Annals of Oncology Advance Access originally published online on August 25, 2006
Annals of Oncology 2006 17(11):1637-1643; doi:10.1093/annonc/mdl177
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© 2006 European Society for Medical Oncology
breast cancer |
Clinical outcomes of ethnic minority women in MA.17: a trial of letrozole after 5 years of tamoxifen in postmenopausal women with early stage breast cancer
1 Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
2 National Cancer Institute of Canada Clinical Trials Group, Kingston, ONT, Canada
3 Mayo Clinic, Rochester, MN, USA
4 McMaster University, Hamilton, ONT, Canada
* Correspondence to: Dr B. Moy, MPH, Massachusetts General Hospital, Gillette Center for Women's Cancers, 55 Fruit Street, YAW 9A, Boston, MA 02114, USA. Tel: +1 (617) 724-6975; Fax: +1 (617) 724-3166. E-mail: bmoy{at}partners.org
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Abstract |
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 Top Abstract introductionpatients and methodspatientsresultsdiscussionReferences |
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Background: Aromatase inhibitors are widely employed in the adjuvant treatment of early stage breast cancer. The impact of aromatase inhibitors has not been established in ethnic minority women.
Patients and methods: The purpose of this study was to evaluate the impact of letrozole on minority women in MA.17, a placebo-controlled trial of letrozole following 5 years of tamoxifen in postmenopausal women with early stage breast cancer. Retrospective comparison of disease-free survival (DFS), side effects, and mean changes in quality of life (QOL) scores from baseline between Caucasian and minority women was performed.
Results: Minority (n = 352) and Caucasian (n = 4708) women were analyzed. There was no difference between these groups in DFS (91.6% versus 92.4% respectively for 4 year DFS). Letrozole, compared with placebo, significantly improved DFS for Caucasians (HR = 0.55; P < 0.0001) but not for minorities (HR = 1.39; P = 0.53). Among women who received letrozole, minorities had a significantly lower incidence of hot flashes (49% versus 58%; P = 0.02), fatigue (29% versus 39%; P = 0.005), and arthritis (2% versus 7%; P = 0.006) compared with Caucasians. Mean change in QOL scores for minority women who received letrozole demonstrated improved mental health at the 6-month assessment (P = 0.02) and less bodily pain at the 12-month assessment (P = 0.046).
Conclusion: Letrozole improved DFS in Caucasians but a definite benefit in minority women has not yet been demonstrated. Minority women tolerated letrozole better than Caucasians in terms of toxicity. These results need confirmation in other trials of aromatase inhibitors.
Key words: early breast cancer, aromatase inhibitors, minority race, ethnicity
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introduction |
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TopAbstractintroductionpatients and methodspatientsresultsdiscussionReferences |
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A major advance over the last few decades in the treatment of women with hormone receptor positive breast cancer has been the use of adjuvant tamoxifen. Recently, several studies have demonstrated that adjuvant aromatase inhibitors which deplete extra-gonadal peripheral estrogen synthesis, result in substantial improvement in disease-free survival in postmenopausal women with operable breast cancer [1–4]. One such study, MA.17, is a placebo-controlled trial of the aromatase inhibitor letrozole given for 5 years to postmenopausal women who were disease-free after approximately 5 years of initial tamoxifen [3]. After a median follow-up of 30 months, letrozole resulted in a significant improvement in disease-free survival (DFS) and distant disease-free survival (DDFS) and an overall survival (OS) benefit in women with node-positive disease. Letrozole caused predictable symptoms of estrogen depletion including hot flashes and urogenital symptoms but had no adverse effects on lipid profiles and patient reported overall mental and physical quality of life (QOL) after 36 months of treatment compared with placebo [5–8].
Based on the results of MA.17 and other trials of aromatase inhibitors in early stage breast cancer, chronic aromatase inhibitor therapy, in otherwise healthy postmenopausal women free of breast cancer recurrence, is now being widely employed. Because most women currently being treated will not experience recurrence of their cancer and because of the cost associated with long-term treatment, attention is now focusing on the identification of women who most need therapy and who are most vulnerable to unwanted side effects and end-organ toxicities. Recently characterized genetic polymorphisms in the aromatase gene and pharmacogenomic differences between individuals leads to the hypothesis that both tumor and host factors may effect response to the inhibitors [9]. One important surrogate marker of host genotypic variation is race. Large ethnic variations in allele frequencies and types in the aromatase gene have been identified between Caucasian Americans, African Americans, Han-Chinese, and Mexican Americans [9]. While the results of MA.17 have changed clinical practice widely, the impact of chronic letrozole therapy after tamoxifen specifically in women of minority races and ethnicities has not been studied.
Breast cancer and its outcome are known to be different in African American than in Caucasian women. African American women have proportionately fewer estrogen receptor-positive tumors and they more commonly develop tumors with unfavorable biologic parameters such as high nuclear grade and high S-phase fraction [10–12]. Despite an improved survival for breast cancer patients over the last 30 years, the disparity in breast cancer survival between African Americans and Caucasians has not improved [13]. There are no specific data about the efficacy and safety of breast cancer therapy, including endocrine therapy, in minority women [14–17]. Minority participation in cancer clinical trials has historically been poor, and therefore, insufficient data exist to draw definitive conclusions about clinical outcomes in this population. Suboptimal anticancer treatment due to premature termination of adjuvant chemotherapy is thought to compromise survival benefits in African American women [18]. The baseline pattern of menopausal symptoms in African American women as well as organ functions that are dependent in part on estrogen such as bone metabolism, cardiovascular status and urogenital function may be different from that in Caucasians [19, 20]. Ethnic factors may also influence the pharmacokinetics and dynamics of aromatase inhibitors. Genetic polymorphisms may cause different baseline incidence of menopausal symptoms in minorities and genetic pharmacogenomic differences may influence response and toxicities to treatment. Thus ethnicity may play a pivotal role in the response to aromatase inhibitors [21]. In this analysis of MA.17, we compared both efficacy and toxicity of letrozole in MA.17 between Caucasian women and women of minority race and ethnicity. Efficacy of letrozole was assessed in terms of disease-free survival, and tolerability in terms of major toxicities and quality of life.
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patients and methods |
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TopAbstractintroductionpatients and methodspatientsresultsdiscussionReferences |
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design
Details of the methods used in the MA.17 trial have been published previously [3]. From August 1998 to September 2002, postmenopausal women with primary breast cancer who had completed approximately 5 years of adjuvant tamoxifen were randomly assigned in a double-blind manner to receive daily oral letrozole 2.5 mg or placebo for 5 years. The multicenter trial involved the following cooperative groups: National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), Southwest Oncology Group, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, North Central Cancer Treatment Group, European Organization for Research and Treatment of Cancer, and the International Breast Cancer Study Group. Women were stratified according to tumor hormone receptor status (positive or unknown), lymph node status (negative, positive, or unknown), and whether they had received prior adjuvant chemotherapy. All patients provided written informed consent and the ethics review board of each participating institution approved the study protocol. The primary end point for the trial was disease-free survival, defined as time from randomization to recurrence of breast cancer in the breast, chest wall, regional nodes, or distant metastasis or a contralateral new primary breast cancer. Secondary end points included overall survival, morbidity, and quality of life. On the advice of the data safety and monitoring committee, the study medication was unblinded in October 2003 when the first interim analysis showed a highly significant improvement in disease-free survival (HR 0.57; P = 0.00008) [3].
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patients |
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Women were eligible for the trial if they were postmenopausal as defined by previously published criteria [3]. Other eligibility criteria included previous adjuvant tamoxifen therapy lasting 4.5 to 6 years, histologically confirmed diagnosis of primary hormone-positive breast cancer with no evidence of metastatic disease, discontinuation of tamoxifen less than 3 months before enrolment, Eastern Cooperative Oncology Group performance status of 0 to 2, and a life expectancy of more than 5 years. Exclusion criteria included concomitant treatment with hormone replacement therapy or a selective estrogen receptor modulator. Intermittent treatment with vaginal estrogens, alternative medicines, and bisphosphonates were permitted. In accordance with standard procedures of the NCIC CTG, eligible women of all ethnicities were approached to participate in the trial but no subcommittee was appointed or effort made to specifically solicit women of ethnic minority. Race/ethnicity status was usually assessed by the clinical research team, although, in some cases, was self-reported by the study participant.
study procedures
Study participants were assessed at one month, through telephone interviews, for compliance and side effects. Clinical evaluation, routine blood work, and evaluation of toxicities were performed semi-annually during year 1 and annually thereafter; mammography was performed annually throughout the study. At baseline, women reported previous diagnoses of bone fractures, osteoporosis, or cardiovascular disease. Subsequently, new diagnoses were reported by women at follow-up visits. Importantly, no specific verification of these diagnoses was undertaken. Baseline adverse events, including symptoms of menopause, were assessed according to the Common Toxicity Criteria of the National Cancer Institute (version 2.0) and documented by the study clinical trial coordinator. Treatment was discontinued if there was recurrence of breast cancer or other serious intercurrent illness developed. Unacceptable side effects, or a request by the patient also resulted in cessation of study medication. SF-36 and Menopause Specific Quality of Life (MENQOL) questionnaires were completed by a subgroup of women [22–24]. Participation in the QOL questionnaires was part of the eligibility criteria for the main trial for all NCIC CTG centers unless patients were unable to complete questionnaires because of illiteracy, loss of sight, or other equivalent reasons. Participation was optional for patients enrolled through other cooperative groups. Recurrence of disease was defined pathologically or on the basis of clinical or radiologic findings, and recurrences were dated at the time they were first detected. Of the 5187 women randomized in MA.17 trial, 3612 (69.6%) participated in the QOL subprotocol.
statistical methods
Disease-free survival was the primary efficacy end point of this analysis. For the analysis of disease-free survival, data for the women who died without a recurrence of breast cancer or a new diagnosis of contralateral primary breast cancer were censored at the date of death. The log-rank test and the Cox regression model were used for the comparison of the treatment and racial groups in terms of disease-free survival [25]. The following covariates were included in the Cox regression model: age (<65 years versus 
65 years), treatment (letrozole versus placebo), duration of prior tamoxifen (
5 years versus >5 years), geographic location (US versus Canada and Europe), t-stage (1 versus others), nodal status (negative versus positive), prior treatment modality (surgery only versus surgery and other treatments), number of comorbidities (none versus at least one), menopausal status at start of tamoxifen (50 years of age versus others), prior chemotherapy (yes versus no). The chi-square test was used for the comparison of the groups in terms of the rates of side effects. The Wilcoxon rank sum test was used to compare mean change of quality-of-life scores from baseline and to compare racial groups.
The SF-36 QOL measure contains eight subscales or domains, which are summarized into two global scores: the physical and mental component summary (PCS and MCS) scores. The results of the two summary scores provide a global indicator of patients' quality of life. Additional details on specific QOL aspects may be ascertained using the individual eight subscales or domains, which include physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health.
All reported P values are two-sided.
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results |
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TopAbstractintroductionpatients and methodspatientsresultsdiscussionReferences |
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A total of 5187 patients were randomized on MA.17. One participating site did not fully comply with Good Clinical Practice guidelines and all 17 patients from this site were excluded from all analyses. Of the 5170 remaining patients, 462 (8.9%) were identified as of minority ethnic origin, not Caucasian. 179 (3.5%) women were black, 77 (1.5 %) were Hispanic, 73 (1.4%) were Asian or Pacific Islander, 23 (0.4%) were native North American or Native Alaskan, 31 (0.6%) were categorized as ‘other’, 44 (0.9%) were categorized as ‘unknown,’ and 35 (0.7%) had missing ethnic data. Women whose race was identified as ‘other,’ ‘unknown,’ or missing were excluded from the analyses, leaving 352 minority women in total.
Baseline patient and disease characteristics are presented in Table 1. Fewer minority women had been treated with chemotherapy. Most of the minority women lived in the United States. Tumor size and nodal status were not significantly different between minority and Caucasian women.
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Prior treatments and major medical problems prior to entering the study are presented in Table 2. Slightly more minority women were treated by surgery only, with chemotherapy or both chemotherapy and radiotherapy. Statistically significantly more minority women had hypertension and diabetes but more Caucasian women had thyroid disease.
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Tables 3 and 4 present the results related to disease free survival (DFS), the primary endpoint of the study: The 4 year DFS was 91.6% for minority women and 92.4% for Caucasian women with a hazard ratio between minority and Caucasian women of 0.95 (95% CI from 0.56 to 1.60). The P-value of the log-rank test for the difference in DFS between these two groups was 0.85. The result remained the same after adjusting for other potential prognostic factors such as age, letrozole or placebo treatment, duration of prior tamoxifen, geographic location, t-stage, nodal status, prior treatment modality, number of comorbidities, menopausal status at the start of tamoxifen and prior chemotherapy (adjusted hazard ratio = 0.96 with 95% CI from 0.57 to 1.62; P = 0.87).
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For the minority women, the difference between letrozole and placebo in DFS was not statistically significant (hazard ratio of letrozole to placebo = 1.39 with 95% CI from 0.50 to 3.91; P = 0.53) while there was a highly statistically significant difference between letrozole and placebo in DFS for Caucasian women (hazard ratio of letrozole to placebo = 0.55 with 95% CI from 0.41 to 0.72; P < 0.0001). The hazard ratio for differences in disease free survival for letrozole versus placebo for minority women (hazard ratio 1.39) was not statistically significant and was in the opposite direction to that observed in the MA.17 trial (hazard ratio 0.57). The hazard ratio for Caucasian women was similar to that observed in the overall trial. The apparent difference in treatment effect between the two groups was not statistically significant (hazard ratio for interaction adjusting for other potential prognostic factors listed above = 2.55 with 95% CI from 0.87 to 7.44; P = 0.09).
The incidences of the major toxicities that occurred on study are summarized in Table 5 for all women treated with letrozole. Minority women had a statistically significant higher incidence of hypertension (9% versus 5%; P = 0.008) and lower incidences of hot flashes/flushes (49% versus 58%; P = 0.02) and fatigue (29% versus 39%; P = 0.005). Minority women also had statistically significantly lower incidences of diarrhea (3% versus 7%; P = 0.033) and arthritis (2% versus 7%; P = 0.006).
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The analysis of SF-36 quality of life change scores from baseline for women treated with letrozole showed only statistically differences in the bodily pain domain at 12 months after randomization (minority women was worse with mean change score –11.28 versus –6.53; P = 0.046) and the mental health domain at 6 month after randomization (minority women were better with a mean change score of 1.59 versus –2.62; P = 0.02). The patterns of change scores over time for these two domains are shown in Figures 1 and 2.
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Compliance with study medication is presented in Table 6. In this analysis, compliance was measured by determining the number of subjects who said they had taken the pills every day and the number of patients who did not lose any pills during evaluation at one month after randomization. Significantly fewer minority patients reported taking their pills every day. Additionally, more minority patients had incorrect pill counts when evaluated one month after randomization.
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discussion |
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TopAbstractintroductionpatients and methodspatientsresultsdiscussionReferences |
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This analysis of MA.17 demonstrates that women of minority race and ethnicity tolerated letrozole better than Caucasian women in terms of significantly less hot flashes, fatigue, arthritis, and mental health scores. However, a beneficial effect on disease free survival, while present in Caucasian women, was not identified in women of minority race and ethnicity. Whether this is a chance finding related to the small number of these women enrolled in the trial, or a true sub-group effect, cannot easily be resolved, as this was an unplanned retrospective analysis, and the test for interaction is not significant. This finding requires further prospective investigation.
A recent study identified large ethnic variations in allele frequencies and types in the aromatase gene between Caucasian Americans, African Americans, Han-Chinese, and Mexican Americans that could contribute to variations in pathophysiology of hormone-dependent breast cancer [9]. Of 88 polymorphisms of the aromatase gene observed, 32 polymorphisms were only seen in African Americans, six were seen only in Han-Chinese Americans, six were seen only in Mexican-Americans, and five were seen only in Caucasians. These ethnic variations may be important because peripheral estrogen synthesis is dependent mainly on the tissue-specific promoter of aromatase in fat and could result in different baseline plasma estrogen levels between women of varying race and ethnicity. Results of the Study of Women's Health Across the Nation reveal ethnic differences in estradiol, serum sex steroid, FSH, and sex hormone-binding globulin levels [26–28]. Racial differences in estrogen-mediated signaling have also been shown between African American and Caucasian women [29]. Pharmacogenetic differences might alter the metabolism of letrozole through the cytochrome p450 system (CYP3A enzymes). Ethnic variations have previously been demonstrated in the CYP3A enzyme [30]. These CYP3A polymorphisms are an important contributor to interracial differences in CYP3A-dependent drug clearance in general, and perhaps with letrozole specifically. However, it is important to note that, to date, there is no clear evidence in the literature of differential treatment effects between minority women and Caucasian women with breast cancer. Prior studies have shown essentially equivalent relative benefit effects of hormonal therapy between blacks and whites [31, 32]. Similarly, blacks and whites have been shown to realize benefits of a similar magnitude from chemotherapy [31–33].
It is important to note that compliance with letrozole was poorer among minority women compared to Caucasian women, possibly contributing to this observation. However, improved tolerability of letrozole among minority women may be related to previously-demonstrated ethnic differences in menopausal symptoms. African women have 1.5 times the risk of Caucasian women for experiencing hot flashes [34] and have a 2- to 8-fold greater risk for an earlier menopause [35]. In contrast, Asian women report fewer vasomotor symptoms [19]. African American women been shown to have a more positive attitude about certain aspects of the menopause, including sexuality, physical changes, and general well-being [36]. These racial differences in the menopause experience may play an important role in the therapeutic index and tolerability of letrozole.
It is also important to consider inequality of treatment between Caucasians and minorities when analyzing different effects of anticancer therapy. Prior data demonstrates that overall quality of cancer care differs by patient race and ethnicity. For example, black women are more likely than white women to receive nonsurgical cancer therapy or to have no cancer-directed therapy [37]. Minority women are 20 to 50% more likely to receive or elect a first course of surgical and radiation treatment that does not meet the 2000 National Comprehensive Cancer Network standards [38].
A weakness of this analysis is the low number of minority women enrolled in MA.17. Low minority enrolment prevents us from drawing definitive conclusions about the efficacy of letrozole in minority populations. Since we were limited by low minority participation in MA.17 overall, all minority ethnic groups were also pooled together in this analysis. We are therefore unable to differentiate effects between minority subgroups. We had also hoped to study potential predictors of survival according to race but were limited by statistical power. We plan to perform these interesting analyses in future trials, providing there is sufficient minority participation. Another weakness of this analysis is that poorer compliance among minority women could account for both reduced efficacy and toxicity. This problem highlights the importance of collecting compliance data, particularly by ethnicity, in future trials of early stage breast cancer.
These weaknesses point out the need for more focused research to fully evaluate women of minority races and ethnicity in future trials. However, this analysis attempted to examine the different effects of a globally-used therapy on minority women in hopes of gaining insight into the effects of genetic variation on anti-cancer therapy. It is important to note that information about the proportion of minority participation was reported in MA.17 but not in the other large adjuvant aromatase inhibitor trials and is thus a weakness in these trials [1, 2, 4]. A pooled meta-analysis of ethnicity data from all the adjuvant aromatase inhibitor trials may allow for a better understanding of these effects. Of note, there is some concern that increased minority participation in cancer clinical trials could reduce the statistical power of trials and blunt effect size. However, it is important to represent the entire breast cancer population in clinical trials in order to make truly generalizeable conclusions about the clinical impact of anticancer treatments.
This analysis represents an attempt to examine the potential importance of genotypic variation by using race and ethnicity as a surrogate marker. We hope to analyze further the clinical outcomes of minority women in future and current clinical trials of aromatase inhibitors. Identification of a group that is either more or less responsive to aromatase inhibitor therapy, whether it be a racial or ethnic group or through testing for certain genetic polymorphisms, could lead to a future algorithm to predict responsiveness to therapy. It is incumbent upon researchers to improve knowledge about the effectiveness of breast cancer therapy among genotypically variable women, and specifically, in women of minority race and ethnicity. We rely on the results of controlled clinical trials that include subjects representing the full range of patients who would receive the treatment once it is marketed. Future research strategies should focus on examining in vivo genotype-phenotype correlations to determine the effects of genetic variation on response to anticancer therapy and on toxicities and end-organ effects.
Received for publication April 26, 2006. Revision received June 23, 2006. Accepted for publication June 26, 2006.
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