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Originally published as JCO Early Release 10.1200/JCO.2007.12.6334 on March 10 2008 © 2008 American Society of Clinical Oncology. 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
From the University of Vermont Cancer Center, Burlington, VT; National Cancer Institute of Canada Clinical Trials Group, Queens University, Kingston; McMaster University, Hamilton; Toronto Sunnybrook Health Sciences Center and the University of Toronto, Toronto, Ontario, Canada; Mayo Clinic Cancer Center, Rochester, MN; Angeles Clinic and Research Institute, Santa Monica CA; Cancer Center, Inova Fairfax Hospital, Fairfax, VA; Oncology, Jules Bordet Cancer Institute, Brussels, Belgium; and Massachusetts General Hospital Cancer Center, Boston, MA Corresponding author: Hyman B. Muss, MD, University of Vermont College of Medicine, 1 South Prospect St, Saint Joseph 3400, Burlington, VT 05401; e-mail: hyman.muss{at}uvm.edu
Purpose: National Cancer Institute of Canada Clinical Trials Group trial MA.17 randomly assigned 5,187 postmenopausal, hormone-receptor–positive patients with early breast cancer who completed 5 years of tamoxifen to receive either letrozole or placebo. At 30 months median follow-up, letrozole significantly improved disease-free survival (DFS) in all patients and overall survival (OS) in node-positive patients. Breast cancer incidence increases with age and more than 1,300 women age 70 years or older were enrolled onto MA.17, making it ideal to explore the benefits, toxicities, and quality of life (QOL) impact of letrozole on older women.
Patients and Methods: In this study, 5,169 randomly assigned patients were divided into three age groups: younger than 60 years (n = 2,152), 60 to 69 years (n = 1,694), and
Results: At 4 years, DFS demonstrated statistically significant differences favoring letrozole only in patients age younger than 60 years (hazard ratio = 0.46; P = .0004); there was no interaction between age and treatment, indicating a similar effect of letrozole among all age groups. There was no difference in toxicity or QOL at 24 months among letrozole- and placebo-treated patients age Conclusion: Healthy patients age 70 years and older completing 5 years of tamoxifen should be considered for extended adjuvant therapy with letrozole.
In the United States, breast cancer incidence and mortality rates rise dramatically with age, and today most women who die of breast cancer are 65 years or older. While the risk of breast cancer is about 1 in 230 for women younger than 39 years old, it rises to 1 in 13 for women between 60 to 79 years of age.1 Extensive data indicate that older age is frequently associated with poorer treatment that can lead to shortened survival.2-4 Life expectancy has dramatically improved in North America, and in the United States the average life expectancy for a woman is now 80 years. Tumor biology in older women is more favorable than in younger patients, but after adjusting for stage, mortality rates are similar among older and younger women except for those younger than age 35 years and older than age 80 years; the latter groups have poorer survival rates.5 At least 70% to 80% of women 65 years or older have hormone-receptor–positive breast cancers, and in this group, the use of adjuvant tamoxifen therapy has significantly improved disease-free survival (DFS) and overall survival (OS).6 However, even in women taking tamoxifen for 5 years, more than half of all breast cancer relapses occur between 5 and 15 years,6 and at least two large trials have failed to show benefit for tamoxifen therapy exceeding 5 years.7-9 Ongoing trials are still exploring the optimal duration of tamoxifen use (see www.cancer.gov for details of Adjuvant Tamoxifen Longer Against Shorter and CRC-TU-Adjuant Treatment Tamoxofen Offers More trials), but at present most clinicians limit treatment to 5 years. Aromatase inhibitors (AIs) have emerged as highly effective endocrine therapies in postmenopausal patients, decreasing relapse rates by approximately 3% when compared with tamoxifen; survival, however, has not been convincingly improved in these trials but follow-up is still short.10-13 Because of the high relapse rate after 5 years of tamoxifen therapy, we designed National Cancer Institute of Canada Clinical Trials Group trial (NCIC CTG) MA.17 to test the efficacy of the AI letrozole in postmenopausal patients who were disease free after 5 years of tamoxifen. At 30 months median follow-up, the hazard ratio (HR) for letrozole compared with placebo-treated patients on NCIC CTG MA.17 was 0.58 (95% CI, 0.45 to 0.76; P = .00004) for DFS, and 0.60 (95% CI, 0.43 to 0.84; P = .002) for distant-disease–free survival (DDFS). OS was significantly improved for letrozole patients in the node-positive (HR = 0.61, range, 0.38 to 0.98; P = .04) but not in the node-negative cohort.14
Currently, a 65-year-old woman in average health can expect to live another 20 years, a 75-year-old woman can expect to live 13 more years, and an 85-year-old woman can expect to live another 7 more years.15 Little data are available on older patients treated with adjuvant AIs. More than 1,300 patients age
Study Design Details of the study design, eligibility criteria, and the patient population of the NCIC CTG Intergroup trial MA.17 have been previously described.14,17 This trial was a phase III, randomized, double-masked, placebo-controlled trial, the primary objective of which was to determine the efficacy of letrozole in preventing disease recurrence in postmenopausal women with primary breast cancer who had completed about 5 years (range, 4.5 to 6 years) of adjuvant tamoxifen. Patients were randomly allocated to letrozole (2.5 mg by mouth daily) or placebo for 5 years and stratified by hormone-receptor status, nodal involvement, and chemotherapy use. In accordance with the protocol-specified guidelines, MA.17 was terminated in 2003 on the recommendation of the data and safety monitoring committee after the first interim analysis demonstrated a statistically significant effect on DFS for patients treated with letrozole as compared with placebo.17
Detailed QOL analyses, also part of this trial, have been published previously.16 Eligibility for the QOL substudy included willingness to complete QOL questionnaires before randomization and fluency in English or French. QOL was measured using the Medical Outcomes Short Form 36-item general health questionnaire (SF-36), a multipurpose QOL measure. SF-36 contains eight subscales (domains), which are summarized into two global scores, the physical and mental component summary (PCS and MCS).18 The eight subscales include physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The instrument has been used extensively in cancer and noncancer populations, and is scored from 0 to 100, with a higher number representing a higher QOL. The PCS and MCS are normalized so that the mean score for a representative sample of the US female population is 50, with a standard deviation of 10. The Menopause-Specific QOL Questionnaire (MENQOL) was chosen specifically to assess menopausal related symptoms that might be worsened by the use of AIs.19 It contains 29 items under four domains (vasomotor, psychosocial, physical, and sexual). The instrument scoring for the MENQOL ranges from 1 to 8, with the higher numbers representing greater symptom discomfort and less favorable QOL. Both instruments have been shown in previous studies to be valid, reliable, and sensitive to change. The instruments were administered before randomization, at 6 months postrandomization, and then yearly. In this unplanned subset analysis that focuses on age, women randomly assigned onto MA.17 were divided into one of the following three age groups: younger than 60 years, 60 to 69 years, and
Patient Population
Statistical Analysis
The study group totaled 5,187 randomly assigned patients, but due to noncompliance with the Good Clinical Practice Guidelines, 17 patients (10 receiving letrozole and seven receiving placebo), all from one center, were excluded from all analyses. Of the 5,170 patients remaining, one had age information missing and was excluded, leaving 5,169 patients for these analyses. Twenty-one patients (seven randomly assigned to letrozole and 14 to placebo) never received study medication, and the safety analysis therefore included 5,149 patients. The median follow-up of patients was 30 months, with a range of 1.5 to 61.4 months. The median age of patients enrolled onto the trial was 62 years, with a range of 32 to 95 years. Of the 5,169 patients, 2,152 (42%) were younger than 60 years, 1,694 (33%) were 60 to 69 years, and 1,323 (26%) were  70 years of age. Among those 70 years and older, 54% (712 patients) were age 70 to 74 years, 31% (411 patients) were age 75 to 79 years, 12% (164 patients) were age 80 to 84 years, and 3% (36 patients) were 85 years of age. Table 1 lists key baseline patient and disease characteristics based on age groups. Both univariate and multivariate analyses demonstrate that a higher proportion of younger women had better performance status, positive lymph nodes, chemotherapy, and lumpectomy or segmental mastectomy. Discontinuation of treatment due to either refusal of further treatment, toxicity, or other reasons was noted in 24% of older patients and was higher than in younger patients (18% of those 60 years and younger, and 19% of those 61 to 69 years; P = .0003), but there were no differences in the percent of older patients who discontinued treatment in the letrozole or placebo groups (24% v 23%; P = .63). In those younger than 60 years of age, significantly more patients receiving letrozole discontinued treatment for toxicity (5% letrozole v 3% placebo; P = .008), whereas more patients receiving placebo discontinued treatment for other reasons (3% letrozole v 5% placebo; P = .03); refusal was 10% for both the letrozole and placebo groups. Among those 60 to 69 years and 70 years of age, there was no difference in the reasons for treatment discontinuation among the letrozole and placebo arms.
Table 2 lists estimates of 4-year DFS, DDFS, and OS by age group. There was no significant difference in DFS and DDFS between the three age groups. As expected, the OS was significantly different between these three age groups due to an increased risk of non–breast cancer-related death with increasing age. The results remain the same after adjusting for other potential prognostic factors such as letrozole or placebo treatment, duration of prior tamoxifen, nodal status, and prior chemotherapy. Table 3 lists the 4-year estimates for the comparison between letrozole and placebo for DFS, DDFS, and OS within each of the three age subgroups and by lymph node status. Figure 1 shows the Kaplan-Meier estimates for DFS and OS by treatment and age. Although statistically, letrozole significantly improved both DFS and DDFS only in women younger than 60 years of age, the interaction between age and treatment was not statistically significant for any of these three outcomes (P = .36, 0.77, and 0.98 for DFS, DDFS, and OS, respectively), indicating no evidence of a heterogeneous effect of letrozole among age groups. Letrozole significantly improved DFS compared with placebo for both node-negative and node-positive patients younger than 60 years and for patients with negative nodes 70 years old. In node-positive patients, letrozole compared with placebo led to a significant improvement in DDFS in those age 60 to 69 years, and a significant improvement in OS for those age 70 years.
Toxicity data are summarized in Table 4 and include any reported adverse event with a 1% or greater difference among the letrozole and placebo groups or noted in 5% or more of either group. The vast majority of reported toxicities were grade 1 and grade 2 (data not shown). As a group, women 70 years of age had significantly higher incidences of edema, hypertension, fatigue, anorexia, constipation, diarrhea, arthritis, dizziness, and dyspnea but lower incidences of hot flushes, sweating, vaginal bleeding, high cholesterol, insomnia, headache, and vaginal dryness compared with younger women. Compared with placebo, women receiving letrozole who were younger than 60 years had a significantly lower incidence of vaginal bleeding and higher incidence of arthralgia; women receiving letrozole who were age 60 to 69 years had a statistically significantly higher incidence of hot flushes, insomnia, arthralgia, and alopecia. In women 70 years of age there was no significant difference in toxicities between the letrozole and placebo groups. Unrelated to treatment, women 70 years of age had significantly higher incidences of fracture, new osteoporosis, and cardiac disease (data not shown). However, in this age group there were no significant differences between the two treatment groups in fractures (6% letrozole v 8% placebo), the development of osteoporosis (10% letrozole v 8% placebo), or cardiac disease (10% letrozole v 11% placebo).
The QOL analyses by treatment and age for the eight dimensions and two overall scales (physical and mental overall) in the SF-36 and four domains in the MENQOL are summarized in Table 5 for women 70 years of age and after 24 months of follow-up. Although fewer women completed follow-up QOL assessments, compliance rates from our previous QOL analysis16 indicate that they represented approximately 90% of women who were expected to complete these assessments. Women age 70 years and older who received letrozole had significantly worse QOL versus those receiving placebo on the vitality score at 6 months (–5.6 v –3.5; P = .03), and in bodily pain (–3.2 v –7.6; P = .01), physical scale (–1.3 v –3.3; P = .009), and MENQOL vasomotor domain (0.03 v –0.37; P = .001) at 12 months. The only significant difference in QOL at 24 months for the age group 70 years and older was increased MENQOL vasomotor symptoms (0.07 v –0.3; P = .02), which became similar to placebo at 36 months (–0.3 v –0.4; P = 1.0). For the SF-36 domains, the differences observed ranged between 2 and 4 points on a 100-point scale, or 0.1 and 0.2 of a standard deviation. For the MENQOL domains, the differences observed were 0.4 points on a 7-point scale, or less than 0.3 of a standard deviation.
Although letrozole was found to be significantly better than placebo for both DFS and DDFS only in women younger than 60 years, and numerical estimates in Tables 2 and 3 indicate that the benefits in terms of DFS and DDFS are greatest in the younger group, there was no statistically significant interaction between age and treatment for DFS, DDFS, or OS, indicating that the effect of letrozole is homogenous among age groups. Moreover, MA.17 showed an OS advantage for all node-positive patients. In this age-directed subset analysis, only node-positive patients age 70 years had significant improvements in OS without significant improvements in DFS and OS—an observation likely due to chance. Overall, our data do suggest that healthy elders should be considered for extended adjuvant endocrine therapy as they are more likely to have both hormone-receptor positive and lower grade tumors.20,21
It has been shown that younger postmenopausal women experience a higher frequency of menopausal symptoms with endocrine therapy than older postmenopausal women.22 In women age QOL for older patients on this trial was initially poorer in those receiving letrozole but only a mild increase in vasomotor symptoms for letrozole-treated patients was noted at 36 months. This is noteworthy because for all patients on this trial, our prior analysis showed a significant worsening in QOL for patients who experienced bodily pain (51% letrozole v 47% placebo) or vasomotor symptoms (29% letrozole v 22% placebo).16 Discontinuation of treatment was noted in 24% of older patients and was significantly higher than in younger patients, but there was no difference in the percent of older patients who discontinued treatment in the letrozole or placebo groups. It is well understood that comorbidity increases with age.25 As age increases, the likelihood of dying of a nonbreast cancer cause increases irrespective of breast cancer stage.26 It is most likely that the higher rate of treatment discontinuation for older women in this trial was due to the development or worsening of other serious illness that minimized the risk of breast cancer relapse and led to discontinuation of treatment. The decision to use letrozole after 5 years of tamoxifen therapy is an important one, and requires a frank discussion between the patient and health care provider. Many older patients with life expectancies of more than 5 years, if offered letrozole, are likely to take it for a small percentage reduction in the chance of relapse. Our data show no interaction between the benefits of letrozole and age, and for patients 70 years or older there is no increase in any reported toxicities compared with placebo. QOL assessment in these older patients showed only a modest decrease with letrozole treatment compared with placebo, and these changes are not likely to have a major effect on function. In summary, letrozole was well tolerated by older women in this trial, and healthy older patients who have completed 5 years of tamoxifen should be considered for extended adjuvant endocrine therapy with letrozole.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: James N. Ingle, AstraZeneca (C), Novartis (C), Pfizer Inc (C); Martine J. Piccart, Novartis (C); Kathleen I. Pritchard, Sanofi-aventis (C), AstraZeneca (C), Roche (C), Pfizer Inc (C), Ortho Biotech (C), YM BioSciences (C), Biomira (C), Novartis (C), Aegera Therapeutics (C); Paul E. Goss, Novartis (C) Stock Ownership: None Honoraria: Martine J. Piccart, Novartis; Kathleen I. Pritchard, Sanofi-aventis, AstraZeneca, Pfizer Inc, Roche, Aegera Therapeutics, YM BioSciences, Novartis Research Funding: Nicholas J. Robert, Novartis; Martine J. Piccart, Novartis; Kathleen I. Pritchard, AstraZeneca, YM BioSciences, Bristol-Myers Squibb Co, Sanofi-aventis, Amgen, Ortho Biotech, Pfizer Inc, Novartis; Paul E. Goss, Novartis Expert Testimony: Kathleen I. Pritchard, Sanofi-aventis (C), AstraZeneca (C) Other Remuneration: None
Conception and design: Hyman B. Muss, Paul E. Goss Administrative support: Joseph L. Pater, Michael J. Palmer Collection and assembly of data: Hyman B. Muss, Dongsheng Tu, James N. Ingle, Joseph L. Pater, Timothy J. Whelan, Michael J. Palmer, Lois E. Shepherd, Zhi He, Paul E. Goss Data analysis and interpretation: Hyman B. Muss, Dongsheng Tu, James N. Ingle, Silvana Martino, Nicholas J. Robert, Joseph L. Pater, Timothy J. Whelan, Michael J. Palmer, Martine J. Piccart, Lois E. Shepherd, Kathleen I. Pritchard, Zhi He, Paul E. Goss Manuscript writing: Hyman B. Muss, Dongsheng Tu, James N. Ingle, Silvana Martino, Nicholas J. Robert, Joseph L. Pater, Timothy J. Whelan, Michael J. Palmer, Martine J. Piccart, Lois E. Shepherd, Kathleen I. Pritchard, Zhi He, Paul E. Goss Final approval of manuscript: Hyman B. Muss, Dongsheng Tu, James N. Ingle, Silvana Martino, Nicholas J. Robert, Joseph L. Pater, Timothy J. Whelan, Michael J. Palmer, Martine J. Piccart, Lois E. Shepherd, Kathleen I. Pritchard, Zhi He, Paul E. Goss
published online ahead of print at www.jco.org on March 10, 2008. Presented in part at a poster-discussion at the San Antonio Breast Cancer Symposium, December 14, 2006, San Antonio TX. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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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 365:1665-1666, 2005[CrossRef][Medline] 7. Stewart HJ, Prescott RJ, Forrest AP: Scottish adjuvant tamoxifen trial: A randomized study updated to 15 years. J Natl Cancer Inst 93:456-462, 2001 8. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor- positive tumors. J Natl Cancer Inst 88:1529-1542, 1996 9. Delozier T, Spielmann DT, 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 94:S10, 2005 (abstr 14) 10. 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 365:60-62, 2005[CrossRef][Medline] 11. Coates AS, Keshaviah A, Thurlimann B, et al: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: Update of study BIG 1-98. J Clin Oncol 25:486-492, 2007 12. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004 13. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2006[CrossRef] 14. 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 97:1262-1271, 2005 15. National Center for Health and Statistics: Tables on trends in health and aging; life expectancy. http://www.cdc.gov 16. 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 23:6931-6940, 2005 17. 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 349:1793-1802, 2003 18. Ware JE, Kosinski M, Keller SD: SF-36 Physical and Mental Summary Scales: A Users Manual (ed 3). Boston, MA, The Health Institute, New England Medical Center, 1994 19. Hilditch JR, Lewis J, Peter A, et al: A menopause-specific quality of life questionnaire: Development and psychometric properties. Maturitas 24:161-175, 1996[Medline] 20. Diab SG, Elledge RM, Clark GM: Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 92:550-556, 2000 21. Daidone MG, Coradini D, Martelli G, et al: Primary breast cancer in elderly women: Biological profile and relation with clinical outcome. Crit Rev Oncol Hematol 45:313-325, 2003[Medline] 22. Day R: Quality of life and tamoxifen in a breast cancer prevention trial: A summary of findings from the NSABP P-1 study—National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci 949:143-150, 2001 23. Chien AJ, Goss PE: Aromatase inhibitors and bone health in women with breast cancer. J Clin Oncol 24:5305-5312, 2006 24. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003 25. Yancik R, Wesley MN, Ries LA, et al: Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 285:885-892, 2001 26. Schairer C, Mink PJ, Carroll L, et al: Probabilities of death from breast cancer and other causes among female breast cancer patients. J Natl Cancer Inst 96:1311-1321, 2004 Submitted May 15, 2007; accepted October 17, 2007. Related Articles
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to perform univariate analyses for the association between age groups and binary variables such as a clinical characteristic, discontinuation of treatment, and toxicities, and the analysis of variance to perform multivariate analyses to identify independent characteristics associated with age. For the time-to-an-event variable, the log-rank test was used to compare the difference between age or treatment groups, and the Cox model was used to estimate the HRs and associated 95% CIs. All P values are two-sided. 
