, Hamilton 6University of Toronto Ontario 2Harvard
Submitted: Feb 28, 2008; Revised: Apr 18, 2008; Accepted: May 9, 2008 Address for correspondence: Paul E. Goss, MD, PhD, FRCPC, FRCP, Massachusetts General Hospital Cancer Center, 55 Fruit St, LH – 302, Boston, MA 02114 Fax: 617-643-0589; e-mail: [email protected]
Trials Group (NCIC-CTG) MA.17 trial, letrozole was given as extended adjuvant therapy to postmenopausal women after 5 years of tamoxifen. Improvement in disease-free survival (DFS) was demonstrated as well as a survival advantage in women with node-positive disease (P ≤ .001)10,11 and in all women with ER/progesterone receptor (PgR)–positive disease.12 This article reviews the benefits of extended adjuvant AI therapy in reducing the risk of late recurrences of breast cancer in postmenopausal women and discusses recent analyses of late extended adjuvant AI therapy, in which treatment was started years after patients completed 5 years of tamoxifen. Also, current trials evaluating the optimal duration of AI therapy and a trial confirming the value of late extended therapy after ≥ 1 year off any previous adjuvant endocrine therapy are reviewed.
Late Recurrence Risk and the Need for Extended Adjuvant Therapy The substantial risk of breast cancer recurrence ≤ 15 years after diagnosis and primary treatment is well established.2,13 Results from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that more than half of breast cancer recurrences and two thirds of breast cancer deaths occur beyond the initial 5 years of
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Clinical Breast Cancer October 2008 • 411
Extended Adjuvant Endocrine Therapy Table 1 MA.17 Updated Efficacy Analysis11,23 Outcome
Intent-to-Treat (All Patients)
Node-Positive
Hazard Ratio*
P Value
Hazard Ratio*
P Value
Disease-Free Survival
0.58
< .001
0.61
Not reported (95% CI, 0.45-0.84)
Distant Disease-Free Survival
0.60
.002
Not reported
.001
Overall Survival
0.82
.3
0.61
.04
.12
Not reported
Not reported
Contralateral Breast Cancer
0.63
*Letrozole †Placebo
versus placebo. followed by letrozole versus no treatment.
tamoxifen therapy.2 Notably, distant metastases are the most common type of late recurrences.14,15 Among 1086 patients from the British Columbia Breast Cancer Outcomes database, 159 patients (15%) developed a breast cancer event between 5 years and 10 years after initial presentation, 53% of whom had distant metastases.14 As expected, distant metastases were associated with a poorer prognosis. In a retrospective cohort study of 1616 patients with early breast cancer (stages I and II; mean age, 60 years) using data from a large integrated healthcare system at a median follow-up of 44.5 months, women with distant metastases showed the highest risk of death (hazard ratio [HR], 13.6; P < .001) compared with disease-free women, followed by patients with a locoregional recurrence (HR, 4.6; P < .001) and a contralateral recurrence (HR, 3.0; P < .01).15 Based on data from 10 adjuvant therapy breast cancer trials conducted by the Eastern Cooperative Oncology Group, the annual rate of recurrence in patients with ER-positive breast cancer is substantial in the later years, at 5.2% annually between years 5 and 8, and 4.6 annually between years 8 and 12, after surgery, and recurrence after year 4 is also higher than that of patients with ER-negative breast cancer.13 Among patients with ER-positive disease not receiving adjuvant therapy, breast cancer demonstrates a continuous recurrence rate ≥ 15 years.13,16 In another study of women with node-negative disease without lymphatic or vascular invasion at presentation, the risk of relapse was > 25%, and the risk of death was approximately 10% at 10 years.16 Most notably, these rates of recurrence and death at year 10 were consistently higher than at year 5, supporting evidence of a significant ongoing risk and the chronic nature of hormone receptor–positive early breast cancer. Even for lower-risk patients (ie, nodenegative, tumor grade I), 10-year outcomes regarding the incidence of late recurrence and death have been found to be substantial.17 The ongoing EBCTCG metaanalysis reports that in patients with ER-positive disease, 5 years of tamoxifen reduces recurrence and contralateral breast cancer by approximately 41% and breast cancer mortality by 34%.2 The EBCTCG established that among patients completing a full 5-year course of adjuvant tamoxifen, the risk of breast cancer relapse continues to increase during years 5 to 15 after surgery, without any indication of a plateau.2,18 Of note, this was confirmed at the 7-year follow-up assessment of the initial patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14
412 • Clinical Breast Cancer
October 2008
trial. This study showed that > 5 years of tamoxifen is not associated with any further benefit and is associated with an increased risk of stroke, endometrial cancer, and pulmonary embolism.5 Similar results were observed in another study, which showed that the annual rate of relapse after 5 years of tamoxifen was similar in both the long-term and short-term tamoxifen groups, suggesting that there is no benefit in receiving tamoxifen for > 5 years.19 The first analysis of the ATLAS (Adjuvant Tamoxifen Longer Against Shorter) trial presented at the 2007 San Antonio Breast Cancer Symposium shows a small improvement with ongoing tamoxifen, but no safety information was provided.6 Of note, a substantially increased cumulative toxicity, especially for serious life-threatening events (ie, venous thromboembolism, endometrial cancer), has been reported in several trials investigating the use of tamoxifen for > 5 years.5,20 The ATTOM (Adjuvant Tamoxifen Treatment, Offer More) trial will provide additional evidence as to the potential efficacy of longer durations of tamoxifen. Currently, its use beyond 5 years is not recommended.5,21 At this time, the data remain insufficient to recommend tamoxifen for > 5 years, and extending treatment beyond 5 years with an AI represents a better option.
The Landmark MA.17 Trial The ongoing risk of breast cancer presents an argument for continuing antiendocrine treatment, particularly in women with hormone-responsive tumors, beyond the standard of 5 years of adjuvant tamoxifen.13 Because of the chronic nature of recurrence risk in hormone receptor–positive early breast cancer, the NCICCTG initiated a large, randomized, double-blind, placebo-controlled trial, MA.17. This trial was designed to test the effectiveness of 5 years of letrozole 2.5 mg daily orally in postmenopausal women with primary breast cancer who had completed 4-6 years of tamoxifen not > 3 months before randomization.10 Subjects (N = 5187) were stratified by their hormone receptor and lymph node status and whether they had received previous adjuvant chemotherapy. The primary endpoint was DFS, defined as the time from randomization to the time of recurrence of the primary disease (in the breast, chest wall, nodal, or metastatic sites) or development of contralateral new primary breast cancer. Secondary endpoints included overall survival (OS), defined as time to the death from any cause; quality of life (QOL); and long-term safety. A planned interim analysis was conducted when 171 recurrences (events) occurred.10 Analysis at 2.4 years (207 events) showed a highly significant improvement in the estimated 4-year DFS for patients treated with letrozole (93% with letrozole compared with 87% for placebo). Extended adjuvant letrozole offered a 43% reduction in recurrence risk (75 with letrozole vs. 132 with placebo; HR, 0.57; 95% CI, 0.43-0.75; P = .00008).10,22 Because of this strong treatment effect, early unblinding of the study was recommended by the data and safety monitoring committee.10 Based upon these impressive initial results from the MA.17 trial, extended adjuvant letrozole represents a new paradigm for breast cancer treatment. With letrozole, postmenopausal women with hormone receptor–positive disease now have the opportunity to effectively reduce their risk of late recurrence without the risk of the life-threatening side effects associated with tamoxifen.10 Updated trial findings at a median follow-up of 30 months revealed a continued significant
Paul E. Goss et al Table 2 MA.17 Updated Safety Analysis11 Side Effect
Letrozole (%)
Placebo (%)
P Value
Clinical Bone Fractures
5.3
4.6
.25
New Osteoporosis
8.1
6
.003
Hypercholesterolemia
16
16
.79
Cardiovascular Disease
5.8
5.6
.76
Hot Flashes
58
54
.003
Myalgia
15
12
.004
Arthralgia
25
21
< .001
Alopecia
5
3
.01
reduction in recurrence risk of 42% (P < .001) with letrozole, a significant 40% improvement in distant DFS (DDFS; P = .002), and a significant survival advantage in patients with node-positive disease (HR, 0.61; P = .04), supporting the initial decision to unblind the trial (Table 1).11,23 A more recent analysis supported the conclusion of the safety monitoring committee to unmask MA.17 early. This analysis showed support for the initial decision to release the interim analysis results and to allow patients on placebo to cross over to letrozole; patients who went on letrozole after placebo had a significantly lower risk of recurrence than patients who declined placebo (DFS: HR, 0.37, P < .0001; DDFS: HR, 0.38, P = .004; contralateral breast cancer: HR, 0.18, P < .0001).10,12,22 The benefits of extended adjuvant therapy were further confirmed in 2 trials, one using anastrozole and another using exemestane.24,25 In the NSABP B-33 trial, extended adjuvant exemestane versus placebo was investigated in patients who were disease-free after 5 years of tamoxifen.24 This trial was unblinded after enrollment of about half (N = 1598) of the planned 3000 patients after the results of NCICCTG MA.17 in 2003, which showed benefit from extended adjuvant letrozole after 5 years of tamoxifen. At the time of unblinding, the NSABP B-33 study found a significant improvement in 4-year relapsefree survival, which included local, regional, distant, and opposite breast recurrence, after 30 months (96% vs. 94%; P = .004) and, although not reaching statistical significance, a trend toward improvement in DFS, which additionally included second primary non–breast cancer and death (91% vs. 89%; P = .07) and in DDFS (HR, 0.69; P = .13).24 The Austrian Breast and Colorectal Cancer Study Group (ABCSG) compared anastrozole (n = 387) with placebo (n = 469) at 5 years of follow-up. Although this small, open-label trial (N = 856) displayed unbalanced treatment arms, significantly fewer patients in the anastrozole group experienced disease recurrence compared with patients in the placebo group (30 patients vs. 57 patients; HR, 0.62; 95% CI, 0.40-0.96; P = .0477).25 These trials, although not as robust as MA.17, lend further support to the use of AIs in the extended adjuvant setting, with letrozole remaining the only AI with this indication approved by regulatory authorities.
MA.17: Safety and Quality of Life Safety The AIs have a safety profile different from tamoxifen in that they are not associated with increased risk of serious life-threatening
Figure 1 MA.17R Re-randomization Recruitment Criteria and Protocol Stratify Previous Tamoxifen
N = 1800
Placebo
Yes or No Tamoxifen
Any Aromatase Inhibitor Letrozole
3-5 Years
5 Years
0-2 Years
5 Years
adverse events such as thromboembolism or uterine cancer.1,3,5,8,9 MA.17 was the only large, blinded trial of an AI wherein not only self-reported side effects but also their effect on QOL were evaluated against a placebo.10,11,26 Important to the interpretation of toxicity and QOL data from MA.17 is that patients were selected by virtue of having been able to complete 5 years of previous tamoxifen. Women most vulnerable to problems with endocrine therapy might therefore not be represented by the patients in this trial. With this proviso, letrozole was generally well tolerated, with overall toxicities as expected.11 The incidence of hot flashes (58% vs. 54%), myalgia (15% vs. 12%), arthralgia (25% vs. 21%), and alopecia (5% vs. 3%) occurred significantly more often in patients receiving letrozole. These adverse events were considered a result of patients’ depleted estrogen levels, and the majority of such side effects can be effectively managed.11 It is interesting to note that these side effects also were frequently experienced by patients receiving placebo, in whom the rate of arthralgia was also high. The incidence of new-onset clinical osteoporosis occurred in 8.1% of patients treated with letrozole compared with 6% of patients treated with placebo. Although there was a trend toward a numerical increase in clinical fractures in patients taking letrozole (5.3%) compared with placebo (4.6%), this difference was not statistically significant (Table 2).11 In patients treated with letrozole experiencing a fracture, median time from randomization to a fracture event was 1.06 years compared with 0.86 years for placebo-treated patients. The median time to any fracture occurrence for those receiving letrozole was 0.70 years versus 0.52 years for patients receiving placebo. To further define the effects of letrozole on skeletal health, a subset of 226 patients enrolled in MA.17 were monitored for bone mineral density (BMD) and bone turnover markers.27 Although at 12 months there was no statistically significant difference between the 2 groups, among patients remaining in the cohort at 24 months, there was a significantly greater decrease in total hip BMD among women taking letrozole (–3.6% vs. –0.71%; P = .044). Evaluation of the bone resorption marker urine N-telopeptide correlated with the BMD findings. Patients treated with letrozole had an increase in N-telopeptide at 6 months (P = .054), 12 months (P < .001), and 24 months (P = .016). However, more patients receiving placebo (10.6%) compared with letrozole (4.1%) were using bisphosphonates, which could have had a positive effect on their BMD. Another observation was that BMD scores were more likely to show a significant decrease in women who were osteopenic at the initiation of letrozole treatment than in patients with BMD within the normal range.
Clinical Breast Cancer October 2008 • 413
Extended Adjuvant Endocrine Therapy Figure 2 Schemata of Ongoing Clinical Trials Evaluating Duration of Aromatase Inhibitor Therapy NSABP B42 (N = 3840) Aromatase Inhibitor 5 Years Tamoxifen Aromatase 2-3 Years Inhibitor 2-3 Years
Tamoxifen Aromatase 2-3 Years Inhibitor 2-3 Years
Placebo (%)
P Value
Hot Flashes
22
17
.0002
Night Sweats
17
14
.047
Sweating
18
14
.003
Change in Sexual Desire
16
15
.36
Anastrozole 3 Years
Vaginal Dryness
22
19
.016
Avoidance of Intimacy
16
15
.5
Anastrozole 6 Years
Poor Memory
14
14
.73
Feeling Depressed
11
11
.96
Muscle and Joint Aches
43
39
.02
Difficulty Sleeping
29
26
.047
Weight Gain
21
22
.45
Letrozole 3-2 Years Tamoxifen 2-3 Years
Placebo 5 Years
Letrozole 5 Years
ABCSG16 SALSA (N = 3500) Aromatase Inhibitor 5 Years
Letrozole (%)
GIM4 LEAD (N = 4050)
Letrozole 5 Years
Dutch DATA (N = 1900)
Anastrozole 2 Years Tamoxifen 2-3 Years Anastrozole 5 Years
Table 3 Symptom Analysis: Percentage of Patients Being “Very Bothered” by a Specific Symptom26
Abbreviations: ABCSG = Austrian Breast and Colorectal Cancer Study Group; DATA = Different Durations of Adjuvant Anastrozole Therapy after 2 to 3 years of Tamoxifen; GIM = Gruppo Italiano Mammella; LEAD = Letrozole Adjuvant therapy Duration; NSABP = National Surgical Adjuvant Breast and Bowel Project; SALSA = Secondary Adjuvant Long-term Study with Arimidex
Symptom According to MENQOL
Abbreviation: MENQOL = Menopause Specific Quality of Life Adapted with permission from TJ Whelan et al. J Clin Oncol 2005; 23:6931-40.
The incidence of cardiovascular disease in patients enrolled in MA.17 was similar among patients in the 2 groups (5.8% letrozole vs. 5.6% placebo), as was the incidence of hypercholesterolemia (16% in both arms; Table 2).11 In the MA.17 lipid substudy, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, lipoprotein (a), and triglycerides were measured at baseline (N = 347), 6 months, 12 months, and yearly thereafter ≤ 36 months.28 The only differences between the 2 cohorts were marginally significant differences in the percentage changes in HDL cholesterol at 6 months (decreased HDL with letrozole vs. increased HDL with placebo; P = .049), in LDL cholesterol at 12 months (increased LDL with both letrozole and placebo; P = .033), and in triglycerides at 24 months (increased triglycerides with letrozole vs. decreased triglycerides with placebo; P = .036) but not at any other time points.28 These findings confirm that AI therapy with letrozole does not increase the risk of hypercholesterolemia, supporting previous findings that although AIs lack the potential cardioprotective effects of tamoxifen, they do not increase the overall risk of cardiovascular events.29 In this aging population treated with endocrine therapy, an increasing cardiovascular risk competes with recurrence as a cause of mortality, making women with cardiovascular disease more likely to die from causes not related to breast cancer.3,8,9,30 In fact, long-term followup of all survivors in the MA.17 trial demonstrated that non–breast cancer occurrences accounted for 72% of deaths among patients aged ≥ 70 years and 48% of deaths among patients aged < 70 years.31
The SF-36 evaluates 36 items, including general physical function, pain, general health, vitality, social functioning, and mental health. From this information, individual and global summary scores of physical and mental status are derived. The MENQOL assesses symptoms specifically related to menopause and estrogen depletion that might be affected by AIs.26,32,33 In the MA.17 QOL substudy, mental and physical summary scores on the SF-36 were similar between patients taking placebo and letrozole, although some small differences were noted in the bodily pain domain.26 On the MENQOL questionnaire, only the vasomotor domain showed a significant difference between groups, with 22% of the placebo group and 29% of the letrozole group reporting worsening in QOL related to vasomotor symptoms (P < .001). These symptoms improved over time for both patient groups. Together, the results demonstrated that, compared with placebo, letrozole did not have a detrimental effect on overall QOL after 36 months of treatment. Bothersome symptoms were noted by a minority of patients in the placebo and letrozole groups, and of these, only hot flashes (17% placebo vs. 22% letrozole; P = .0002) and sweating (14% placebo vs. 18% letrozole; P = .003) were significantly different between groups (Table 3).26 The incidences of night sweats, vaginal dryness, muscle and joint aches, difficulty sleeping, change in sexual desire, avoidance of intimacy, poor memory, feeling depressed, or weight gain did not differ significantly between treatment arms.
Additional MA.17 Analyses Quality of Life Analyses Although it is clear that adjuvant AI therapy results in substantial improvements in DFS and OS, the QOL associated with AI treatment is an important consideration for clinical decision-making. To address this issue, the MA.17 trial evaluated a group of healthy women free of recurrent cancer. Data were collected using 2 surveys: a general QOL instrument, the 36-Item Short-Form Health Survey (SF-36); and a symptom-specific instrument, the Menopause Specific Quality of Life (MENQOL) questionnaire.
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Several additional analyses of women enrolled in MA.17 have been conducted. A cohort analysis of all events up to the date of study unblinding by length of time on therapy showed that the HRs significantly decreased from 0.59 at 6 months to 0.19 at 48 months (P < .0001), corresponding with a 41%-81% reduction in recurrence risk over time.34 These significantly decreasing HRs achieved with letrozole for ≤ 48 months for the primary study endpoint of DFS suggest a greater benefit with letrozole the longer patients remain on therapy (Table 4).12,34-37 In this analysis, DDFS
Paul E. Goss et al Table 4 MA.17 Updated Sub-analysis Subanalysis Optimal Duration of Extended Adjuvant Letrozole34
Effect of Hormone Receptor Status35
Effect of Age36
Intent-to-Treat Analysis37
Post-Unblinding Analysis12
Number of Patients
5170 (n = 2360, node-positive)
5187 (n = 3809, ER/ PgR–positive tumors; n = 636, ER-positive/ PgR-negative tumors)
5169 (n = 2152, aged < 60 years; n = 1694, aged 60-69 years; n = 1323, aged > 70 years)
5187
2383
Median Follow-up
Key Findings*
Implications
6, 12, 24, 36, and 48 months were analyzed
DFS: significantly decreasing HRs with letrozole over time (P < .0001); DDFS: significantly decreasing HRs with letrozole over time (P = .0013); OS: significantly decreasing HRs with letrozole over time for patients with node-positive disease (P = .038)
At q 48 months, the longer the exposure to letrozole, the greater the benefit
30 Months
DFS: HR, 0.49 for ER/PgR–positive tumors; HR, 1.21 for ER-positive/PgR-negative tumors; significant treatment effect between ER/PgR–positive and ER-positive/ PgR-negative (P = .02); DDFS: HR, 0.53 for ER/PgR–positive tumors; no significant treatment effect (P = .06); OS: HR, 0.58 for ER/PgR–positive tumors; no significant treatment effect (P = .09)
Letrozole appears to have a greater benefit in tumors with a functional ER; PgR status should not be regarded as a reason for denying or prescribing adjuvant AI therapy for patients for whom it is indicated until this finding is confirmed
30 Months
4-Year DFS: significant benefit in subgroup of patients aged < 60 years (HR, 0.46; P = .0004); 4-year OS: significant benefit in subgroup of patients aged > 70 years with node-positive disease (P = .04); toxicities: no difference for letrozole vs. placebo in patients aged > 70 years; QOL at 36 months: similar for letrozole vs. placebo for patients aged > 70 years
For patients aged > 70 years in good health, letrozole has benefits similar to those in younger patients, without any significant increase in toxicity or decrease in QOL compared with placebo; older patients should also be considered for letrozole after 5 years of tamoxifen
4-Year DFS: HR, 0.68 (P = .0001); 4-year DDFS: HR, 0.80 (P = .089); 4-year OS: HR, 0.98 (P = .828); CBC annual rate: HR, 0.61 (P = .033)
Patients who were originally randomized to letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS, DDFS, and CBC despite 73% of placebo patients crossing over to letrozole after unblinding
DFS: HR, 0.37 (P < .0001); DDFS: HR, 0.38 (P = .004); OS: HR, 0.30 (P = .004); CBC: HR, 0.18 (P < .0001)
Patients can receive benefit from letrozole even if a period of time has elapsed since treatment with tamoxifen (a 5 years) and should be considered for late extended adjuvant therapy
64 Months
63.6 Months
*All hazard ratios are for letrozole versus placebo or placebo to letrozole versus placebo (for post-unblinding analysis). Abbreviations: AI = aromatase inhibitor; CBC = contralateral breast cancer; DDFS = distant disease-free survival; DFS = disease-free survival; ER = estrogen receptor; HR = hazard ratio; OS = overall survival; PgR = progesterone receptor; QOL = quality of life
showed a similar pattern of increasing superiority for letrozole over time, with the test for trend being highly significant (P < .0013). A retrospective analysis of the effect of hormone receptor status on clinical outcome with extended adjuvant letrozole was also performed. Letrozole demonstrated the greatest efficacy in women with ER/PgR–positive tumors (n = 3809), the most hormone-dependent subset.35 A significant survival benefit was also observed in this large patient population. Women in this group showed a 51% improvement in DFS compared with placebo. Those with ER-negative/ PgR-positive (n = 200) tumors also benefited, with a 44% reduction in events compared with placebo. By comparison, women (n = 636) with ER-positive/PgR-negative tumors did not appear to experience
a DFS benefit with letrozole. However, the following caveats should be considered: there were very few patients in this subgroup, the confidence interval in the ER-positive/PgR-negative subgroup for DFS was very wide (95% CI, 0.63-2.34), and the receptor levels were measured locally. Although the best outcomes were observed in the ER/PgR–positive patients, because receptor levels were measured locally rather than centrally and in light of the small number of patients in the other subgroups, the data require confirmation before PgR is incorporated into treatment decisions. The benefits of letrozole in postmenopausal women with earlystage breast cancer were independent of age.36 Benefits in DFS and DDFS were observed with letrozole in all age groups. In particular,
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Extended Adjuvant Endocrine Therapy among patients aged ≥ 70 years and in good health, the benefits of letrozole were similar to those observed in younger patients, without any increase in toxicity or decrease in QOL compared with placebo. A separate intent-to-treat (ITT) analysis, which assessed all outcomes (DFS, DDFS, OS, and contralateral breast cancer), was also performed. It did not take into account whether patients in the placebo group switched to letrozole at the unblinding of the data. This ITT analysis, which included all events before and after the unblinding, based on the original randomization of letrozole versus placebo, showed a significant benefit for women originally randomized to letrozole compared with patients initially receiving placebo at a median follow-up of 64 months.37 Furthermore, women originally randomized to letrozole within 3 months of completing tamoxifen did better than placebo patients even though 73% of placebo patients crossed over to letrozole after unblinding. This benefit was noted for DFS (P = .0002), DDFS (P = .041), and contralateral breast cancer (P = .037). An additional post-unblinding analysis also showed the benefit of late extended adjuvant letrozole. When MA.17 was unblinded in 2003, most patients who were receiving letrozole chose to continue their 5 years of planned therapy. Patients who had been receiving placebo were given the chance to switch to letrozole: about two thirds of patients treated with placebo (n = 1579) crossed over to letrozole, but 804 patients decided to be followed annually and not receive treatment.12,38,39 This analysis was performed after a median follow-up of 63.6 months in all patients who had a recurrence or died before unblinding or discontinued treatment because of any toxicity. The 2 groups studied also had different baseline characteristics, with the women electing to switch to letrozole at increased risk for disease recurrence (ie, younger age, node-positive disease, previous chemotherapy). The multivariate analysis was adjusted for all known risk factor imbalances. Efficacy results from the post-unblinding analysis showed that patients who received late extended adjuvant letrozole experienced a significant reduction in DFS (HR, 0.37; P < .0001), DDFS (HR, 0.38; P = .004), risk of contralateral breast cancer (HR, 0.18; P = .004), and an improvement in OS (HR, 0.30; P < .0001) despite a gap between the completion of tamoxifen and the initiation of letrozole. Safety analysis after unblinding was comparable to that observed in the main trial. In patients who received late extended adjuvant letrozole, there was an increased incidence of osteoporosis (self-reported; 5.3% vs. 1.6%) and fractures (5.2% vs. 3.1%) but no increase in the incidence of cardiovascular events (4.2% vs. 3.1%).12
Ongoing Trials of Extended Adjuvant Aromatase Inhibitor Therapy To determine whether adjuvant AI therapy for > 5 years is superior to AI therapy for 5 years, a randomized, placebo-controlled trial (MA.17R) is being conducted (Figure 1). This trial randomizes women completing 5 years of any AI (after any duration of previous tamoxifen or no previous tamoxifen) to 5 more years of letrozole or placebo. This trial includes women who completed 5 years of letrozole after 5 years of tamoxifen in the original MA.17 trial.29,40,41 Disease stratification includes receptor status (positive vs. unknown), lymph node status (negative, positive, unknown), previous adjuvant chemotherapy (yes or no), interval between last dose of AI and randomization (< 6 months, 6 months, 2 years), and duration of tamoxifen use (0 years, < 2 years,
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2-4.5 years, > 4.5 years).41 Companion translational studies in this trial will examine whether common genetic single nucleotide polymorphisms for genes encoding proteins involved in the pharmacokinetic and/or pharmacodynamic pathways for letrozole contribute to a variation in toxicity and efficacy of letrozole in individual patients. In addition to the extension of MA.17, several other trials are under way to determine the optimal duration of AI therapy (Figure 2). The NSABP B-42 trial will examine specifically whether 10 years of endocrine therapy is superior to 5 years. Women who have completed 5 years of endocrine treatment with any AI, or 2-3 years of tamoxifen, followed by 2-3 years of AI, will be randomized to receive letrozole for an additional 5 years versus placebo.42 In a similar trial using anastrozole (ABCSG 16; SALSA [Secondary Adjuvant Long-term Study in Arimidex®]), > 1700 postmenopausal patients (of a total 3500) who have been free of breast cancer recurrence after approximately 5 years of any endocrine therapy have already been enrolled. Patients are randomized to receive 2 years or 5 years of extended adjuvant anastrozole. The primary outcome measure is DFS, and assessments of OS and fracture rates are planned.43,44 Two additional trials will evaluate letrozole use in patients treated with 2-3 years of tamoxifen after primary resection. In the LEAD (LEtrozole Adjuvant therapy Duration) study, patients will be randomized to receive shorter-term letrozole for 2-3 years or letrozole for 5 years.45 In a similar population, the Dutch DATA (Different Durations of Adjuvant Anastrozole Therapy after 2 to 3 years of Tamoxifen) trial will analyze differences between 3 years and 6 years of anastrozole in postmenopausal women with hormone-sensitive breast cancer.46 A primary endpoint of DFS has been established for both trials.
Conclusion In women with early-stage hormone receptor–positive breast cancer, the risk of disease recurrence is highest after 5 years, with the most common and serious late relapse event being distant metastases. This risk is observed in patients treated with tamoxifen and in untreated patients. The MA.17 trial has demonstrated that extended adjuvant letrozole allows patients to further reduce their risk of relapse following 5 years of tamoxifen. Extended adjuvant letrozole significantly reduced the risk of recurrence by 42% and distant metastases by 40%. These results from the MA.17 trial have led to the approval of letrozole as the only approved extended adjuvant therapy. All current guidelines support the use of letrozole as an extended adjuvant therapy,47,48 and results from the MA.17 cohort analysis show that the longer the use of letrozole, the greater the benefit (≥ 4 years).34 When considering extended adjuvant therapy after the completion of tamoxifen, clinicians and patients should consider the residual risk of recurrence and individual patient preferences.47 The MA.17 results clearly show that the benefit of extended adjuvant letrozole is observed irrespective of nodal status and that the option of extended adjuvant therapy should be discussed with all patients completing tamoxifen. MA.17 post-unblinding results show that women with hormonedependent breast cancer who were prescribed letrozole following a prolonged delay after completing tamoxifen also experienced a significant improvement in outcomes. Women who have not been given letrozole immediately after completing tamoxifen should be
Paul E. Goss et al considered candidates for late extended adjuvant therapy. Of note, AIs and tamoxifen are now appropriate choices for initial adjuvant therapy for postmenopausal women with hormone-sensitive breast cancer.48 For patients who have received initial adjuvant tamoxifen, extended adjuvant and late extended adjuvant letrozole therapy offers an opportunity for further protection against late relapses. The results of the MA.17R re-randomization trial and others, including NSABP B-42, will build upon current information and help determine the optimal duration of AI therapy for women with hormone receptor–positive breast cancer.
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